Unrecoverable downregulation of progesterone receptors by progestins as an etiological factor in the development of polycystic ovarian syndrome

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Unrecoverable downregulation of progesterone receptors by progestins as an etiological factor in the development of polycystic ovarian syndrome

Authors:

Dmitri I. Dozortsev, MD, PhDac, Michael P. Diamond, MDb

aAdvanced Fertility Center of Texas, Houston, Texas

bDepartment of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia

cCITMER Medicina Reproductiva, Mexico City, Mexico

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In a recent publication we reconciled the ability of progesterone to trigger ovulation at the end of the follicular phase while preventing gonadotropins surge at other times throughout the ovarian cycle. We postulated that progesterone is a hypothalamic GnRH agonist and a true physiological trigger of ovulation in the human (1). Similar to GnRH receptor agonists, its continued administration depletes anterior pituitary LH and FSH, preventing their surge as well as consequent ovulation. This profound change in the generally recognized and accepted ovulation paradigm has many implications for diverse facets of female reproductive physiology and pathology. In particular, it became a basis for our hypothesis that the leading etiological cause of idiopathic Polycystic Ovarian Syndrome (PCOS) is desensitization of hypothalamic progesterone receptors by excessive amounts of progesterone produced by a supra-physiological number of follicles in otherwise highly fertile females (2). In the current article we demonstrate how progesterone receptors desensitization by progestins, the main active component of birth control formulations, may be responsible for development of PCOS. 

Anecdotal evidence linking cessation of birth control pills (BCP) with the development of PCOS is common. However, a causative link between progestins and PCOS has not been investigated, in part perhaps because the typical patient is seen for PCOS years after beginning a birth control regimen, making it likely to presume that PCOS was present before starting the BCPs. Therefore, if a patient develops a PCOS phenotype following the cessation of a BCP regimen, it is commonly assumed that use of the pills was masking the pre-existing disease, with cessation allowing PCOS to physically manifest.

The defining central feature of PCOS is a woman’s impaired ability to ovulate. Ovulation failure alone is sufficient to produce elevation of testosterone as long as ovarian follicles are present (3). Even short-term ovulation delay using a moderate dose of progesterone in cows results in persisting follicles, that begin producing testosterone at levels inappropriate for that stage of the bovine cycle (3). However, women do not develop PCOS when ovulation is disrupted by pregnancy or lactation. This is likely because circulating progesterone (or prolactin) is so high that it suppresses FSH and LH to levels where follicular recruitment and development become inefficient. Without the new follicles, and with suppressed LH, testosterone production and its level is bound to remain low.

Progesterone receptors belong to the group of G-protein coupled receptors. This type of receptor is well known to be vulnerable to desensitization. A common example of such desensitization occurs in dopamine receptors which also belong to this group. After prolonged exposure to highly active opioids, these receptors become desensitized, with the result that they no longer respond to physiological levels of endogenous opioids. Further, in some individuals with a genetic and/or epigenetic predisposition, this desensitization cannot be fully reversed even after a complete and prolonged withdrawal. Furthermore, some synthetic dopamine agonists have been shown to cause irreversible downregulation of receptors after a mere one hour exposure (4).  

During pregnancy, progesterone levels remains continuously elevated at around 200 ng/ml.  At such a level, progesterone desensitizes hypothalamic progesterone receptors so that they are unable to respond to the physiological ovulation triggering level of progesterone, which is under 1 ng/ml (1). Variation in the duration of time to resume normal cyclicity after pregnancy can be explained by individual variability in the recovery of the progesterone receptors sensitivity.  

Since BCP activity targets the progesterone level seen during pregnancy, it would be expected that it may also take a couple of months to restore a normal menstrual cycle after pill cessation; this is what in fact happens in the majority of females. Yet, all progestins have higher affinity to progesterone receptors than progesterone, with some being thousands of times more active (1). Although their amount is usually adjusted to mimic physiological level of progesterone activity of an average female during pregnancy, it does not consider personal individual characteristics including weight, rate of metabolism, endogenic progesterone levels, or genetic traits.  Furthermore, unlike during pregnancy, birth control pills are often taken for several years. Collectively, these create the possibility that in predisposed patients, deeply desensitized P4 receptors are unable to recover sensitivity to the physiological ovulation triggering level of progesterone following cessation of birth control pills. In such a scenario, ovulation would fail, while follicular recruitment continue since the baseline FSH level is not affected. The accumulating stagnated ovarian follicles (historically incorrectly referred to as cysts), as we discussed earlier, endocrinologically contributes with production of testosterone, thus leading to manifesting PCOS. Thus, according to our hypothesis, secondary PCOS develops while on BCP, but PCOS manifestations will not be apparent as long as the patient keeps taking the pills.  

