Testosterone for Prevention and Treatment of Breast Cancer

Testosterone Prevents Breast Cancer, Why Do Women Need Testosterone ? 
by Jeffrey Dach MD

Peggy is a 44 year old interior designer from Idaho who arrived in my office to tell her story.

Upper Left Header image: Ultrasound of Breast showing Spiculated Mass, typical for breast cancer. Courtesy of wikimedia commons Attribution: © Nevit Dilmen. 2015 This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Five years ago, Peggy felt a nodule in the right breast and brought it to medical attention. Image guided needle biopsy confirmed it was breast cancer, and Peggy underwent right lumpectomy. The pathology report showed infiltrating ductal carcinoma, an invasive cell type. Surgical margins were good, and no additional treatment was offered. Peggy did well for two years at which time she had a recurrence. The breast cancer returned with a new mass in the right breast and palpable nodes in the right axilla. In addition, CAT scan showed multiple metastatic nodules in the lungs. Her doctors offered her chemotherapy which Peggy declined. Instead she did her own research and found a doctor in Ohio, Rebecca Glaser MD, who treats breast cancer with testosterone. Peggy went to Dr. Glaser’s Clinic, and started Dr. Glaser’s protocol. A testosterone pellet was implanted, and letrozole started. Letrozole is an aromatase inhibitor drug which prevents conversion of testosterone to estrogen. Over time, the breast mass and axillary nodes gradually decreased in size and disappeared. A follow up CAT scan one year later showed the lungs were clear. Peggy was in complete remission from breast cancer using Dr. Rebecca Glaser’s testosterone/ letrozole protocol. I was impressed with this, as using testosterone for treatment of breast cancer was new to me.

In this newsletter, we will examine the medical literature on using testosterone as prevention and treatment for breast cancer, and secondly, discuss the benefits and adverse effects of testosterone for women, when combined routinely with estrogen and progesterone post-menopausal hormone replacement.

Testosterone: 39% Reduction in Breast Cancer

In 2013 and 2019, Drs. Rebecca Glaser,York and Constantine Dimitrakis studied the incidence of breast cancer in a 10-year prospective cohort study of 1,267 pre and postmenopausal women receiving at least two testosterone pellet insertions. The 10 year follow up data showed 39 percent reduction for invasive breast cancer in women treated with testosterone compared with the ‘‘age-matched’’ population. (1)

Second Study : Testosterone Prevents Breast Cancer

In 2021, Dr. Gary Donovitz conducted a retrospective observational study over 10 years of 2,377 pre- and post-menopausal women treated with Testosterone pellets, alone or combined with Estradiol. This study showed 35-50% reduction in the incidence of breast cancer for testosterone treated women, thus confirming the earlier findings of Dr. Rebecca Glaser.(1-2)

Case Reports of Treating Breast Cancer with T/AI pellets

Above Image is Courtesy of Dr. Rebecca Glaser, Figure 3 from Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention.” Maturitas 82.3 (2015): 291-295.

In 2015, Drs. Rebecca Glaser, and Constantine Dimitrakakis wrote a case report of a female patient with palpable breast mass and axillary nodes. This was an infiltrating lobular, hormone receptor positive breast cancer (ER+, PR+, AR+). Baseline mammogram demonstrated the mass and axillary nodes (increased density in upper left image). Follow up mammogram (upper right image) 19 weeks after treatment with testosterone and aromatase inhibitor pellet, reveals significant reduction in tumor size and absence of previously palpable axillary lymph nodes. (regression of mammographic densities, upper right image). (4) Fig 3. from Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention.” Maturitas 82.3 (2015): 291-295.

Second Case Report

In 2021, Dr. Rebecca Glaser wrote a case report of a 67 year old female with a large breast mas presenting with acute respiratory failure. CAT scan of the chest showed multiple metastatic nodules. Core biopsy showed the mass was invasive ductal carcinoma (ER+, estrogen receptor positive). The patient declined conventional treatment, surgery and chemotherapy. Instead she agreed to treatment with testosterone pellet with letrozole (aromatase inhibitor), which, fortunately, induced a favorable response with regression of disease. Dr. Rebecca Glaser writes:

The patient refused conventional therapy and was treated with T+letrozole pellet implants (320 mg T + 24 mg letrozole every 9 weeks). She also began a ‘‘whole food’’ low glycemic diet. One year later, CT scan …showed considerable improvement in the size and number of nodules throughout the lungs. The patient lost 13.6 kg… remains asymptomatic, and ‘‘feels amazing.’’ The large 8-cm breast mass has markedly decreased in size and axillary nodes are no longer palpable. (3)

Third Case Report

In 2021, Dr. Rebecca Glaser provided another case report of a 58 year old female with a large breast cancer mass fixed to the sternum. The patient declined conventional therapy with surgery or chemotherapy, and instead was treated with Testosterone and Letrozole combination pellets, with complete remission. After 14 weeks, the mass no longer palpable. Dr. Glaser writes:

FIG. 7. [shows a] Fifty-eight-year-old patient referred with large immobile breast cancer fixed to sternum. [The patient] refused conventional therapy. She was treated with Testosterone 180–240 mg +12 mg letrozole combination pellet implants at baseline, weeks 6, 14, and 26. She also implemented dietary changes…baseline [exam and clinical photograph], 6-cm tumor fixed to chest wall (sternum) UIQ R [Upper Inner Quadrant Right] breast, skin discoloration… Baseline ultrasound, tumor invading periosteum (sternum) and skin—[tumor is] too large to be measured (extends off screen)…[Follow Up Exam and Clinical Photograph] week 14, complete clinical response, mass no longer palpable… [Follow Up Ultrasound] week 26, complete response confirmed on ultrasound. Patient continues on T + A pellets and remains healthy and disease free at 2 years. (3) Fig 7.

Testosterone/AI pellet with Chemotherapy for Breast Cancer

Left image: ultrasound demonstration of breast mass before (upper) and after treatment (below) with Testosterone/Aromatase Inhibitor Pellet.(5)

In 2017, Dr. Rebecca Glaser reported a 51 year old female who developed breast cancer (ER +) while on testosterone pellet/AI  therapy. This is the first case report of concurrent use of testosterone/aromatase inhibitor during chemotherapy. Dr. Glaser writes:

JR is a 51-year-old postmenopausal patient, with a 30-year smoking history (1978-2008) followed on a prospective IRB trial examining the incidence of breast cancer in women treated with subcutaneous T implants. She began treatment with T implants in October of 2008 for symptoms of hormone deficiency. Since February of 2013, she occasionally received T in combination with a low dose (ie, 4 mg) of anastrozole combined in the implant for symptoms of excess estrogen including irritability, fluid retention, and weight gain….Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet…Ultrasound measurements demonstrated a 43% reduction in tumor volume (12.28 vs 6.96 cc) 41 days after the patient’s initial 180 mg Testosterone + 12 mg Letrozole subcutaneous implant therapy and dietary changes… This significant reduction in tumor volume occurred before the initiation of chemotherapy…after five cycles of chemotherapy, the tumor was no longer palpable on clinical examination and unable to be identified on ultrasound, that is, complete clinical response. Most significant, there was no residual invasive cancer at the time of definitive surgery, that is, complete pathologic response… (5)

Note: AI=aromatase inhibitor drugs such as anastrozole, letrazole, exemestane, etc. This family of drugs inhibit the aromatase enzyme responsible for conversion of testosterone to estradiol. Breast fibroblast cells in vicinity of a breast cancer mass express high levels of aromatase which feeds estradiol into the cancer cells, serving as a growth factor for the cancer. Blocking the conversion of testosterone to estradiol with an AI (aromatase inhibitor) essentially turns off estrogen as a cancer growth factor and causes regression of the cancr mass.(11-17)

Innovative Treatment for Breast Cancer: Placement of Multiple Testosterone Implants at Tumor Site.

In 2014, Dr. Glaser writes a case report of a 90 year old female with a left breast mass discovered incidentally on CAT scan. Subsequent mammogram and ultrasound showed a deep 2.3 centimeter mass. Ultrasound guided core biopsy revealed infiltrating ductal carcinoma (estrogen receptor [ER]–positive, progesterone receptor [PR]–positive, AR-positive, and HER2-negative). The patient refused lumpectomy, and instead took 20 mg tamoxifen daily. After 4 months of tamoxifen a follow up ultrasound showed no change in the mass, still measuring 2.3 cm. The patient was then treated with three Testosterone/ Anastrazole(aromatase inhibitor) implants directly at the tumor site. Dr Glaser writes:

Through a 5-mm lateral incision, three compounded 60 mg T [testosterone] + 4 mg A [anastrozole] pellets were implanted into the breast tissue surrounding the tumor approximately 1 cm superior to, 1 cm inferior to, and anterior to the subareolar tumor through a disposable trocar (Fig. (Fig.1).1). Tamoxifen was discontinued…Follow-up examination of the left breast 2 weeks after intramammary T + A pellet implantation revealed a marked decrease in tumor size on physical examination and office US. The periareolar “thickening” was no longer palpable. By week 4, the patient’s (previously unreported) left breast pain had subsided… 46 days after intramammary T + A therapy, follow-up left breast mammogram and US…the tumor measured 1.6 × 1.1 × 0.8 cm… indicating a sevenfold reduction in tumor volume compared with 5.12 mL [at baseline]…Three additional implants (ie, total dose of 180 mg T + 12 mg A) were again placed peritumorally in the left breast on [day 48]…Follow-up mammogram …on week 13, …revealed that the size of the carcinoma had continued to decrease, measuring 1.5 × 0.8 × 0.6 cm on US,…[a] 12-fold reduction in tumor volume from the original measurement… In the future, this combination [Testosterone/AI] may have the potential for both systemic and local therapies for breast cancer in subgroups of patients, possibly eliminating surgical operation, radiation therapy, and adverse effects of oral medication.(8)

see mammogram Fig 2.

Benefits and Risks of Testosterone for Post-Menopausal HRT

Breast Cancer Prevention Program

For the past 20 years in our office we use topical testosterone cream rather than implanted pellets to achieve a serum testosterone level of 80-160 ng/dl. As mentioned above, an important benefit of testosterone therapy is breast cancer prevention. However, there is more to a breast cancer prevention program.  Here are additional measures which are listed in my recently published book, Natural Thyroid Toolkit:

1) Iodine testing and iodine supplementation to optimize urinary iodine excretion (We typically use a 12.5 mg Iodoral tablet daily for all female patients on hormone replacement). (18-20)

2) DIM (Di-Indole Methane) is a breast cancer preventive agent. (21-22)

3) Optimize Vitamin D3 levels. (23)

4) Optimize selenium levels. (24-25)

5) Methyl-folate containing multivitamin to cover those patients with MTHFR mutation, and methylation defects. (26-27)

Health Benefits of Testosterone

Health benefits of testosterone for women are described in 2021 by Dr. Glaser, who writes:

T [Testosterone] has a profound effect on lean muscle mass, bone density, and confidence as well as sex drive and performance in both sexes…Adequate amounts of (local) bioavailable T [testosterone] at the AR [Androgen Receptor] are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health…Thus, clinical indications for T therapy include many signs and symptoms caused by T deficiency (Table 1)…Unlike adipose tissue, which can contribute to the circulating pool of estrogens, E2 [estradiol] from local aromatization would not be measurable in serum. Therefore, similar to serum T levels, serum levels of E2 should be interpreted with caution and taken into context with clinical evaluation.(3)

Clinical Signs and Symptoms of Androgen Deficiency

As mentioned above, rather than relying on serum hormone levels to initiate and monitor testosterone treatment. Dr. Glaser relies on clinical signs and symptoms of androgen deficiency, which are listed below. Dr. Glaser writes:

[Symptoms of androgen deficiency include] a diminished sense of well-being, Dysphoric mood, anxiety, and irritability, Fatigue, Decreased libido, sexual activity, and pleasure, Vasomotor instability, Bone loss, Decreased muscle strength, Insomnia, Changes in cognition and memory loss, Urinary symptoms and incontinence, Vaginal dryness and atrophy, Joint and muscular pain. (3)

One may recognize the above list as identical for menopausal symptoms commonly associated with estrogen deficiency, all relieved by testosterone implant therapy, as discussed below.

Testosterone Implants Relieve Menopausal Symptoms

In 2011, Dr Glaser conducted a prospective study of 300 pre- and post menopausal women treated with testosterone pellet therapy for menopausal symptoms. No aromatase inhibitor was given to this cohort. Using a self reported questionairre, called the Menopause Rating scale, Dr. Glaser showed testosterone pellet therapy alone was sufficient for complete relief of menopausal symptoms. Supplemental estrogen was not needed nor administered. This is explained by Dr. Glaser writing:

Adequate levels of continuous testosterone, provided by the subcutaneous implant, most likely protect against estrogen deficiency thus explaining why testosterone alone is effective therapy in post-menopausal patients. In our clinical practice (not included in this cohort of 300 patients), an aromatase inhibitor is used in combination with testosterone when estrogen is contraindicated (i.e. breast cancer survivors). (6)

As mentioned above, for breast cancer survivors, an aromatase inhibitor (letrozole) is added to the compounded testosterone pellet formulation. This prevents conversion of testosterone to estrogen, rendering estradiol levels undetectable. A few of the oral aromatase inhibitors currently in clinical use include: Exemestane (Aromasin®), Anastrozole (Arimidex®), and Letrozole (Femara®). (15-17)

Testosterone/AI Treatment for Breast Cancer Survivors- No Breast Cancer Recurrence after 8 years of Follow Up

By 2014, Dr. Glaser had treated 1000 breast cancer survivors with Testosterone/ Aromatase Inhibitor pellet therapy. Of this group, 72 breast cancer survivors were included in a formal prospective study. This study showed no breast cancer recurrence after 8 years of follow up. (7)

Avoid Testosterone Blocker Drugs

Once it is understood that testosterone is breast cancer preventive, one then easily comes to the conclusion that interfering with the AR (androgen receptor) blocking the effect of testosterone is a bad thing causing an increase in breast cancer risk. This explains the increased breast cancer with the use of MPA (medroxyprogesterone) demonstrated in the 2002 Women’s Health Initiative Study. Further studies show that MPA (medroxyprogestreone) has anti-androgenic effects at the dose used, and interferes with the AR, androgen receptors. This explains the increased breast cancer incidence for women receiving MPA compared to placebo in the Women’s Health Initiative Study. Mortality from breast cancer was doubled in the MPA group compared to placebo.

At high dosage, MPA has androgenic effects and has actually been used to treat metastatic breast cancer with dramatic regression in some cases. At lower doses, MPA has an anti-androgen effect, blocks androgen receptors and increases the incidence of breast cancer.  (28-37)

Testosterone for Women: My Office Protocol

Inserting a testosterone pellet provides initial total testosterone serum levels of about 600 ng/dl immediately after pellet insertion, and this declines to about 100 ng/dl after 120 days (4 months) (Fig. 10)  (3)

In my office, rather than pellets, we use topical testosterone cream (12 mg per gram), providing a serum testosterone level of 80-160 ng/dl. In general, this testosterone dosage is well tolerated. Starting dosage is a quarter gram of cream which provides 3 mg of topical testosterone topically. A small amount of cream may be applied directly to the outer eyelids, and the remainder topically to the face around the eyes, rendering a cosmetic result. Testosterone application to the eyelid improves lubrication to the eye, and relieves dry eye syndrome. The eye is lubrication by oil from the meibomian glands at the base of the eye lashes in the eye lids, and these oil glands are controlled by testosterone. In 2003, this was reported by Dr. Charles Connor from the Southern College of Optometry, in Memphis Tennessee. A patent was granted in 2007. (9-10)

For more on Testosterone for Dry Eye Syndrome, see my previous newsletter on this topic.

Testosterone Excess Symptoms

Testosterone excess symptoms are fairly obvious and easy to recognize. These include acne and facial hair. If these symptoms occurs, the topical cream is stopped for 4-7 days. After about a week or so, symptoms have resolved, and the testosterone topical cream may be restarted at half dosage.

