In the first part of this article, the different roles of natural progesterone with regard to the brain, thyroid gland, bone health, and heart health were discussed. This overview continues with the main role of this incredible hormone in this second part.

Progesterone and the breasts

With the near-epidemic increase in breast cancer, if there is one tissue that women are most worried about, it would be the breast tissue! Everything that protects it automatically takes on a highly precious aura! You will not be surprised to learn that natural progesterone supports the health of this tissue.

Progesterone prevents the excessive proliferation of cells in the breast tissue. Indeed, estrogen stimulation not compensated by progesterone promotes breast diseases including cyst formation, the swelling that is accompanied by the menstrual cycle, and cancer. According to the results of a meta-analysis of 86,881 postmenopausal women, the use of natural progesterone is reported to be associated with a significantly lower risk of breast cancer compared to synthetic progestins. Lack of ovulation and low serum progesterone levels have been associated with a significantly higher risk of breast cancer in premenopausal women. The use of natural progesterone is also linked to lower rates of uterine and colon cancers and may also be useful in the treatment of other cancers such as ovarian, melanoma, mesothelioma, prostate, and thyroid. (19-22)

In addition, a deficiency in progesterone would contribute to increasing the number of tumor growth factor receptors and would represent a risk factor linked to breast cancer. (23) We also know that natural progesterone downregulates the formation of metalloproteinases; enzymes required by cancer cells to enhance their invasive capacity. (24-26)

The majority of breast cancers contain both estrogen and progesterone receptors (called ER-positive/PR-positive tumors or hormone-dependent cancers). This type of cancer gets better outcomes from treatment. What are estrogen and progesterone receptors and what exactly do they do? It was a scientific team affiliated with the UK Cancer Research along with the University of Adelaide in Australia that shed light on this major point. (27)

Hormone receptors are transcription factors, meaning they are both involved in turning genes on and off in cells. They represent the mechanism that allows estrogen and progesterone to modify the behavior of our cells. Breast cancer cells have an increased sensitivity to estrogen. Once estrogen binds to its receptor on the cell surface, it activates and enters the cell into the nucleus, where it binds to specific regions of DNA. This binding activates the transcription of a group of genes (including Bcl-2) that promote cellular division and therefore, potentially, tumor growth, but also deactivates other genes involved, among others, in cellular death. This reprogramming is central to the tumor process and its treatment with hormone modulators such as Tamoxifen, Femara, Arimidex, and Zoladex.

The progesterone receptors have, on their side, an astonishing action. When activated by this hormone, they bind directly to estrogen receptors and inhibit the activation of genes that promote cellular growth in addition to activating genes (including p53) that promote cancer cell death (apoptosis) and the growth of healthy, normal cells! (28) The researchers found that the estrogen receptor binds to different regions of DNA depending on whether or not progesterone is present, and concluded that the involvement of progesterone was crucial to ensure a safe environment.

This same observation was observed in mice expressing hormone-dependent cancer. The research team found that tumors in mice that received estrogen alone grew, compared with a decrease in size in tumors in mice that received both estrogen and progesterone. From there came the idea of ​​exposing the tumors to a combination of Tamoxifen and natural progesterone, and noticed a marked decrease in tumor growth compared to tumors treated only with Tamoxifen. (29)

Progesterone does two things. First, it can prevent healthy breast tissue cells from mutating into tumors. Second, it can limit the growth of existing breast tumors or even reduce them in size. These benefits are exclusively related to natural progesterone and not synthetic progestins which increase, rather than reduce, the risk of breast cancer. Thus, it can be concluded that if women have healthy progesterone levels, through natural progesterone supplementation, they could significantly improve their treatment outcomes.

