Polycystic Ovary Syndrome

Polycystic Ovary Syndrome/Disease is often talked about, because it is common among females, but what is it? What causes it? What is happening to the body? In this article, we will investigate and answer all of these questions.

What is Polycystic Ovary Syndrome?

Polycystic Ovary Syndrome (PCOS) is a condition in which a woman’s ovaries over produce androgen (aka, male) hormones [1].

What are the Symptoms?

There are several, rather dramatic symptoms, including, but not limited to, loss of ovulation, fewer menstrual cycles, excess body hair relative to other females, acne, and usually cysts on the ovaries (more on this later) [1][5].

Causes of PCOS?

PCOS is largely genetic – so, if women in your family have PCOS, there is a heightened chance you will have it [2]. However, the severity of PCOS is strongly inversely impacted by environmental factors, like nutrition and physical activity [2].

Understanding the Pathophysiology

The ovaries produce 25-75% (depending on direct testosterone production or precursor/androgen production) of the androgens in the body, and their levels are considerably lower (~10x less) than in males [3][4]. However, with polycystic ovary syndrome, the hypothalamus of the brain overproduces gonadotropin releasing hormone (GnRH), which binds to a receptor on the pituitary gland, primarily (also located in the brain); although, the receptor is found in many peripheral tissues, as well [2][6]. This binding leads to the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) [2][6]. Follicle stimulating hormone either remains the same or is decreased, yet luteinizing hormone increases [2].

As luteinizing hormone and follicle stimulating hormone play a major role in androgen release and fertility, it is understandable they play a major role in the pathophysiology of PCOS [7].

Androgen Synthesis

Increases in luteinizing hormone binding to theca cells in the ovaries, which are closely tied to the follicles, which house the ovum (aka, immature reproductive ovary cell), and leads to increases in the production of pre-androgenic hormones like 17-hydroxyprogesterone from the adrenal glands and theca cells of the ovary [8][11]. 17-hydroxyprogesterone can be, eventually, converted to testosterone (through androstenedione production in the theca cells) or cortisol (through 11-deoxycortisol in the adrenals) [9]. However, there are many with PCOS symptoms that do not show increases in luteinizing hormone, yet still see greater levels of androstenedione, so there may be other factors – possibly increases in sensitivity through more receptors on the theca cells [7][8].

Aside from luteinizing hormone, the action of follicle stimulating hormone on granulosa cells (aka, follicular related cells) can also play a role [8]. There is evidence that follicle stimulating hormone is especially potent in PCOS, as women with PCOS may exhibit heightened sensitivity to the hormone [8]. Granulosa cells seem to exhibit more receptors, so greater binding of follicle stimulating hormone, leading to more estrogen or progesterone release (depending on the menstrual cycle phase), but also the release of another protein named inhibin [8][10][13]. Inhibin is supposed to inhibit follicle stimulating hormone release from the pituitary gland, and while it may do so, the combination of increased sensitivity (in PCOS) leading to possibly greater potency, as well as inhibin’s action on the theca cells, leading to an increased sensitivity to luteinizing hormone (and subsequent rise in androgen production), would mean there is a double action, via endocrine and paracrine communication in the further synthesis of estrogen or progesterone from the granulosa [8][10]. Progesterone can be reconverted, however, to 17-hydroxyprogesterone, in the adrenals and theca cells, and then subsequently act on theca cells to be resynthesized as androstenedione [14]. Estradiol (aka, estrogen) production, via estrogen aromatase, plays a further inhibitory role on follicle stimulating hormone (always) and luteinizing hormone (in the early follicular phase of the menstrual cycle), yet greatly stimulates luteinizing hormone (in the late follicular phase) through stimulation of the gonadotropin releasing hormone from the hypothalamus [14]. So, both progesterone production and estrogen production from the granulosa cells lead to greater androstenedione production from the theca cells, and inevitably, potentially greater testosterone production.

Androstenedione can be converted to testosterone, via the enzyme 17-beta hydroxysteroid dehydrogenase [14].

Testosterone can then be converted to dihydrotestosterone (DHT) via 5’ reductase, which can also potently act on cells [14].

Adding insult to injury, cytokines like insulin growth factor (IGF) may also be released from granulosa cells binding to theca cells, further increasing the sensitivity of theca cells to luteinizing hormone [8].

Hyperinsulinemia

Hyperinsulinemia, or excess secretion of insulin from the beta cells of the pancreas. Although it is not entirely clear why this happens in PCOS, it seems that people with PCOS have dysfunctional insulin receptors [16]. This means that when insulin binds to the receptor, the cascade that should follow, intracellularly, is blunted. If this is the primary mechanism is unclear. However, a lack of responsiveness, or insulin resistance, means the pancreas generates and secretes more insulin to compensate.

Unfortunately, insulin seems to bind to independent insulin receptors on the thecal cell (in the ovary) membrane, which further stimulates the production of androstenedione and testosterone [15]. So, a person with PCOS becomes hyperglycemic, hyperinsulinemic, and hyperandrogenic through this action alone.