Our Complete Program

In addition to the testosterone cream, we also provide a second cream containing the Bi-Est (20% estradiol E2, 80% estriol E3) and progesterone combination cream. Starting formula is 50 mg/gram progesterone and 5 mg per gram Bi-Est. Usual starting  dosage is half gram topically twice a day. This may be titrated up for complete relief of menopausal symptoms, or titrated down for estrogen excess symptoms of breast enlargement and tenderness. A third component is a 100 mg progesterone capsule taken at bed time.

Testosterone is Breast Cancer Preventive: Mechanism of Action

There are two estrogen receptors, Alpha and Beta. The Alpha receptor is pro-carcinogenic. The Beta Receptor is protective and suppresses carcinogenesis. Estradiol attached to both receptors 50:50. Estrone (E1) attaches mostly to ER-alpha, while Estriol (E3) attached mosty to ER Beta (protective). The most like likely mechanism for testosterone’s protective effect in breast cancer prevention is the testosterone metabolite 3β-Adiol which attaches to Estrogen Receptor Beta (ER-Beta), thus upregulated ER-Beta expression, thus inhibiting breast cancer cell growth.(38-49)

This is illustrated in 2014 by Dr. Pietro Rizzo who writes:

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. …..Collectively, these data provide evidence for a novel mechanism by which activated AR [Androgen Receptor], through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.(45) Emphasis Mine.

Conclusion: Thanks and credit goes to Dr. Rebecca Glaser and  Dr. Gary Donovitz for revealing the benefits of testosterone as a breast cancer preventive, and for testosterone as a treatment of breast cancer.  The assumption here is that topical testosterone provides the same breast cancer prevention as testosterone pellets. Although we have the two studies done by Drs. Glaser and Donovitz  with testosterone pellets showing 40-50% reduction in breast cancer, unfortunately, we do not have the same clinical studies for topical testosterone. However, in my opinion, the benefits should be the same for topical testosterone as for pellets.

Many of the benefits of topical testosterone can be readily observed, and the adverse effects as well. Occasionally, dosage is reduced because of adverse effects of excess testosterone. When comparing pellets to topical cream, one obvious advantage with topical cream is the ease of dosage adjustment. Simply take a few days off the topical cream, levels decline promptly, and restart after symptoms have resolved. Obviously, this can not be done with the pellets. It may take a few months for pellet levels to come back down.

Another benefit shown by Dr. Glaser’s group is that testosterone alone may provide complete relief from menopausal symptoms. This is useful in the post menopausal breast cancer survivor treated with combined testosterone and aromatase inhibitor pellet to block conversion to estrogen. Dr. Glaser’s study showed no breast cancer recurrence after 8 years of follow up when this protocol is used for breast cancer survivors.

Articles with related interest:

Iodine as Breast Cancer Prevention Part One

Iodine as Treatment for Breast Cancer Part Two

Dont Monkey With My Hormones

All Article on Bioidentical Hormones

Jeffrey Dach MD
7450 Griffin Rd. Suite 180/190
Davie, Fl 33314
954-792-4663

References:

1) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study.BMC cancer 19 (2019): 1-10.

demonstrated reduced incidence of invasive breast cancer in T users by 39% compared with the ‘‘age-matched’’ population. Thus, the data in the contemporary literature suggest that TTh in women is unlikely associated with an increased risk of breast carcinoma. 10,12,43,71,74,78,81,84,86

2) Donovitz G., Cottoen M. Breast Cancer Incidence Reduction in Women Treated with Subcutaneous Testosterone: Testosterone Therapy and Breast Cancer Incidence Study. Eur. J. Breast Health. 2021;17:150–156.

3) Glaser, Rebecca, and Constantine Dimitrakakis. “Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence.” Clinical Research and Therapeutics 2.1 (2021): 94-110.

Many physicians are not aware that serum T levels are markedly (10- to more than 15-fold) higher than E2 levels throughout the female lifespan, barring pregnancy

Serum levels of T are not a valid marker of tissue exposure in women, reflecting <20% of the total androgen activity. Accordingly, serum T levels would not be expected to correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency. 30 This concept is extremely important to comprehend. Serum T levels should not be relied on to diagnose T deficiency or manage T dosing in women.

It is well recognized that T has a profound effect on lean muscle mass, bone density, and confidence as well as sex drive and performance in both sexes.

It is important to recognize that there are active ARs located in every major organ system throughout the body.33–38 Adequate amounts of (local) bioavailable T at the AR are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health (Supplementary Data S1). 32–42 Thus, clinical indications for T therapy include many signs and symptoms caused by T deficiency (Table 1).1,4

Unlike adipose tissue, which can contribute to the circulating pool of estrogens, E2 from local aromatization would not be measurable in serum. 31,46,47 Therefore, similar to serum T levels, serum levels of E2 should be interpreted with caution and taken into context with clinical evaluation.

Table 1. Signs and Symptoms of Aging Related to Androgen Deficiency

A diminished sense of well-being
Dysphoric mood, anxiety, and irritability
Fatigue
Decreased libido, sexual activity, and pleasure
Vasomotor instability
Bone loss
Decreased muscle strength
Insomnia
Changes in cognition and memory loss
Urinary symptoms and incontinence
Vaginal dryness and atrophy
Joint and muscular pain

A 67-year-old female presented with acute respiratory failure. Baseline CT scan (left column) of the chest showed multiple noncalcified pulmonary nodules—bilateral and throughout the lungs—compatible with metastatic disease. Core biopsy (breast mass) revealed ER+ invasive ductal carcinoma. The patient
refused conventional therapy and was treated with T+letrozole pellet implants (320 mg T + 24 mg letrozole every 9 weeks). She also began a ‘‘whole food’’ low glycemic diet. One year later, CT scan (right column) showed considerable improvement in the size and number of nodules throughout the lungs. The patient lost 13.6 kg (note significant decrease in fatty tissue on CT), remains asymptomatic, and ‘‘feels amazing.’’ The large 8-cm breast mass has markedly decreased in size and axillary nodes are no longer palpable. CT, computed tomography; ER, estrogen receptor

4) Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention.” Maturitas 82.3 (2015): 291-295.

5) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications.” Menopause (New York, NY) 24.7 (2017): 859.

This is the first case report of the concurrent use of T combined with an AI during neoadjuvant chemotherapy.

A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to “testosterone-letrozole” and subsequently, “testosterone-letrozole with chemotherapy” was monitored using serial ultrasounds and calculating tumor volume.

There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy.

pellets containing 60 mg of T and 4 mg of letrozole (60 mg T + 4 mg L).

Ultrasound measurements demonstrated a 43% reduction in tumor volume (12.28 vs 6.96 cc) 41 days after the patient’s initial 180 mg T + 12 mg L subcutaneous implant therapy and dietary changes (Fig. (Fig.1).1). This significant reduction in tumor volume occurred before the initiation of chemotherapy…

after five cycles of chemotherapy, the tumor was no longer palpable on clinical examination and unable to be identified on ultrasound, that is, complete clinical response. Most significant, there was no residual invasive cancer at the time of definitive surgery, that is, complete pathologic response.

Subcutaneous T + L therapy in conjunction with a whole food, low (processed)-carbohydrate diet was beneficial in the neoadjuvant therapy of breast cancer. In addition, T + L did not interfere with chemotherapy, supporting preclinical and clinical data. The T + AI combination implant seems to be a promising therapy that has the potential to simultaneously treat breast cancer, prevent side effects of chemotherapy, and improve health and quality of life in breast cancer survivors.

6) Glaser, Rebecca, Anne E. York, and Constantine Dimitrakakis. “Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS).” Maturitas 68.4 (2011): 355-361.

7) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors.” J Clin Oncol 32.Suppl 2 (2014): 109.

Over 1000 Testosterone + Anastrozole (T + A) pellet
insertions have been performed in breast cancer survivors
since 2006. Between April 2013 and May 2014, 72
patients had been enrolled in the study and were eligible
for analysis. T implant dosing is weight based3. Over 90% of patients were treated with 8 mg of A combined with T in the
implant. A lower dose of A (4 mg) is occasionally used in
smaller patients and/or patients with lesser or more remote
disease. A higher dose of A (12 mg) is occasionally used in
obese patients with advanced disease, or in the neo-
adjuvant setting*. Subcutaneous implants are inserted in
the gluteal or inguinal area** at 3-month intervals on
average. Therapeutic T levels were confirmed without
elevation of estradiol in any postmenopausal survivor.
There have been no cancer recurrences in up to 8 years
of therapy.

8) Glaser, Rebecca L., and Constantine Dimitrakakis. “Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer.” Menopause (New York, NY) 21.6 (2014): 673.

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Dry Eye Syndrome

9) Connor, C. G. “Treatment of dry eye with a transdermal 3% testosterone cream.” Investigative Ophthalmology & Visual Science 44.13 (2003): 2450-2450.

10) Treatment for dry eye using testosterone and progestagen
Patent WO2008070728A3 (Date: 2007-12-05)
Abstract The present invention comprises a composition and methods for treating eye conditions using a composition having a therapeutically effective amount of a progestagen, a therapeutically effective amount of a testosterone and pharmaceutically acceptable carrier, wherein the composition is applied to the palpebral part of the eye and/or ocular surface. Application filed by Southern College Of Optometry, Charles G Connor, Charles Haine

Aromatase in Breast Cancer Tissue

11) Bulun, S. E., et al. “Regulation of aromatase expression in breast cancer tissue.” Annals of the New York Academy of Sciences 1155.1 (2009): 121-131.

12) Kijima, Ikuko, Toru Itoh, and Shiuan Chen. “Growth inhibition of estrogen receptor-positive and aromatase-positive human breast cancer cells in monolayer and spheroid cultures by letrozole, anastrozole, and tamoxifen.” The Journal of steroid biochemistry and molecular biology 97.4 (2005): 360-368.

13) Mukhopadhyay, Keya De, et al. “Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.” PloS one 10.4 (2015): e0121136.

In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

14) Smith, Ian E., and Mitch Dowsett. “Aromatase inhibitors in breast cancer.” New England Journal of Medicine 348.24 (2003): 2431-2442.

15) Chumsri, Saranya, et al. “Aromatase, aromatase inhibitors, and breast cancer.” The Journal of steroid biochemistry and molecular biology 125.1-2 (2011): 13-22.

16) Fabian, Carol J. “The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer.” International journal of clinical practice 61.12 (2007): 2051-2063.

17) Narashimamurthy, J., A. Raghu Ram Rao, and G. Narahari Sastry. “Aromatase inhibitors: a new paradigm in breast cancer treatment.” Current Medicinal Chemistry-Anti-Cancer Agents 4.6 (2004): 523-534.

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Our Breast Cancer Prevention Program (Iodine, DIM, Vit D3, selenium, MFolate)

18) Mendieta, Irasema, et al. “Molecular iodine exerts antineoplastic effects by diminishing proliferation and invasive potential and activating the immune response in mammary cancer xenografts.” BMC cancer 19.1 (2019): 1-12.

19) Moreno-Vega, Aura, et al. “Adjuvant effect of molecular iodine in conventional chemotherapy for breast cancer. randomized pilot study.” Nutrients 11.7 (2019): 1623.

20) Manjer, Jonas, Malte Sandsveden, and Signe Borgquist. “Serum Iodine and Breast Cancer Risk: A Prospective Nested Case-Control Study Stratified for Selenium Levels.” Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 29.7 (2020): 1335-1340.

21) Williams, David E. “Indoles derived from glucobrassicin: Cancer chemoprevention by indole-3-carbinol and 3, 3′-diindolylmethane.” Frontiers in Nutrition 8 (2021): 734334.

22) Amarakoon, Darshika, et al. “Indole-3-Carbinol: Occurrence, Health-Beneficial Properties, and Cellular/Molecular Mechanisms.” Annual Review of Food Science and Technology 14 (2023): 347-366.

23) Benarba, Bachir, and Adel Gouri. “Role of vitamin D in breast cancer prevention and therapy: Recent findings.” Journal of Medicine 21.1 (2020): 46.

24) Szwiec, Marek, et al. “Serum selenium level predicts 10-year survival after breast cancer.” Nutrients 13.3 (2021): 953.

25) Kim, Seung Jo, et al. “Antitumor effects of selenium.” International Journal of Molecular Sciences 22.21 (2021): 11844.

26) Li, Zhen, et al. “The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism is associated with breast cancer subtype susceptibility in southwestern China.” Plos one 16.7 (2021): e0254267.

27) Omran, Moataza H., et al. “Strong Correlation of MTHFR Gene Polymorphisms with Breast Cancer and its Prognostic Clinical Factors among Egyptian Females.” Asian Pacific Journal of Cancer Prevention: APJCP 22.2 (2021): 617.

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Progestins cause breast cancer WHI

28) Chlebowski, Rowan T., et al. “Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.” Jama 304.15 (2010): 1684-1692.
mean follow-up of 11.0 (2.7) years thru August 14, 2009.
estrogen plus progestin increased invasive breast cancers compared with placebo (385 [0.42%/yr] vs 293 [0.34%/yr] cases; hazard ratio [HR] 1.25, 95% confidence interval (CI) 1.07-1.46; P=.004). The breast cancers in the estrogen plus progestin group were similar in histology and grade but were more likely to be node positive (81 [23.7%] vs 43 [16.2%], respectively; P=0.03). Deaths directly attributed to breast cancer were greater in the estrogen plus progestin group (25 [0.03%/yr] vs 12 [0.01%/yr] deaths; HR, 1.96; 95% CI 1.00-4.04, P=.049) as were deaths from all causes occurring after a breast cancer diagnosis (51 [0.05%/yr] vs 31 [0.03%/yr] deaths; HR 1.57, 95% CI 1.01-2.48; P=.045)…Estrogen plus progestin increases breast cancer incidence with cancers more commonly node positive. Breast cancer mortality also appears to be increased with combined estrogen plus progestin use.

Progestins Disrupt Androgen Signalling

free pdf

29) Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT.

We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.—

Nevertheless, given that more than 25% of postmenopausal
women who require HRT use a combination of estrogen and synthetic progestins, it is important to understand the actions of progestins in the breast at a molecular level. Whereas synthetic progestins are generally
considered to act via progesterone receptor (PR)- mediated pathways in female reproductive tissues (10), we have demonstrated that treatment failure with the progestin medroxyprogesterone acetate (MPA) in advanced breast cancer is associated with reduced levels of
androgen receptors (AR) or impaired AR function.

MPA binds to the AR with an affinity comparable to the native androgenic ligand, 5-dihydrotestosterone (DHT)…In addition, the observation
that MPA interacts with the glucocorticoid receptor
(GR) to increase levels of the metastasis suppressor
gene, nm-23, in human breast cancer (13) provides
further evidence for extensive crosstalk by progestins
with non-PR signaling pathways in breast cancer cells.

Notably, in France the majority of women taking combined HRT receive
oral micronized progesterone rather than a synthetic progestin. In two French studies- the E3N-EPIC cohort of 54,548 women and a smaller study of 3175 women, no significant increase in breast cancer risk due to HRT use with micronized progesterone was observed compared
with untreated women (32, 33).

Medroxyprogesterone Inhibits via Androgen Receptor

30) Hackenberg, Reinhard, et al. “Medroxyprogesterone acetate inhibits the proliferation of estrogen-and progesterone-receptor negative MFM-223 human mammary cancer cells via the androgen receptor.” Breast cancer research and treatment 25 (1993): 217-224.

31) Bentel, Jacqueline M., et al. “Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.” Molecular and cellular endocrinology 154.1-2 (1999): 11-20.

32) Dran, G., et al. “Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma.” Breast cancer research and treatment 35.2 (1995): 173-186.

33) Zaucha, R., K. Sosińska-Mielcarek, and J. Jassem. “Long-term survival of a patient with primarily chemo-resistant metastatic breast cancer treated with medroxyprogesterone acetate.” The Breast 13.4 (2004): 321-324.