Progesterone and the reproductive system

Progesterone acts strongly on the uterus: it allows the establishment of an environment favorable to reproduction. Its contribution to fertility is well documented and pregnancy cannot be foreseen in the absence of this hormone. It is also used regularly in assisted reproduction centers. The most compelling evidence confirming the difference between progestins and natural progesterone is that progesterone is frequently prescribed to maintain pregnancy and reduce the risk of miscarriage, whereas progestins are, in their case, absolutely contraindicated because they interfere with fertilization by thickening the cervical mucus, which is more dangerous for the fetus! (30, 31) Despite these differences in action, many doctors and researchers continue to believe that progesterone and artificial progestins are synonymous!

The more a woman advances in her thirties and forties, the more she feels the hormonal fluctuations which are characterized by a decrease in the ovulatory cycles and consequently of progesterone. A condition called luteal insufficiency is frequently encountered in pre-menopause. It means that the corpus luteum does not produce enough progesterone, despite normal ovulation. It is also possible to have anovulatory cycles due to the lack of development of the corpus luteum, where the egg is lodged. This is without the exclusion of women who use birth control pills, as they do not enjoy the benefits of progesterone throughout their contraception.

What is a progesterone deficiency like? This would be estrogen dominance. We owe this concept to Dr. John Lee. He was the first to mention that during peri-menopause, despite a drop in the overall production of hormones, the body remained, in the majority of cases, under an estrogenic rule caused by a marked decrease in progesterone. Dominance represents this gap. According to this doctor, this situation is detrimental since the main role of progesterone is to watch over the proliferative nature of estrogen. No wonder many of the symptoms that accompany progesterone deficiency are identical to those caused by excess estrogen. This does not mean that estrogens are dangerous in nature, but that their balance is synonymous with safety! Shorter cycles, heavy bleeding with clots, uterine fibroids, premenstrual syndrome, irritability, anxiety, insomnia, musculoskeletal and menstrual pain, heart palpitations, increased breast tenderness, constipation, bloating, abdominal distension and others are signs that appear with an increased need for progesterone.

Atypical endometrial hyperplasia is a precancerous condition that consists of excessive proliferation of abnormal cells. If left untreated, the risk of developing uterine cancer increases. Having anovulatory cycles represents a determining factor of this condition since it leaves estrogens unopposed. Treatment options include (what a surprise!) progesterone. (32)

I briefly mentioned the protective role of progesterone on endometrial (uterine) cancer. This cancer is the most frequent among cancers within the gynecological sphere. Early detection greatly facilitates treatment and ensures remission in 95% of cases. If the causes of cancer are always multifactorial, we note, all the same, that in 80% of cases estrogen dominance is apparent. (33) Indeed, its incidence is strongly associated with prolonged estrogenic action without being neutralized by progesterone. Since a high level of the latter interferes with the number of estrogen receptors and consequently opposes the cellular growth induced by estrogen, progesterone represents the main tumor suppressor of the endometrium. (33,34) Among the other risk factors, apart from genetic predisposition, we find overweight, arterial hypertension, and atypical hyperplasia, which are conditions sensitive to the action of progesterone!

Hormonal balance in a world saturated with endocrine disruptors

It is increasingly accepted that there is a direct link between environmental quality and hormonal balance. Certain molecules that we encounter every day have the ability to mimic our hormones by binding to their specific receptors. This phenomenon leads to a cascade of metabolic disorders and unpredictable consequences on our cells and on our entire organism. These usurping substances to which we are exposed bear the common name of endocrine disruptors or xenobiotics.

As defined by the European Union in 2002, endocrine disruptors are “substances which, by interfering with the functions of the hormonal system, risk negatively influencing the processes of synthesis, secretion, transport, action or elimination of hormones”. These molecules are suspected of being involved in the majority of cancers, infertility, allergies, autoimmune diseases, birth defects, increasing bacterial resistance to antibiotics, and others. (35) According to the European Commission, 99% of the more than 100,000 chemicals introduced into the environment over the past 70 years are still today under-regulated and therefore difficult to control. These endocrinotoxic saboteurs are all around us; in water and food, plastics, paints, furniture, detergents, textiles, and medicines, in addition to being concentrated in personal hygiene products and cosmetics.

