Progesterone for PMS, and Peri-Menopause, Part Two by Jeffrey Dach MD
For part one, click here.
for part three: Click Here
Progesterone is a key player in the female menstrual cycle, ovulation and fertility. The name progesterone means “for gestation”. And this hormone is required for pregnancy, implantation of the oocyte and growth of the developing fetus. Blocking progesterone receptors with a drug (RU-486, Mifepristone) is the basis for drug induced abortion.
Left Image: Woman with a Parasol – Madame Monet (1875). Oil on canvas. National Gallery of Art, Washington, D.C. Courtesy of Wikimedia Commons.
Understanding the Normal Menstrual Cycle – Hormone Charts
The chart below from college level biology class, showing the idealized normal menstrual cycle.
Estrogen and Progesterone
To understand progesterone and estrogen, one must review the above chart showing the major events of the menstrual cycle. Estrogen and progesterone are natural human hormones produced in harmony by the ovary. Estrogen is produced throughout most of the month, from days 5-26 with a peak just before ovulation (day 11) and another peak around day 19.
Corpus Luteum
Progesterone is produced the last two weeks of the monthly cycle by the corpus luteum, a specialized ovarian structure, representing the remnant of the ovulatory follicle after ovulation. During ovulation, the egg (aka ovum, oocyte) is expelled from the ovarian follicle, and starts its long journey down the fallopian tube to the endometrial cavity where fertilization and implantation may occur (aka ovulation). Ovulation usually occurs on day 11 (vertical dotted line on chart), so progesterone levels start rising on day 12, peaking on day 19-20 or so.
Above image: Ovulation, Source Selbst erstellt von H. Hoffmeister Author:Lanzi at German Wikipedia.Courtesy of Wikimedia commons.
Women Who Take Progesterone Capsules for PMS, RIA vs. HPLC ?
To determine if ovulation is occurring normally in women, progesterone serum levels can be checked on Day 19 of the monthly cycle with RAI (radio-immunoassay) or HPLC (High Pressure Liquid Chromatography). (1) These are two different lab techniques. If the female patient is also taking progesterone capsules for PMS, typically on days 12-26, then false elevated serum progesterone readings may be obtained. The progesterone metabolites from the oral progesterone capsule give a false elevated reading for RIA, but not for HPLC. The RIA reading may be (falsely) 8 times higher than the HPLC. In this case, the HPLC test is more accurate and is preferred over RIA.(1)
Sudden Decline in Hormone Levels Leads to Bleeding
Both progesterone and estrogen levels decline suddenly around day 26 of the menstrual cycle. This sudden drop in hormone levels initiates menstrual bleeding, the endometrial lining has lost hormonal support and sloughs off (aka menstrual bleeding).
Idealized Normal Menstrual Cycle
The above schematic diagram shows the idealized menstrual cycle in the normal female. Firstly, look at the top row. The yellow donut like-structure is the corpus luteum in the ovary which makes progesterone. The next row down is body temperature which spikes up at the time of ovulation around day 11. The vertical dotted line represents ovulation around day 11. The next row down we see that FSH and LH spike at the time of ovulation. FSH and LH are pituitary hormones. FSH is follicle stimulating hormone, and LH is leutinizing hormone. The next row down, we see charts of serum estrogen (yellow) and progesterone (purple). Estrogen spikes just before ovulation, and then has a second peak around day 19. Progesterone starts rising after ovulation, peaks around day 19 and then falls off around day 26. The bottom row shows a schematic of the endometrial lining which thickens with hormonal stimulation, and then sloughs off as hormone levels drop off at day 26.
Anovulation, Estrogen Dominance and Menstrual Irregularities
The above chart shows a normal ovulatory cycle. What happens if ovulation does not occur? This is called anovulation, a common problem in young women. in which the ovum is not expelled, no corpus luteum is formed, and no progesterone is produced. Without ovulation, menstrual bleeding becomes irregular, and the cycle length is variable. This leads to a condition known as “estrogen dominance” in which body tissues respond to estrogenic stimulation without progesterone to counter act the estrogen.
Once ovulation occurs, usually around day 11, the production of progesterone by the corpus luteum inhibits further ovulation of remaining follicles. The anti-ovulatory effect of progesterone was first demonstrated in 1937 by Dr. A. W. Makepeace by injecting progesterone into mated female rabbits. Thus progesterone inhibits ovulation and serves as birth control. The first birth control pills used contained natural bioidentical progesterone. However, it was more profitable to market a patented drug, synthetic progestins were developed, and synthetic progestins then became the dominant birth control pill, replacing natural progesterone which can not be patented. Note: natural substances can not be patented. (44-47)
The anti-ovulatory effect of progesterone is of importance in the treatment of PMS [prementrual synfrome] in younger cycling females. For this age group, progesterone is given on a schedule beginning just after ovulation, for days 12-26 of the menstrual cycle. If progesterone is taken prior to ovulation, this will create an anovulotory cycle which may alarm the patients unless pre-warned about this effect. In older post-menopausal women who are not ovulating, progesterone may be given straight through the month with no concern for cycling.