The prognosis of breast cancer patients with liver metastases is extremely poor. Here we present the case of a 66-year-old female breast cancer patient with multiple liver metastases diagnosed 2 years after a radical modified mastectomy followed by adjuvant tamoxifen. At progression, anthracycline-based chemotherapy was administered, but a CT scan following two cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide) showed progression of the liver metastases. Chemotherapy was therefore switched to medroxyprogesterone acetate (MPA). After 3 months the patient’s general status improved, and disease stabilization was observed at the next CT scan. A further 4 months of MPA treatment resulted in complete response of all liver lesions. Treatment with oral MPA was continued for 4 years. At present, 11 years after the diagnosis of metastatic liver involvement, the patient is alive, free of cancer, and fully ambulatory. Despite bulky visceral disease and chemoresistance, hormonal treatment with MPA resulted in a spectacular and long-lasting response.

34) Buchanan, Grant, et al. “Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate.” Cancer research 65.18 (2005): 8487-8496.

35) Poulin, R., et al. “Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells.” Breast cancer research and treatment 13.2 (1989): 161-172.

Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.

Anti-Androgen Action of MPA in normal breast tissue- POST MENOPAUSAL WOMEN

36) Ochnik, Aleksandra M., et al. “Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.” Menopause 21.1 (2014): 79-88.
Objective: Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue.

Methods: Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry.

Results: DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels.

Conclusions: In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.

37) Ochnik, Aleksandra Monica. The molecular actions of medroxyprogesterone acetate on androgen receptor signalling and the promotion of breast cancer. Diss. 2012. (Doctoral dissertation).

Using the ex vivo breast explant tissue model, I have demonstrated that MPA [medroxyprogesterone] impedes DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling in post-menopausal non-malignant human breast epithelial cells. Importantly, these studies have established a potential biological link between the effects of MPA [medroxyprogesterone] promoting increased breast epithelial proliferation in post-menopausal women taking cHRT [estrogen/MPA] by the disruption of the DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling.

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38) The Anticancer Testosterone Metabolite 3β-Adiol
Hormones
Dr. Jonathan V. Wright, MD
Published in: Townsend Letter
By. Dr. Jonathan V. Wright, MD

39) Warner, Margaret, et al. “25 years of ERβ: a personal journey.” Journal of Molecular Endocrinology 68.1 (2022): R1-R9.

40) Rymbai, Emdormi, et al. “Role of estrogen receptors in cancer: a special emphasis on the therapeutic potential of estrogen receptor ß.” Pharmaceutical Sciences Asia 49.5 (2022).

41) Wu, Wan-fu, et al. “Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.” Proceedings of the National Academy of Sciences 118.13 (2021): e2011269118.

42) Chimento, Adele, et al. “Estrogen receptors-mediated apoptosis in hormone-dependent cancers.” International journal of molecular sciences 23.3 (2022): 1242.

free pdf
43) Vasconsuelo, Andrea, et al. “Role of 17β-estradiol and testosterone in apoptosis.” Steroids 76.12 (2011): 1223-1231.

17b-Estradiol (E2) and Testosterone (T) exert actions in most animal tissues, in addition to the reproductive system. Thus, both sex steroid hormones affect growth and different cell functions in several organs. Accordingly, the nuclear estrogen (ER) and androgen (AR) receptors are ubiquitously expressed. Moreover, ER and AR may have non-classical intracellular localizations, e.g. plasma membrane, mitochondria and endoplasmic reticulum, raising additional complexity to the functional roles of E2 and T. In addition
to the modulation of gene transcription by direct interaction with  their cognate nuclear receptors, the steroids can rapidly activate signaling pathways by a non-genomic mechanism mediated by receptors identical to or different from known steroid receptors. Among various functions, E2 and T can regulate apoptosis through those pathways. In mitochondria, the presence of ER and AR and actions of estrogen and androgen have been shown, in keeping with the organelle being a control point of apoptosis. The most recurrent action for each steroid hormone is the protection of mitochondria against different
insults, resulting in antiapoptosis. This review summarizes the molecular basis of the modulation of programmed cell death by E2 and T in several tissues.

44) Vasconsuelo, Andrea, et al. “Role of 17β-estradiol and testosterone in apoptosis.” Steroids 76.12 (2011): 1223-1231.

However, under some specific conditions E2 could trigger apoptosis in breast cancer cells, opposed to its well studied antiapoptotic role. This peculiar hormone behavior has been observed in cells from breast cancer which have been longterm estrogen-deprived (LTED) or treated exhaustively with antiestrogens [87]. Curiously, the paradoxical induction of apoptosis by estrogen has been established under several unusual circumstances.
For example, in this case, the pre-conditions of prolonged estrogen depletion or exhaustive treatment with anti-estrogens of the breast cancer cells are mandatory requisites to trigger apoptosis by E2 and could explain the dual action of the steroid to stimulate growth or apoptosis. Thus, the development of antihormone resistance over years of therapy, reprograms the survival mechanism of the breast cancer cell so that estrogen no longer
functions as a survival factor but as a death signal.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
45) Rizza, Pietro, et al. “Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines.” Breast cancer research 16 (2014): 1-13.

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. Emerging data have reported that androgen receptor (AR) activation inhibits ER-positive breast cancer progression mainly by antagonizing ER-alpha signaling. However, to date no studies have specifically evaluated a potential involvement of ER-beta in the inhibitory effects of androgens…Collectively, these data provide evidence for a novel mechanism by which activated AR, through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.

46) Pietri, Elisabetta, et al. “Androgen receptor signaling pathways as a target for breast cancer treatment.” Endocrine-related cancer 23.10 (2016): R485-R498.

https://pubmed.ncbi.nlm.nih.gov/33462444/
47) Hickey, Theresa E., et al. “The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer.” Nature medicine 27.2 (2021): 310-320.

Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

48) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739178/
You, Chan-Ping, et al. “Modulating the activity of androgen receptor for treating breast cancer.” International Journal of Molecular Sciences 23.23 (2022): 15342.

49) Traphagen, Nicole A., et al. “High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer.” Oncogene 40.19 (2021): 3408-3421.

 

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Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas. 2013;76(4):342–349.

Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study. BMC Cancer. 2019;19(1):1271.

——————————– –

You, Chan-Ping, et al. “Modulating the activity of androgen receptor for treating breast cancer.” International Journal of Molecular Sciences 23.23 (2022): 15342.

Glaser R, Wurtzbacher, D, Dimitrakakis C. Efficacy of
Testosterone Therapy Delivered by Pellet Implant.
Maturitas 2009, 63(Suppl 1);283.

Dimitrakakis C, Bondy C. Androgens and the breast.
Breast Cancer Research 2009;11(5):212.

Traish AM, Fetten K, Minor M, Hansen ML, Guay A.
Testosterone and risk of breast cancer: appraisal of
existing evidence. Hormone Molecular Biology and
Clinical Investigation. 2010; 2 (1): 177

Boni, Corrado, et al. “Therapeutic activity of testosterone in metastatic breast cancer.Anticancer Research 34.3 (2014): 1287-1290.

Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT.

We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.—

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Traish, Abdulmaged M., and Abraham Morgentaler. “Androgen therapy in women with testosterone insufficiency: looking back and looking ahead.” Clinical Research and Therapeutics 3.1 (2022): 2-13.

TTh Effects on Sexual Function
a host of clinical studies have demonstrated significant benefits of TTh on improving sexual function and metabolism without serious safety concerns.

Effects of TTh on Other Metabolic Function in Women

Although the benefits of TTh in women with sexual dysfunction have been well recognized for many decades, 16,19,20,28–51 T treatment also improved bone mineral density, fat-free mass, and fat mass and improved metabolic function. 29,31–34,47,50–64
TTh was also shown to improve mood in women with anxiety and depression, and in women with anorexia nervosa.

Safety of TTh in Women

Several adverse side effects of TTh in women have been anecdotally reported, which include body hair growth, acne, and voice changes. However, no medically serious adverse side effects have been reported in clinical studies 63–74 and findings in clinical trials reported in Table 1. Nevertheless, persistent concerns of serious adverse effects remain an obstacle for the use of TTh in women. Foremost among these has been the fear that androgen therapy could lead to an increased risk of
breast cancer due to aromatization of T to estradiol.75–79
This alarming possibility has not been supported by the available data. Indeed, in the years since the first reports on T in women1,2–7 to modern-day clinical trials,16,19,20,28–51 no major safety concerns have arisen (Table 1). Regarding heart disease, Islam et al. concluded, ‘‘From a contemporary therapeutic perspective, there is no evidence that TTh, when used for the treatment of HSDD, is associated with adverse CV effects.’’65

As discussed by Traish and Gooren 71 and Traish et al., 80,81 several lines of evidence argue against increased breast cancer risk with TTh. These include:

1. Data from breast tumor cell lines treated with androgens do not support the notion that T increases breast cancer risk. On the contrary, androgens inhibit tumor cell growth, and thus they appear to be protective;

2. several epidemiological studies reporting an association between T and breast cancer failed to adjust for estrogen levels.82–84 Studies that did adjust for estrogen levels have shown no association between T and breast cancer.

3. Clinical studies with TTh have not shown any increased incidence of breast cancer.

4. Women with polycystic ovary disease do not appear to be at an increased risk of breast cancer compared with the general population, despite higher serum androgen concentrations.

5. Female to male transsexuals, who receive supra-physiological doses of T for long time periods before surgical procedures, have not been shown to have an increased risk of breast cancer.

6.Finally, women with hormone responsive primary breast cancer were treated with aromatase inhibitors, which block conversion of androgens to estrogens, thus elevating androgen levels. These women do not experience increased incidence of contralateral breast cancer, nor do they experience increased tumor growth.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Key article !!!!!!!!!!!!!!!!

A recent report 85 suggested that a 10-year analysis of the Dayton study

Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study.BMC cancer 19 (2019): 1-10.

demonstrated reduced incidence of invasive breast cancer in T users by 39% compared with the ‘‘age-matched’’ population. Thus, the data in the contemporary literature suggest that TTh in women is unlikely associated with an increased risk of breast carcinoma. 10,12,43,71,74,78,81,84,86

Events Negatively Impacting Adoption of TTh in Women

In our view, several key events have contributed to the
failure of the medical community to recognize the importance of androgen insufficiency in women, and to adopt the treatment of affected women. These include:
(1) response to publication of findings from the Women’s Health Initiative (WHI),
(2) lack of approval for T formulations for women by the U.S. FDA, (3) the Endocrine Society Guidelines on TTh in women with
T deficiency, and
(4) lack of education and training of health care professionals (HCPs) in this field much of the fundamental information regarding both the impact of T insufficiency and the benefits of treatment with TTh have been known for 80 years.

And yet, the plight of affected women is that they are unlikely to be diagnosed, and even less likely to be treated. If they do receive treatment, it will be off-label via compounded medications since
there are no regulatory-approved T products available through most of the world…

The impact of this is enormous, affecting millions of women in the United States alone, depriving them (and their partners) of satisfying sexual relations, strength, and vigor…the lack of education regarding women’s sexual dysfunction, and T insufficiency, needs to be addressed during medical education and training…it will be helpful if professional organizations lend their support to the importance of diagnosing and treating women with T deficiency…it is to be hoped that one or more T products for women obtain regulatory approval in the United States and other countries…Looking back, we are struck by the failure of science to effect meaningful change in clinical practice for women with T insufficiency over such a long period of time. Looking forward, we are encouraged by numerous developments in the field, perhaps especially by the growing calls to make women’s health a priority. We can easily envision a time in the not-too-distant future when women with symptoms of T insufficiency are evaluated respectfully and without dismissing the importance of their symptoms, undergo prompt and thorough evaluation, and are offered effective treatment when appropriate. The consequences of this vision are not only improved health and well-being for those women, but also a happier existence for their families, friends, and society as a whole.

=============================== =

Donovitz, Gary S. “A personal prospective on Testosterone therapy in women—What we know in 2022.” Journal of Personalized Medicine 12.8 (2022): 1194.

women … remain without any Food and Drug Administration (FDA)-approved testosterone therapies, while more than 30 FDA-approved testosterone therapies are available for men in the United States.

This has resulted in millions of women suffering in silence with very common symptoms of perimenopause and menopause that could easily be addressed with the use of testosterone. There is growing evidence to support the use of physiologic doses of testosterone for sexual function, osteoporosis prevention, brain protection, and breast protection. The safety of testosterone use in women has been evaluated for the past 80 years. A recent publication on the complications of subcutaneous hormone-pellet therapy, looking at a large cohort of patients over 7 years, demonstrated long-term safety. In addition, there have been two large long-term peer-reviewed studies showing a significant reduction in the incidence of invasive breast cancer in women on testosterone therapy.

certain clinicians promoting inaccurate narratives regarding safety concerns that are not truly validated in the scientific peer-reviewed literature.

——-

2. Women’s Health Initiative (WHI) and Its Impact on Hormone Replacement Therapy (HRT)

The findings of the conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) arms of the WHI were published in 2002 and dramatically changed the prescribing practices of physicians in the United States []. The trial demonstrated adverse cardiovascular disease events and an increased risk of breast cancer, deep vein thrombosis, and Alzheimer’s disease in female patients in the combined estrogen plus progestin (E + P) arm, but not in the CEE-only arm. The number of women for whom estrogen and progestin are prescribed had been steadily increasing, from 58 million in 1995 to 90 million in 1999 []. After the publication in 2002, prescriptions for HRT plummeted by more than 60%.

Since the WHI studies almost twenty years ago, much confusion has occurred regarding estrogen supplementation, and this has led to many negative and inaccurate perceptions around the use of testosterone in women.

Testosterone has been used in women for over 80 years to treat perimenopause and menopause symptoms [].

In England and Australia, testosterone has been licensed for use in women for more than 60 years.

A study by Glaser et al. effectively documents that testosterone can improve most common post-menopausal symptoms []. Pre- and post-menopausal patients may experience symptoms of androgen deficiency, including hot flashes, night sweats, decreased libido, irritability, anxiety, depression (also known as dysphoric moods), fatigue, a decreased feeling of well-being, poor memory, poor focus and concentration, insomnia, joint pains, vaginal dryness, urinary complaints, and incontinence, all of which are becoming increasingly recognized by practitioners. A double-blind randomized trial demonstrated that androgens affect sexual desire, bone density, muscle mass and strength, adipose tissue distribution, mood, energy, and psychological well-being [].

According to Panay and Fenton [], young women’s ovaries produce approximately three to four times more testosterone than estrogen daily.

In 2002, Dimitrakakis et al. [] stated that testosterone is the most abundant biologically active gonadal hormone throughout the female lifespan. However, unfortunately, due to a plethora of misconceptions, women remain without any FDA-approved testosterone therapies, while more than 30 approved testosterone therapies are available for men. This has resulted in millions of women suffering in silence with very common symptoms that could easily be addressed with the use of testosterone.

Testosterone Optimization in Women

There are data [] to support the use of testosterone in patients suffering from sexual dysfunction and, more specifically, from what is termed hypoactive sexual desire disorder (HSDD). In Islam’s study, there were 36 RCTs encompassing 8480 patients, showing that testosterone use benefited women with HSDD. In addition, this meta-analysis demonstrated that non-oral testosterone was better at maintaining neutral lipid profiles than was oral testosterone [].

HSDD is a sexual disorder characterized by distress related to a loss of or decline in sexual interest. It is estimated to affect approximately one in ten women. Menopausal status has a significant impact on the prevalence of HSDD, with several studies showing that the prevalence of HSDD is greatest in younger, surgically menopausal women (16–26%) compared with naturally pre-menopausal women (7–14%). This most likely relates to the significant decrease in testosterone in surgically induced menopausal women []. Dr. Davis and her consensus panel agreed that HSDD is a clinical diagnosis and that, therefore, serum testosterone levels should not be used to make a diagnosis []. The panel, on the one hand, recommended that treatment with testosterone should attempt to mirror pre-menopausal serum levels to achieve the desired clinical response, but then recommended using testosterone products in female patients that are FDA-approved products for males.

