Safety and Adverse effects of Natural Progesterone

I received this email from a patient:

Hello Dr Dach,
I mentioned to my mom this evening that I would start to take progesterone pills next month for a portion of my cycle. She said that a few years ago, she used a progesterone cream. She said she couldn’t remember the reason why her doctor put her on a cream instead of a pill so she wanted me to ask about the health risks that go along with taking a progesterone pill. I didn’t think to ask Dr. Dach when I spoke with him today about the side effects of using progesterone (pill or cream). Are there any side effects that I should be concerned about or aware of? Is there any difference in health risks between the progesterone pill or cream?Thank you all for the time that you spend with me answering questions and planning my treatment! I really appreciate it!
Sincerely, Nancy

———————————————————————-
My Reply to Nancy:

Hi Nancy,

Progesterone is the natural hormone made by the ovary after ovulation, so it is very safe with no adverse effects. Excess dosage however, can cause drowsiness, which is helpful for treating insomnia if taken before bedtime to get a good night’s sleep. For the cycling female, the usual dosage is 100 mg capsule twice a day with food for days 12-26 of the cycle. This may be increased to 200 mg of micronized oral progesterone at bedtime and 100 mg in the AM with breakfast or lunch as a treatment for PMS (Premenstural Syndrome). If the morning progesterone dosage causes drowsiness, then this is omitted and instead both capsules are taken at night around bed time.
Regards from Jeffrey Dach MD

Header Image: Greta Garbo Courtesy of Wikimedia Commons

Progesterone is NOT a Progestin

Graphic Illustration of difference in chemical structure:

Left Images: Chemical Structure for Progesterone (Above) and Medroxyprogesterone (MPA) (Below).

Notice MPA (below) has an added methyl group at position 6 and added carboxy group at position 17. (these in RED)

Confusing Progesterone with other Synthetic Progestins. The medical literature is replete with examples of using the name progesterone for a progestin such as MPA or levonorgestrol. This is an error. Occasionally, a patient or even their doctor mistakenly confuses progesterone with the progestins. Progestins are synthetic hormones which are chemically altered forms of progesterone. The progestins are known to cause cancer and heart disease, and have other adverse effects which are not shared by natural progesterone. For this reason, we do not recommend progestins in my office. The one exception is dysfunction uterine bleeding where synthetic progestins have a justifiable use (see below). For all others, we use the safe, protective natural progesterone. In my opinion, for clarity we should use the word progesterone only for natural human bioidentical progesterone, and reserve the word progestin for all other synthetic versions of progesterone.

The MPA mouse breast cancer model

Today, progestins can be found in birth control pills liberally handed out to younger women. Although not recommended, the progestin, medroxyprogesterone (MPA) is still being prescribed by mainstream OB/Gyne doctors for menopausal hormone replacement. This is no longer recommended as we will discuss below. MPA is the progestin used by 95 million women, and same MPA used in the 2002 Women’s Health Initiative Study which demonstrated MPA was shown carcinogenic. MPA is routinely used to induce breast cancer in laboratory mice. This is called the MPA Mouse Model of Breast Cancer. Would you take a carcinogenic synthetic hormone that is routinely used to to induce breast cancer in mice? I wouldn’t recommend it. (28) (30-32)

Progesterone for PMS

Let us now return to the discussion of natural human bioidentical progesterone for premenstrual syndrome (PMS). In 1953, Katharina Dalton coined PMS, premenstrual syndrome, and was the first to popularize progesterone as an effective treatment for PMS using injectable progesterone. In 1953, Dr. Dalton established a PMS clinic, and presided over it for the next 40 years. (54-55) (51-76)

In 1985, Dr. L. Dennerstein studied the use of (300mg/d) oral micronized progesterone for treatment of PMS. The progesterone was given on a schedule for 10 days starting three days after ovulation, which was determined by urine estrogen and pregnanediol concentrations (pregnanediol is a metabolite of progesterone). This is roughly days 12-26 of the menstrual cycle. Day one is first day of bleeding. Dr. L. Dennerstein writes:

Women were instructed to take one 100 mg capsule in the morning and two 100 mg capsules at night as there had been reports of drowsiness of short duration. Treatment was prescribed for 10 days of each menstrual cycle starting roughly three days after ovulation. In each cycle ovulation was confirmed by determinations of urinary 24 hour pregnanediol and total oestrogen concentrations…Our findings confirm descriptive reports of beneficial effects of progesterone on the symptoms of premenstrual tension. Improvements were attained both in mood symptoms such as anxiety, depression, and stress and in the physical complaints of swelling and hot flushes. Although not all variables reached a significant level of improvement, the direction of change for premenstrual complaints, with the exception of arousal, was always in favour of progesterone treatment…Taken together the analyses also show the general positive effects of treatment. There was a trend to general improvement in almost all the physical and psychological variables over the four months of treatment, an improvement even more appreciable for the months of progesterone treatment alone…This study showed that an oral formulation of micronised progesterone was effective in alleviating many premenstrual complaints including those of anxiety, stress, depression, hot flushes, swelling, and water retention.(57)

Vitex Consumption by Wild Chimpanzees in Gombe Park

In 2008, Dr. Melissa Emery Thompson observed wild chimpanzees in Africa consumed Vitex, an herbal remedy for PMS commonly used by humans. Dr. Thompson did further studies measuring urinary hormone concentrations finding “dramatic and abrupt elevation” of progesterone during time of intense Vitex fruit consumption, writing:

Vitex, also called ChasteBerry is a commonly used over-the-counter (OTC) herbal remedy for PMS and Cyclic Mastalgia. Vitex mechanism of action is on the HPA (hypothalamic pituitary axis, where the herb stimulates production of LH and FSH by the pituitary which results in greater progesterone levels. Vitex has been found to reduce prolactin levels and is useful for Premenstrual Mastalgia symptoms (breast pain) thought to be caused by elevated prolactin levels during the premenstrual phase of the menstrual cycle. Vitex has anti-inflammatory activity and is a COX (Cyclo-Oxygenase) Inhibitor. Vitex also has anti-cancer activity in numerous preclinical studies. (67-72)

Progesterone for Peri-Menopause

In 2011, Dr. Jerilynn Prior suggested progesterone would be useful in treatment of women going through the peri-menopausal transition. This is the time period of skipping menses, fluctuating hormones levels, and mood disorders lasting 3-6 months and ending with full transition into menopause with characteristic decline in estrogen levels, vasomotor symptoms of hot flashes and night sweats. Dr Prior writes:

Because P4 [progesterone] and E2 [estradiol] complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS [vasomotor symptoms], improves sleep and premenstrual mastalgia [breast pain]. (4)

Progestins for DUB

Although the use of progestins such as MPA are not recommended for menopausal hormone replacement, progestins such as MPA and Norethisterone are commonly prescribed for the short term control of dysfunctional uterine bleeding (DUB). In my opinion, the use of synthetic progestins is justified for the treatment of abnormal uterine bleeding because, if sucessful, the patient avoids hysterectomy, estimated in up to 30 percent of these patients. In Europe, other progestins such as Norethisterone rather than MPA are used. The fact these are carcinogenic is overlooked when dealing with uterine bleeding. (44-50)

Progesterone as Breast Cancer Preventive Agent

A commonly used animal model of breast cancer is the use of DMBA, a carcinogenic chemical, to induce breast cancer in mice. What if we gave progesterone to the mice before inducing breast cancer with DMBA. Would this be beneficial? In 1982, Dr. Anne G Jabara found pretreatment of the mice with progesterone inhibited DMBA induced breast carcinogenesis. This study nicely illustrates the protective effect of progesterone. Dr. Anne Jabara concluded,

progesterone acts directly on the mammary gland to inhibit carcinogenesis. (1)

In 1998, Dr. Bent Formby and T. S, Wiley studied two breast cancer cell lines in-vitro showing progesterone “exhibited a strong anti-proliferative effect” and induced apoptosis in the cancer cell line expressing the progesterone receptor. (2)

In 2007, Drs. Gianluigi Ferretti and Joseph Jerry suggest a protective role for progesterone, citing the work of Dr. Rajkumar who showed a protective effect of combined estrogen and progesterone in animal models of breast cancer.(3-5)

Human Breast Biopsy Study Progesterone vs MPA

As mentioned above, in both human and animal studies, progesterone inhibits the proliferative effect of estrogen on breast tissue. (34-42)

However synthetic progestins such as MPA (medroxyoprogesterone) markedly increases the breast proliferation induced by estrogen. This is graphically demonstrated by Dr. Lorne Hofseth (1999). The following images are histology slides from human breast biopsies in postmenopausal women treated with A) No Hormones B) Estrogen Alone, or C) Estrogen combined with MPA (medroxyprogesterone), courtesy of Dr. Lorne Hofseth (1999). Notice the TDLUs (terminal ductal lobular unit) demonstrate worsening proliferation when MPA is added to the estrogen. (33)

Above Image A: Breast Biopsy in postmenopausal woman on NO Hormone Therapy. TDLU= Terminal Ductal Lobular Unit

Above Image C: Estrogen Alone showing proliferation of TDLUs.

Above Image (C): Estrogen Plus MPA (medroxpyprogesterone, pregestin) showing more severe proliferation of TDLU compared to Estrogen alone. Note: MPA is referred to by the letter P on the slide. This is an error and should be referred to as MPA. (33)

Human Breast Biopsy Study of Estrogen + Progesterone vs. Estrogen + MPA

In 2011, Dr. Daniel Murkes from Sweden studied the proliferation effect of progesterone compared to MPA. Dr. Murkes replicated the WHI study in 77 post menopausal women for 2 months, using CEE (0.625mg oral equine estrogen) and MPA (5mg oral medroxyprogesterone). This first group of women was then compared to a second group given natural, bioidentical estradiol (1.5 mg topical) + progesterone (200mg oral) for 14 days each month for two months. The proliferative effect of the two different hormone treatments was studied by obtaining breast cells by core needle biopsy prior to, and two months after HRT. The core breast biopsy cells were then immunostained for KI-67, and also the antiapoptotic protein bcl-2. This was a prospective randomized controlled trial. Note: Ki-67 is a commonly used marker for cell proliferation. Dr Daniel Murkes writes:

Seventy-seven women were assigned randomly to receive sequential HT with two 28-day cycles of either oral 0.625 mg conjugated equine estrogens or 2.5 g 0.06% percutaneous E2 gel (1.5 mg E2), daily, with the addition of respectively 5 mg of oral medroxyprogesterone acetate (MPA) or 200 mg of oral P, daily, for the last 14 days of each cycle. (9)

Above image: Core biopsy breast tissue samples for two female subjects. Upper Row (Red Dot) patient treated with CEE+MPA. Lower Row (Green Dot) patient treated with estradiol+progesterone. Left column: before HRT. Right column: 2 months after HRT. Notice the CEE+MPA treated sample reveals increased numbers of cells with nuclei staining for KI-67 (Red Ellipse and Arrow) indicating greater proliferation when compared to the estradiol+progesterone treated patient (Green Ellipse and Arrow). Images Courtesy of Daniel Murkes, (2011) Fig.1. Fertil Steril 2011;95:1188–91. (9)