PMS – PreMenstrual Syndrome – Estrogen Dominance
Estrogen causes fluid retention and breast tissue stimulation. In the absence of enough progesterone to counter balance the estrogen, the patient may experience bloating, breast enlargement and tenderness, and fluid retention. Estrogen also causes psycho-stimulation, so the patient may complain of insomnia and mood disorders, migraine headaches etc.. As estrogen levels drop, the serum binding protein levels also drop, thus liberating testosterone to cause acne, oily skin and aggressive, “snappy” behavior.
In some cases, ovulation occurs , yet progesterone production is insufficient to balance the massive amounts of estrogen. Similarly these patients suffer from “estrogen dominance” and a similar symptom complex also called “PMS”. premenstrual syndrome.
Treatment for PMS and Irregular Menstrual Cycles
Since progesterone is the missing or deficient element in the PMS syndrome, it would be logical to assume providing progesterone in the form of creams or capsules would benefit the patient. In fact, many doctors and patients report dramatic resolution of PMS symptoms with progesterone capsules and creams. Of course, an annual pelvic exam by the local gynecologist as well as pelvic sonogram is warranted for pre-menopausal women prior to treatment with natural progesterone. Although we will typically perform laboratory testing of hormone levels on day 19 of the menstrual cycle, this type of lab testing is not required by mainstream medicine, and in fact rarely done for treatment of PMS or irregular menstrual bleeding. For more on this, see my article on the importance of the pelvic sonogram.
Progesterone for the Peri-Menopausal Transition
Progesterone is also commonly used for treatment of the menopausal transition characterized by irregular menstrual cycles, high or fluctuating estrogen levels, and low or non-existent progesterone levels. During this menopausal transition, hormone fluctuations cause mood disturbance, which is relieved by oral micronized progesterone. (48-54)
In 2011, Dr. Jerilynn 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, (48)
Regarding the utility of progesterone for relief of peri-,menopausal depressive symptoms, in 2020 De. Hadine Joffe, writes:
Consistent with our observation of an inverse relationship between depressive symptoms and concurrent exposure to progesterone is the recent finding of an antidepressive effect of the progesterone-derived neurosteroid allopregnanolone for treatment of postpartum depression, leading to the approval of allopregnanolone by the FDA for postpartum depression. As a treatment for another reproductive hormone-associated mood disturbance, allopregnanolone’s efficacy for postpartum depression challenges earlier presumptions that progestins adversely affect mood. Allopregnanolone may act as a neurosteroid to mediate the protective effect of peripheral progesterone on mood through direct inhibition of γ-aminobutyric acid (GABA) receptors. (49-50)
Still Not Accepted by Mainstream Medicine
Although progesterone is an FDA approved drug, mainstream medicine has yet to accept bioidentical natural human progesterone as a treatment for PMS and irregular menstrual cycles. Instead, mainstream medicine relies on synthetic forms of progesterone called “progestins” such as medroxyprogesterone (MPA, Provera) which increased breast cancer by 26 percent in the ill fated Women’s Health Initiative Study (first arm 2002). In 2000, Dr. Catherine Schairer found the women taking the estrogen/ MPA combination suffered and increased breast cancer risk by 800 prercent compare to women taking estrogen-alone. Increased breast cancer risk with the estrogen/MPA combination was confirmed in 2000 by Dr. Ronald K Ross, and in 2003 by Dr. Håkan L Olsson. Why hasn’t mainstream medicine accepted natural progesterone and rejected synthetic versions progesterone such as MPA? This is explained by the “War Against Natural Medicine”. Natural substances can not be patented and are therefore unprofitable for the drug industry. (54-57)
The War Against Natural Medicine
In my first book, Natural Medicine 101, I delved into the reasons for the information war between natural medicine and mainstream medicine. In short, mainstream medicine is dominated by the drug industry whose profits are dependent on the patented drug system. A patented drug is a natural molecule whose chemical structure has been altered in order to obtain a patent. Molecular structures naturally occurring in the human body or in nature by definition cannot be patented, and are therefore of no interest to the drug industry. Rather, these natural substances such as progesterone represent economic competition to the patented counterparts. That is why progesterone has not taken its rightful place in mainstream medicine treatment of PMS.