In addition, androgens act on multiple tissue and receptor sites. One of the major organs that testosterone has a beneficial effect on is the central nervous system.

Most peer-reviewed publications about osteoporosis and testosterone, and the most cited related papers, have discussed osteoporosis in men. Approximately 10 million men and women in the United States have osteoporosis, a metabolic bone disease characterized by low bone density and the deterioration of bone architecture, which increases the risk of fractures []. A total of 80 percent of these patients are female. One in seven women will develop osteoporosis after the age of 50. In those who have a significant decrease in their bone mineral density (BMD), more than 50% will sustain a fracture in their lifetime. The major cause of osteoporosis in women has erroneously been thought to be estrogen deficiency due to menopause, while in men, age-related testosterone deficiency []. Osteoporosis medications include bisphosphonates, receptor activator of nuclear factor kappa-B ligand inhibitors, estrogen agonists/antagonists, parathyroid hormone analogues, and monoclonal antibodies [,]. This list, while extensive, is missing a hormone that has been used for decades to treat osteoporosis: testosterone. Almost all studies demonstrate that androgen upregulates the expression of androgen receptors in osteoblasts []. However, the evidence generally suggests that androgens stimulate the differentiation of osteoblasts. Mature osteoblasts have been shown to increase bone formation and increase BMD in both women and men. The 2012 Endocrine Society osteoporosis guidelines also recommend the use of testosterone therapy in men with symptomatic low testosterone who are at high risk of fracture but fail to mention women.

However, many physicians continue to promote narratives that we should [] continue to hold back on treating these patients because of the unknown effects of testosterone, and that if they are treated, they should only be treated with FDA-approved preparations used in men.

The argument behind these statements is based on

(1) an erroneous belief that bioidentical hormones are not regulated,
(2) a lack of awareness of the published data on the safety and efficacy of testosterone,
(3) the preference to claim that the administration of testosterone should only be transdermal, as sub-cutaneous administration via pellets is dangerous, and
(4) the FDA’s view that since there have been risks with estrogen and progesterone, there will be risks with testosterone.

The statement that bioidentical hormones are not regulated is inaccurate. There currently exist long-standing regulations at the Federal and State levels. The Drug Quality and Security Act in 2014 gave the FDA additional powers to regulate compounding pharmacies, including establishing the requirement of compliance with Current Good Manufacturing Practice (cGMP) [], as is required by the pharmaceutical industry. This allowed for improved testing for manufacturing processes, assuring purity, potency, and quality testing, in addition to improved sterility protocols.

DOSING not tied to testo levels

For the thousands of practitioners who have utilized testosterone therapy for testosterone deficiency (TD) in females, the standard of care is to evaluate and treat TD as a clinical syndrome that is not tied to specific laboratory values.

In the study “Low complication rates of testosterone and estradiol implants for androgen and estrogen replacement therapy in over 1 million procedures” [], a proprietary dosing algorithm was used to achieve testosterone levels between 150 and 250 ng/dL. This individualized approach was successful in resolving symptoms with minimal side effects. Additional long-term dosing studies are being performed at this time.

Both the Global Consensus of Testosterone use in Women [] and the International Society for the Study of Women’s Sexual Health (ISSWSH) practice guidelines make the point that the testing of testosterone levels in women is not diagnostic and should be used only to establish a baseline. They also allow for the testing of levels to monitor therapy. The North American Menopause Society (NAMS) concurs, stating that hormone testing in general has very limited use in menopause and is usually employed to evaluate whether there is poor absorption if there is no symptom relief []. These opinions are not new. The Princeton Consensus Group, in 2002 [], published their opinion that there are no age-specific normal testosterone values established for women. This is consistent with the International Consensus’ paper on Testosterone Deficiency and Treatment in Women, which states that TD is a clinical syndrome with its foundation firmly rooted in the multiple symptoms that comprise this widespread syndrome [].

BREAST CANCER

In the United States, 240,000 women develop breast cancer annually, and 40,000 will die from the disease []. The lifetime risk of developing breast cancer is one in eight.

It has been known for over 70 years that [Testosterone] it is anti-proliferative in the breast and inhibits the stimulatory actions of estrogens. Studies have shown that testosterone has been successfully used to treat breast cancer [].

A recent study, The Dayton Study, noted that testosterone was associated with a 39% lower incidence of breast cancer than predicted by Surveillance Epidemiologic End Result (SEER) data. The conclusions are based on the treatment of over 1200 women with testosterone, with follow-up for 10 years []. (Glaser R., York A.E., Dimitrakakis C, 2019)

Another more recent long-term cohort study, entitled the Testosterone Therapy and Breast Cancer Incidence Study, followed over 2300 pre- and post-menopausal women receiving testosterone with and without estrogen. The results demonstrated that the incidence of breast cancer was 40% lower than predicted by the SEER data [].(Donovitz G., Cottoen M., 2021)

13. Society Consensus and Position Statements—Misinformation Has Again Led to Confusion in Women’s Health

Finally, multiple consensus statements from a variety of societies have consistently stated that bioidentical hormones should not be used, and that only FDA-approved preparations should be used. However, these opinions are not substantiated or validated with any scientifically published data.

In conclusion, there is growing evidence in support of using individualized doses of testosterone for sexual function, osteoporosis prevention, and breast protection. The safety has been evaluated for the past 80 years.

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Combined Testo and Estrogen in post Hyx women/surgical menopause placebo controlled double blind crossover study 1985

Sherwin, Barbara B., and Morrie M. Gelfand. “Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause.” American Journal of Obstetrics and Gynecology 151.2 (1985): 153-160.

The investigation of estrogen and/or androgen administration on physical and psychological symptoms in the surgical menopause was carried out in a prospective, double-blind, crossover design. When patients who received either a combined estrogen-androgen drug or androgen alone were compared with those who received estrogen alone or placebo, energy level, well-being, and appetite were increased (p less than 0.01). The androgen-containing preparations also induced lower somatic, psychological, and total scores on the menopausal index. Superior functioning in the androgen-treated groups occurred in association with higher plasma testosterone levels during the treatment phases (p less than 0.01).

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Donovitz, Gary S. “Society Position Statements on Bio-Identical Hormones-Misinformation Leads to a Dilemma in Women’s Health.” Healthcare. Vol. 9. No. 7. MDPI, 2021.

Following the WHI, which reported an increased risk of cardiovascular disease, invasive breast cancer, venous thromboembolism, and stroke associated with the use of the single drug PremPro® (an oral combination synthetic hormone pill) (Pfizer Inc., New York, NY, USA), the indications and utilization of Hormone Replacement Therapy (HRT) have changed dramatically. Many physicians, fearing reported side effects, have stopped prescribing HRT. Moreover, many patients have retreated to the sidelines, feeling that no HRT may be the safer alternative. Time magazine dramatized the outcome further by stating that hormone replacement therapy was “riskier than advertised” [].

Thus, treatment for longevity and long-term quality of life are no longer indications for menopausal hormone therapy. This has limited HRT to short-term treatment of menopausal symptoms. The reduction in estrogen replacement therapy that occurred after the WHI has led to tens of thousands of deaths in women according to one study []. The North American Menopause Society reports that nearly 2 million women enter menopause yearly and that 40% of menopause patients are using bio-identical hormones.

In 2017 [], the North American Menopause Society published its Position Statement….As these are the most updated statements and opinions, they remain outdated and are not accurate in depicting the current state of compounded bio-identical hormone therapy.

3. Compounding

Just as pharmaceutical manufacturing has evolved and improved over the past decades, the same can be said for compounding. In a world where HRT has been more established for women, the availability of individualized dosing of hormones has relied heavily on compounding pharmacies to achieve products of the greatest need for women’s health. Individualized dosing more precisely addresses the hormone deficiencies of each patient and contributes to greater benefits while simultaneously minimizing risk. This is especially true of testosterone where there are no commercially available products for practitioners to prescribe for women.

The slogan to take hormones in the lowest dose possible for the shortest time possible should be phased out based on newer evidence in the existing literature [].

The statement from the ACOG [] that “evidence lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy” is unfounded and outdated based on multiple studies. Silverman et al. found that 17 β Estradiol was three standard deviations better than conjugated equine estrogen with or without synthetic progestin []. In addition, bioidentical progesterone (micronized) does not increase the risk for DVT and neither does the synthetic counterpart medroxyprogesterone acetate. The non-oral administration of estradiol does not increase the risk of hypercoagulability, whereas the oral synthetic Prempro® does pose that risk [].

Finally, a landmark finding is that bio-identical testosterone with and without bio-identical estradiol can significantly reduce the risk of breast cancer. Both of these studies have the additional benefit of long-term safety data, which was collected prospectively over 10 years [,].

side effects do exist even with improvements in formulations and routes of administration. Patients may experience weight gain, acne, additional facial hair, somnolence, and hair thinning.

A more contemporary position statement is needed from both the ACOG and NAMS. Such statements should provide a more accurate depiction of the current state of compounded Bio-identical hormones. These statements should also note that the stringent conditions imposed by the FDA on 503b outsourced pharmacies have improved the purity, potency, and sterility of these products, comparable to that of commercially available hormone products. The question concerning the long-term safety of bio-identical hormones has been answered through years of experience utilizing estradiol patches (e.g., Vivelle® [Manufactured by: Noven Pharmaceuticals Inc., Miami, FL, USA. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA] and Climara® [Bayer Healthcare, Montville, NJ, USA]) and sub-cutaneous hormone pellet therapy with testosterone and estradiol.

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Silverman, Daniel HS, et al. “Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD.Psychoneuroendocrinology 36.4 (2011): 502-513.
Postmenopausal women (n=53) at elevated risk for Alzheimer’s disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17β-estradiol (E) performed 3 standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke’s (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca’s area (p<0.0005).

In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

Observational studies support a decreased risk of clinically diagnosed AD for women on HT (). Surgical menopause has been associated with increased risk of cognitive impairment dementia later in life (). Surgically menopausal HT users have also been reported to have higher verbal memory performance compared to non-users in clinical trials with randomized, placebo-controlled design (), as well as cross-sectional studies (; ).

estrogen plus progestin therapy in the form of CEE and medroxyprogesterone acetate (MPA) specifically diminished verbal memory performance (; ).

Evidence from functional brain imaging studies, on the other hand, has been more consistent. Neuroimaging studies in healthy aging women have demonstrated enhanced function of medial temporal structures, including the hippocampus, amygdala, and entorhinal cortex among estrogen users vs. non-users ().

Eighty-one subjects were initially recruited; baseline data from 53 subjects were included in the final analysis;

The results presented here provide support for estrogen having a neuroprotective role in brain regions affected during aging.

========================= =

Renke, Guilherme, and Francisco Tostes. “Cardiovascular Safety and Benefits of Testosterone Implant Therapy in Postmenopausal Women: Where Are We?.” Pharmaceuticals 16.4 (2023): 619.

Symptoms of androgen deficiency may rarely affect women in the reproductive phase. However, in postmenopausal women, these symptoms can be devastating. This includes decreased memory, sense of well-being and libido, reduced muscle mass and bone mass, increased irritability, anxiety, fatigue, and symptoms of depression [,,].

Subcutaneous testosterone therapy (STT) administered by silastic or bioabsorbable implants has been used successfully in women since the 1930s. Published studies demonstrate promising results and safety in doses ranging from 75 to 225 mg [,,,,]. Thus, higher doses of T (500–1800 mg) in subcutaneous implants have been used effectively to treat patients with breast cancer [,]. Because it is not excreted in breast milk, T has been used to treat symptoms of postpartum depression and fatigue during lactation and the puerperium []. T therapy alone, at physiological doses, has been reported to be more effective than estradiol (E2)-T therapy or E2 alone for relieving postmenopausal symptoms with the same cardiovascular (CV) safety [].

For over 60 years, hormone replacement therapy (HRT) with T has been used to treat perimenopausal and menopausal symptoms []. In some countries such as Brazil, T therapy has been approved for use in women with hypoactive sexual desire disorder [].

Unfortunately, androgen use is uniquely associated with masculinity or male sexual function. This has undoubtedly contributed to the lack of recognition of the effects of low-dose androgen therapy use in women. Androgens are essential for women in both female reproductive function and hormonal balance and as vital precursors in synthesizing female hormones such as E2 [].

 

====================== =

Marko, Kathryn I., and James A. Simon. “Androgen therapy for women after menopause.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101592.

Androgens are essential hormones in women. Yet, androgen therapy is understudied and underutilized despite showing improvement in postmenopausal hypoactive sexual desire disorder (HSDD) and the genitourinary syndrome of menopause (GSM). Additionally, regulatory concerns have left a significant gap in commercially available testosterone preparations, formulated specifically for women, in most countries. This has led to off-label use of male formulations and compounded therapies which are under-regulated. Beyond HSDD and GSM, testosterone likely influences the brain, breast, cardiovascular and musculoskeletal systems. These effects are not well studied, and therefore it is difficult to counsel patients on testosterone therapy when used for these endpoints. Ultimately, further study is needed to elucidate these effects, create a fuller picture of the risks and benefits, and encourage product development specifically designed for women.

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Friedman, A. Edward. “Global Consensus Position Statement on the Use of Testosterone Therapy for Women.” The Journal of Clinical Endocrinology & Metabolism 105.6 (2020): e2308-e2309.

A. Edward Friedman Department of Mathematics, University of Chicago, Chicago, Illinois

I have read with interest the guidelines published by Davis et al (1) regarding the use of testosterone therapy in women.

This article ignores the theoretical and observed benefits of testosterone in the prevention and treatment of breast cancer. An article (2) that presented an explanation as to why medroxyprogesterone acetate (MPA) increased the risk of breast cancer stated that “Androgens have a predominantly inhibitory effect on the growth of breast cancer cells, both in vitro and in vivo.” It also stated that “We propose that the observed excess of breast malignancies associated with combined hormone replacement therapy (HRT) may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast.” It is not surprising that testosterone would act to prevent breast cancer since both the intracellular androgen receptor and the membrane androgen receptor downregulate the production of the protein bcl-2 which protects cancer cells from apoptosis (3).

The fact that testosterone can kill breast cancer cells was demonstrated in the case of a 90-year old woman with invasive breast cancer (IBC). Treating her solely with supraphysiological serum levels of testosterone along with anastrozole (to prevent the conversion of testosterone to estradiol) resulted in a 12-fold decrease in tumor volume in 3 months with no adverse side effects (4).

The fact that supraphysiological serum levels of testosterone can prevent IBC was shown in a 5-year interim report of a 10-year study (5). The incidence of IBC in the treated women was 142 cases per 100 000 person-years with the age-specific Surveillance, Epidemiology, and End Results (SEER) incidence rate being 293/100,000. Women who totally adhered to the
therapy had an IBC rate of 73/100,000. Subsequent to
the publication of the Davis et al article (1), the final report of the above 10-year study was published (6). The treated women had an IBC rate of 165/100,000, with the age-specific SEER incidence rate being 271/100,000. The rate of ductal carcinoma in situ was 45/100,000 for the treated women, with the age-specific SEER in-
cidence rate being 84/100,000. There were no adverse side effects observed other than cosmetic androgenic side effects.

While the Davis et al article states that “Use of any testosterone preparation that results in supraphysiologic concentrations of testosterone, including pellets and injections, is not recommended (Expert Opinion),” this conclusion cites no evidence to support it and is contradicted by the studies cited above. Absent evidence to the contrary, further studies using supraphysiologic concentrations of testosterone in the treatment and prevention of breast cancer appear to be warranted.

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Traish, Abdulmaged M., and Abraham Morgentaler. “Androgen therapy in women with testosterone insufficiency: looking back and looking ahead.” Clinical Research and Therapeutics 3.1 (2022): 2-13.

Effects on Sexual Function
a host of clinical studies have demonstrated significant benefits of TTh on improving sexual function and metabolism without serious safety concerns.