Dr. Daniel Murkes compares his study with the French E3N cohort study which found the estrogen+progesterone combination preferable, finding no increased risk of breast cancer risk for natural progesterone, and increased risk with use of MPA. Dr. Daniel Murkes suggested this could be explained by his findings of higher breast cell proliferative activity for the CEE+MPA combination compared to the less proliferative activity seen with the estrogen+progesterone combination, writing:

In the French E3N cohort there was an absence of breast cancer risk increase for women taking estrogen in combination with natural P [progesterone] for at least 5 years of treatment (17, 25). This is in line with the indication in the current study of a higher proliferative activity in the breast imposed by oral conjugated equine estrogens–MPA versus percutaneous E2–micronized P [progesterone] orally, maintaining an E2 dose of 1.5 mg daily, which is needed by many women at least in an initial phase of postmenopausal symptoms. French(9)

In Defense of Progesterone

In 2017, Dr. Alan Lieberman reviewed the medical literature to examine the benefits and safety of natural progesterone as compared to synthetic progestins such as MPA (medroxyprogesterone). Dr. Lieberman found 3 studies involving 87,000 postmenopausal women in which the use of natural progesterone carried significantly less risk of breast cancer than the synthetic progestins. In addition, progesterone is protective for many other cancers other cancers such as endometrial, colon, ovarian, melanoma, mesothelioma, and prostate and has benefits in preventing cardiovascular disease, and neuroprotective effects in stroke and traumatic brain injury patients. Dr, Lieberman writes:

Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury…Physicians should have no hesitation prescribing natural progesterone, as the evidence is clear that progesterone does not cause breast cancer. Indeed,
progesterone is protective and preventative of breast cancer. (43)

In view of Dr. Lieberman’s claim that progesterone is anti-proliferative and protective regarding breast cancer, and knowing about the the two estrogen receptors, ER-alpha (proliferative) and the ER-beta (Protective), one might think that progesterone works through one of these two receptors. But which one?

Progesterone Acts As Proliferative Brake

In 2015, Dr. Hisham Mohammed was thinking the same thing. Dr Mohammed did a series of studies using in vitro and in vivo mouse xenografts, finding activation of the progesterone receptor (with exogenous progesterone) results in a “robust association between PR and the ERα complex” which then acts as a “proliferative brake” and blocks breast tumor growth in mouse xenografts. Remember, ER-alpha is the proliferative receptor, while ER-Beta is the protective one. In this scenario, progesterone receptor protein binds to ER-alpha and brakes (halts) ER-alpha induced proliferation, resulting in a good clinical outcome. Dr. Hisham Mohammed writes:

PR is a critical determinant of ERα function due to crosstalk between PR and ERα. In this scenario, under estrogenic conditions, an activated PR functions as a proliferative brake in ERα+ breast tumours by re-directing ERα chromatin binding and altering the expression of target genes that induce a switch from a proliferative to a more differentiated state 6…In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions…the increased risk of breast cancer associated with progestogen-containing HRT is mainly attributed to specific synthetic progestins, in particular medroxyprogesterone acetate (MPA), which is known to also have androgenic properties2. The relative risk is not significant when native progesterone is used3. In ERα+ breast cancers, PR is often used as a positive prognostic marker of disease outcome4… progesterone treatment has been shown to be antiproliferative in ERα+ PR+ breast cancer cell lines5-7 and progestogens [natural progesterone, not progestins] have been shown to oppose estrogen-stimulated growth of an ERα+ PR+ patient-derived xenograft8. In addition, exogenous expression of PR in ERα+ breast cancer cells blocks estrogen-mediated proliferation and ERα transcriptional activity9…These observations imply that PR activation in the context of estrogen-driven, ERα+ breast cancer, can have an anti-tumourigenic effect. In support of this, PR agonists [progesterone] can exert clinical benefit in ERα+ breast cancer patients that have relapsed on ERα antagonists. (100)

Conclusion: Progesterone is safer than synthetic progestins such as MPA. The addition of progesterone does not induce more breast proliferation than estrogen alone, while the addition of MPA to estrogen induces far greater proliferation, which means greater risk for carcinogenesis. This is the exact point I made in my reply in 1977 when Dr. Economou asked, “Does estrogen cause breast cancer? My answer was not entirely correct. Rather than the estrogen, the breast cancer culprit is the MPA. It has taken me decades of scouring the medical literature, and learning from others to reach this level of understanding. Progesterone is useful as a very effective treatment for PMS in young cycling females,. Progesterone is highly effective for symptom relief in women undergoing the perimenopausal transition, as these women are anovulatory with low progesterone levels and wildly fluctuating estrogen levels which can be quite high. For dysfunctional uterine bleeding, MPA and other progestins still have a justified use despite cancarcinogenic effects on breast tissue.

This is part one of a series, for part two, click here: Progesterone for PMS Part Two

Jeffrey Dach MD
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Articles with Related Interest:

Progesterone for PMS Part Two

The Safety of Bio-Identical Hormones

The Importance of Bioidentical Hormones

Waking Up from the Synthetic Hormone Nightmare

Russell Marker and the Origins of Bioidentical Hormones

All articles on Bioidentical Hormones

References:

1) Jabara, Anne G., and P. S. Anderson. “Effects of progesterone on mammary carcinogenesis when various doses of DMBA were applied directly to rat mammae.” Pathology 14.3 (1982): 313-316. When smaller doses of DMBA (100 microgram or less) were applied, Progesterone pretreatment markedly reduced carcinogenesis, the inhibitory effect being statistically significant in the group dusted with the smallest dose of carcinogen. ” results support the suggestion that progesterone acts directly on the mammary gland to inhibit carcinogenesis”

2) Formby, Bent, and T. S. Wiley. “Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.” Annals of Clinical & Laboratory Science 28.6 (1998): 360-369. Progesterone inhibits growth induces apoptosis in breast cancer cells Formby Bent T S Wiley Annals Clin Lab Sci 1998

3) Ferretti, Gianluigi, Alessandra Felici, and Francesco Cognetti. “The protective side of progesterone.” Breast Cancer Research 9.6 (2007): 402. Protective Side of Progesterone Ferretti Gianluigi Alessandra Felici Francesco Cognetti Breast Cancer Research 2007

4) Jerry, D. Joseph. “Roles for estrogen and progesterone in breast cancer prevention.” Breast Cancer Research 9 (2007): 102. Estrogen and Progesterone in Breast Cancer Prevention Jerry D Joseph Breast Cancer Research 2007

“Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer.”

5) Rajkumar, Lakshmanaswamy, et al. “Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.” Breast Cancer Research 9.1 (2007): R12. Hormone-induced protection of mammary tumorigenesis genetically engineered mouse Rajkumar Lakshmanaswamy Breast Cancer Research 2007

6) Eisen, Andrea, et al. “Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers.” Journal of the National Cancer Institute 100.19 (2008): 1361-1367. Hormone therapy and Risk of Breast Cancer in BRCA1 Mutation Carriers Eisen Andrea Journal of the Nat Cancer Institute 2008

7) Chlebowski, Rowan T., et al. “Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial.” Jama 289.24 (2003): 3243-3253. Influence of Estrogen Plus Progestin on Breast Cancer in Postmenopausal Womens Health Initiative Chlebowski Rowan T Jama 2003

8) Barrett-Connor, Elizabeth, et al. “The postmenopausal estrogen/progestin interventions study: primary outcomes in adherent women.” Maturitas 27.3 (1997): 261-274. NIH study used by Solvay for Prometium approval. Showing progesterone prevents endometrial hyperplasia.

**************** Nice Histology Slides ********************

9) Murkes D, Conner P, Leifland 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. Fertil Steril. 2011 Mar 1;95(3): 1188-91.

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.

Although we now have found it clearly less proliferative than MPA, it is important to stress that P was not found to be antiproliferative in normal breast tissue (9). Furthermore, both MPA and P have been found to reactivate stem cells with potential for malignancy, in vitro, but the clinical implications of this finding for women are not elucidated (29). Recently we reported that so far the only antiproliferative drug in normal breast tissue in vivo is the anti-P mifepristone, which significantly reduced breast cell proliferation in premenopausal women (30).

The findings of this study suggest that 2 months of treatment with percutaneous E2 in combination with 14 of 28 days of micronized P has less-adverse effects on normal human breast proliferation in vivo, and it also seems to facilitate apoptosis.

10) Murkes D, Lalitkumar PG, Leifland et al. Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol. 2012 Oct;28 Suppl 2:12-5.

significant increase in mammographie density of at least one BI-RADS density class in seven of 37 patients (18.9%) using synthetic hormones (CEE/MPA group) between baseline and days 54-56
{p = 0.01). By contrast, only two of the 32 patients (6.3%) using natural hormones (E2/P group) had an increase in mammographie density.

A total of around 33,000 genes were analyzed by microarray. In women using synthetic estrogen (CEE/MPA), the expression of approximately 2,500 genes in breast cells was altered with absolute fold change >1.5, compared with arotmd 600 genes in women using natural estrogens (E2/P).

Our group bas previously demonstrated a significant positive correlation between breast
epitbelial proliferation (Ki-67 positivity) and insulin-like growth factor 1 (IGF-1) mRNA during bormonal treatment in eight premenopausal women using synthetic hormonal contraception which was not found in women witb untreated menstrual cycles [33]. This suggests tbat tbe proliferative response of breast tissue to HT goes beyond tbe direct action of sex steroid receptors to potentially include a role for IGF-1 [33], a known mitogen for several cancer cell lines [34,35],

In tbe large General Practitioners Database, systemic treatment witb oral estrogens but not transdermal topical estrogens significantly increased breast cancer risk [7,37,38].

11) Fournier A, Berrino F, Riboli E et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005; 114(3): 448-54. Breast cancer risk in relation to different hormone replacement E3N‐EPIC cohort Fournier Agnes International Journal of Cancer 2005

12) Chang KJ et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995; 63(4):785-91.

To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo.
Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery.
Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses.
Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells.
exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo.

13) Wood CE, Register TC, Lees CJ et al. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34. Effects Estradiol with micronized progesterone or medroxyprogesterone on risk markers breast cancer postmenopausal monkeys Wood Charles Breast cancer research 2007

14) Campagnoli, C., Abbà, C., Ambroggio, S., & Peris, C. (2005). Pregnancy, progesterone and progestins in relation to breast cancer risk. J Steroid Biochem, 97(5), 441-450. Carlo Campagnoli Progestins progesterone hormone replacement risk breast cancer steroid biochemistry 2005 – Copy

15) Stanczyk FZ, Paulson RJ, Roy S. Percutaneous administration of progesterone: blood levels and endometrial protection. Menopause. 2005 Mar;12(3) 232-7. Percutaneous administration of progesterone blood levels endometrial protection Stanczyk Frank Menopause 2005

16) Anasti J, Leonetti H, Wilson K. Topical progesterone cream has antiproliferative effect on estrogen-stimulated endometrium. Fertil. Steril. 2003 Jan;79(1):221-2.

17) Sendag F, Terek MC, Karadadas N. Sequential combined transdermal and oral postmenopausal hormone replacement therapies: effects on bleeding patterns and endometrial histology. Arch Gynecol Obstet. 2001 Nov;265(4):209-13.

18) Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med. 2005 Nov-Dec, 11(6):36-8.Transdermal Progesterone As Alternative Progestin in Hormone Therapy Leonetti HB Landes J Altern Ther Health Med 2005

19) Holtorf, K. (2009). The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med, 121(1), 73-85. Bioidentical Hormone Debate Safer More Efficacious Than Synthetic Kent Holtorf Postgraduate Medicine 2009

20) L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Hermite_Could_Transdermal_estradiol_Progesterone_be_Safer_HRT

21) Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Tr, 107(1), 103-111.
Unequal_Risks_Breast_Cancer_hormone_replacement_E3N_French_cohort_study_Fournier_2008

22) Fournier, A., Fabre, A., Mesrine, S., Boutron-Ruault, M.-C., Berrino, F., & Clavel-Chapelon, F. (2008). Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol, 26(8), 1260-1268. Use of Different Postmenopausal Hormone Therapies and Risk Invasive Breast Cancer Fournier Agnès J Clin Oncology 2008

23) Markey, C., Luque, E., Munoz-de-Toro, M., Sonnenschein, C., & Soto, A. (2001). In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod, 65, 1215-1223.In utero exposure to bisphenol A alters development tissue organization of mouse mammary gland Markey Caroline M Biology of reproduction 2001

24) Jobling S, Reynolds T, White R, et al. (1995). A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Perspect, 103:582-587.

25) Arumugam, Arunkumar, Elaine A. Lissner, and Rajkumar Lakshmanaswamy. “The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model.” Reproductive Biology and Endocrinology 12.1 (2014): 66. Role of hormones aromatase inhibitors on breast tumor growth in postmenopausal mouse model Arumugam Arunkuma Rajkumar Lakshmanaswamy Repro Biology Endo 2014

Mimic Pregnancy-Prevents Breast Cancer

26) Lai, Yen-Chang, et al. “Short-term pregnancy hormone treatment of N-methyl-N-nitrosourea-induced mammary carcinogenesis in relation to fatty acid composition of serum phospholipids in female Lewis rats.” in vivo 24.4 (2010): 553-560.

Short-term oestrogen and progesterone treatment (STEPT) mimics the pregnancy hormone milieu. This study compared the development of N-methyl-N-nitrosourea (MNU)-induced mammary cancer in female Lewis rats that received STEPT in early or later life.
MATERIALS AND METHODS:
Rats in Groups 1 and 2 received a single intraperitoneal injection of 50 mg/kg MNU at 4 weeks old.
Pellets containing 0.5 mg 17beta-estradiol and 32.5 mg progesterone (EP) were subcutaneously implanted in rats in Group 1 during 6-9 weeks old.
Rats in Groups 3 and 4 received 50 mg/kg MNU at 22 weeks old and again at 23 weeks old.
EP pellets were implanted in rats in Group 3 during 24-27 weeks old. At the time of EP removal and 8 weeks afterward, 4 randomly selected rats in each group were sacrificed for blood sampling. The fatty acid composition of serum phospholipids was measured by capillary gas chromatography. The remaining rats were sacrificed when they developed mammary tumours >or=1 cm in diameter or at the termination of the experiment, which was at 18 weeks old for Groups 1 and 2 and at 64 weeks old for Groups 3 and 4. Mammary cancer was histologically confirmed.
RESULTS:
Group 1 had a significantly suppressed incidence of mammary cancer compared to Group 2 (7% vs. 90%), whereas the cancer incidence in Group 3 was similar to that of Group 4 (50% vs. 56%). … These data suggest that the age at which STEPT is administered is important, since its mammary cancer-suppressing potential was lost in aged animals.

27) deleted

28) Lanari, Claudia, et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” Endocrine-related cancer 16.2 (2009): 333-350.The MPA mouse breast cancer model Lanari Claudia 2009

29) Prior, J. C. “Progesterone for Symptomatic Perimenopause Treatment–Progesterone politics, physiology and potential for perimenopause.” Facts, views & vision in ObGyn 3.2 (2011): 109.

Because P4 and E2 complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia.

30) Kordon, Edith, et al. “Hormone dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate.” Breast cancer research and treatment 17 (1990): 33-43.

31) Molinolo, A. A., et al. “Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors.” Journal of the National Cancer Institute 79.6 (1987): 1341-1350.

32) Montecchia, Marı́a Fernanda, et al. “Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas.” The Journal of Steroid Biochemistry and Molecular Biology 68.1-2 (1999): 11-21.

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33) Hofseth, Lorne J., et al. “Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.” The Journal of Clinical Endocrinology & Metabolism 84.12 (1999): 4559-4565.

All hormones were taken on a continuous, daily basis. Subjects had taken E in one of three forms: conjugated equine estrogens (CEEs; dose, 0.3–2.5 mg; n 5 27); micronized estradiol (dose, 0.5–1 mg; n 5 4); or ethinyl estradiol (dose, 0.05 mg; n 5 1). The progestin taken was medroxyprogesterone acetate (MPA; dose, 2.5–5 mg; n 5 25), which was taken in combination with CEE (n 5 19) or micronized estradiol (n 5 6). Herein, all types of estrogens are referred to as E, and MPA is referred to as P.

Progestins decrease endometrial cell proliferation in the uterus (11–13), but their effect on the breast is less clear. In premenopausal women, proliferation of breast epithelial tissue is greatest during the luteal phase of the menstrual cycle, when progesterone levels are maximal (14 –22). In animal studies, progestins increase mammary gland epithelial cell proliferation. In the mouse, progesterone [error this is MPA], when combined with estrogen, is mitogenic in the adult mammary gland to a greater extent than estrogen alone (23, 24).

Similarly, in adult, ovariectomized cynomolgus macaques, estrogen1 progestin induces greater breast epithelial cell proliferation than estrogen alone (25, 26). In contrast, in human/mouse xenograft studies, estrogen1progesterone increased proliferation
but no more than estrogen alone (27, 28). The doses of estrogen and progesterone used in these xenograft studies, however, have been questioned because of the absence of sex steroid binding globulin in the serum of mice vs. its presence in humans (29)

Our results demonstrate, for the first time, that:
1) combination HRT with E+P is associated with higher levels of epithelial proliferation in the TDLU of the postmenopausal breast, based on PCNA and Ki67 indices; and
2) E alone and E+MPA HRT are positively associated with greater epithelial density. In addition, the morphology of the breast epithelium in the E+MPA group is consistent with the morphology seen in mammary tissue during the luteal phase in cycling women. The amount of epithelial proliferation was also similar to that of luteal-phase premenopausal women. These results also indicate that the mitogenic activity associated with progestins is localized to the TDLU of the human breast. Furthermore, the histological appearance of lobules in the no-HRT, CEE-alone, and CEE+MPA-treated monkey glands were strikingly similar to human breast tissues obtained from similar postmenopausal HRT groups herein (26). Thus, the greater proliferation observed in postmenopausal women treated with E1MPA herein is consistent with the mitogenic effect of E+MPA in mouse and monkey mammary glands.

animal studies

34) Cline JM, Soderqvist G, von Schoultz E, Skoog L, vonSchoultz B. 1996 Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol. 174:93–100.

35) Cline JM, Soderqvist G, vonSchoultz E, Skoog L, vonSchoultz B. 1998 Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques. Br Cancer Res Treat. 48:221–229.

36) Laidlaw IJ, Clarke RB, Howell A, Owen AWMC, Potten CS, Anderson E. 1995 The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology. 136:164 –171.

37) McManus MJ, Welsch CW. 1984 The effect of estrogen, progesterone, thyroxine and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice. Cancer. 54:1920 –1927.

38) Pike MC. 1996 Experiments on proliferation of normal human breast tissue in nude mice do not show that progesterone does not stimulate breast cells. Endocrinology. 137:1505.

39) Wood, Charles E., et al. “Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys.” Breast cancer research and treatment 101 (2007): 125-134.

40) Stute, Petra, L. Wildt, and J. Neulen. “The impact of micronized progesterone on breast cancer risk: a systematic review.” Climacteric 21.2 (2018): 111-122.

41) Murkes D, Lalitkumar PG, Leifland K, Lundstrom E, Soderqvist G.
Percutaneous estradiol/oral micronized progesterone has less adverse
effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol 2012; 28:12–15

42). Murkes D, Conner P, Leifland K, 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. Fertil Steril 2011;95:1188–91

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43) Lieberman, Allan, and Luke Curtis. “In defense of progesterone: a review of the literature.” Alternative Therapies in Health & Medicine 23.7 (2017).

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Progestins for Dysfunctional Uterine bleeding

44) Maness, David L., et al. “How best to manage dysfunctional uterine bleeding.” Journal of Family Practice 59.8 (2010).

45) Leal, Caio RV, et al. “Abnormal uterine bleeding: The well-known and the hidden face.” Journal of endometriosis and uterine disorders (2024): 100071.

46) Ely, John W., et al. “Abnormal uterine bleeding: a management algorithm.” The Journal of the American Board of Family Medicine 19.6 (2006): 590-602.

47) Jain, Varsha, et al. “Uterine bleeding: how understanding endometrial physiology underpins menstrual health.” Nature reviews endocrinology 18.5 (2022): 290-308.

48) Shoupe, Donna. “The Progestin Revolution: progestins are arising as the dominant players in the tight interlink between contraceptives and bleeding control.” Contraception and Reproductive Medicine 6.1 (2021): 3.

49) Dikke, Galina B., et al. “Experience of treating patients with abnormal uterine bleeding associated with ovulatory dysfunction.” Obstetrics and Gynecology 3 (2024): 142-152.

Abnormal uterine bleeding (AUB) associated with ovulatory disfunction (OD) is the most common finding among women with chronic AUB, accounting for 57.7% of cases. Oral progestogens are often prescribed for irregular and copious menstruation. However, a course of hormonal rehabilitation after AUB-OD may not be enough. Inositols have been shown to be highly effective in restoring ovulation, normalizing the menstrual cycle, correcting carbohydrate and lipid metabolism, and reducing body weight.

Objective: To evaluate the effectiveness of complex treatment consisting of a combination of gestagen, iron medication and complex containing myoinositol, D-chiroinositol (5:1), folic acid and manganese in reproductive-aged patients with abnormal uterine bleeding associated with type I–III ovulatory dysfunction.

Materials and methods: The multicentre study in real clinical practice included 2,042 women with OD. The patients received dydrogesterone or micronized progesterone for 3 cycles (from 14 to 25 days), a medication containing myoinositol 1000 mg, D-chiroinositol 200 mg, folic acid 200 mg, manganese 5 mg (Dikirogen) for 6 cycles, iron sulfate/ascorbic acid for 3–4 months (according to indications). The parameters of the menstrual cycle (MC), hemoglobin, serum ferritin, and body weight were assessed at 3, 6 and 12 months from the start of treatment.