It is important to mention that once established, over time PCOS’s, irrespective of how it was initially triggered, extend beyond the ovaries (5), which we propose to refer to as secondary PCOS. This is likely a consequence of chronically elevated LH which has been shown to induce excessive number of its own receptors in the adrenal gland and fat tissues that become the secondary source of abnormally high androgen production in these women (5). It has in fact been shown that excess fat tissues predisposes females (but not males) to elevated testosterone levels (6). Although elevated, even in severe PCOS, testosterone remains below the threshold of 200 ng/dL where it would be expected to downregulate gonadotropin production.

At this time, this proposed association between PCOS and BCP is clearly speculative. Furthermore, one could argue if one exists, it would already appear in epidemiological studies, which is not the case (7,8). Yet, if less than 1 in 10 patients develop pathological response, it would not be detectable by current epidemiological observations, particularly given large geographical disparity in diagnostic criteria, differences in progestin formulations, and variations in reporting methods. Thus, current observations can neither disprove, nor support our hypothesis.

Fortunately, it can be tested prospectively by, for example, recruiting healthy females starting BCP regimens and following them up for several years until they stop the pills. If this phase of the trial demonstrates the non-random increase in PCOS, those patients who developed the syndrome would be offered genetic testing to determine whether they share a variation of the progesterone receptor gene that could explain why they became affected. 

In summary, we hypothesize that desensitization of progesterone receptors in the hypothalamus by progestins is responsible for inducing PCOS in some predisposed patients. Once developed, it leads to the failure of ovulation, while FSH and LH remain sufficiently high, causing continued recruitment of new follicles, with multisystem manifestations of PCOS to follow. This hypothesis, while incorporating all known associations of PCOS, such as high AMH, genetic predisposition, obesity, abnormal ovarian cycle etc. (2), provides for a specific etiology of this syndrome, moving it a step closer to becoming classified as a disease. Thus, BCP induced PCOS may be real, and warrants additional in vitro studies and clinical investigation.  

References

  1. Dozortsev DI, Diamond MP. Luteinizing hormone-independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human. Fertil Steril. 2020 Aug;114(2):191-199. Fertil Steril, 2020 
  2. Dozortsev DI, Pellicer A, Diamond MP. Premature progesterone rise as a trigger of polycystic ovarian syndrome. Fertil Steril. 2020 Nov;114(5):943-944
  3. Díaz PU, Stangaferro ML, Gareis NC, Silvia WJ, Matiller V, Salvetti NR, Rey F, Barberis F, Cattaneo L, Ortega HH. Characterization of persistent follicles induced by prolonged treatment with progesterone in dairy cows: an experimental model for the study of ovarian follicular cysts. Theriogenology. 2015 Oct 15;84(7):1149-60. doi: 10.1016/j.theriogenology.2015.06.015. Epub 2015 Jun 27. PMID: 26187329.
  4. Lin CW, Bianchi BR, Miller TR, Stashko MA, Wang SS, Curzon P, Bednarz L, Asin KE, Britton DR. Persistent activation of the dopamine D1 receptor contributes to prolonged receptor desensitization: studies with A-77636. J Pharmacol Exp Ther. 1996 Mar;276(3):1022-9. PMID: 8786531.
  5. Azziz R, Chang WY, Stanczyk FZ, Woods K. Effect of bilateral oophorectomy on adrenocortical function in women with polycystic ovary syndrome. Fertil Steril. 2013 Feb;99(2):599-604. doi: 10.1016/j.fertnstert.2012.10.016. Epub 2012 Oct 31. PMID: 23122827; PMCID: PMC3563739.
  6. Pasquali R. Obesity and androgens: facts and perspectives. Fertil Steril. 2006 May;85(5):1319-40. doi: 10.1016/j.fertnstert.2005.10.054. PMID: 16647374.
  7. Jingjing Liu, Qunhong Wu, Yanhua Hao, Mingli Jiao, Xing Wang, Shengchao Jiang, Liyuan Han, Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017, Human Reproduction, Volume 36, Issue 4, April 2021, Pages 1108–1119
  8. UNITED NATIONS DEPARTMENT FOR ECONOMIC AND SOCIAL AFFAIRS. Family Planning and the 2030 Agenda for Sustainable Development (data Booklet). UN, 2019.