Effects of TTh on Other Metabolic
Function in Women
Although the benefits of TTh in women with sexual dysfunction have been well recognized for many decades, 16,19,20,28–51 T treatment also improved bone mineral density, fat-free mass, and fat mass and improved metabolic function.29,31–34,47,50–64 TTh was also shown to improve mood in women with anxiety and depression, and in women with anorexia nervosa.

Safety of TTh in Women

Several adverse side effects of TTh in women have been
anecdotally reported, which include body hair growth,
acne, and voice changes. However, no medically seri-
ous adverse side effects have been reported in clinical
studies 63–74 and findings in clinical trials reported in
Table 1. Nevertheless, persistent concerns of serious ad-
verse effects remain an obstacle for the use of TTh in
women. Foremost among these has been the fear that
androgen therapy could lead to an increased risk of
breast cancer due to aromatization of T to estradiol.75–79
This alarming possibility has not been supported by
the available data. Indeed, in the years since the first re-
ports on T in women1,2–7 to modern-day clinical tri-
als,16,19,20,28–51 no major safety concerns have arisen
(Table 1). Regarding heart disease, Islam et al. con-
cluded, ‘‘From a contemporary therapeutic perspective,
there is no evidence that TTh, when used for the treat-
ment of HSDD, is associated with adverse CV effects.’’65
As discussed by Traish and Gooren 71 and Traish
et al., 80,81 several lines of evidence argue against in-
creased breast cancer risk with TTh. These include:
(1) Data from breast tumor cell lines treated with an-
drogens do not support the notion that T increases
breast cancer risk.

On the contrary, androgens inhibit tumor cell growth,
and thus they appear to be protective; (2) several epide-
miological studies reporting an association between T
and breast cancer failed to adjust for estrogen lev-
els.82–84

Studies that did adjust for estrogen levels have shown no association between T and breast cancer. (3)

Clinical studies with TTh have not shown any increased incidence of breast cancer. (4) Women with polycystic ovary disease do not appear to be at an increased risk of breast cancer compared with the general population, despite higher serum androgen
concentrations. (5)

Female to male transsexuals, who
receive supra-physiological doses of T for long time pe-
riods before surgical procedures, have not been shown
to have an increased risk of breast cancer.

(6) Finally, women with hormone responsive pri-
mary breast cancer were treated with aromatase
inhibitors, which block conversion of androgens to es-
trogens, thus elevating androgen levels. These women
do not experience increased incidence of contralateral
breast cancer, nor do they experience increased tumor
growth.
A recent report 85 suggested that a 10-year analysis
of the Dayton study demonstrated reduced incidence
of invasive breast cancer in T users by 39% compared
with the ‘‘age-matched’’ population. Thus, the data in
the contemporary literature suggest that TTh in women
is unlikely associated with an increased risk of breast
carcinoma. 10,12,43,71,74,78,81,84,86

Events Negatively Impacting Adoption
of TTh in Women
In our view, several key events have contributed to the
failure of the medical community to recognize the im-
portance of androgen insufficiency in women, and to
adopt the treatment of affected women. These include
(1) response to publication of findings from the Wom-
en’s Health Initiative (WHI), (2) lack of approval for
T formulations for women by the U.S. FDA, (3) the
Endocrine Society Guidelines on TTh in women with
T deficiency, and (4) lack of education and training
of health care professionals (HCPs) in this field

much of the fundamental information
regarding both the impact of T insufficiency and the
benefits of treatment with TTh have been known for
80 years. And yet, the plight of affected women is
that they are unlikely to be diagnosed, and even less
likely to be treated. If they do receive treatment, it
will be off-label via compounded medications since
there are no regulatory-approved T products available
through most of the world…The impact of this is enormous, affecting millions of women in the United States alone, depriving them (and
their partners) of satisfying sexual relations, strength,
and vigor…the lack of education regarding women’s
sexual dysfunction, and T insufficiency, needs to be
addressed during medical education and training…it will be helpful if professional organizations lend their support to the importance of diagnosing and treating women with T deficiency…it is to be hoped that one or more T products for women obtain regulatory approval in the United States and other countries…Looking back, we are struck by the failure of science to effect meaningful change in clinical practice for women with T insufficiency over such a long period
of time. Looking forward, we are encouraged by numerous developments in the field, perhaps especially by the growing calls to make women’s health a priority. We can easily envision a time in the not-too-distant future when women with symptoms of T insufficiency
are evaluated respectfully and without dismissing the importance of their symptoms, undergo prompt and thorough evaluation, and are offered effective treatment when appropriate. The consequences of this vision are not only improved health and well-being for
those women, but also a happier existence for their families, friends, and society as a whole.

 

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Testosterone reduces Breast Cancer

Donovitz, Gary, and Mandy Cotten. “Breast cancer incidence reduction in women treated with subcutaneous testosterone: Testosterone therapy and breast cancer incidence study.” European journal of breast health 17.2 (2021): 150.

Testosterone (T) therapy has been shown to be breast protective in both pre- and post-menopausal patients. Additionally, estradiol (E) does not cause breast cancer (BC) in the majority of the world’s literatures. This study aimed to investigate the incidence of invasive BC (IBC) in pre- and postmenopausal women treated with T therapy and T in combination with E (T/E).
Materials and Methods:

Since January 2010, a total of 2,377 pre- and post-menopausal women were treated with T or T/E implants. IBC rates were reported based on newly diagnosed IBC cases in the total study. Total cases divided by the total sample size and years in study was expressed as an incidence per 100,000 person-years (P-Ys). The BC incidence was compared with age-specific Surveillance Epidemiology and End Results (SEER) incidence rates.
Results:

As of October 2020, 14 cases diagnosed with IBC have been found in 9,746 P-Y of follow up for an incidence of 144 cases per 100,000 P-Y, substantially less than the age-specific SEER incidence rates (223/100,000), placebo arm of Women’s Health Initiative Study (330/100,000), and never users of hormone therapy from the Million Women Study (312/100,000).
Conclusion:

T and/or T/E pellet implants significantly reduced the incidence of BC in pre- and post-menopausal women. The addition of E did not increase the incidence over using T alone. This is the second multi-year long-term study demonstrating the benefits of T therapy in reducing the incidence of IBC.

Hickey, Theresa E., et al. “The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer.” Nature medicine 27.2 (2021): 310-320.

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

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You, Chan-Ping, et al. “Modulating the activity of androgen receptor for treating breast cancer.” International Journal of Molecular Sciences 23.23 (2022): 15342.

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

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pdf
Laing, Abbie J., Louise Newson, and James A. Simon. “Individual benefits and risks of intravaginal estrogen and systemic testosterone in the management of women in the menopause, with a discussion of any associated risks for cancer development.” The Cancer Journal 28.3 (2022): 196-203.

Improvements in sexual desire,arousal, orgasmic function, pleasure, and sexual responsiveness together with a reduction in sexual concerns have been demonstrated among placebo-controlled RCTs in women with hypoactive sexual desire disorder.78 Suggested reasons for this include an increased dopamine release in the central nervous system79 and/or an amplified activation of brain areas involved with sexual arousal (such as the limbic system).86

Lastly, testosterone may also have beneficial effects on lower urinary tract function. A recent analysis of data from the National Health and Nutrition Examination Survey found that women with low serum testosterone were significantly more likely to have stress or mixed urinary incontinence.89 A suggested reason for this was an anabolic effect of androgens on skeletal muscle and the role of pelvic musculature in maintaining urethral support.8

39% lower breast cancer w/ subcut testo implants

in a large 10-year prospective cohort study, there was a 39% lower incidence of invasive breast cancer in users of subcutaneous testosterone implants compared with the age-matched expected incidence, and the authors concluded that, although not novel, testosterone therapy should be investigated as breast cancer prevention.106 There are increasing data demonstrating antiproliferative, proapoptotic, and antiestrogenic
stimulatory effects of testosterone in the breast.

106. Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study. BMC Cancer. 2019;19:1271.

107. Dimitrakakis C, Bondy C. Androgens and the breast. Breast Cancer Res.2009;11:212.

108. Dimitrakakis C, Zhou J, Wang J, et al. A physiological role for testosterone in limiting estrogenic stimulation of the breast. Menopause.2003;10:292–298.

109. Hickey TE, Robinson JL, Carroll JS, et al. Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol. 2012;26:1252–1267.

110. Eigeliene N, Elo T, Linhala M, et al. Androgens inhibit the stimulatory action of 17β-estradiol on normal human breast tissue in explant cultures. J Clin Endocrinol Metab. 2012;97:E1116–E1127.

111. Davis SR, Wahlin-Jacobsen S. Testosterone in women—the clinical significance. Lancet Diabetes Endocrinol. 2015;3:980–992.

76. Glaser R, Dimitrakakis C. Testosterone and breast cancer prevention. Maturitas. 2015;82:291–295.

80. Davis SR, McCloud P, Strauss BJ, et al. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas. 2008;61:17–26.

81. Davison SL, Bell RJ, Gavrilescu M, et al. Testosterone improves verbal learning and memory in postmenopausal women: results from a pilot study. Maturitas. 2011;70:307–311.

82. Davis SR, Davison SL, Gavrilescu M, et al. Effects of testosterone on visuospatial function and verbal fluency in postmenopausal women: results from a functional magnetic resonance imaging pilot study. Menopause. 2014;21:410–414.

83. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010;56:1310–1316.

84. Ebinger M, Sievers C, Ivan D, et al. Is there a neuroendocrinological rationale for testosterone as a therapeutic option in depression? J Psychopharmacol. 2009;23:841–853.

85. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification,and assessment. Fertil Steril. 2002;77:660–665.

86. Archer JS, Love-Geffen TE, Herbst-Damm KL, et al. Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women. Menopause. 2006;13:528–537.
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Testosterone and bone mass bone density preventing osteoporosis

Nunes, Elsa, et al. “Steroid hormone levels and bone mineral density in women over 65 years of age.” Scientific Reports 13.1 (2023): 4925.
Slemenda C, Longcope C, Peacock M, Hui S, Johnston CC. Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. J Clin Invest 1996;97:14–21.

Perimenopausal women with higher testosterone con-
centrations have slower rates of bone loss than those with
lower concentrations, independent of their estrogen status (7)

Premenopausal women with androgen excess have higher than
normal bone mass with or without (8, 11) normal menstrual cy-
cling.

Bone loss was significantly associated with lower androgen
concentrations in premenopausal women, and with lower
estrogens and androgens in peri- and postmenopausal women.
Sex steroids are important for the maintenance of skeletal
integrity before menopause, and for as long as 20–25 yr after-
wards.

 

33 Lee JS, LaCroix AZ, Wu L, Cauley JA, Jackson RD, Kooperberg C, et al. Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women. J Clin Endocrinol Metab 2008;93:1796–803.

https://www.nature.com/articles/s41598-022-21008-7
Zhang, Han, et al. “Association between testosterone levels and bone mineral density in females aged 40–60 years from NHANES 2011–2016.” Scientific Reports 12.1 (2022): 16426.

We included 2198 female participants in the study, and testosterone levels were positively associated with lumbar BMD after adjusting for all the covariates (β = 1.12, 95% CI 0.31, 1.93)…In US adult females aged 40–60 years, the testosterone level was a positive predictor of the lumbar BMD after adjusting for covariates.

Yang, JinXiao, et al. “Association between serum total testosterone level and bone mineral density in middle-aged postmenopausal women.” International Journal of Endocrinology 2022 (2022).

Conclusions. Serum total T level was positively associated with lumbar BMD in middle-aged postmenopausal women up to a T level >30 ng/dL. Therefore, increasing T level in women with a low serum total T level may have beneficial outcomes on bone health.

pdf
Frazzetta, Gayle. “Effect of Testosterone Pellet Therapy on Bone Mineral Density in Postmenopausal Women.” Journal of Clinical Densitometry 26.3 (2023): 101392.

BMD was measured in 35 postmenopausal women aged 53-84 years, receiving low-dose E2/T pellet therapy. Pellets were administered every 3 to 5 months. Replacement of T alone or with 10 mg or less of E2 was considered minimal or no E, while T in combination with greater than 10 mg was considered low E2. BMD at hip and spine was measured at baseline or within three months of initiating pellet therapy and repeated every 12 ± 5 months. All patients received counseling regarding exercise, vitamin D and calcium.

All patients in this study had improved BMD or cessation of bone loss. The average BMD improvement was 1.6% at the hip and 6.2% at the spine. Patients who received low-dose E2 had greater improvement of BMD at the spine than those who received minimal or no E2, 6.8% vs. 5.4%. The change at the hip was more closely correlated 1.6% vs. 1.7% respectively.

MALE osteporosis

Snyder, Peter J., et al. “Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial.” JAMA internal medicine 177.4 (2017): 471-479.

Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.

Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.
Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months.
Results

There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.
Conclusions and Relevance

Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.

 

Tracz, M. J., et al. “Testosterone use in men and its effects on bone health: a systematic review and meta-analysis of randomized placebo-controlled trials.” Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet] (2006).

Results of the review

Eight RCTs (n=365) were included: seven parallel-group RCTs and one crossover RCT…Intramuscular testosterone moderately increased lumbar bone spine density in men, but the effects on femoral neck density were uncertain.

 

Ng Tang Fui, Mark, et al. “Effect of testosterone treatment on bone microarchitecture and bone mineral density in men: a 2-year RCT.” The Journal of Clinical Endocrinology & Metabolism 106.8 (2021): e3143-e3158.

Conclusion: In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!

Corona, G., et al. “Testosterone supplementation and bone parameters: a systematic review and meta-analysis study.” Journal of Endocrinological Investigation 45.5 (2022): 911-926.

Abstract
Background The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the
object of an intense debate.
Methods All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect
of TRT on different bone parameters were considered.
Results Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6 weeks. TRT
improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-
controlled RTCs showed a positive effect of TRT only at lumber spine and when trials included only hypogonadal patients
at baseline (total testosterone < 12 nM). The effects on aBMD were more evident in subjects with lower T levels at baseline
and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at
endpoint contributed to aBMD improvement. TRT was associated with a significant reduction of bone resorption markers
in observational but not in controlled studies.
Conclusion TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when
the duration is long enough to allow the anabolic effect of T and estrogens on bone metabolism to take place.

==============================

Testosterone for prevention and treatment of breast cancer
————————————-

Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT.

We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.—

===============================

DeRosa, Angela Marie. “Gender bias in medicine:“How women continue to Get the shaft when It comes to testosterone therapies”.” Androgens: Clinical Research and Therapeutics 2.1 (2021): 82-84.

Testosterone deficiencies in women, especially prevalent in the years before and during menopause, can cause a wide variety of symptoms—including mood disorders, weight gain, cognitive impairment, insulin resistance/diabetes, and low libido, among many others.4,9,10

Despite these potentially life-changing symptoms, there are zero FDA-approved testosterone products for women.

Compare this consensus statement with the 2019 publication “Testosterone Insufficiency and Treatment in Women: International Expert Consensus,” which was released by a group of established experts in the field of compounded bioidentical hormone replacement therapy. This group of experts had >100,000 patient-years’ experience with testosterone supplementation in women.10

This real-world experience coupled with the roughly 100 references/studies (vs. the 1 meta-analysis/14 references in the mentioned Davis et al., testosterone consensus) guided their recommendations, which included:

  • Testosterone is not a male-exclusive hormone. It is the most abundant gonadal hormone throughout a women’s life.

  • Serum testosterone levels do not correlate with symptoms of testosterone deficiency in women. Optimal ranges of serum testosterone levels in women have not been established.

  • Female testosterone insufficiency is a clinical syndrome that may occur during any decade of adult life.

  • Testosterone therapy may be breast protective.

  • Testosterone insufficiency in women negatively affects sexuality, general health, and quality of life. Supplementation may positively influence sexuality, general health, and quality of life.

  • Testosterone insufficiency may be associated with an increased risk of cardiovascular disease in women.

  • Testosterone optimization may be brain protective and may enhance cognitive function.

  • Testosterone optimization may be a key component for improved bone health.

  • Testosterone therapy in women has no adverse effects on lipids and/or cardiovascular risk.