Results: The age of the patients ranged from 18 to 45 years, the average age was 30 (25; 35) years. The number of patients with a normal MC rhythm after 3 and 6 months was observed in 76.5 and 90.9% of patients versus 46.9% before treatment, p<0.001, and with a moderate volume of menstruation in 77.9 and 89.9% versus 45.4%, respectively, p<0.001; iron deficiency anaemia decreased from 39.9% to 18.2% of patients after 3 months, p<0.001, and there were no patients with anaemia by 6 months. Menstrual cyclicity remained at the achieved level, and the volume of blood loss decreased statistically significantly by 12 months. BMI decreased from 26.8 (21.3; 27.3) to 23.4 (21.3; 24.3) kg/m2 by 6 months of treatment, p=0.001, and stabilized at this level until 12 months.

Conclusion: Therapy for OD with progestin/Dikirogen in the first 3 months followed by administration of only Dikirogen for 3 months and symptomatic treatment with iron is effective in achieving regular menstrual cycle and volume of menstrual blood loss, eliminating anaemia and normalizing body weight.

50) Kader, Mohammad Irfan Abdul, V. Karthikeyan, and J. Sabitha. “A Comparative Study On Efficacy of Norethisterone and Medroxyprogestrone in The Management of Dysfunctional Uterine Bleeding: A Prospective Observational Study.”

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Progesterone for PMS

51) !!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!
Stefaniak, Małgorzata, et al. “Progesterone and its metabolites play a beneficial role in affect regulation in the female brain.” Pharmaceuticals 16.4 (2023): 520.

Abstract: Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to
result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.

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52) Stiernman, Louise, et al. “Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids.” Translational psychiatry 13.1 (2023): 124.

53) Geng, Xiwen, et al. “ShuYu capsule alleviates emotional and physical symptoms of premenstrual dysphoric disorder: Impact on ALLO decline and GABAA receptor δ subunit in the PAG area.” Phytomedicine: international journal of phytotherapy and phytopharmacology 130: 155549.

54) Interview: Katharina Dalton, MD: Progesterone and Related Topics, Int Jounnal of Pharmaceutical Compounding 1999

I think the minimum dose, if you’re going to use vaginal suppositories, is 400 mg twice a day. First of all, you want a high dose. But the second thing we know about the unique characteristics of the progesterone receptor is that the first initial dose of progesterone, when you give it in rats, is effective; subsequently, they need a dose 40 times higher than the first dose to maintain the effect. What we tend to do there to overcome that is to use a high dose initially.

1953 BMJ Katharina Dalton

55) Greene, Raymond, and Katharina Dalton. “The premenstrual syndrome.” British medical journal 1.4818 (1953): 1007.

emotional instbility, headache, backache, depression, abd bloating, fluid retention, weight gain, breast pain,

84 cases of PMS

treated with ethisterone
and/or progesterone,

All the cases had attacks of various symptoms, which occurred during the premenstrual phase, during menstruation or ovulation, or at the time of a missed period, and all cases were symptom-free at other times. All cases included in the series had experienced attacks during each of the last three menstrual cycles; thus any chance coincidence between the attack and menstruation was eliminated.

patients were asked to keep a calendar.

Headache. nausea, irritability, depression , joint pain, pitting edema, asthma, epilepsy, mastalgia, acne, eczema, glossitis,

The visual symptoms noted
in these 10 cases of migraine were: photophobia, 4; mistiness,
1; hemianopia, 2; burning pain, 2; flashes of light,

In this series 70 patients expected attacks in the premenstrual week,
9 at the onset of menstruation, and 4 during menstruation.

The series is conspicuous for the normality of the menstrual
history.

Is Water Retention the Cause of the Syndrome ?
That the symptoms are due to water retention is strongly
suggested by the oliguria and gain in weight which announces
their arrival and the diuresis and loss of weight which accompanies
their relief at, or soon after, the onset of menstruation.

the trouble was not so much a high level of oestradiol as a lack of antagonism by progesterone.

the cause of the syndrome is an abnormally high oestradiol/progesterone ratio

painful breasts, so common a feature of the syndrome, are due to a high
oestrogenic level,

the administration of progesterone is effective in relieving it

Migraine and lesser degrees of headache may well be due
to an increased hydration within the indistensible cranium.

The rhinorrhoea of the premenstrual syndrome-and perhaps
the asthma as well-is thus explicable by the excessive
local activity of oestradiol

Treatment
Dehydration
Androgens
Vitamins
Progesterone

ethisterone, given in oral doses of 30 to 150 mg.
daily for twelve days from the fourteenth day of the cycle

intramuscular injections of progesterone
instead, in doses at first of 10 mg. daily during the
second half of the cycle. Later it was found that an injection
of 25 mg. on alternate days was equally effective. Severe
cases were treated by this method from the outset.

The oral administration of ethisterone gave complete relief in 22
cases (47.9%) and partial relief in a further 8 cases (17.4%).

The results with intramuscular progesterone in 61 cases were
more satisfactory-51 (83.5%) became free from symptoms,
4 (6.6%) improved, and 4 (6.6%) obtained no relief.

A large proportion of women, estimated by one author
as 40%, suffer a variety of distressing symptoms during
the final week or so of the menstrual cycle. In occasional
cases, similar symptoms may occur at monthly
intervals at other points of the cycle. They are probably
produced by water-retention, and the evidence
at present aVailable suggests that this in its turn is due
to abnormal elevation of the oestradiol/progesterone
ratio.
Various treatments aimed at either dehydration or a
correction of the disturbed hormonal ratio have proved
partially effective. Treatment with a progestogen is
almost invariably successful. In mild cases relief is
usually obtained by the oral administration of ethisterone
in a dosage of 25 mg. twice daily during the second half
of the menstrual cycle. A larger proportion of patients
can be relieved by the intramuscular injection of progesterone,
25 mg. on alternate days during the same
phase of the cycle. Such cases are more effectively
treated, with less labour for the patient, by the implantation
of progesterone, w~hich remains effective for many
months.

=======================
56) O’Brien, P. M. “Helping women with premenstrual syndrome.” BMJ: British Medical Journal 307.6917 (1993): 1471.

Progesterone and progestogens

The widespread use of progesterone probably results from the enthusiasm of its advocacy rather than its pharmacotherapeutic efficacy.’6 Extensive anecdotal evidence has led to claims for efficacy by a few authors but randomised double blind placebo controlled trials
do not support this view.’7

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Supportive Study Progesterone for pms
300 MG po MICRONIZED PROGESTERONE

57) Dennerstein, L., et al. “Progesterone and the premenstrual syndrome: a double blind crossover trial.” Br Med J (Clin Res Ed) 290.6482 (1985): 1617-1621.

Our findings confirm descriptive reports of beneficial effects of progesterone on the symptoms of premenstrual tension. Improvements were attained both in mood symptoms such as anxiety, depression, and stress and in the physical complaints of swelling and hot flushes. Although not all variables reached a significant level of improvement, the direction of change for premenstrual complaints, with the exception of arousal, was always in favour of progesterone treatment.

Taken together the analyses also show the general positive effects of treatment. There was a trend to general improvement in almost all the physical and psychological variables over the four months of treatment, an improvement even more appreciable for the months of progesterone treatment alone.

This study showed that an oral formulation of micronised progesterone was effective in alleviating many premenstrual complaints including those of anxiety, stress, depression, hot flushes, swelling, and water retention.

==================================
58)The Prophet of PMS: New York Times.
Dalton and Greene coined the term PMS in a pivotal paper they wrote in 1953. And it was Dalton’s tireless efforts that put PMS on the map. She wrote up case studies of women brought back from the brink by progesterone therapy. She did large-scale studies that showed schoolgirls’ grades declined by 10 percent premenstrually, followed by a 20 percent increase postmenstrually. She found that half of all female suicides in England in the 50’s and 60’s occurred in the four days before menstruation, as did half of crimes committed by women.

GP who coined the term ‘premenstrual syndrome’ in 1953, then set up the first clinic to treat PMS and ran it for 40 years.

59) Katharina Dorothea Dalton (1916–2004)
By: Bianca Zietal Published: 2017-05-24

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60) Premenstrual Syndrome; A Natural Approach
by Tori Hudson, N.D. Chaste Tree (Vitex agnus castus) by Tori Hudson

The single most important plant for the treatment of premensrual syndrome is chaste tree berry. The effect of chaste tree is on the hypothalamus-hypophysis axis. It increases secretion of luteinizing hormone and also has an effect which favors progesterone. Two surveys were done covering 1,542 women with PMS who had been treated with a German liquid extract of chaste tree for periods of up to 16 years. The average dose was 42 drops daily. Effectiveness as recorded by the patients’ doctors was either very good, goo, or satisfactory in 92 percent of the cases. Use 35 drops of liquid tincture daily or a standardized extract containing .75% acubin at 175 mg per day or .6% aucubin at 215 mg per day.

The newest study using chaste tree was a clinical trial of 170 women with PMS; this has been the most well designed trial yet studying the efficacy of chaste tree in women’s health. Women were assigned to take either a tablet containing an extract of chaste tree berry (20 mg) or a placebo tablet once daily for three months. Subjective reporting of irritability, mood changes, anger, headache, breast tenderness and bloating were recorded. At the end of the three months, women taking the chaste tree reported a 52% reduction in PMS symptoms versus 24% reduction for those in the placebo group. Women in the chaste tree group reported their significant reduction in all symptoms except for bloating before the menses.

A study by Dennerstein and colleagues in 1985 found an overall beneficial effect using 300 mg/day (100 mg a.m., 200 mg p.m.) for 10 days of each menstrual cycle starting 3 days after ovulation. After only one month of treatment, those receiving progesterone could be clearly distinguished from those receiving placebo in areas of stress, anxiety, and concentration. Most all other symptoms also continued to improve with each menstrual cycle.

Natural progesterone creams have not been subjected to scientific scrutiny although tens of thousands of women can attest to their benefit. In my practice, I largely use the transdermal creams that contain at least 400 mg of natural progesterone per ounce. Using Â¼ tsp per dose, that will deliver approximately 20 mg of USP natural progesterone, the same progesterone that is in oral micronized progesterone. I recommend applying Â¼ tsp twice daily starting at mid-cycle and stopping the day before the menses is due. For women whose significant symptoms begin at ovulation, I recommend Â¼ tsp per day from day 8 to day 14 and then Â¼ tsp twice daily until just before the menses begins, as described above. The best sites for rubbing in the cream include the palms, inner upper arms, chest, and inner thighs.

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61) Barnes, Kylie N., Claire M. Vogl, and Leigh Anne Nelson. “Zuranolone: The first FDA-approved oral treatment option for postpartum depression.” Annals of Pharmacotherapy 58.7 (2024): 728-734.

62) Reddy, Doodipala Samba, Robert H. Mbilinyi, and Emily Estes. “Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.” Psychopharmacology 240.9 (2023): 1841-1863.

63) Kargbo, Robert B. “Neurosteroids and Postpartum Depression: The Mechanism, Efficacy, and Approval of Brexanolone and Zurzuvae.” ACS Medicinal Chemistry Letters 14.10 (2023): 1326-1328.

================= BEST ===================

64) Gao, Q., et al. “Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.” Frontiers in Psychiatry 14 (2023).

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65) Tiranini, Lara, and Rossella E. Nappi. “Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome.” Faculty reviews 11 (2022).

The spectrum of symptoms is wide and the most common are breast tenderness, bloating, headache, mood swings, depression, anxiety, anger, and irritability.