Dysfunctional Uterine Bleeding
Dysfunctional bleeding related to anovulatory cycles in younger, pre-menopausal females is frequently associated with the low thyroid condition and usually responds to administration of thyroid hormone. Cyclic progesterone for days 12-26 of the menstrual cycle and Myoinositol has also shown efficacy. Mainstream OB/Gyne practice uses synthetic progestins such as MPA, medroxyprogestrone given as a short course. Carcinogenic effects of MPA are generally overlooked in cases of uterine bleeding. (24-31)(37)(53) (58-63)
Uterine bleeding in the post menopausal female will always trigger a pelvic sonogram, and if there is endometrial stripe thickening, endometrial biopsy at the local OG/Gyne clinic. For the post menopausal female on bioidentical hormone replacement withdrawal bleeding may occur indicating excessive estrogen dosage. Temporary withdrawal of the hormone replacement program usually resolves the bleeding and allows time for a pelvic sonogram which may demonstrate uterine fibroids or other pathology. In the event of a normal pelvic sonogram without thickening of the endometrial strip, the HRT may be resumed at a lower dosage, usually without resumption of bleeding.(24-31)(37)(53) (58-63)
John R Lee MD and Uzzi Reiss M
Thanks and credit goes to Uzzi Reiss MD and John R Lee MD, Most of the material in this article can be found in John R Lees’ chapter on progesterone in his book, “What the doctor wont tell you about premenopause”. Also Uzzi Reiss’s chapter on progesterone and PMS from his book, “Natural Superwoman” was another source for this article. Additional Sources for this article: Carol Petersen and the Wellness by Design Project…
Click here for Carol Petersen’s Newsletters on Progesterone and other topics.
Articles with Relateed Interest:
For part one of Progesterone for PMS, and Peri-Menopause,Click here.
For part three of Progesterone for PMS, and Peri-Menopause, Click Here
For all other Bioidentical hormone articles: Click Here
Jeffrey Dach MD
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Davie, Florida 33314
954-792-4663
Links and References:
1) Levine, Howard, and N. Watson. “Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women.” Fertility and sterility 73.3 (2000): 516-521.
However, when present in large quantities, such as is the case after oral administration (i.e., when greater than 90% of the dose is metabolized during first hepatic pass) (5, 22), these metabolites may cross-react significantly. This cross-reactivity appears to be of particular concern when progesterone was measured by RIA either directly (4, 21, 24) or where chromatographic purification was inadequate (3) and led to erroneously high blood levels of progesterone after oral administration.
The present study supports this contention because mean peak serum progesterone concentration after oral administration by RIA was eightfold higher than that measured by progesterone-specific LC-MS (i.e., 19.40 ± 12.64 ng/mL vs. 2.43 ± 5.01 ng/mL).
2) Progesterone FDA Approval Prevention Endometrial Hyperplasia
4) Mood Biochemistry of Women at Mid-life Phyllis Bronson 2001 J Ortho Mol Med
6) Conservative management of endometrial hyperplasia Childs OBG MANAGEMENT 2003 Childs, A. J., W. E. Check, and W. J. Hoskins. “Conservative management of endometrial hyperplasia: New strategies, experimental options.” OBG MANAGEMENT 15.9 (2003): 15-26.
7) Progesterone for Symptomatic Perimenopause Prior 2011 Prior, J. C. “Progesterone for Symptomatic Perimenopause Treatment–Progesterone politics, physiology and potential for perimenopause.” Facts, Views & Vision in ObGyn 3.2 (2011): 109.
8) Natural progesterone Jane Murray Womens Health Primary Care 1998 Murray, Jane L. “Natural progesterone: what role in women’s health care.” Women’s Health Primary Care 1.8 (1998): 671-87.
9) progesterone_booklet Lawley Pharmaceuticals 2010
10) Estrogen carcinogenesis in breast cancer James Yager New England Journal of Medicine 2006
11) Dose dependent effects oral progesterone oestrogenised postmenopausal endometrium Lane BMJ 1983
12) Oral micronized progesterone de Lignières Clinical therapeutics 1999 de Lignières, Bruno. “Oral micronized progesterone.” Clinical therapeutics 21.1 (1999): 41-60.
13) Premenstrual Syndrome Chart American Family Physician
14) Endometrial_Hyperplasia_Progesterone_ACOG_Brochure
15) http://www.thelancet.com/pdfs/
Katharina Dorothea Dalton
A gynaecologist who popularised the concept of premenstrual syndrome and wrote the best- selling book Once a Month. . Born in London, UK, on Nov 11, 1916, she died on Sept 17, 2004, aged 87 years
Letter containing basic incorrect statements about progesterone
16) http://www.bmj.com/rapid-
17) BMJ 2004; 329 doi: http://dx.doi.org/10.1136/bmj.
Removal of the ovaries has long been used to prevent endogenous progesterone production as a treatment for breast cancer. Recent studies confirm that progesterones cause more breast cancer than oestrogens. Progesterone is also potentially teratogenic.
17) Freeman, ELLEN W., et al. “A placebo‐controlled study of effects of oral progesterone on performance and mood.” British journal of clinical pharmacology 33.3 (1992): 293-298.
18) http://www.drkaslow.com/html/
Jeremy E. Kaslow, MD, FACP, FACAAI Physician and Surgeon
Board Certified Internal Medicine Hormones and the Menstrual Cycle
19) http://www.ncbi.nlm.nih.gov/
Pharmacotherapy. 1996 May-Jun;16(3):453-7.
Oral administration of micronized progesterone: a review and more experience.
McAuley JW1, Kroboth FJ, Kroboth PD.