A large majority of these disruptors mimic estrogen by interacting with the receptors for this hormone, which induces a direct action on estrogen-sensitive genes. Breasts, endometrium, brain, genitals, adipose tissue, and liver unfortunately represent target organs for these toxic molecules. Since they are chemically and clinically active, and we understand how much they can contribute to hormonal imbalance and accentuate estrogen dominance. There is definitely something to be concerned about! In a context so favorable to estrogens, progesterone is essential because of its protective and highly essential effects!

Progesterone plays an important role at all ages of a woman’s life and this remains true even during menopause. The fact that progesterone receptors are found far beyond the boundaries of reproductive tissues allows us to consider the important contribution of this hormone to overall health. The hormone of temperance and benevolence, it accurately contains the excesses of its sister, estrogen, while completing its essential functions. This partnership is essential to achieve the coveted hormonal balance. The estrogen dominance that characterizes hormonal instability in many women accentuates the risk factors for many conditions, impacting cognitive faculties, bone capital, breast health, and the cardiovascular profile, to name a few. Unfortunately, too many doctors have been trained to believe that synthetic progestins are actually progesterone and produce similar effects. This confusion is fed by quantities of publications that lack rigor only in the terminology used. It is high time to separate the information so that natural progesterone finally overcomes the weight of the disadvantages linked, for the most part, exclusively to synthetic progestins.

Article initially published in Vitalité Québec, February 2021

Véronique Bourbeau, Certified Naturopath

www.cliniqueintegrative.com

 

 

References:

 