  • Studies of testosterone supplementation show benefits exceed the risk and that consistent purity and potency can be achieved.

The sad truth is that the failure to approve a female testosterone product began over two decades ago. This failure is not only alarming, but also embarrassing to the medical profession as a whole due to our inability to provide equal access to essential hormones that have been made available for men, but not to women.

The medical community and pharmaceutical industry need to do better at addressing this outage, but until then, the compounding pharmacies and compounding outsourcing facilities are filling the void of this unmet clinical need. As patient advocates, it is important to remember the unique needs of our patients—in particular, women—and we must fight to protect our abilities to treat them as such. The time has come to eliminate the gender bias that has plagued our profession. Our female patients deserve much better.

================================

Davis, Susan R. “Use of testosterone in postmenopausal women.” Endocrinology and Metabolism Clinics 50.1 (2021): 113-124.
Based on the cumulative data from these studies, loss of sexual desire with associated personal distress currently is the only agreed-on indication for judicious testosterone supplementation for postmenopausal women.

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Faresjö, Åshild, et al. “Decreased Testosterone Levels Precede a Myocardial Infarction in Both Men and Women.” The American Journal of Cardiology 186 (2023): 223-227.
=========================
!!!!!!!!!!!!!!!!!!!!! Breast Cancer and Aromatase !!!!!!!!!!!!!!!!! ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ

Breast cancer cells have upregulated aromatase to make their own estrogen, serving as growth factor. Usefulness of letrazole. for ER+ Breast cancer.

Kijima, Ikuko, Toru Itoh, and Shiuan Chen. “Growth inhibition of estrogen receptor-positive and aromatase-positive human breast cancer cells in monolayer and spheroid cultures by letrozole, anastrozole, and tamoxifen.” The Journal of steroid biochemistry and molecular biology 97.4 (2005): 360-368.

Mukhopadhyay, Keya De, et al. “Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.” PloS one 10.4 (2015): e0121136.

In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

Role of Androgens on Breast Cancer Cells

Macedo, Luciana F., et al. “Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole.” Cancer research 66.15 (2006): 7775-7782.

Previous work has shown that androgens inhibit breast cancer
cells and tumor growth. On the other hand, androgens can be
converted to mitogenic estrogens by aromatase in breast
cancer cells. Here, we report that androgens, such as the
aromatizable androstenedione and the non-aromatizable
5A-dihydrotestosterone, inhibit MCF-7 cell proliferation.

We also show that suppression of the estrogen-induced anti-
apoptotic protein Bcl-2 may be involved in the antiprolifer-
ative effects of androgens and letrozole. ..Bcl-2protein has been extensively characterized as an inhibitor of apoptosis.

The results showed that MCF-7 breast cancer cells are responsive to androgens and estrogens. Estrogens stimulate MCF-7 and Ac1 (MCF-7 aromatase transfected) cell proliferation over a physiologic range of concentrations, and their effects are mediated by the ER.
In contrast, androgens show the opposite effect and inhibit cell growth. MCF-7 cell proliferation was inhibited by androstenedione and 5a-dihydrotestosterone at concentrations found in women and breast cancer patients (1-10 and 0.3-0.7 nmol/L, respectively;ref. 2).

We show that androstenedione and dihydrotestosterone at physiologic concentration act by strongly reducing Bcl-2expression in MCF-7 cells, and that the androgenic inhibitory effect is mediated by the AR. Estradiol showed
an opposite effect and increased the Bcl-2levels of expression. The finding that Bcl-2expression was reduced by letrozole is consistent with the inhibition of the conversion of androstenedione to estradiol.

In summary, our results suggest that there are two hormonal
forces regulating proliferation in AR- and ER-positive breast cancer cells. The androgenic signaling, through the AR, induces cell growth inhibition, whereas the estrogen-mitogenic signaling is mediated by the ER. The dominance of an inhibitory or stimulatory response seems to depend on the estrogen milieu. A change in the balance between androgenic and estrogenic influences could modify the overall growth rate of breast cancer cells. The balance can be shifted to stimulate proliferation when sufficient amounts of
estrogens are produced due to expression of cellular aromatase and also due to blockade or down-regulation of the AR. On the other hand, the balance can be shifted to inhibit proliferation when ER is down-regulated or blocked and when the production of estrogens is reduced by aromatase inhibitors, such as letrozole. During aromatase inhibition, precursor androgens, such as androstenedione, can act directly or be converted to dihydrotestosterone and
exert their antiproliferative effect by interacting with the AR. Thus, it seems that estrogens and androgens act in concert to regulate cell growth. The antiproliferative actions of androgens exposed by inhibiting estrogen production seem to play an important role in the efficacy of aromatase inhibitors in controlling breast cancer.
Our studies show that not only the inhibition of estrogenic
production but also the activation of the intracellular androgenic signaling are involved in the actions of aromatase inhibitors.

Lapointe, Jacques, et al. “Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells.” Endocrinology 140.1 (1999): 416-421.

POULIN, RICHARD, et al. “Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line.” Endocrinology 125.1 (1989): 392-399.

Ortmann, J., et al. “Testosterone and 5α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines.” Gynecological Endocrinology 16.2 (2002): 113-120.

Takagi, Kiyoshi, et al. “Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment.” Endocrine-related cancer 17.2 (2010): 415-430.

These findings suggest that intratumoral androgen actions are increased during exemestane treatment.

Zhou, Dujin, et al. “Aromatase gene is amplified in MCF-7 human breast cancer cells.” The Journal of Steroid Biochemistry and Molecular Biology 46.2 (1993): 147-153.

Medroxyprogesterone Inhibits via Androgen Receptor

Hackenberg, Reinhard, et al. “Medroxyprogesterone acetate inhibits the proliferation of estrogen-and progesterone-receptor negative MFM-223 human mammary cancer cells via the androgen receptor.” Breast cancer research and treatment 25 (1993): 217-224.

Bentel, Jacqueline M., et al. “Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.” Molecular and cellular endocrinology 154.1-2 (1999): 11-20.

Dran, G., et al. “Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma.” Breast cancer research and treatment 35.2 (1995): 173-186.

Zaucha, R., K. Sosińska-Mielcarek, and J. Jassem. “Long-term survival of a patient with primarily chemo-resistant metastatic breast cancer treated with medroxyprogesterone acetate.” The Breast 13.4 (2004): 321-324.
Abstract

The prognosis of breast cancer patients with liver metastases is extremely poor. Here we present the case of a 66-year-old female breast cancer patient with multiple liver metastases diagnosed 2 years after a radical modified mastectomy followed by adjuvant tamoxifen. At progression, anthracycline-based chemotherapy was administered, but a CT scan following two cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide) showed progression of the liver metastases. Chemotherapy was therefore switched to medroxyprogesterone acetate (MPA). After 3 months the patient’s general status improved, and disease stabilization was observed at the next CT scan. A further 4 months of MPA treatment resulted in complete response of all liver lesions. Treatment with oral MPA was continued for 4 years. At present, 11 years after the diagnosis of metastatic liver involvement, the patient is alive, free of cancer, and fully ambulatory. Despite bulky visceral disease and chemoresistance, hormonal treatment with MPA resulted in a spectacular and long-lasting response.

Buchanan, Grant, et al. “Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate.” Cancer research 65.18 (2005): 8487-8496.

Poulin, R., et al. “Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells.” Breast cancer research and treatment 13.2 (1989): 161-172.

Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.

Anti-Androgen Action of MPA in normal breast tissue- POST MENOPAUSAL WOMEN

Ochnik, Aleksandra M., et al. “Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.” Menopause 21.1 (2014): 79-88.
Objective: Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue.

Methods: Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry.

Results: DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels.

Conclusions: In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.

Ochnik, Aleksandra Monica. The molecular actions of medroxyprogesterone acetate on androgen receptor signalling and the promotion of breast cancer. Diss. 2012. (Doctoral dissertation).

Using the ex vivo breast explant tissue model, I have demonstrated that MPA [medroxyprogesterone] impedes DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling in post-menopausal non-malignant human breast epithelial cells. Importantly, these studies have established a potential biological link between the effects of MPA [medroxyprogesterone] promoting increased breast epithelial proliferation in post-menopausal women taking cHRT [estrogen/MPA] by the disruption of the DHT [dihydrotestosterone]-induced AR [androgen receptor]-signalling.

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Testosterone inhibits Estrogen Signalling

norethisterone acetate

Hofling, Marie, Angelica Lindén Hirschberg, and Lambert Skoog. “Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women.” Menopause: The Journal of The North American Menopause Society 14.2 (2007): 183-190.

Objective: During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast.
Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy.

Design: We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with
either a testosterone patch releasing 300 Kg/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody.
Results: A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P G 0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%).

During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells. Conclusions: Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.

Comparing Oral E2/P with CEE/MPA

Murkes, Daniel, et al. “Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women.” Fertility and sterility 95.3 (2011): 1188-1191.

In a prospective, randomized clinical study 77 women were assigned randomly to receive sequential hormone therapy with either conventional oral conjugated equine estrogens (0.625 mg) with the addition on 14 of the 28 days of oral medroxyprogesterone acetate (5 mg) or natural E2 gel (1.5 mg) with oral micronized P (200 mg) on 14 of the 28 days of each cycle. Because oral conjugated equine estrogens–medroxyprogesterone acetate induced a highly significant increase in breast cell proliferation in contrast to percutaneous E2–oral P with a difference between therapies approaching significance, the former therapy has a marked impact on the breast whereas natural percutaneous E2–oral micronized P has not.

Androgens are Inhibitory to Estradiol Stimulation

Eigėlienė, Natalija, et al. “Androgens inhibit the stimulatory action of 17β-estradiol on normal human breast tissue in explant cultures.” The Journal of Clinical Endocrinology & Metabolism 97.7 (2012): E1116-E1127.

Conclusion: T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT [Human Breast Tissue] and opposed E2 [estradiol] -stimulated proliferation and cell survival in an AR [androgen receptor]-dependent manner. These effects were associated with changes in the proportions of ER - and AR-positive epithelial cells

Dimitrakakis, Constantine, et al. “Low salivary testosterone levels in patients with breast cancer.” BMC cancer 10 (2010): 1-8.

ZZZZZZZZZZZZZZZZZZZZZZZ Nice Summary ZZZZZZZZZZZZZ

Labrie, Fernand. “Combination of breast cancer prevention with tissue-targeted hormone replacement therapy.” Breast Cancer-Prognosis, Treatment, and Prevention. 2nd ed. New York: Informa Healthcare, USA (2008): 201-252.

While estrogens are well known to be the predominant stimulatory factor in the development and growth of the mammary gland and breast cancer, a long series of data indicate that androgens have an opposite inhibitory effect able to decrease or neutralize the action of estrogens.
Accordingly, in women receiving testosterone in addition
to estrogen, the stimulatory effect of estrogen on mam-
mary gland proliferation was completely blocked. More-
over, clinical situations of hyperandrogenism such as the
polycystic ovary syndrome and in athletes taking anabolic
steroids, there is an inhibition of mammary gland devel-
opment while the incidence of breast cancer is decreased
by 50% in the polycystic ovary syndrome. In support of
these data obtained in women, experiments performed in
the monkey have clearly demonstrated that physiological
doses of androgens completely inhibit mammary gland
proliferation stimulated by estrogens.

In clinical studies, androgens have been well demon-
strated to inhibit breast cancer; as early as in 1939,
testosterone and anabolic steroids have been used for the
treatment of breast cancer in women with a success
comparable to other hormonal therapies. However, the
virilizing effects of androgens have limited the use of
these compounds that have been replaced by the much
better-tolerated tamoxifen. While the data obtained fol-
lowing administration of androgens are clear and straight-
forward, the epidemiological studies have shown
equivocal results, which can be explained, as mentioned
above, by the complete lack of reliability of serum tes-
tosterone as parameter of androgenic activity in women.

It is thus important to combine with DHEA, a tissue-specific precursor of both androgens and estrogens and thus provide a tissue-targeted physiological HRT limited to the tissues in need of specific levels of each sex steroid, thus avoiding exposure of the
other tissues and minimizing the adverse effects of traditional estrogen and estrogen plus progestin replacement
therapy.

_______________ ——————-_——————-

Millennium Wellness Center, Dayton, Ohio, USA.
Rebecca L. Glaser, M.D., FACS
Rhoads Center East
228 E. Spring Valley Road
Dayton, Ohio 45458
937-436-9821

see (3) above

Glaser, Rebecca, and Constantine Dimitrakakis. “Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence.” Clinical Research and Therapeutics 2.1 (2021): 94-110.

T implant therapy has been (safely) used in female patients since 1937 in doses of 50–400 mg without excessive androgenic effects. 3–6,8,9 In addition, significantly higher doses (500–1800 mg) have been safely used to treat breast cancer patients. 3,10

T is the most abundant biologically active hormone in women. It is produced in the ovaries, adrenal gland, and locally at the cellular level in target organs from androgen precursors. The major portion of serum T is bound to albumin and sex hormone-binding globulin.
T has a direct effect at the androgen receptor (AR). It is metabolized through the enzyme 5a-reductase to the more potent androgen, dihydrotestosterone. T is also aromatized to estradiol (E2) in the ovaries and locally in all peripheral tissues, thereby having a secondary effect through the estrogen receptor (ER). Many physicians are not aware that serum T levels are markedly
(10- to more than 15-fold) higher than E2 levels throughout the female lifespan, barring pregnancy.

The major source of androgenic activity in both pre and postmenopausal women is the local intracrine production of T from the adrenal precursor steroids dehydroepiandrosterone-sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione

Serum levels of T are not a valid marker of tissue exposure in women, reflecting <20% of the total androgen activity. Accordingly, serum T levels would not be expected to correlate with androgen deficiency symptoms or clinical conditions caused by androgen
deficiency. 30 This concept is extremely important to comprehend. Serum T levels should not be relied on to diagnose T deficiency or manage T dosing in women.

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It is well recognized that T has a profound effect on
lean muscle mass, bone density, and confidence as well
as sex drive and performance in both sexes.

Adequate amounts of (local) bioavailable T at the AR are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health (Supple-
mentary Data S1). 32–42 Thus, clinical indications for
T therapy include many signs and symptoms caused
by T deficiency (Table 1).1,43

Table 1. Signs and Symptoms of Aging Related
to Androgen Deficiency
A diminished sense of well-being
Dysphoric mood, anxiety, and irritability
Fatigue
Decreased libido, sexual activity, and pleasure
Vasomotor instability
Bone loss
Decreased muscle strength
Insomnia
Changes in cognition and memory loss
Urinary symptoms and incontinence
Vaginal dryness and atrophy
Joint and muscular pain

T is the direct precursor for E2 in every major organ
system, including the ovaries.

The main source of estrogen in postmenopausal women is the local conversion (paracrine/intracrine) of T to biologically
active E2. Unlike adipose tissue, which can contribute
to the circulating pool of estrogens, E2 from local aro-
matization would not be measurable in serum. 31,46,47
Therefore, similar to serum T levels, serum levels of
E2 should be interpreted with caution and taken into
context with clinical evaluation.

Obesity, medications, xenoestrogens, certain disease
states (endometriosis and fibroids) and cancers (breast
and endometrial) upregulate aromatase resulting in ex-
cess intracellular (local) E2 production.

Symptoms of androgen deficiency can occur be-
fore menopause and are not related to estrogen
levels. 1,3–6,43 In fact, many premenopausal women
have symptoms of estrogen excess in addition to andro-
gen deficiency.1

T implant therapy has been safely used in women since
1937

Premenopausal women: contraception mandated to avoid fetal virilization

In the United States, androgens are listed as a ‘‘class X’’ teratogen and premenopausal patients are instructed that they ‘‘must use birth control’’ (listed on the consent) with the ‘‘warning’’ that T could masculinize a female fetus.