Historically, oral progesterone has been regarded clinically ineffective because of its poor absorption and rapid clearance. Recent evidence suggests that an oral micronized form of natural progesterone is readily absorbed, produces luteal phase serum concentrations, provokes an end-organ response, and has no detrimental effect on the lipoprotein profile. Thus it is considered by many to be an attractive alternative to synthetic progestin. We evaluated the effects of a single oral dose of micronized progesterone 300 mg in eight healthy postmenopausal women. The maximum serum concentration ranged from 15.72-625.98 ng/ml.
20) http://www.ncbi.nlm.nih.gov/
Efficacy of oral micronized progesterone in the treatment of luteal phase defects.
Frishman GN1, Klock SC, Luciano AA, Nulsen JC.
Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects.
STUDY DESIGN: Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation.
RESULTS: On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration.
CONCLUSION: We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.
21) http://www.bmj.com/content/
Dose dependent effects oral progesterone oestrogenised postmenopausal endometrium Lane, G., et al. “Dose dependent effects of oral progesterone on the oestrogenised postmenopausal endometrium.” BMJ 287.6401 (1983): 1241-1245.
Full free- BEST
22) http://www.fertstert.org/
Fitzpatrick, Lorraine A., and Andrew Good. “Micronized progesterone: clinical indications and comparison with current treatments.” Fertility and sterility 72.3 (1999): 389-397.
Objective: To integrate and evaluate the pharmacokinetic, endocrine, and clinical effects of micronized progesterone formulations.
Design: Published articles concerning the pharmacokinetics of orally administered progesterone and the potential clinical uses of oral micronized progesterone were reviewed. Results concerning their use for secondary amenorrhea, premenopausal bleeding disorders, luteal phase dysfunction, termination of premature labor, hormone replacement therapy, and premenopausal syndrome are summarized. Critical issues to be resolved through ongoing preclinical and clinical research are highlighted.
Result(s): Because of the enhanced bioavailability of oral micronized progesterone, the compound may be useful for a variety of therapeutic indications. Oral micronized progesterone is available in France, and a formulation recently has been approved in the United States for the treatment of secondary amenorrhea and postmenopausal hormone replacement therapy. A large body of evidence, including the Postmenopausal Estrogen/Progestin Interventions study, suggests that the use of a combination of estrogen and oral micronized progesterone is optimal for long-term hormone replacement therapy. There also are data indicating that oral micronized progesterone could be of potential use for the treatment of premenopausal bleeding disorders, luteal phase disorders, and premature labor.
Conclusion(s): Oral micronized progesterone has widespread clinical potential, particularly for the treatment of secondary amenorrhea and dysfunctional premenopausal bleeding, and as a component of postmenopausal hormone replacement therapy.
In summary, oral micronized progesterone has the potential for widespread clinical utility. For indications in which oral delivery of the synthetic progestins currently are used, the theoretic benefits of oral delivery of the natural form of the hormone are obvious. In addition to the decreased potential for adverse effects, there are clear advantages in convenience, cost, compliance, and quality of life.
Acknowledgements
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23) Li, Quanxi, et al. “The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2.” Science (New York, Ny) 331.6019 (2011): 912.
P counteracts E-induced endometrial hyperplasia.
pdf available
24) Munro, Malcolm G., et al. “medroxyprogesterone for acute uterine bleeding Munro Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial.” Obstetrics & Gynecology 108.4 (2006): 924-929.
25) Bitzer, Johannes, et al. “Medical Management of Heavy Menstrual Bleeding: A Comprehensive Review of the Literature.” Obstetrical & gynecological survey 70.2 (2015): 115-130.
26) Quinn, Stephen, and Jenny Higham. “Available management options for heavy menstrual bleeding.” Prescriber 25.18 (2014): 18-25.
27) Matteson, Kristen A., et al. “Nonsurgical management heavy menstrual bleeding systematic review Nonsurgical management of heavy menstrual bleeding: a systematic review.” Obstetrics & Gynecology 121.3 (2013): 632-643.
28) Matteson, Kristen A., et al. “Practice patterns and attitudes about treating abnormal uterine bleeding: a national survey of obstetricians and gynecologists.” American journal of obstetrics and gynecology 205.4 (2011): 321-e1.
29) Kaunitz, A. M., et al. “Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial.” Obstetrics and gynecology 116.3 (2010): 625.
30) Managing acute heavy menstrual bleeding
Recommendations for hormonal regimens to halt blood loss in the outpatient
January 01, 2014 By Anita L. Nelson, MD
31) Aksu, M. Feridun, et al. “High‐Dose Medroxyprogesterone Acetate for the Treatment of Dysfunctional Uterine Bleeding in 24 Adolescents.” Australian and New Zealand journal of obstetrics and gynaecology 37.2 (1997): 228-231.