Thus, new therapeutic approaches to PMS/PMDD include inhibition of progesterone receptors in the brain (i.e., with ulipristal acetate), reduced conversion of progesterone to its metabolite allopregnanolone with dutasteride, and possible modulation of the action of allopregnanolone on the brain GABAergic system with sepranolone.

The most severe form of PMS is defined as premenstrual dysphoric disorder (PMDD), characterized predominantly by emotional and affective symptoms not due to another psychiatric condition4. PMDD was included as a new diagnostic category of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)5,6 and recently (2019) coded as a gynecological diagnosis in the World Health Organization’s International Classification of Diseases (ICD-11)7. A PMDD diagnosis requires the presence of at least one mood symptom (marked affective lability, irritability, depressed mood, anxiety, or tension) in a group of at least five (including loss of interest, subjective difficulty in concentrating, fatigue, marked appetite change with overeating or food cravings, insomnia or hypersomnia, feeling emotionally overwhelmed, and physical symptoms). Such symptoms should occur during the luteal phase of the majority of menstrual cycles over the previous year. Furthermore, they must be associated with clinically significant distress regarding social, academic, or working activities; they should not be the exacerbation of a chronic condition or the effect of medications, and they need to be confirmed by prospective daily ratings during at least two symptomatic cycles6.

According to a recent meta-analysis, premenstrual symptoms are very common, affecting about half of women of reproductive age worldwide8.

PMS is estimated to affect 20 to 30% of women in the United States2,

First-line treatments

Currently, the first-line treatment for PMDD consists of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, sertraline, and escitalopram21. Serotonin is a pivotal neurotransmitter modulating mood and behavior. It plays a fundamental role in the pathophysiology of PMS/PMDD because women with the condition have atypical serotonergic transmission, a lower density of serotonin transporter receptors, decreased plasmatic serotonin levels in the luteal phase, and higher serotonin responsiveness in the follicular rather than in the luteal phase22.

Combined hormonal contraception (CHC) may represent an alternative to treatment. The rationale for CHC is the blockade of an ovulatory surge of sex steroids since premenstrual symptoms are not observed during anovulatory cycles29 and disappear when women undergo treatment with agonists of gonadotropin-releasing hormone (GnRH)30 or bilateral oophorectomy31. The most effective CHC is a combination of the progestogen drospirenone and ethinyl estradiol in a regimen with a shorter hormone-free interval (4 rather than 7 days)32,33

Converging evidence suggests that fluctuations of ovarian sex steroids (in particular, progesterone) are key factors for PMS/PMDD35, given the synchrony with the post-ovulatory phase and the reinstatement of symptoms during GnRH agonist treatment when add-back progesterone is administered36. Since women with PMDD have progesterone serum concentrations similar to those of healthy women37, the underlying mechanism of PMDD is presumed to be an increased sensitivity to fluctuations of this steroid38,39. Progesterone interacts with the chemistry of the central nervous system (CNS)40–42 by easily passing through the blood-brain barrier. Progesterone receptors (PRs) are indeed widespread in the amygdala, hippocampus, hypothalamus, and frontal cortex43,44.

Extensive research demonstrates that the central effects of progesterone on mood result largely from its metabolite allopregnanolone, a neuroactive steroid that acts as a strong positive modulator of the gamma-aminobutyric acid (GABA) receptor51–53. GABA is the main inhibitory neurotransmitter within the CNS and is a pivotal regulator of stress, anxiety, vigilance, and seizures37. The involvement of the GABAergic system in the pathophysiology of PMS/PMDD has recently aroused growing interest in finding new therapies directly focused on premenstrual symptoms. At high concentrations, allopregnanolone can cause sedation by activating the GABA receptor, but it may also induce paradoxical reactions with adverse moods in susceptible women54. Those with severe PMS/PMDD have normal levels of plasma allopregnanolone41,55–57, but some evidence showed diminished concentrations of allopregnanolone and its precursor progesterone and a blunted response to the GnRH test during the luteal phase of the menstrual cycle58. Fluctuations of allopregnanolone induce changes in the conformation of the GABA-A receptor sufficient to determine anxiety-like behaviors in predisposed women59,60. In light of these findings, the development of new treatments for PMDD attempted to stabilize allopregnanolone signaling50. Dutasteride, an inhibitor of the enzyme 5alpha-reductase that converts progesterone to allopregnanolone, was recently tested with the aim of modulating progesterone/allopregnanolone balance in women with PMDD. Dutasteride prevented the luteal phase increase in allopregnanolone and improved most PMDD symptoms (i.e., irritability, anxiety, sadness, food cravings, and bloating) without exerting any effect on healthy controls61. At present, dutasteride is a potential off-label option for women experiencing side effects or lacking benefits of SSRIs61.

The US Food and Drug Administration recently approved allopregnanolone itself (brexanolone) for the treatment of postpartum depression (PPD)68,69, a disorder extensively associated with PMS/PMDD70,71 in the context of reproductive depression72. Exposure to high allopregnanolone levels during pregnancy has a protective and mood-stabilizing effect, while in susceptible women, the sudden decrease in allopregnanolone following placental detachment at birth alters the GABAergic signaling73–76.

!!!!!!!!!!!!!!!!!!!!!!! GOOD !!!!!!!!!!!!!!!!!!!!!!!!!!!!

66) Roomruangwong, Chutima, et al. “Lowered plasma steady-state levels of progesterone combined with declining progesterone levels during the luteal phase predict peri-menstrual syndrome and its major subdomains.” Frontiers in psychology 10 (2019): 488965.

============= Vitex Wild Chimpanzees ======================

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67) Emery Thompson, Melissa, et al. “Hyperprogesteronemia in response to Vitex fischeri consumption in wild chimpanzees (Pan troglodytes schweinfurthii).” American Journal of Primatology: Official Journal of the American Society of Primatologists 70.11 (2008): 1064-1071.

Chimpanzees in Gombe National Park consume fruits of Vitex fischeri during a short annual fruiting season. This fruit species is a member of a genus widely studied for phytoestrogen composition and varied physiological effects. One particularly well-studied species, V. agnus-castus, is noted for its documented effects on female reproductive function, evidenced in increased progesterone levels and consequent regulation of luteal function. We examined reproductive hormone levels in both male and female chimpanzees during a 6-week period of intense V. fischeri consumption. V. fischeri consumption was associated with an abrupt and dramatic increase in urinary progesterone levels of female chimpanzees to levels far exceeding the normal range of variation. Female estrogen levels were not significantly impacted, nor were male testosterone levels. These are some of the first data indicating that phytochemicals in the natural diet of a primate can have significant impacts on the endocrine system, though the fluctuating nature of chimpanzee diet and reproductive function does not allow us
to determine whether the effects observed during this short period had a broader positive or negative impact on female fertility. Given the widespread use of various Vitex species by African primates and the as-yet-undescribed phytochemical properties of these species, we predict that our observations may be indicative of a broader phenomenon. Am. J. Primatol. 70:1064–1071, 2008.

68) FARHOODI, MOGHADAM M., and S. M. A. Khalafi. “The effect Vitex Agnus-Castus on serum concentration of cortisol, progesterone and luteinizing hormone in dairy cows.” (2018): 2597-2606.

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69) Haerifar, Naiyereh, et al. “The effect of vitex agnus castus extract on the blood level of prolactin, sex hormones levels, and the histological effects on the endometrial tissue in hyperprolactinemic women.” Crescent Journal of Medical & Biological Sciences 7.4 (2020).

Materials and Methods: To this end, of women at reproductive age with hyperprolactinemia who had referred to healthcare centers, 105 cases were selected and randomly assigned to three groups of bromocriptine, Dostinex, and Vitagnus. During the time of research (4 cycles), patients were treated with these drugs, and finally, the titer of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone, and estrogen, and progesterone of the blood serum sample were measured accordingly. At the beginning of the follicular phase, the ultrasound scan was done to determine the endometrial thickness and if necessary, the histological study was conducted using the endometrial biopsy sample.
Results: Based on the results, the prolactin level in the bromocriptine group started to show a significant difference from previous cycles in the second cycle, and in the first cycle in the other two groups (P < 0.05). In addition, the rate of the decrease in endometrial thickness in the Vitagnus group was significant compared to other groups (P < 0.05). At the third stage and later, bromocriptine and Dostinex had a significant effect on the FSH level while the effect of Vitagnus was not significant at any of the stages. The results further revealed that the amounts of estradiol in the Vitagnus group had a significant increase compared to other groups (P < 0.05). The effect of Vitagnus and Dostinex tablets on the HL level appeared from the 4th and 3rd cycles onward, respectively, while no significant effect of bromocriptine was found at any of the stages. Eventually, the effect of the Vitagnus tablet on progesterone was remarkable compared to the other two mediations in the 2nd and 3rd cycles.
Conclusions: Similar to other drugs, Vitagnus has a significant effect on the amount of prolactin and sex hormones and thus can be successfully used in treating hyperprolactinemia. Finally, reductions in endometrial thickness were significant in the Vitagnus group compared to the other two groups.

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70) Wuttke, Wolfgang, et al. “Chaste tree (Vitex agnus-castus)–pharmacology and clinical indications.” Phytomedicine 10.4 (2003): 348-357.

Extracts of the fruits of chaste tree (Vitex agnus castus = AC) are widely used to treat premenstrual symptoms. Double-blind placebo-controlled studies indicate that one of the most common premenstrual symptoms, i.e. premenstrual mastodynia (mastalgia) is beneficially influenced by an AC extract. In addition, numerous less rigidly controlled studies indicate that AC extracts have also beneficial effects on other psychic and somatic symptoms of the PMS. Premenstrual mastodynia is most likely due to a latent hyperprolactinemia, i.e. patients release more than physiologic amounts of prolactin in response to stressful situations and during deep sleep phases which appear to stimulate
the mammary gland. Premenstrually this unphysiological prolactin release is so high that the
serum prolactin levels often approach heights which are misinterpreted as prolactinomas. Since AC extracts were shown to have beneficial effects on premenstrual mastodynia serum prolactin levels in such patients were also studied in one double-blind, placebo-controlled clinical study. Serum prolactin levels were indeed reduced in the patients treated with the extract. The search for the prolactin-suppressive principle(s) yielded a number of compounds with dopaminergic properties: they bound to recombinant DA2-receptor protein and suppressed prolactin release from cultivated lactotrophs as well as in animal experiments. The search for the chemical identity of the dopaminergic compounds resulted in isolation of a number of diterpenes of which some clerodadienols were most important for the prolactin-suppressive effects. They were almost identical in their prolactin-suppressive properties than dopamine itself. Hence, it is concluded that dopaminergic compounds present in Vitex agnus castus are clinically the important compounds which improve premenstrual mastodynia and possibly also other symptoms of the premenstrual syndrome

71) Zahid, Hina, Ghazala H. Rizwani, and Sumaira Ishaqe. “Phytopharmacological review on Vitex agnus-castus: a potential medicinal plant.” Chinese Herbal Medicines 8.1 (2016): 24-29.

72) Niroumand, Mina Cheraghi, Fatemeh Heydarpour, and Mohammad Hosein Farzaei. “Pharmacological and Therapeutic Effects of Vitex agnus‑castus L.: A Review.” Pharmacognosy Reviews 12.23 (2018).