As expected, there was no relationship between base-
line T levels and presenting symptoms (other than sex-
ual complaints) or response to therapy. Premenopausal
women reported a higher incidence of psychological
complaints (depressive mood, anxiety, and irritability),
which may be contributed to by higher—or fluctuating—
levels of estrogen relative to declining T levels. 3,60
Postmenopausal women reported more hot flashes, vag-
inal dryness, and urological symptoms, which may be
contributed to by lower levels of estrogen. T alone (no es-
trogen) delivered subcutaneously resulted in statistically
significant improvement ( p < 0.0001) in all 11 MRS
symptom categories (Fig. 3)

There were no adverse drug events reported in 285 patients treated for >1 year (mean 28.1 – 10.4 months).

clinical studies have reported positive effects in conditions caused by excess estrogen, including hypermenorrhea, uterine fi-
broids, endometriosis, premenstrual tension, dysmen-
orrhea, breast pain, and chronic mastitis. 3,5,6 We have
also published a case report on T implant therapy dur-
ing breastfeeding—a 100-mg subcutaneous T pellet
was effective in relieving maternal symptoms of de-
pression, anxiety, fatigue, decreased libido, memory
problems, and pain—T was not measurably increased
in breast milk or infant serum. 6

Neuroprotective

Evidence supports that T is neuroprotective (Supple-
mentary Data S1). 32,41,42 T’s neuroprotective effect is
consistent with our experience in clinical practice,
where ‘‘self-reported’’ memory issues are improved
on therapy, returning toward the end of the T implant
cycle. Essential tremors are also improved on T therapy
(Fig. 4).
A significant finding noted in the past 15 years is the
consistent relief of migraine headaches in pre- and post-
menopausal women, which we documented in a small
pilot study.15 Hormonal stabilization may improve
headaches and other conditions, including epilepsy.6

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Premenopausal women with estrogen fluctuation disorders are treated with testosterone plus anastrozole.

Currently in clinical practice, premenopausal women with migraine headaches, seizures, dysfunctional uterine bleeding, and endometriosis—are treated with an AI (anastrozole [A]) combined with T in the implant—as these conditions are affected by excess or fluctuating estrogens.44–53,62–64 Since serum levels of E2 do not reflect the local production of estrogen, the clinical signs and symptoms of excess estrogen should be monitored, including breast pain, fluid retention, anxiety, emotional disturbances, irritability, aggression, and lack of effect from T therapy. 1

Some women discontinue T therapy for cosmetic and
skin side effects, including facial hair growth, acne, mild
clitoromegaly, and hirsutism. Some women choose to lower their T dose, whereas others prefer the benefits of higher T doses and choose to treat the side effects.

63% HAIR Regrowth

In a questionnaire study on 285 patients, 48 of 76 (63%) patients who complained of age-related hair loss before therapy reported hair regrowth on T pellet therapy.13

Primate Model

Subsequently, in an experimental in vivo primate model, we showed that the addition of T to ‘‘conventional’’ hormone replacement therapy attenuated the proliferative effects of estrogens on breast tissue.65

We found that breast cancer patients had lower T levels
and a lower ratio of T to estrone, suggesting that higher
bioavailable T counters the proliferative effects of estro-
gen in the breast.67

Ten-year results revealed a reduced incidence of invasive breast cancer in women treated with T therapy. 19,20 A total of 11 (vs. 18 expected) cases of infiltrating breast cancer were diagnosed in patients on T pellet therapy equating to an incidence rate
of 165/100,000 person-years (p-y), which was significantly less than the age-matched ‘‘Surveillance, Epidemiology, and End Results’’ expected incidence rate of 271/100,000 p-y ( p < 0.001) and historical controls.

(T + AI) Revolutionized Breast Cancer Therapy

The innovative yet obvious use of an AI combined with T in a solitary pellet implant (T+AI) has revolutionized the use of T therapy in breast cancer patients. The combination T+AI subcutaneous implant enables the simultaneous and continuous delivery of both pharmaceutical active ingredients while avoiding the first pass effect.69 The combined use of T and an AI provides women with the beneficial effects of T without compromising these results with the conversion of T to estrogens and their possible adverse effects in estrogen-dependent diseases, for example, hormone receptor- positive breast cancer.

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Case Reports of T/AI Remission from BREast Cancer

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Glaser, R., and C. Dimitrakakis. “Testosterone and breast cancer prevention.” Maturitas 82.3 (2015): 291-295.

Mammograms before and 19 weeks after testo/AI showing
Fig. 3. Comparison mammography, right medial lateral oblique view at baseline (left) and at follow up (right), week 19 following neoadjuvant, intramammary T + A therapy of infiltrating lobular, hormone receptor positive BCA (ER+, PR+, AR+). Note the significant reduction in tumor size and absence of previously palpable axillary lymph nodes. (Previously unpublished images, Glaser, Dimitrakakis).

Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications.” Menopause (New York, NY) 24.7 (2017): 859.

This is the first case report of the concurrent use of T combined with an AI during neoadjuvant chemotherapy.

A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to “testosterone-letrozole” and subsequently, “testosterone-letrozole with chemotherapy” was monitored using serial ultrasounds and calculating tumor volume.

There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy.

pellets containing 60 mg of T and 4 mg of letrozole (60 mg T + 4 mg L).

Ultrasound measurements demonstrated a 43% reduction in tumor volume (12.28 vs 6.96 cc) 41 days after the patient’s initial 180 mg T + 12 mg L subcutaneous implant therapy and dietary changes (Fig. (Fig.1).1). This significant reduction in tumor volume occurred before the initiation of chemotherapy…

after five cycles of chemotherapy, the tumor was no longer palpable on clinical examination and unable to be identified on ultrasound, that is, complete clinical response. Most significant, there was no residual invasive cancer at the time of definitive surgery, that is, complete pathologic response.

Subcutaneous T + L therapy in conjunction with a whole food, low (processed)-carbohydrate diet was beneficial in the neoadjuvant therapy of breast cancer. In addition, T + L did not interfere with chemotherapy, supporting preclinical and clinical data. The T + AI combination implant seems to be a promising therapy that has the potential to simultaneously treat breast cancer, prevent side effects of chemotherapy, and improve health and quality of life in breast cancer survivors.

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from : (3) 3) Glaser, Rebecca, and Constantine Dimitrakakis. “Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence.” Clinical Research and Therapeutics 2.1 (2021): 94-110.

FIG. 7. Fifty-eight-year-old patient referred with large immobile breast cancer fixed to sternum. Refused conventional therapy. She was treated with T 180–240 mg +12 mg letrozole combination pellet implants at baseline, weeks 6, 14, and 26. She also implemented dietary changes. Top left: baseline, 6-cm tumor fixed
to chest wall (sternum) UIQ R breast, skin discoloration. Top right: baseline ultrasound, tumor invading periosteum (sternum) and skin—too large to be measured (extends off screen). Bottom left: week 14, complete clinical response, mass no longer palpable. Note indentation/shadow where tumor had stretched
skin. Bottom right: week 26, complete radiographic response confirmed on ultrasound. Patient continues on T + A pellets and remains healthy and disease free at 2 years. UIQ, upper inner quadrant.

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Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors.” J Clin Oncol 32.Suppl 2 (2014): 109.

Over 1000 Testosterone + Anastrozole (T + A) pellet
insertions have been performed in breast cancer survivors
since 2006. Between April 2013 and May 2014, 72
patients had been enrolled in the study and were eligible
for analysis.
T implant dosing is weight based3. Over 90% of patients
were treated with 8 mg of A combined with T in the
implant. A lower dose of A (4 mg) is occasionally used in
smaller patients and/or patients with lesser or more remote
disease. A higher dose of A (12 mg) is occasionally used in
obese patients with advanced disease, or in the neo-
adjuvant setting*. Subcutaneous implants are inserted in
the gluteal or inguinal area** at 3-month intervals on
average. Therapeutic T levels were confirmed without
elevation of estradiol in any postmenopausal survivor.
There have been no cancer recurrences in up to 8 years
of therapy.

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Monkey Studies

Testo Reduces c- MYC oncogene signalling in monkeys

65. Dimitrakakis, Constantine, et al. “A physiologic role for testosterone in limiting estrogenic stimulation of the breast.” Menopause 10.4 (2003): 292-298.
We show that androgen receptor blockade in normal female monkeys results in a more than twofold increase in MEP [mammary epithelial proliferation ], indicating that endogenous androgens normally inhibit MEP. Moreover, we show that addition of a small, physiological dose of T to standard estrogen therapy almost completely attenuates estrogen-induced increases in MEP in the ovariectomized monkey, suggesting that the increased breast cancer risk associated with estrogen treatment could be reduced by T supplementation. Testosterone reduces mammary epithelial estrogen receptor (ER)  and increases ER expression, resulting in a marked reversal of the ER/ ratio found in the estrogen-treated monkey. Moreover, T treatment is associated with a significant reduction in mammary epithelial MYC expression, suggesting that T’s antiestrogenic effects at the mammary gland involve alterations in ER signaling to MYC.
Conclusions: These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure.

Dhanasekaran, Renumathy, et al. “The MYC oncogene—the grand orchestrator of cancer growth and immune evasion.” Nature reviews Clinical oncology 19.1 (2022): 23-36.

The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

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This is exactly what Testosterone Does !!!!

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Davis, Susan R., and Sarah Wahlin-Jacobsen. “Testosterone in women—the clinical significance.” The Lancet Diabetes & Endocrinology 3.12 (2015): 980-992.

Clinical trials suggest that exogenous testosterone enhances cognitive performance and improves musculoskeletal health in postmenopausal women.

MPA Animal Studies – Androgenic/Anti-Androgenic

Pannuti, F., et al. “Experimental study on the anabolic and androgenic/antiandrogenic activity of different dose levels of medroxyprogesterone acetate (MAP) in rats.” Oncology 38.5 (1981): 307-310.

The authors treated three groups of rats with medroxyprogesterone acetate (MAP) at different dosages (0, 2.5, 5, 10, 20, 40, 80 mg/kg) i.p. and orally for 7 days to evaluate its anabolic and its androgenic/antiandrogenic effect. 70 rats had been previously castrated and 35 were intact.

The anabolic effect is evident in all groups of animals which were treated. The androgenic action predominates in castrated animals, while the antiandrogenic action predominates in intact [non-castrated] animals. The above-mentioned actions are more marked when very high doses are used. After suggesting the possible mechanism of action of MAP, the authors point out that the anabolic effect confirms what has already been reported in clinical oncology after treatment with very high doses of MAP (1,000-2,000 mg orally or i.m. for 30 days) in different types of tumors (breast, kidney, prostate).

Lelli, G., et al. “The anabolic effect of high dose medroxyprogesterone acetate in oncology.” Pharmacological research communications 15.6 (1983): 561-568.

Ten advanced cancer patients not amendable to conventional therapy were treated with high dose (greater than 500 mg/day, for 30 days) Medroxyprogesterone Acetate (MAP) both orally and intramuscularly, in order to evaluate a possible anabolic effect of this hormone. During the treatment, mean protein intake increased from 37.2 gr/day to 58.8 gr/day (p less than 0.01), nitrogen intake from 5.8 to 9.4 gr/day (p less than 0.01) and caloric intake from 1407.9 to 2075 Kcal/day (p less than 0.01). Nitrogen balance also showed a significant increase (p less than 0.05), as well as elementary strength (p less than 0.02). Lean body mass and body weight did not show significant variations. The above data confirms what was already been documented by us in animals and proposed in man-that MAP has an anabolic effect.

HIGH DOSE MPA – Regression of DMBA Breast Cancer MICE

Racca, S., et al. “Effects of medroxyprogesterone acetate on DMBA-induced mammary tumors.” Chemioterapia: International Journal of the Mediterranean Society of Chemotherapy 4.3 (1985): 236-238.
Rats with DMBA-induced mammary tumors were treated for 30 days i.m. with medroxyprogesterone acetate (MPA) at doses of 7.5, 15 or 75 mg/kg. Complete regression (disappearance of tumor) was observed in 60% and 20% of tumors from rats treated with 75 or 15 mg/kg MPA respectively. Partial regression (50% decrease in tumor area) was found in the remaining 20% of tumors from rats treated with 15 mg/kg MPA. The dose of 7.5 mg/kg MPA resulted in being devoid of effectiveness. Estrogen receptor (ER) levels were significantly reduced at all doses of MPA injected both in responsive and non-responsive tumors. However, only tumors with ER levels above 15 fmol/mg before therapy resulted in being responsive to MPA treatment. Progesterone receptors were so reduced at the end of the experiment as to not be detectable in all treated groups. It was concluded that MPA is effective as an antitumoral drug also in DMBA-induced mammary tumors and that this effect is at least in part related to ER levels before treatment.

MPA Induces Breast Cancer

Nagasawa, Hiroshi, et al. “Medroxyprogesterone acetate enhances spontaneous mammary tumorigenesis and uterine adenomyosis in mice.” Breast cancer research and treatment 12 (1988): 59-66.

we studied the effects of different schedules of MPA treatment on spontaneous mammary tumorigenesis and uterine adenomyosis in SHN virgin mice. Mice received a subcutaneous pellet of MPA every 2 months: I) during the limited period of 1–3 months of age; II) throughout the experiment beginning at 6–8 months of age; and III) throughout the experiment beginning at 2–3 months of age. All treatments significantly enhanced mammary tumorigenesis with little difference in the effects among treatments. The progression of uterine adenomyosis was also stimulated in Experiments I and III, but not in Experiment II.

Pazos, Patricia, et al. “Mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) in BALB/c mice.” Breast cancer research and treatment 20 (1991): 133-138.

MPA induces mammary tumors in virgin BALB/c mice with an average latency of 52 weeks.

Lanari, Claudia, et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocrine-Related Cancer 16 (2009): 333-350.

We developed a model of breast cancer in which the
administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants.

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5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis.

Progesterone Metabolites- One stimulates, the other inhibits

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Huber, Gary. “Progesterone Use as Hormone Replacement Therapy: Myths, Facts, and Solutions.”

Wiebe, John P., et al. “Opposing actions of the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines.” The Journal of steroid biochemistry and molecular biology 118.1-2 (2010): 125-132.

Previous studies have shown that breast tissues and breast cell lines convert progesterone (P) to 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) and that 3alphaHP suppresses, whereas 5alphaP promotes, cell proliferation and detachment. The objectives of the current studies were to determine if the 5alphaP- and 3alphaHP-induced changes in cell numbers are due to altered rates of mitosis and/or apoptosis, and if 3alphaHP and 5alphaP act on tumorigenic and non-tumorigenic cells, regardless of estrogen (E) and P receptor status. The studies were conducted on tumorigenic (MCF-7, MDA-MB-231, T47D) and non-tumorigenic (MCF-10A) human breast cell lines, employing several methods to assess the effects of the hormones on cell proliferation, mitosis, apoptosis and expression of Bcl-2, Bax and p21. In all four cell lines, 5alphaP increased, whereas 3alphaHP decreased cell numbers, [(3)H]thymidine uptake and mitotic index. Apoptosis was stimulated by 3alphaHP and suppressed by 5alphaP. 5alphaP resulted in increases in Bcl-2/Bax ratio, indicating decreased apoptosis; 3alphaHP resulted in decreases in Bcl-2/Bax ratio, indicating increased apoptosis. The effects of either 3alphaHP or 5alphaP on cell numbers, [(3)H]thymidine uptake, mitosis, apoptosis, and Bcl-2/Bax ratio, were abrogated when cells were treated simultaneously with both hormones. The expression of p21 was increased by 3alphaHP, and was unaffected by 5alphaP. The results provide the first evidence that 5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis. The opposing effects of 5alphaP and 3alphaHP were observed in all four breast cell lines examined and the data suggest that all breast cancers (estrogen-responsive and unresponsive) might be suppressed by blocking 5alphaP formation and/or increasing 3alphaHP. The findings further support the hypothesis that progesterone metabolites are key regulatory hormones and that changes in their relative concentrations in the breast microenvironment determine whether breast tissues remain normal or become cancerous.

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breast cell tumorigenesis and tumor growth accompanying progesterone treatment is due to the progesterone metabolite 5aP, and that breast tumorigenesis can be blocked with the 5a-reductase inhibitor, finasteride.