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PMS
32) Once a Month: Understanding and Treating PMS Paperback – March 23, 1999 Katharina Dalton (Author)
33) http://www.johnleemd.com/
Dr. Phil Interview with Holly Anderson: Treating PMS Symptoms With Natural Progesterone . The treatment that works is vaginal or rectal natural progesterone. [Progesterone cream works just as well or better because it’s not messy and drippy! It is delivered to cells throughout the body within minutes of application.] Oral [pill] progesterone does not work for PMS. […because it stresses the liver and creates a lot of metabolites or byproducts, and also only delivers about 20 percent of the dose to the cells].
34) http://www.aafp.org/afp/2003/
Premenstrual Daily Symptom Diary. Premenstrual Syndrome
LORI M. DICKERSON, PHARM.D., PAMELA J. MAZYCK, PHARM.D., and MELISSA H. HUNTER, M.D., Medical University of South Carolina, Charleston, South Carolina. Am Fam Physician. 2003 Apr 15;67(8):1743-1752.
35) http://www.ncbi.nlm.nih.gov/
Br Med J (Clin Res Ed). 1985 Jun 1;290(6482):1617-21.
Progesterone and the premenstrual syndrome: a double blind crossover trial.
Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD.
A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos’s menstrual distress questionnaire, Beck et al’s depression inventory, Spielberger et al’s state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.
36) Emerita Pro-Gest Cream, 4 oz. tube (PACKAGING MAY VARY)
by Emerita on Amazon
37) http://www.drnorthrup.com/
Heavy Menstrual Bleeding (Menorrhagia) Christiane Northrup, M.D.
Although I prefer to try natural progesterone first, if that doesn’t work, a strong synthetic progestin such as medroxyprogesterone acetate (Provera) can help. (This is the only circumstance in which I recommend the synthetic.) T – See more at: http://www.drnorthrup.com/
38) http://www.pmstreatmentclinic.
PMS Treatment Clinic using bioidentical hormones to treat premenstrual syndrome.
Treatment of Premenstrual Syndrome
Premenstrual Syndrome is a condition of estrogen dominance-progesterone deficiency. It occurs in the two weeks before the period and goes away when the period is over. 150 emotional and physical symptoms can occur. Symptoms may include headaches, migraines, menstrual cramps, depression, irritability, fatigue, emotional outbursts, low blood sugar, rage, out of control behavior, dizziness, decreased resistance to infection and epileptic seizures. An underactive thyroid is commonly an underlying disorder that is present.
Patients can become symptom-free on natural progesterone therapy. If the patient is hypothyroid, treatment involves thyroid supplements.
39) https://www.womentowomen.com/
by Marcelle Pick, OB/GYN NP
Advanced Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD) Treatment
40) http://www.
Dysfunctional Uterine Bleeding
==============================
41) http://www.
UNOPPOSED ESTROGEN AND THE PERI-MENOPAUSAL TRANSITION
42) http://press.endocrine.org/
Is Estradiol a Genotoxic Mutagenic Carcinogen? Joachim G. Liehr July 01, 2013 Endocrine Reviews
43) Yager, James D., and Nancy E. Davidson. “Estrogen carcinogenesis in breast cancer.” New England Journal of Medicine 354.3 (2006): 270-282.
44) Campagnoli, Carlo, et al. “Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.” The Journal of steroid biochemistry and molecular biology 96.2 (2005): 95-108.
45) Dhont, Marc. “History of oral contraception.” The European Journal of Contraception & Reproductive Health Care 15.sup2 (2010): S12-S18.
46) Foran, Terri. “A Tale of Two Hormones.” Fertility & Reproduction 1.01 (2019): 39-42.
47) A Garside, Deborah, et al. “An update on developments in female hormonal contraception.” Current Women’s Health Reviews 8.4 (2012): 276-288.
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48) Prior, J. C. “Progesterone for Symptomatic Perimenopause Treatment–Progesterone politics, physiology and potential for perimenopause.” Facts, Views & Vision in ObGyn 3.2 (2011): 109.
Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically – some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels.
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,
49) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075107/
Joffe, Hadine, et al. “Impact of estradiol variability and progesterone on mood in perimenopausal women with depressive symptoms.” The Journal of Clinical Endocrinology & Metabolism 105.3 (2020): e642-e650.
Consistent with our observation of an inverse relationship between depressive symptoms and concurrent exposure to progesterone is the recent finding of an antidepressive effect of the progesterone-derived neurosteroid allopregnanolone for treatment of postpartum depression (34), leading to the approval of allopregnanolone by the FDA for postpartum depression. As a treatment for another reproductive hormone-associated mood disturbance (35), allopregnanolone’s efficacy for postpartum depression challenges earlier presumptions that progestins adversely affect mood. Allopregnanolone may act as a neurosteroid to mediate the protective effect of peripheral progesterone on mood through direct inhibition of γ-aminobutyric acid (GABA) receptors.
50) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838629/
Gordon, Jennifer L., et al. “Efficacy of transdermal estradiol and micronized progesterone in the prevention of depressive symptoms in the menopause transition: a randomized clinical trial.” JAMA psychiatry 75.2 (2018): 149-157.