  1. Juan Carlos González-Orozco, Ignacio Camacho-Arroyo. Progesterone Actions During Central Nervous System Development. Front Neurosci. 2019; 13: 503
  2. Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”. Psychoneuroendocrinology. 34 Suppl 1: S143-61.
  3. Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”. Mini Reviews in Medicinal Chemistry. 12 (11): 1040–8. 
  4. Murray B. Herda, Delia Belellia and Jeremy J. Lambert, Neurosteroid modulation of synaptic and extrasynaptic GABA-A receptors,  Ther., Volume 116, Issue 1, October 2007, Pages 20-34.
  5. Rubinow D. R., P. J. Schmidt, Roca C. A., Hormonal and gender influences on mood regulation, Neuropsychopharmacology: The Fifth Generation of Progress, Chapter 80: Hormonal and Gender Influences on Mood Regulation, Pages 1165-1178.
  6. “FDA approves first treatment for post-partum depression”. U.S. Food and Drug Administration(FDA) (Press release). 19 March 2019. Archived from the original on 11 October 2019. Retrieved 21 March 2019.
  7. Frieder A, Fersh M, Hainline R, Deligiannidis KM (March 2019). “Pharmacotherapy of Postpartum Depression: Current Approaches and Novel Drug Development”. CNS Drugs. 33 (3): 265–282.
  8. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. (2010). Allopregnanolone reverses neuron and cognitive deficits in a mouse model of Alzheimer’s disease.[archive] Proc Natl Acad Sci U S A. 107:6498–6503.
  9. Muye Zhy Roberta Brinton. How Progestin, a Synthetic Female Hormone, Could Affect the Brain. HEALTHJOURNAL.JANUARY 14, 2012
  10. Farshid Noorbakhsh, Kristofor K. Ellestad, Ferdinand Maingat, Kenneth G. Warren, May H. Han, Lawrence Steinman, Glen B. Baker, Christopher Power. Impaired neurosteroid synthesis in multiple sclerosis. Brain, Volume 134, Issue 9, September 2011, Pages 2703–2721.
  11. P Sathi 1, S Kalyan, C L Hitchcock, M Pudek, J C Prior. Progesterone therapy increases free thyroxine levels–data from a randomized placebo-controlled 12-week hot flush trial. Clin Endocrinol (Oxf) . 2013 Aug;79(2):282-7.
  12. Estrogen and progesterone: two important hormones, TaylorMedicalGroup.net https://taylormedicalgroup.net/hormones/estrogen-and-progesterone
  13. J C Prior Progesterone as a bone-trophic hormone. Endocr Rev,1990 May;11(2):386-98.
  14. R Kent Hermsmeyer, Theresa L Thompson et al. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity? Nat Clin Pract Cardiovasc Med. 2008 Jul;5(7):387-95.
  15. Stephenson K et al. Topical Progesterone Cream Does Not Increase Thrombotic and Inflammatory Factors in Postmenopausal Women. Blood Journal, Nov 16, 2004
  16. Kenna Stephenson, Pierre F Neuenschwander, Anna K Kurdowska. The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Int J Pharm Compd. Jan-Feb 2013;17(1):74-85.
  17. https://www.health.harvard.edu/heart-health/fluid-retention-what-it-can-mean-for-your-heart
  18. Yifan Jiang, Weijie Tian. The effects of progesterones on blood lipids in hormone replacement therapy. Lipids Health Dis. 2017; 16: 219.
  19. Allan Lieberman, Luke Curtis. In Defense of Progesterone: A Review of the Literature. Altern Ther Health Med. 2017 Nov;23(6):24-32.
  20. Noor Asi, Khaled Mohammed et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016 Jul 26;5(1):121.
  21. Carlo Campagnoli, Françoise Clavel-Chapelon et al. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
  22. Yavropoulou MP, Panagiotou G, Topouridou K, et al. Vitamin D receptor and progesterone receptor protein and gene expression in papillary thyroid carcinomas: associations with histological features. Journal of Endocrinological Investigation2017 Dec;40(12):1327-1335.
  23. Sylvie Demers. Hormones au féminin, Éditions de l’Homme, 2009.
  24. Lydia Nakopoulou, Ioanna Giannopoulou et al. Matrix metalloproteinase-1 and -3 in breast cancer: Correlation with progesterone receptors and other clinicopathologic features. Human Pathology, Volume 30, Issue 4, April 1999, Pages 436-442.
  25. Lisa ADi Nezza, TomJobling, Lois ASalamonsen Progestin suppresses matrix metalloproteinase production in endometrial cancer. Gynecologic Oncology, Volume 89, Issue 2, May 2003, Pages 325-333.
  26. Shlomit Goldman,Eliezer Shalev. Difference in Progesterone-Receptor Isoforms Ratio Between Early and Late First-Trimester Human Trophoblast Is Associated with Differential Cell Invasion and Matrix Metalloproteinase 2 Expression. Biology of Reproduction, Volume 74, Issue 1, 1 January 2006, Pages 13–22.
  27. Mohammed, Hisham, et al “Progesterone receptor modulates ER-a action in breast cancer,” Nature 2015; 523; 313-317.
  28. Perks, Bea “Progesterone receptor could slow breast cancer growth,” Pharmaceutical Journal, PJ 17 Jul 2015.
  29. Kroon, New Research Shows Natural Progesterone Can Help Treat Breast Cancer. The ZRT laboratory blog, décember 11, 2015
  30. Suzan L. Carmichael, Gary M. Shaw et al. Maternal Progestin Intake and Risk of Hypospadias. Arch Pediatr Adolesc Med. 2005;159(10):957-962.
  31. https://www.drugs.com/pregnancy/medroxyprogesterone.html#:~:text=Medroxyprogesterone%20Pregnancy%20Warnings,masculinization%20of%20the%20female%20fetus.
  32. https://www.cancer.ca/fr-ca/cancer-information/cancer-type/uterine/uterine-cancer/?region=mb
  33. Shujie Yang, Kristina W. Thiel, Kimberly K. Leslie. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab. 2011 Apr; 22(4): 145–152.
  34. Julie Kim, Eloise Chapman-Davis, Role of Progesterone in Endometrial Cancer. Semin Reprod Med. 2010 Jan; 28(1): 81–90.
  35. https://www.inserm.fr/information-en-sante/dossiers-information/perturbateurs-endocriniens