Vitex Chasteberry for PMS

https://clinphytoscience.springeropen.com/articles/10.1186/s40816-016-0038-z

73) Seidlova-Wuttke, Dana, and Wolfgang Wuttke. “The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution.” Clinical Phytoscience 3 (2017): 1-11.

The dried fruits of the chaste tree Vitex agnus castus (VAC) were traditionally used by monks as a substitute for pepper and was therefore also called Monk’s pepper. For the last 50 years it is commercially provided for the treatment of premenstrual symptoms, particularly to prevent premenstrual mastodynia (mastalgia). Most studies were performed with the preparation containing an aqueous/ethanolic ectract BNO 1095. A number of placebo controlled studies gave proof that extracts of VAC had beneficial effects on premenstrual breast pain. This breast sensation is induced by latent hyperprolactinemia which is characterized by secretory episodes of prolactin release by the pituitary in response to stress and deep sleep phases. This latent hyperprolactinemia induces also often a corpus luteum insufficiency which is a common reason for infertilty.

It is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype (D2 receptors) which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts.

The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced.

Adverse events with VAC were mild and generally infrequent.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2529385/
74) Carmichael, A. R. “Can Vitex agnus castus be used for the treatment of mastalgia? What is the current evidence?.” Evidence‐Based Complementary and Alternative Medicine 5.3 (2008): 247-250.

There have been many treatments suggested for the management of mastalgia; one of these is the fruit extract of Vitex Agnus castus L. commonly known as Agnus castus, a deciduous shrub native to Mediterranean Europe and Central Asia. The use of herbal treatments in the management of pain is well documented (2). Agnus castus, like other herbal treatments (3), has been used in the treatment of many conditions of women’s health such as menstrual disorders (amenorrhea, dysmenorrhea), premenstrual syndrome, corpus luteum insufficiency, hyperprolactinemia, infertility, acne, menopause and disrupted lactation (4–12). Agnus castus is thought to be affective in the management of mastalgia because of its dopminergic effects. It is postulated that A. castus suppresses the stress-induced latent hyperprolactinemia in patients suffering from cyclical mastalgia. The purpose of this review is to analyze the current evidence available for the efficacy and safety of A. castus in the management of mastalgia.

Agnus castus may have therapeutic role in the management of cyclical mastalgia by controlling hyper-secretion of prolactin. The ability to lower the prolactin level in women with cyclical mastalgia has been shown in clinical and laboratory studies (15–17). A prolactin-suppressive effect of A. castus is thought to be due to a number of diterpenes including clerodadienols (15). These compounds manifest their dopminergic properties by binding to recombinant DA2-receptor protein, which has been shown to suppress prolactin release from cultivated lactotrophs and also in-vivo in animal experiments. These substances are almost identical in their prolactin-suppressive properties as dopamine itself (15). Addition of A. castus significantly inhibits basal as well as TRH-stimulated prolactin secretion of rat pituitary cells in vitro, as demonstrated in the primary cell culture experiments (18). These experiments also found that adding a dopamine receptor blocker could prevent this A. castus-induced inhibition of prolactin secretion. Authors suggested that because of its dopaminergic effect A. castus could be considered as an efficient alternative phytotherapeutic drug in the treatment of hyperprolactinemia. Other studies have demonstrated that inhibition of prolactin secretion by A. castus is dependent on the initial level of prolactin and the dose of A. castus and is independent of gonadotrophins (19,20).

The most frequent adverse events associated with the use of A. castus are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritus and erythematous rash. Data available from clinical trials, post-marketing surveillance studies, surveys, spontaneous reporting schemes, manufacturers and herbalist organizations have recently been reviewed (28). The adverse events following A. castus treatment are mild and reversible indicating that A. castus is a safe herbal medicine. (28). Data of The German Commission E has approved the use of A. castus for mastalgia. No drug interactions have been reported.

There is convincing laboratory-based and clinical evidence available that A. castus is safe, effective and efficient in the treatment of cyclical mastalgia. It has a safe side effect profile and can be used safely for the treatment of cyclical mastalgia.

https://pubmed.ncbi.nlm.nih.gov/28237870/
75) Verkaik, Saskia, et al. “The treatment of premenstrual syndrome with preparations of Vitex agnus castus: a systematic review and meta-analysis.” American Journal of Obstetrics and Gynecology 217.2 (2017): 150-166.

Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual syndrome symptoms.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC26589/
76) Schellenberg, Ruediger. “Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.” Bmj 322.7279 (2001): 134-137.

Institute for Health Care and Science, 35625 Hüttenberg, Germany

Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles.
Setting General medicine community clinics.
Participants 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days.
Interventions Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles.
Main outcome measures Main efficacy variable: change from baseline to end point (end of third cycle) in women’s self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms).
Results Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment.
Conclusions Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.

77) Zamani, Mehrangiz, Nosrat Neghab, and Saadat Torabian. “Therapeutic Effect of Vitex Agnus Castus in Patients with Premenstrual Syndrome.” Acta Medica Iranica 50.2 (2012): 101-106.

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https://www.contemporaryobgyn.net/view/premenstrual-syndrome-part-2
78) Premenstrual Syndrome, Part 2
November 15, 2011 By OBGYN.net Staff

1. Hudson T. Premenstrual Syndrome. The Female Patient. 2002;27(5):47-49,59.

2. American College of Obstetrics and Gynecology (ACOG). Committee opinion. Int J Gynecol Obstet. 1995;50:80.

3. Dittmar F. Das pramenstruelle Spannungssyndrome. J Gynakol. 1989; 5(6):4-7.

4. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. BMJ. 2001;20:134-137.

5. Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstrual syndrome: a case study.Complement Ther Med. 1993;1:73-77.

6. Tamborini A, Taurelle R. “Value of standardized Ginkgo biloba extract in the management of congestive symptoms of premenstrual syndrome.” Gynecol Obstet. 1993;88: 447-457.

7. Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. Br J Obstet Gynaecol. 2000;107:870-876.

8. Schildge E. Essay on the treatment of premenstrual and menopausal mood swings and depressive states. Rigelh Biol Umsch. 1964;19(2):18-22

9. Dalton K. The Premenstrual Syndrome and Progesterone Therapy. 2nd ed. Chicago, Ill: Year Book Medical Publishers; 1976.

10. Keye W Jr. Medical treatment of premenstrual syndrome. Can J Psychiatry. 1985;30:483-487.

11. Sampson G. Premensrual syndrome: a double-blind controlled trial of progesterone and placebo. Br J Psychiatry. 1979;135:209.

12. Van Der Meer Y, Benedek-Jaszmann L, Van Loenen A. Effect of high-dose progesterone on the pre-menstrual syndrome; a double-blind cross-over trial. J Psychosomatic Obstet Gynaecol. 1983;2:220.

13. Maddocks S, Hahn P, Moller F, et al. A double-blind placebo-controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome. Am J Obstet Gynecol. 1986;154:573.

14. Freeman E, Rickels K, Sonheimer S, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA. 1990;264:349-353.

15. Dennerstein L, Spencer-Gardner C, Gotts, G et al. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J. 1985;290:1617-1621.

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https://www.sciencedirect.com/science/article/pii/S0254629921000375
Anti-Cancer Activity

79) Ibrahim, Faten M., et al. “Vitex agnus-castus L.(Chasteberry) extracts shows in vitro and in vivo anti-inflammatory and anti-tumor propensities via reduction of cyclooxygenase-2 activity and oxidative stress complications.” South African Journal of Botany 143 (2021): 363-373.
This study tend to show that vitex extract/fractions possess anti-inflammatory, antioxidant propensities and cyclooxygenase inhibitory properties which could justify the promising antitumor properties and be further studied in the development of biomedicine.

Vitex is well known as a natural botanical supplement used to manage a panoply of ailments.
•Extracts and ethyl acetate fractions significantly and selectively suppressed COX-2.•Extracts significantly reduced the viable Ehrlich cell count in vivo.
•The promising antitumor properties shall open new industrial application of vitex.

80) El-Newary, Samah A., Eman R. Youness, and Abeer Ibrahim. “Vitex Berries Attenuates Chemically-Induced Mammary Carcinomas in Rats through modulation of the cancer growth rate-limiting enzymes activities: aromatase and Na+/K+ ATPase.” Egyptian Journal of Chemistry 67.5 (2024): 235-255.

Vitex (Vitex agnus-castus) berries have shown potent antioxidant, selective anti-inflammatory against cyclo-oxygenase-2 (COX-2), and cytotoxicity effect against human breast cancer cells (MCF-7), as we recorded in our previous study”. Additionally, we found that Ethanolic extract (70%) and its ethyl acetate fraction have exhibited anti-tumor ability on
Ehrlich’s Ascites Carcinoma in mice model in our previous study. The present study was planned to evaluate the protective and therapeutic effects of berries ethanolic extract and its ethyl acetate fraction on breast cancer using a 7, 12- dimethylbenz(a)anthracene-induced breast cancer model. Results showed that Vitex materials exhibited protective and
therapeutic effects on chemically-induced breast cancer Sprague-Dawley female rats, where breast cancer biomarkers including the number of tumors devolved, weight and volume of tumor mass, and carcinoembryonic antigen level were significantly reduced compared to the cancer control group. Interestingly, the therapeutic effects of vitex materials were better
than the protective effects, and ethyl acetate fraction was more effective than ethanolic extract. Finally, the obtained data showed that Vitex ethanolic extract (70%) and its ethyl acetate fraction can protect and treat chemically-induced breast cancer with a good safety margin. Vitex struggled with chemically-induced breast cancer through inhibition of the overexpression of cancer growth rate-limiting enzymes; Na+/K+ ATPase and aromatase as well as estrogen overproduction. Also, Vitex prevented overexpression of COX-2 and oxidative stress.

81) El Kamari, Fatima, et al. “Anti-inflammatory and analgesic effects of aqueous extracts of Vitex agnus cactus L. and Cymbopogon nardus L. against carrageenan-induced inflammation in rats.” Trends in Phytochemical Research 1.1 (2024): 18.

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78) Lazennec, Gwendal, et al. “ERβ inhibits proliferation and invasion of breast cancer cells.” Endocrinology 142.9 (2001): 4120-4130.

79) Gustafsson, Jan-Åke, and Margaret Warner. “Estrogen receptor β in the breast: role in estrogen responsiveness and development of breast cancer.” The Journal of steroid biochemistry and molecular biology 74.5 (2000): 245-248.

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Progesterone Pre-operatively Protects Breast Cancer Pt

80) Hrushesky, WilliamJ M., Avrum Z Bluming, and ScottA Gruber. “Menstrual influence on surgical cure of breast cancer.” The Lancet 335.8695 (1990): 984.

In a retrospective study of 44 premenopausal women who underwent resection of a primary breast cancer and were followed for 5 to 12 years, disease recurrence and metastasis were more frequent and more rapid in women who had been operated upon during the perimenstrual period (days 0-6 and 21-36 of the menstrual cycle). By multivariate analysis, the time of resection in relation to the menstrual cycle is an independent predictor of the likelihood of future metastatic disease. Patients who underwent resection during the perimenstrual period had a more than quadrupled risk of recurrence and death compared with women operated upon during days 7 to 20 of the menstrual cycle.