51) Prior, J. C. “Progesterone for treatment of symptomatic menopausal women.” Climacteric 21.4 (2018): 358-365.
52) Prior, Jerilynn C. “Clearing confusion about perimenopause.” BC Med J 47.10 (2005): 538-42.
At present, no perimenopause
therapies have been adequately vali-
Clearing confusion about perimenopause
VOL. 47 NO. 10, DECEMBER 2005 BC MEDICAL JOURNAL 541
dated in randomized controlled trials.
However, based on the endocrine
changes of perimenopause, cyclic or
daily oral micronized progesterone in
doses of 300 to 400 mg at bedtime
appears to help with heavy flow, hot
flushes, breast tenderness, and sleep
(J.C.P., unpublished data, 2001).
Menorrhagia, irregular bleeding
Vitamin A for Uterine Bleeding – More than Just Fibroids !!!
53) Lithgow, DM* & Politzer, WM. “Vitamin A in the treatment of menorrhagia.” South African Medical Journal 51.7 (1977): 191-193.
Hypovitaminosis A was found to be an important cause of menorrhagia, and a statistically significant difference between
the fasting serum vitamin A values of healthy controls and patients with menorrhagia was noted. Vitamin A is a co-factor of 3,B-dehydrogenase in steroidogenesis and deficiencies of this vitamin may result in impaired enzyme activiiy. The level of endogenous 17Beta-oestradiol appears to be elevated with vitamin A therapy, and menorrhagia was alleviated in more than 92% of patients.
Table 11 details the causes of menorrhagia in 174 patients. Vitamin A deficiency appeared to be the major aetiological factor in 43,68% of these women. The aetiology was unknown in 17,24%. A number of patients (11,49%) had previously been subjected to sterilization. Pyridoxine (vitamin B.) deficiency was found in 9,77% and was diagnosed clinically’··11 and subsequently biochemically.” Eight
patients with both vitamin B. and vitamin A deficiency were classified as vitamin A-deficient. The causative factors most frequently observed were deficient diet, malabsorption, recent infections, overexposure to sunlight” and excessive intake of alcohol.”
The rise in 17,Beta-oestradiol following vitamin A therapy (Table Ill) is significant, since graphs of the menstrual cycle indicate an association in the peaks of 17f3 -oestradiol and vitamin A.”,’4 Should vitamin A fail to raise oestradiol levels or alleviate menorrhagia, then checks for hypoproteinaemia, vitamin E (which improves vitamin A storage and utilization)” and zinc (required to mobilize hepatic vitamin A)'” are indicated.
Vitamin A (retinol) deficiency decreaes estrogen production
Uterine Bleeding Rx:
MK7 Vitamin K
Vitamin A (retinol) 25,000 iu BID
or 100000 IU vitamin A per day for 15 day.
Vitamin E
Zinc
54) Rossouw, Jacques E., et al. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial.” Jama 288.3 (2002): 321-333.
55) Schairer, Catherine, et al. “Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.” Jama 283.4 (2000): 485-491.
56) Ross, Ronald K., et al. “Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.” Journal of the National Cancer Institute 92.4 (2000): 328-332.
57) Olsson, Håkan L., Christian Ingvar, and Anna Bladström. “Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden.” Cancer: Interdisciplinary International Journal of the American Cancer Society 97.6 (2003): 1387-1392.
Dysfunctional Uterine Bleeding DUB
58) Maness, David L., et al. “How best to manage dysfunctional uterine bleeding.” Journal of Family Practice 59.8 (2010).
59) Leal, Caio RV, et al. “Abnormal uterine bleeding: The well-known and the hidden face.” Journal of endometriosis and uterine disorders (2024): 100071.
60) 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.
61) Jain, Varsha, et al. “Uterine bleeding: how understanding endometrial physiology underpins menstrual health.” Nature reviews endocrinology 18.5 (2022): 290-308.
62) 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.
Myo-Inositol
63) 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.
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Progesterone Hypersensitivity
64) Azadi, Negar, et al. “Effect of progesterone administration on tissue mast cell population and histamine content in mice uterus after ovulation induction.” JBRA Assisted Reproduction 27.3 (2023): 436.
65) Uchida, Hitoshi, et al. “Neurosteroid-induced hyperalgesia through a histamine release is inhibited by progesterone and p, p′-DDE, an endocrine disrupting chemical.” Neurochemistry international 42.5 (2003): 401-407.
66) Mittman, Robert J., et al. “Progesterone-responsive urticaria and eosinophilia.” Journal of allergy and clinical immunology 84.3 (1989): 304-310.
67) Vliagoftis, Harissis, Violetta Dimitriadou, and Theoharis C. Theoharides. “Progesterone triggers selective mast cell secretion of 5-hydroxytryptamine.” International Archives of Allergy and Immunology 93.2-3 (1990): 113-119.