Wiebe, John P., et al. “Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed by the 5α-reductase inhibitor, finasteride.” The Journal of steroid biochemistry and molecular biology 149 (2015): 27-34.

The objective of the current studies was to determine in an in vivo mouse model if the presumptive progesterone-induced mammary tumorigenesis is due to the progesterone metabolite, 5aP. BALB/c mice were challenged with C4HD murine mammary
cells, which have been shown to form tumors when treated with progesterone or the progestin, medroxyprogesterone acetate. Cells and mice were treated with various doses and combinations of progesterone, 5aP and/or the 5a-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored.

The results provide the first in vivo demonstration that stimulation of breast cell tumorigenesis and tumor growth accompanying progesterone treatment is due to the progesterone metabolite 5aP, and that breast tumorigenesis can be blocked with the 5a-reductase inhibitor, finasteride.

Trabert, Britton, et al. “Association of circulating progesterone with breast cancer risk among postmenopausal women.” JAMA network open 3.4 (2020): e203645-e203645.

It has been hypothesized16 and laboratory studies have confirmed17,18,19,20 that breast cancer promotion may be associated with relative concentrations of progesterone metabolites, in particular the cancer-inhibiting 4-pregnenes (eg, 3α-dihydroprogesterone [3αHP]) and cancer-promoting 5α-pregnanes (eg, 5α-dihydroprogesterone [5αP])

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Progesterone Metabolites DO NOT Convert DCIS to cancer

Sourouni, M., et al. “Effect of 3α-dihydroprogesterone and 5α-dihydroprogesterone on DCIS cells and possible impact for postmenopausal women.” Climacteric 26.3 (2023): 275-283.

Objective: Progesterone metabolites 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αP) have opposite effects on proliferation, apoptosis and metastasis in the breast. Evidence regarding their influence on ductal carcinoma in situ (DCIS) lesions is lacking.

Methods: MCF10DCIS.com cells were cultured in a 3D culture system and treated with 5αP or 3αP. After 5 and 12 days of treatment, polymerase chain reaction (PCR) of proliferation, invasion/metastasis, anti-apoptotic or other markers was performed. Cells treated with the tumor-promoting 5αP were observed under the light and confocal microscopes to reveal possible morphological changes that could indicate a transition from an in situ to an invasive phenotype. As a control, the morphology of the MDA-MB-231 invasive cell line was examined. The invasive potential after exposure to 5αP was also assessed using a detachment assay.

Results: The PCR analysis of the chosen markers showed no statistically significant difference between naive cells and cells treated with 5αP or 3αP. DCIS spheroids retained their in situ morphology after treatment with 5αP. The detachment assay showed no increased potential for invasion after exposure to 5αP. Progesterone metabolites 5αP and 3αP do not facilitate or prohibit tumor promotion/invasion in MCF10DCIS.com cells, respectively.

Conclusion: As oral micronized progesterone has been proved effective for hot flushes in postmenopausal women, first in vitro data propose that progesterone-only therapy could possibly be considered for women after DCIS suffering from hot flushes.

Godbole, Mukul, et al. “Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status-a short report.” Cellular oncology 40 (2017): 411-417.

Pre-operative progesterone treatment of breast cancer has been shown to confer survival benefits to patients independent of their progesterone receptor (PR) status.

We found that progesterone induces de-phosphorylation of 12 out of 43 kinases tested, which are mostly involved in cellular invasion and migration regulation. Consistent with this observation, we found through cell-based phenotypic assays that progesterone inhibits the invasion and migration of breast cancer cells independent of their PR status.

Our results indicate that progesterone can inhibit breast cancer cell invasion and migration mediated by the de-phosphorylation of kinases. This inhibition appears to be independent of the PR status of the breast cancer cells. In a broader context, our study may provide a basis for an association between progesterone treatment and recurrence reduction in breast cancer patients,

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Yadav, Neelima, et al. “Progesterone modulates the DSCAM-AS1/miR-130a/ESR1 axis to suppress cell invasion and migration in breast cancer.” Breast Cancer Research 24.1 (2022): 97.

Montalto, Francesca Ida, et al. “Progesterone receptor B signaling reduces breast cancer cell aggressiveness: role of cyclin-D1/Cdk4 mediating paxillin phosphorylation.” Cancers 11.8 (2019): 1201.

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Chakravorty, Gaurav, et al. “Deciphering the mechanisms of action of progesterone in breast cancer.” Oncotarget 14 (2023): 660.

A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. This research perspective summarizes evidences from our studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. Non-coding RNAs, particularly DSCAM-AS1, play a regulatory role in this process, along with the upregulation of the kinase gene SGK1 and activation of the SGK1/AP-1/NDRG1 axis. Progesterone-induced modification of the progesterone receptor and estrogen receptor genomic binding pattern is also involved in orchestrating estrogen signaling in breast cancer, preventing cell migration and invasion, and improving patient outcomes. We also highlight the role of progesterone in endocrine therapy resistance, which could lead to novel treatment options for patients with hormone receptor-positive breast cancer and for those who develop resistance to traditional endocrine therapies.

To test the hypothesis, in a landmark phase III randomized clinical trial on patients with operable breast cancer, a single dose of hydroxyprogesterone was administered before surgery to mimic the luteal (progestogenic) phase; the analyses demonstrated a significantly increased duration of disease-free survival in patients with node-positive breast cancer, suggesting a protective effect of progesterone in breast cancer [].

Specifically, the study revealed that preoperative hydroxyprogesterone manifests its effect in patients with breast cancer by downregulating genes involved in inflammatory response and production of TNF that are known to induce proliferative, invasive, and malignant behavior of breast cancer cells. The study also identified upregulation of a tumor metastasis suppressor gene, N-Myc downstream regulated gene 1, NDRG1, along with increased expression of the AP-1 network genes, suggesting that preoperative progesterone intervention may modulate the effect of surgical stress on breast cancer by altering the expression of several protein-coding genes, thereby improving patient survival []. Additionally, a significant deregulation of the central node ubiquitin gene UBC, in the study, in response to progesterone, further underlined the downstream stress-regulating activities modulated by progesterone in breast cancer cells, potentially independent of the progesterone receptor (PR) []. Overall, these findings indicate that pre-operative hydroxyprogesterone may act to curb cellular stress responses and potentially mediate the pro-survival effects through a negative regulation of inflammation.

This is the human pre=op progrestreone study referred to the above article

Pre-op Progesterone Improves Survival After Surgery for breast Cancer

Badwe, Rajendra, et al. “Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial.” J Clin Oncol 29.21 (2011): 2845-2851. (Mumbai, India)

We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial .

One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An
analysis by axillary lymph node status was preplanned

In multivariate analysis, DFS [disease free survival] was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P  .02), whereas there was no significant effect in node-negative patients (P for interaction  .04).

Androgen receptors and Breast Cancer 234

Birrell, Stephen N., et al. “Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer.” The FASEB Journal 21.10 (2007): 2285-2293.

Peters, Amelia A., et al. “Androgen receptor inhibits estrogen receptor-α activity and is prognostic in breast cancer.” Cancer research 69.15 (2009): 6131-6140.

Thike, Aye Aye, et al. “Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer.” Modern pathology 27.3 (2014): 352-360.

Africander, Donita J., Karl-Heinz Storbeck, and Janet P. Hapgood. “A comparative study of the androgenic properties of progesterone and the progestins, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A).” The Journal of steroid biochemistry and molecular biology 143 (2014): 404-415.

Meijer, Mathias, et al. “Finasteride treatment and male breast cancer: a register‐based cohort study in four Nordic countries.” Cancer Medicine 7.1 (2018): 254-260.

An increased risk of MBC [Male Breast Cancer] was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11–1.88) compared to nonusers.

https://pubmed.ncbi.nlm.nih.gov/10509795/

Bentel, Jacqueline M., et al. “Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells.” Molecular and cellular endocrinology 154.1-2 (1999): 11-20.

Medroxyprogesterone acetate (MPA), which is frequently used as second line hormonal therapy for the treatment of metastatic breast cancer, binds with high affinity to the progesterone receptor (PR). However, the androgenic side-effects of MPA suggest that it may also activate androgen receptor (AR) regulated pathways. Treatment of the human breast cancer cell lines MDA-MB-453, ZR-75-1 and T47-D with high dose (100 nM) MPA resulted in 26-30% inhibition of cell growth, which was partially reversed by co-treatment with a 10-fold excess of the synthetic antiandrogen, anandron. Scatchard analysis demonstrated specific, high affinity (non-PR) binding of [3H]MPA to cytosols prepared from the PR-/AR+ MDA-MB-453 and PR+/AR+ ZR-75-1, but not the PR-/AR- BT-20 breast cancer cell lines. Competition of [3H]MPA binding to MDA-MB-453 cytosols by equimolar concentrations of androgens (5alpha-dihydrotestosterone (DHT), R1881) and the antiandrogen, anandron was consistent with binding of MPA to the AR. In ZR-75-1 cell cytosol fractions, DHT, R1881 and anandron only partially competed out [3H]MPA binding, suggesting that androgens displace [3H]MPA binding to AR but not to PR. Induction by MPA of AR transactivation was demonstrated in MDA-MB-453 and ZR-75-1 cells, and in the CV-1 cell line transfected with a full-length AR. In these cell lines the increased activity of the androgen responsive reporter gene (MMTV-CAT) by 1 nM MPA was fully (MDA-MB-453, CV-1) or partially (ZR-75-1) inhibited by co-culture with 1 microM anandron. These findings indicate that MPA is an AR agonist and suggest that the in vivo effects of MPA in breast cancer patients may in part be mediated by the AR.

Ponnusamy, Suriyan, et al. “Androgen receptor is a non-canonical inhibitor of wild-type and mutant estrogen receptors in hormone receptor-positive breast cancers.” Iscience 21 (2019): 341-358.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651649/
Hickey, Theresa E., Amy R. Dwyer, and Wayne D. Tilley. “Arming androgen receptors to oppose oncogenic estrogen receptor activity in breast cancer.” British Journal of Cancer 125.12 (2021): 1599-1601.

The first evidence that sex hormone antagonism could be therapeutically harnessed to treat breast cancer arose in the 1950’s, when androgenic drugs were used to successfully treat patients prior to advent of the selective ER modulator (SERM) tamoxifen [13, 14]. Although androgen therapy equalled tamoxifen in therapeutic efficacy, masculinising side effects underpinned its clinical demise. At that time, androgen therapy was thought to work via effects on the hypothalamic-pituitary-ovarian axis. It is now known that normal and malignant breast epithelial cells express AR and we demonstrate that greater than 60% of cells within ER+ breast cancer lesions co-express both receptors [12], indicating strong potential for genomic crosstalk within a cell. All steroid receptors act as ligand-activated transcription factors that share common features, including co-factors needed to modify chromatin and engage with the transcriptional machinery. Exploiting chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) to interrogate genome-wide interaction of transcription factors and associated co-factors with chromatin, we clearly show that activation of AR opposes ER binding at key regulatory elements that control transcription of cell cycle genes as a means of inhibiting proliferation in vitro and in vivo [12]. This AR-mediated antagonism of ER activity involves sequestration of key co-regulatory proteins (p300, SRC-3) from ER target genes to AR target genes, some with tumour suppressor functions (Fig. 1). Importantly, this AR genomic activity requires an agonist, not an antagonist ligand, which explains why AR antagonists (e.g. enzalutamide, bicalutamide) did not inhibit growth of ER+ breast cancer models. Fortunately, selective AR modulators (SARMs) that lack virilising activity in women but have AR agonist activity in breast epithelial cells proffer a means to clinically advance an AR agonist strategy to treat breast cancer. A phase II clinical trial testing Enobosarm in women with ER+ breast cancer that had disease progression on a standard-of-care endocrine therapy has shown this strategy to be efficacious and very well tolerated [15].

More critically, the role of AR in the context of breast cancers that lack ER is an important conundrum to resolve. Pre-clinical studies suggest that ER-negative breast cancer sub-types (e.g. HER2+ or TNBC) may be driven by AR [17], but clinical trials testing AR antagonists for these cancers have also shown limited efficacy [18, 19]. Rigorous pre-clinical testing with relevant patient-derived models of HER2+ and TNBC and appropriate companion biomarkers are needed to develop a clear rationale for AR targeting in specific ER-negative disease contexts.

free pdf
Hickey, Theresa E., et al. “The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer.” Nature medicine 27.2 (2021): 310-320.

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10166165/
Dai, Charles, and Leif W. Ellisen. “Revisiting Androgen Receptor Signaling in Breast Cancer.” The Oncologist 28.5 (2023): 383-391.

Although many questions remain, recent molecular investigations and clinical trials have provided some clarity with respect to the role of AR in breast cancer. AR may very well be context-specific and distinct in ER+, HER2+, and ER− disease. In ER+ disease, AR appears to oppose ER action, and AR modulation could be a promising therapeutic approach for endocrine-resistant ER+ breast cancer. In contrast, AR may play a different role in ER− disease, possibly serving as an oncogenic driver in a subset of TNBCs defined by high AR, luminal gene expression, and potential sensitivity to AR antagonists. More work is thus required to elucidate the seemingly divergent effects of AR, which can hopefully be achieved through context-specific molecular studies on the biologically relevant and clinically actionable pathways mediated by AR in breast cancer.

https://aacrjournals.org/cancerres/article/80/4_Supplement/GS2-03/646048/Abstract-GS2-03-The-androgen-receptor-is-a-tumour

Lim, Elgene, et al. “Abstract GS2-03: The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer.” Cancer Research 80.4_Supplement (2020): GS2-03.

The Androgen receptor (AR) is expressed in up to 90% of primary ER-positive (ER+) breast cancer and high expression of AR is an independent prognostic factor associated with good outcome. Its role in the context of ER+ breast cancer is very controversial and has constrained clinical implementation of new drugs that influence AR activity for treatment of women with this disease, resulting in concurrent clinical trials of opposite AR agonist and antagonist strategies. Herein, using RNA-seq and Chip-seq approaches, we demonstrate that therapeutic activation of AR for treatment of breast cancer leverages a natural regulatory mechanism that inhibits estrogen-stimulated proliferation and induction of cell cycle genes in patient-derived explants (PDE) of primary ER+ breast cancers, and in contemporary in vivo patient-derived xenograft (PDX) and cell line xenograft models of ER+ breast cancer resistant to standard-of-care ER targeting agents, including those harbouring genomic aberrations of ESR1. AR-mediated growth inhibition mechanistically involved loss of ER or co-activator p300 recruitment to chromatin at key cell cycle genes, leading to transcriptional down-regulation. A signature of AR activity derived from the xenograft models positively predicted disease survival in multiple large clinical cohorts of ER+ breast cancer, outperforming other breast cancer-specific prognostic signatures. Finally, the combination strategy of a new class of non virilising Selective Androgen Receptor Modulator (SARM) in combination with CDK4/6 inhibitors demonstrated additive effects in our preclinical models. Collectively, these findings provide compelling evidence that AR has a tumour suppressor role in ER+ breast cancer and advocate an AR agonist strategy for treatment, even in the context of therapy-resistant, ESR1 mutant disease, and should dispel widespread confusion over the role of AR in ER-driven breast cancer, an issue that currently hinders progress in leveraging modern AR-targeted therapies, including available SARMs that lack the undesirable side-effects of androgens, for clinical benefit.

Last updated on by Jeffrey Dach MD

One thought on “Testosterone for Prevention and Treatment of Breast Cancer

  1. On page 11 there is carboxytherapy of the breast cancer in 1794
    CO2 is lactate/estrogen antagonist
    Just a bottle of soda stream CO2 and plastic bag could do the same carboxytherapy now.
    https://iiif.wellcomecollection.org/pdf/b30369629

    The history of two cases of ulcerated cancer of the mamma ; one of which has been cured, the other much relieved, by a new method of applying carbonic acid air / [John Ewart].
    Ewart, John
    Date:
    1794

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