81) Ratajczak, H. V., R. B. Sothern, and W. J. Hrushesky. “Estrous influence on surgical cure of a mouse breast cancer.” The Journal of experimental medicine 168.1 (1988): 73-83.

However, estrous stage at time of surgical removal ofthe tumor, as reflected by cell types in vaginal smear, markedly affected whether or not metastases ultimately appeared. Because the estrous cycle in mice, comparable to the human menstrual cycle, reflects high-amplitude, rhythmic changes in hormone concentrations, it may be that the hormonal status of a woman at the time of tumor resection is an important determinant of whether or not that breast cancer ultimately metastasizes.

82) Badwe, R. A., et al. “Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer.” The Lancet 337.8752 (1991): 1261-1264.

Timing of operation in relation to menstrual phase might affect outlook in premenopausal women with operable breast cancer. We examined the records of 249 such women treated between 1975 and 1985, and compared overall and recurrence-free survival in those whose operation was 3-12 days after their last menstrual period (LMP) (group 1, n=75) with those in whom it was 0-2 or 13-32 days after LM P (group 2, n=174). Overall and recurrence-free survival were greatly reduced in group 1 women (p<0·001 for both). Actuarial survival at 10 years was 54% in group 1 versus 84% in group 2. This effect was independent of other factors, was of much the same importance as nodal status in multivariate analysis, was largely confined to histologically node-positive cases, seemed to be greater in women with small tumours (≤2 cm), and was seen in patients with oestrogen-receptor positive and negative tumours. Thus phase of menstrual cycle at operation is of great importance for long-term outlook in premenopausal women with breast cancer.

83) Badwe, R. A., et al. “Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer.” European Journal of Cancer 30.4 (1994): 445-448.
Serum progesterone and oestradiol levels have been measured in 210 premenopausal women with operable breast cancer on samples taken within 3 days of tumour excision. There was no relation between oestradiol level and time since last menstrual period, nor any effect of oestradiol value on prognosis. However, serum progesterone levels were related to the phase of the cycle as determined by time since last menstrual period. When divided on a basis of levels > 1.5 ng/ml (luteal phase) and < or = 1.5 ng/ml, it was found that there was no difference in survival between the two groups among 117 axillary node negative cases. However, in the 93 patients with positive axillary nodes, higher progesterone levels were associated with significantly better survival. Thus, serum progesterone levels at the time of surgery may affect the prognosis of premenopausal node positive patients with operable breast cancer.

84) Badwe, Rajendra, et al. “Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial.” (2011).
In 471 node-positive patients, the 5-year DFS [Disease Free Survival] and OS [Overall survival] rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P .04), respectively. In multivariate analysis, DFS 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).

85) Pujol, Pascal, et al. “A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.” Cancer: Interdisciplinary International Journal of the American Cancer Society 91.10 (2001): 1854-1861.

86) Zhang, Baoning. “Prognosis of patients with breast cancer related to the timing of operation during menstrual cycle.” Chinese Journal of Cancer Research 10 (1998): 138-142.
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Samples

87) Atif, Fahim, et al. “Progesterone treatment attenuates glycolytic metabolism and induces senescence in glioblastoma.” Scientific reports 9.1 (2019): 988.

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which control glycolytic metabolism through upstream PI3K/Akt/mTOR signaling in GBM. In addition, progesterone administration attenuated EGFR/PI3K/Akt/mTOR signaling, which is highly activated in grade IV GBM. High-dose progesterone also induced senescence in GBM as evidenced by changes in cell morphology and β-galactocidase accumulation. In conclusion, progesterone inhibits the modulators of glycolytic metabolism and induces premature senescence in GBM cells and this can help to reduce/slow tumor progression.

88) Luo, Hui, et al. “Prognostic value of progesterone receptor expression in ovarian cancer: a meta-analysis.” Oncotarget 8.22 (2017): 36845.

• In order to address the disagreement of progesterone receptor in ovarian cancer survival, we conducted this meta-analysis. …CONCLUSION: Progesterone receptor expression can be
used as a favorable prognostic predictor in ovarian cancer m …

89) Progesterone decreases ovarian cancer cells migration and invasion.Lima MA, Silva SV, Jaeger RG, Freitas VM.Steroids. 2020 Sep;161:108680. doi: 10.1016/j.steroids.2020.108680.
Epub 2020 Jun 18.PMID: 32562708

• Also, progesterone is involved in antitumorigenic process in different types of cancer. …Our
results suggest that progesterone interferes with migration and invasion of ovarian cells. …

90) Kim, Olga, et al. “Targeting progesterone signaling prevents metastatic ovarian cancer.” Proceedings of the National Academy of Sciences 117.50 (2020): 31993-32004.

91) Tamburello, Mariangela, et al. “Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines.” International Journal of Molecular Sciences 24.7 (2023): 6829.
Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. Methods: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Results: Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Conclusion: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical stud

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92) Seki, T., et al. “Liposome-encapsulated progesterone efficiently suppresses B-lineage cell proliferation.” Biochemistry and Biophysics Reports 38 (2024): 101710-101710.

We previously developed liposome-encapsulated progesterone (Lipo-P4) with enhanced anticancer effects, which strongly suppressed triple-negative breast cancer cell proliferation in humanized mice. In this study, we aimed to clarify whether Lipo-P4 effectively suppresses the proliferation of B-lineage cancer cells. We selected six B-cell lymphoma and two myeloma cell lines, and analyzed their surface markers using flow cytometry. Next, we prepared liposome-encapsulated progesterone and examined its effect on cell proliferation in these B-lineage cancer cells, three ovarian clear cell carcinoma cell lines, two prostate carcinoma cell lines, and one triple-negative breast cancer adenocarcinoma cell line. Lipo-P4 suppressed the proliferation of all cancer cell lines. All B-lineage cell lines, except for the HT line, were more susceptible than the other cell types, regardless of the expression of differentiation markers. Empty liposomes did not suppress cell proliferation. These results suggest that progesterone encapsulated in liposomes efficiently inhibits the proliferation of B-lineage cells and may become an anticancer drug candidate for B-lineage cancers.

Peri-operative Progesterone brain surgery

https://www.tandfonline.com/doi/pdf/10.1080/11101849.2022.2112014
93) Mohamed, Omyma Shehata, et al. “Cytoprotective effect and clinical outcome of perioperative progesterone in brain tumors, a randomized microscopically evidence study.” Egyptian Journal of Anaesthesia 38.1 (2022): 466-475.

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Prior, Jerilynn

94) Prior, Jerilynn C., et al. “Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women.” PLoS One 9.1 (2014): e84698.

95) Prior, Jerilynn C. “Women’s reproductive system as balanced estradiol and progesterone actions—a revolutionary, paradigm-shifting concept in women’s health.” Drug Discovery Today: Disease Models 32 (2020): 31-40.

96) Prior, Jerilynn C., et al. “Oral micronized progesterone for perimenopausal night sweats and hot flushes a Phase III Canada-wide randomized placebo-controlled 4 month trial.” Scientific Reports 13.1 (2023): 9082.

97) Prior, J. C., et al. “Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy-a systematic review and meta-analysis of controlled trials with direct randomization.” Journal of Musculoskeletal & Neuronal Interactions 17.3 (2017): 146.

98) Prior, J. C. “Progesterone for treatment of symptomatic menopausal women.” Climacteric 21.4 (2018): 358-365.

99) Nolan, Brendan J., Bonnie Liang, and Ada S. Cheung. “Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data.” The Journal of Clinical Endocrinology & Metabolism 106.4 (2021): e942-e951.

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Progesterone Modulates ER-Alpha

100) Mohammed, Hisham, et al. “Progesterone receptor modulates ERα action in breast cancer.” Nature 523.7560 (2015): 313-317.

We conclude that activation of PR results in a robust association between PR and the ERα complex. Progesterone blocks ERα+ tumour growth

PR is a critical determinant of ERα function due to crosstalk between PR and ERα. In this scenario, under estrogenic conditions, an activated PR functions as a proliferative brake in ERα+ breast tumours by re-directing ERα chromatin binding and altering the expression of target genes that induce a switch from a proliferative to a more differentiated state 6.

Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

There is compelling evidence that inclusion of a progestogen as part of hormone replacement therapy (HRT) increases risk of breast cancer, implying that PR signalling can contribute towards tumour formation1. However, the increased risk of breast cancer associated with progestogen-containing HRT is mainly attributed to specific synthetic progestins, in particular medroxyprogesterone acetate (MPA), which is known to also have androgenic properties2. The relative risk is not significant when native progesterone is used3. In ERα+ breast cancers, PR is often used as a positive prognostic marker of disease outcome4, but the functional role of PR signalling remains unclear. While activation of PR may promote breast cancer in some women and in some model systems, progesterone treatment has been shown to be antiproliferative in ERα+ PR+ breast cancer cell lines5-7 and progestogens have been shown to oppose estrogen-stimulated growth of an ERα+ PR+ patient-derived xenograft8. In addition, exogenous expression of PR in ERα+ breast cancer cells blocks estrogen-mediated proliferation and ERα transcriptional activity9. Furthermore, in ERα+ breast cancer patients, PR is an independent predictor of response to adjuvant tamoxifen10, high levels of PR correlate with decreased metastatic events in early stage disease11 and administration of a progesterone injection prior to surgery can provide improved clinical benefit12. These observations imply that PR activation in the context of estrogen-driven, ERα+ breast cancer, can have an anti-tumourigenic effect. In support of this, PR agonists can exert clinical benefit in ERα+ breast cancer patients that have relapsed on ERα antagonists13.

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Slide Deck 10 Progesterone Pre-operatively Protects

https://pubmed.ncbi.nlm.nih.gov/2571865/
Hrushesky, WilliamJ M., Avrum Z Bluming, and ScottA Gruber. “Menstrual influence on surgical cure of breast cancer.” The Lancet 335.8695 (1990): 984.

Ratajczak, H. V., R. B. Sothern, and W. J. Hrushesky. “Estrous influence on surgical cure of a mouse breast cancer.” The Journal of experimental medicine 168.1 (1988): 73-83.

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https://www.sciencedirect.com/science/article/abs/pii/014067369192927T
Badwe, R. A., et al. “Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer.” The Lancet 337.8752 (1991): 1261-1264.

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https://pubmed.ncbi.nlm.nih.gov/8018400/
Badwe, R. A., et al. “Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer.” European Journal of Cancer 30.4 (1994): 445-448.
Serum progesterone and oestradiol levels have been measured in 210 premenopausal women with operable breast cancer on samples taken within 3 days of tumour excision. There was no relation between oestradiol level and time since last menstrual period, nor any effect of oestradiol value on prognosis. However, serum progesterone levels were related to the phase of the cycle as determined by time since last menstrual period. When divided on a basis of levels > 1.5 ng/ml (luteal phase) and < or = 1.5 ng/ml, it was found that there was no difference in survival between the two groups among 117 axillary node negative cases. However, in the 93 patients with positive axillary nodes, higher progesterone levels were associated with significantly better survival. Thus, serum progesterone levels at the time of surgery may affect the prognosis of premenopausal node positive patients with operable breast cancer.