68) Jo, Eun-Jung, Seung-Eun Lee, and Hye-Kyung Park. “Clinical characteristics of exogenous progestogen hypersensitivity.” Asian Pacific Journal of Allergy and Immunology 37.3 (2019): 183-187.
Results: Nine patients had exogenous PH. Six patients were treated with progesterone for threatened abortion, and three for ARTs. Their mean age was 33.6 years, and their mean body mass index was 26.3 kg/m2. They had never experienced an adverse drug reaction. The mean latency to symptom onset was 5.8 days (range 1 h to 11 days). The patients complained of
hives, erythema and itching, and one developed anaphylaxis. All patients were treated with antihistamines, and six patients were treated with systemic corticosteroids. Epinephrine was administered to one patient with hypotension. The symptom duration was 1-14 days. Skin tests were performed in four patients; all were positive. Two patients were treated successfully by progesterone desensitization.
Conclusions: The clinical features of exogenous PH were similar to those of type I hypersensitivity reactions, but tended to develop later and did not respond to antihistamines or steroids. As use of progesterone increases, an understanding of the
clinical features of exogenous PH becomes ever-more important
69) Sandru, Florica, et al. “Progesterone Hypersensitivity in Assisted Reproductive Technologies: Implications for Safety and Efficacy.” Journal of Personalized Medicine 14.1 (2024): 79.
70) Sashidhar, Nivedita, Venkataram Mysore, and G. V. Thejavathy. “Exogenous Progestogen Hypersensitivity and its Increasing Association with Assisted Reproductive Techniques (ART)/in vitro Fertilization (IVF).” Indian Dermatology Online Journal 15.1 (2024): 24-32.
71) Jensen, Federico, et al. “Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation.” PloS one 5.12 (2010): e14409.
72) Bernstein, I. Leonard, et al. “A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis.” Journal of Women’s Health 20.4 (2011): 643-648.
Progesterone ALS
73) Deniselle, Maria Claudia Gonzalez, et al. “Basis of progesterone protection in spinal cord neurodegeneration.” The Journal of steroid biochemistry and molecular biology 83.1-5 (2002): 199-209.
74)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322133/
Kolatorova, Lucie, et al. “Progesterone: a steroid with wide range of effects in physiology as well as human medicine.” International Journal of Molecular Sciences 23.14 (2022): 7989.
Amyotrophic lateral sclerosis is a motor neuron disease and, after Alzheimer’s disease and Parkinson’s disease, is the third most common neurodegenerative disorder. PROG has been implicated in various neuroprotective properties, of which longevity [236], muscle strength [237], cell health [238], lowered oxidative stress in the spinal cord, and nitric oxide [236,239] are the most relevant. It has been shown to increase brain-derived neurotrophic factor [237] and normalizes mRNA levels in components of the sodium-potassium pump, which is important for cell nutrition and neurotransmission and is also crucial for mitochondrial health [239]. Moreover, PROG was observed to inhibit the activity of astrocytes, which have predominately deleterious effects in the context of amyotrophic lateral sclerosis because they correspond to increased inflammation. PROG also protects against glutamate excitotoxicity in vitro, one of the major sources of pathology in amyotrophic lateral sclerosis [40]. Synthetic 19-norprogesterone derivatives may also play a role in attenuating motoneuron degeneration and thus have potential in amyotrophic lateral sclerosis treatment [218].
75) De Nicola, Alejandro F., et al. “Progesterone and allopregnanolone neuroprotective effects in the wobbler mouse model of amyotrophic lateral sclerosis.” Cellular and Molecular Neurobiology 42.1 (2022): 23-40.
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************** Anti-Inflammatory Drug ******************************
https://www.mdpi.com/2218-273X/12/9/1299/pdf
76) Fedotcheva, Tatiana A., Nadezhda I. Fedotcheva, and Nikolai L. Shimanovsky. “Progesterone as an anti-inflammatory drug and immunomodulator: new aspects in hormonal regulation of the inflammation.” Biomolecules 12.9 (2022): 1299.
77) Al‐Kuraishy, Hayder M., et al. “New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects.” Immunity, Inflammation and Disease 11.11 (2023): e1100.
P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ‐aminobutyric acid (GABAA) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID‐19 patients. Conclusion: Taken together, the anti‐inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID‐19.\
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11122352/
78) Balan, Irina, et al. “Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders.” Life 14.5 (2024): 582.
Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for th erapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.
Neuroactive steroids are synthesized within both endocrine glands and the brain. In the brain, neurons are the primary producers of neurosteroids [14,15,16,17,18,19,20]. Neuroactive steroids, synthesized from cholesterol, can be classified into three categories: pregnane, androstane, and sulfated neuroactive steroids.
Pregnanes, including allopregnanolone, pregnanolone, and 3α,5α-THDOC, act as positive modulators of GABAA receptor subtypes. These compounds enhance inhibitory neurotransmission mediated by GABAA receptors, leading to anxiolysis, sedation, anti-convulsant activity, and the enhancement of inhibitory circuits in the brain [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Importantly, their anti-inflammatory actions are distinct from their GABAergic mechanisms [36,37,38].
Preclinical and clinical studies have highlighted reduced levels of pregnane neuroactive steroids, such as pregnenolone and allopregnanolone, in conditions like stress, depression, post-traumatic stress disorder (PTSD), and alcohol use disorder (AUD)
Allopregnanolone and its precursors, pregnenolone and progesterone, have shown promise in animal models of AUD, chronic stress-induced depression, traumatic brain injury (TBI), multiple sclerosis (MS), and Alzheimer’s disease (AD)
In clinical studies, progesterone has demonstrated efficacy in TBI and cocaine craving, while pregnenolone has shown benefits in alcohol and cannabis use disorders, and allopregnanolone has been effective in treating postpartum depression (PPD)
Clinical observations further support the therapeutic potential of compounds like brexanolone, a Food and Drug Administration (FDA)-approved intravenous formulation of allopregnanolone, in conditions such as PPD, attributed to their inhibition of TLR inflammatory pathways
pregnane neuroactive steroids, possess anti-inflammatory properties that operate independently of their effects on GABAA receptors. This suggests potential mitigation of excessive TLR signaling and the related inflammatory and neuroinflammatory conditions.
79) Pinna, Graziano. “Allopregnanolone, the neuromodulator turned therapeutic agent: thank you, next?.” Frontiers in endocrinology 11 (2020): 236.
Collectively, these and many more observations in the field by many talented neurosteroid scientists, led to clinical trials that demonstrated the efficacy of intravenous allopregnanolone in postpartum depression (40, 41). Given the remarkable pharmacological efficacy of this novel therapeutic, on March
19th, 2019, the FDA approved intravenous allopregnanolone (i.e., brexanolone) as the first specific treatment for postpartum depression (Figure 1)
Pharmacological treatments, including finasteride and oral contraceptives, that inhibit 5a-RI, which results in a blood and brain allopregnanolone decrease also affect subunit expression of GABAA receptor and are associated with mood symptoms and suicide and are part of postfinasteride syndrome (57, 58). Post-finasteride syndrome, in addition to depression, anxiety and cognitive
deficits also induces sexually-related side effects, such as loss of libido, erectile dysfunction, decreased arousal and difficulty in achieving an orgasm that persist despite drug withdrawal
(58).
Brexanolone is superior to traditional antidepressants in the treatment of mood disorders
Following this concept, brexanolone, a b-cyclodextrinbased parenterally-administered soluble formulation of allopregnanolone, was developed and FDA-approved for treating post-partum depression. In an open-label study, a single brexanolone IV administration showed rapid and
long-lasting antidepressant effects in severe post-partum depression (40).
https://www.researchgate.net/publication/370588123_Role_of_PPAR-allopregnanolone_signaling_in_behavioral_and_inflammatory_gut-brain_axis_communications
pdf
80) Pinna, Graziano. “Role of PPAR-allopregnanolone signaling in behavioral and inflammatory gut-brain axis communications.” Biological Psychiatry 94.8 (2023): 609-618.
Both PPAR-α and allopregnanolone are abundantly expressed in the colon and they exert potent anti-inflammatory actions by blocking toll-like receptor-4-NFkB pathway in peripheral immune cells, neurons, and glia. The perspective that PPAR-α regulation in the colon by gut microbiota or metabolites influences central allopregnanolone content after trafficking to the brain -thereby serving as a mediator of gut-brain axis communications- is examined.
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81) Parks, Eileen E., et al. “Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.” Journal of Lipid Research 61.10 (2020): 1308-1319.
Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.
!!!!!!!!!!!!!!!!!!!!!!!!!! Anti Cancer effects
https://www.mdpi.com/1422-0067/24/1/560/pdf
82) Zamora-Sánchez, Carmen J., and Ignacio Camacho-Arroyo. “Allopregnanolone: Metabolism, Mechanisms of Action, and Its Role in Cancer.” International Journal of Molecular Sciences 24.1 (2022): 560.
Recently the study of 3-Alpha-THP [Allopregnanolone] has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer,
such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we
explore current knowledge on the metabolism and mechanisms of action of 3 -THP in normal and
tumor cells.
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Progesterone Pre-operatively Protects
https://pubmed.ncbi.nlm.nih.gov/2571865/
83) 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.
84) 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.
https://www.sciencedirect.com/science/article/abs/pii/014067369192927T
85) 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.
https://pubmed.ncbi.nlm.nih.gov/8018400/
86) 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.
87) https://www.academia.edu/download/89170085/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).
88) 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.
89) 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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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353890/
90) 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482703/
91) 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 …
92) 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
93) 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/
94) 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
95) 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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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540053/
96) Fedotcheva, Tatiana A., Nadezhda I. Fedotcheva, and Nikolai L. Shimanovsky. “Progestins as anticancer drugs and chemosensitizers, new targets and applications.” Pharmaceutics 13.10 (2021): 1616.
97) 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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