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Click to access JCO.2010.33.pdf

Badwe, Rajendra, et al. “Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial.” (2011).
In 471 node-positive patients, the 5-year DFS [Disease Free Survival] and OS [Overall survival] rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P .04), respectively. In multivariate analysis, DFS 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).

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Pujol, Pascal, et al. “A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.” Cancer: Interdisciplinary International Journal of the American Cancer Society 91.10 (2001): 1854-1861.

Zhang, Baoning. “Prognosis of patients with breast cancer related to the timing of operation during menstrual cycle.” Chinese Journal of Cancer Research 10 (1998): 138-142.
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Samples

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353890/
Atif, Fahim, et al. “Progesterone treatment attenuates glycolytic metabolism and induces senescence in glioblastoma.” Scientific reports 9.1 (2019): 988.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482703/
Luo, Hui, et al. “Prognostic value of progesterone receptor expression in ovarian cancer: a meta-analysis.” Oncotarget 8.22 (2017): 36845.

• Progesterone decreases ovarian cancer cells migration and invasion.Lima MA,
Silva SV, Jaeger RG, Freitas VM.Steroids. 2020 Sep;161:108680. doi: 10.1016/j.steroids.2020.108680.
Epub 2020 Jun 18.PMID: 32562708

• Also, progesterone is involved in antitumorigenic process in different types of cancer. …Our
results suggest that progesterone interferes with migration and invasion of ovarian cells. …

https://www.pnas.org/doi/full/10.1073/pnas.2013595117
Kim, Olga, et al. “Targeting progesterone signaling prevents metastatic ovarian cancer.” Proceedings of the National Academy of Sciences 117.50 (2020): 31993-32004.

Abstract
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095539/
Tamburello, Mariangela, et al. “Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines.” International Journal of Molecular Sciences 24.7 (2023): 6829.
Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. Methods: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Results: Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Conclusion: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical stud

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https://www.tandfonline.com/doi/pdf/10.1080/11101849.2022.2112014
Mohamed, Omyma Shehata, et al. “Cytoprotective effect and clinical outcome of perioperative progesterone in brain tumors, a randomized microscopically evidence study.” Egyptian Journal of Anaesthesia 38.1 (2022): 466-475.

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Progesterone is Neuroprotective

Sayeed, Iqbal, and Donald G. Stein. “Progesterone as a neuroprotective factor in traumatic and ischemic brain injury.” Progress in brain research 175 (2009): 219-237.

Sofuoglu, Mehmet, Maria Mouratidis, and Marc Mooney. “Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers.” Psychoneuroendocrinology 36.1 (2011): 123-132.

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JAPAN 2023 OB/GyNEs PMS

Yoshimi, Kana, et al. “Current status and problems in the diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder from the perspective of obstetricians and gynecologists in Japan.” Journal of Obstetrics and Gynaecology Research 49.5 (2023): 1375-1382.

The most commonly used medication was oral contraceptive pills (OCPs) (98.1%), followed by the Kampo, traditional Japanese herbal medicines, Kamishoyosan (73.6%). Concern-
ing first-line drugs for treatment, OCPs were the most common (76.8%), followed by Kampo medicine (19.5%); selective serotonin reuptake inhibitors (SSRIs) were less frequently used (2.6%). Regarding first-line drugs among OCPs, 65.1% respondents reported drospirenone-ethinylestradriol use.

Takeda, Takashi. “Premenstrual disorders: Premenstrual syndrome and premenstrual dysphoric disorder.” Journal of Obstetrics and Gynaecology Research 49.2 (2023): 510-518.

Recently, the term premenstrual disorders (PMDs), which includes premenstrual syndrome and premenstrual dysphoric disorder as a continuum, has been proposed. Although the precise etiology of PMDs remains unknown, the involvement of hormonal fluctuations is clear. The brain transmitters, serotonin and γ-amino butyric acid, also seem to be involved. Serotonin reuptake inhibitors and oral contraceptives are the current mainstay of treatment, but these are insufficient. Even the currently used prospective two period symptom diary is not widely used in actual clinical practice, creating a major problem of discrepancy between research and clinical practice. In this review, I would like to outline the latest information and problems in the etiology, diagnosis, and treatment of PMDs, with an emphasis on promising new therapies.

Usually, five types of treatments are used: (1) nonpharmacologic, (2) antidepressants, (3) hormone therapy, (4) vitamin and complementary medicine, and (5) surgery.

Antidepressants
There is strong evidence for the use of SSRIs for the treatment of PMDD75 and they are considered a first line of treatment.4,33,76 Unlike the treatment of depression, the efficacy of SSRIs administered after the onset of symptoms has been reported in the case of PMDD, assuming a different mechanism of action.77

Hormone therapy
The purpose of hormonal treatment is to suppress ovulation., Oral contraceptives (OCPs) were the first drugs to be used. OCPs containing drospirenone and ethinyl estradiol significantly improved PMDD symptoms.78 Continuous dosing regimens are advantageous for improving premenstrual symptoms because they eliminate the hormone-free period compared with regimens with classical withdrawal periods.33 There are reports suggesting the effectiveness of sequential dosing.79,80

Vitamins and complementary medicine
A variety of alternative medicines are being used around the world, but the evidence is limited.33
Among them, vitamin B6 (pyridoxine) has been extensively studied and moderate benefit was
reported in 100 mg of pyridoxine treatment for premenstrual symptoms.83 In the RCOG guidelines, vitamin B6 is listed as one of the first choices in the treatment algorithm.33
Calcium carbonate supplementation with 1200 mg daily was reported to be effective compared with
placebo for premenstrual symptoms.84 However, this effect was only weak compared with that of
fluoxetine.85

Vitex agnus castus (chasteberry) is widely used in Europe and has been the subject of numerous studies, with a meta-analysis of 17 trials reporting efficacy compared with placebo.86

In Japan, Kampo, a type of herbal medicine, has traditionally been used in general practice. In a survey of Japanese obstetricians and gynecologists, the frequency of use of Kampo medicine as a first-line treatment for PMDs was 19%, ranking second after OCPs. Kampo medicines are available as extracted powder manufactured as industrial products by pharmaceutical companies, and can be prescribed in the same way as Western medicines. Kampo medicines have a
high degree of uniformity of ingredients, and in the field of obstetrics and gynecology, their efficacy in the treatment of menopausal symptoms was examined using a placebo-controlled trial.87 The only efficacy studies for PMDD have been preliminarily conducted using one of the Kampo formula Kamisyoyosan.88

Kamisyoyosan has been reported to act on the brain serotonin system in a mouse model of depression,89 making it a promising therapeutic agent for PMDs.

Surgery
Surgical intervention, total hysterectomy and bilateral adnexectomy, is a permanent treatment limited to
cases of recurrence of intense symptoms.90
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American family physician 2016 PMS

Hofmeister, Sabrina, and Seth Bodden. “Premenstrual syndrome and premenstrual dysphoric disorder.” American family physician 94.3 (2016): 236-240.
Premenstrual disorders affect up to 12% of women. The subspecialties of psychiatry and gynecology have developed overlapping but distinct diagnoses that qualify as a premenstrual disorder; these include premenstrual syndrome and premenstrual dysphoric disorder. These conditions encompass psychological and physical symptoms that cause significant impairment during the luteal phase of the menstrual cycle, but resolve shortly after menstruation. Patient-directed prospective recording of symptoms is helpful to establish the cyclical nature of symptoms that differentiate premenstrual syndrome and premenstrual dysphoric disorder from other psychiatric and physical disorders. Physicians should tailor therapy to achieve the greatest functional improvement possible for their patients. Select serotonergic antidepressants are first-line treatments. They can be used continuously or only during the luteal phase. Oral contraceptives and calcium supplements may also be used. There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy.

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Dickerson, Lori M., Pamela J. Mazyck, and Melissa H. Hunter. “Premenstrual syndrome.” American family physician 67.8 (2003): 1743-1752.

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Safety and Adverse effects of Natural Progesterone

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Safety and Adverse effects of Natural Progesterone

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7 thoughts on “Safety and Adverse Effects of Natural Progesterone”

Phyllis Bronson,Ph.D. on January 16, 2014 at 10:31 AM said:

The interface of the neurosteroid, progesterone, and GABA, an inhibitory neurotransmitter and amino acid -both- is very significant in understanding the mechanism by which GABA works, particularly in women. We have helped many women get off benzodiazepine drugs by learning this.
In the presence of the progesterone metabolite allopregnanolone, the subunit on the GABA-AR is activated and downregulated- meaning one becomes calmer. if there is not sufficient alloprgnanolone, then GABA can become an excitatory (stimulant) molecule instead of calming. GABA is fantastic for calmness but because of these complex mechanisms, little is obvious about its uptake as it does not cross the BB in the usual sequences.

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Larry Frieders on January 16, 2014 at 1:53 PM said:

A large part of the ‘problem’ is the language we use. Both progesterone USP and medroxyprogesterone are progestins. I have a strong feeling that he definitions were intentionally made confusing so that the drug versions could be passed off as a kind of progesterone. Insidious?

regards from Larry Frieders

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Phyllis Bronson on February 7, 2017 at 12:44 PM said:

AS A BIOCHEMIST HAVING DONE YEARS OF RESEARCH ON THE DISTINCTIONS BETWEEN REAL (PROGESTERONE) AND SYNTHETIC PROGESTINS HERE ARE A FEW THOUGHTS:
TRANSDERMAL PROGESTERONE IS WONDERFUL FOR ANXIETY, ORAL ( EVEN IF REAL PROGESTERONE) PROGESTERONE OFTEN MAKES WOMEN SLEEPY BEFORE THEY GET CALM, BECAUSE OF UPPER GI INVOLVEMENT THAT MAKES MOLECULE THAT IS A FIRST COUSIN OF PHENOBARBITAL, A POTENT BARBITUATE.
WE OFTEN HAVE WOMEN WITH ANXIETY SPREAD OUT 100 MG DOSES OF CREAM PROGESTERONE DURING THE DAY-NOT MORE THAN THAT IN ONE DOSE OVER 2-3 HOURS- THEN OFTEN USE QUITE A BIT MORE AT NIGHT.
THE VERY FEW WOMEN WHO DO NOT CALM DOWN MAY BE SHUNTING PROGESTERONE TO CORTISOL BECAUSE OF ADRENAL FATIGUE- WHICH IS SOMETIMES GREATLY HELPED BY ACTUAL NATURAL HC. (HYDROCORTISONE DROPS)

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Ruužica Marunica on September 17, 2017 at 9:04 AM said:

Hello. My name is Ružica I’m old for 56 years. I’ve been postmenopausal for six years now. I also have hypothyroidism for which I use natural hormones. a little painful and high pressure and probably the dominance of estrogen, I also have a problem with sleeping, if I do not drink my pills I do not sleep well. I also have the right hip arthrosis. I’m interested in bio-progesterone, would it be good to take it? Where can I buy it? My libido and apathy are at zero. I would like your advice. Thank you.

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Jeffrey Dach MD

Bioidentical Hormones Natural Thyroid

Safety and Adverse Effects of Natural Progesterone

Safety and Adverse effects of Natural Progesterone

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