Fertility

PCOS can drastically decrease one’s chance of getting pregnant, and it does so by a couple of mechanisms. The first is through the potential inhibition of follicle stimulating hormone; this does not occur in all, as PCOS is a rather heterogeneous issue and affects people differently [17]. However, since follicle stimulating hormone is a key to ovulation as it allows a follicle to begin maturing into its tertiary state (aka, gaafian follicle), decreased levels mean that less mature follicle cells are produced, decreasing the chance of oocyte release into the fallopian tubes when the follicle bursts [17][18]. Secondly, the chronically elevated luteinizing hormone levels lead to the failure to produce the corpora lutea which secrete progesterone and estrogen to propagate the pregnancy [18]. All of this is compounded by the fact that with elevated androgen release, the menstrual cycle has a lowered predictability and occurs less frequently considering the increased background “noise” of elevated luteinizing hormone leading to less pronounced, necessary “surge” that leads to ovulation (the release of the oocyte from the follicle bursting and the production of the corpora lutea.

Writer: Nicolas Verhoeven

References

[1] Pmhdev. (n.d.). Polycystic Ovary Syndrome - National Library of Medicine - PubMed Health. Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024506/

[2] Ndefo, U. A. (2013). Polycystic Ovary Syndrome: A Review of Treatment Options With a Focus on Pharmacological Approaches. Pharmacy and Therapeutics, 38(6), 336-338. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737989/

[3] Testosterone insufficiency in women: fact or fiction? » Sexual Medicine » BUMC. (n.d.). Retrieved from http://www.bumc.bu.edu/sexualmedicine/publications/testosterone-insufficiency-in-women-fact-or-fiction/

[4] Clifton, S., Macdowall, W., Copas, A. J., Tanton, C., Keevil, B. G., Lee, D. M., … Wu, F. C. (2016). Salivary Testosterone Levels and Health Status in Men and Women in the British General Population: Findings from the Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). The Journal of Clinical Endocrinology & Metabolism, 101(11), 3939-3951. doi:10.1210/jc.2016-1669

[5] Diamanti-Kandarakis, E., Kandarakis, H., & Legro, R. S. (2006). The Role of Genes and Environment in the Etiology of PCOS. Endocrine, 30(1), 19-26. doi:10.1385/endo:30:1:19

[6] Harrison, G. S. (2004). Gonadotropin-releasing hormone and its receptor in normal and malignant cells. Endocrine Related Cancer, 11(4), 725-748. doi:10.1677/erc.1.00777

[7] Balen, A. H. (1993). Hypersecretion of luteinizing hormone and the polycystic ovary syndrome. Human Reproduction, 8(suppl 2), 123-128. doi:10.1093/humrep/8.suppl_2.123

[8] Wachs, D. S., Coffler, M. S., Malcom, P. J., Shimasaki, S., & Chang, R. J. (2008). Increased Androgen Response to Follicle-Stimulating Hormone Administration in Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism, 93(5), 1827-1833. doi:10.1210/jc.2007-2664

[9] Pubchem. (n.d.). Hydroxyprogesterone. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/hydroxyprogesterone#section=Top

[10] Chada, M. (2003). Inhibin B, follicle stimulating hormone, luteinizing hormone, and estradiol and their relationship to the regulation of follicle development in girls during childhood and puberty. Physiological Research, 52(3), 341-6. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12790766

[11] Tsang, B.K., Tahéri, A., Ainsworth, L., & Downey, B.R. (1987). Secretion of 17 alpha-hydroxyprogesterone, androstenedione, and estrogens by porcine granulosa and theca interna cells in culture. Canadian journal of physiology and pharmacology, 65 9, 1951-6.

[12] Burger, H. G. (2001). Androgen production in women. Fertility and Sterility, 77(4), 3-5. Retrieved from doi.org/10.1016/S0015-0282(02)02985-0
[13] Garzo, V., & Dorrington, J. (1984). Aromatase activity in human granulosa cells during follicular development and the modulation by follicle-stimulating hormone and insulin. American Journal of Obstetrics and Gynecology, 148(5), 657-662. doi:10.1016/0002-9378(84)90769-5

[14] Rotstein, A. (n.d.). Sex hormone synthesis, regulation, and function | McMaster Pathophysiology Review. Retrieved from http://www.pathophys.org/sexhormones/

[15] Nestler, J. E. (1998). Insulin Stimulates Testosterone Biosynthesis by Human Thecal Cells from Women with Polycystic Ovary Syndrome by Activating Its Own Receptor and Using Inositolglycan Mediators as the Signal Transduction System. Journal of Clinical Endocrinology & Metabolism, 83(6), 2001-2005. doi:10.1210/jc.83.6.2001

[16] Dunaif, A. (1997). Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis. Endocrine Reviews, 18(6), 774-800. doi:10.1210/er.18.6.774

[17] Hamilton-Fairley, D. (2003). Anovulation. British Medical Journal (BMJ), 327(7414), 546-549. doi:10.1136/bmj.327.7414.546

[18] Chapter 22 - Reproductive System. (n.d.). Retrieved from http://droualb.faculty.mjc.edu/Course%20Materials/Physiology%20101/Chapter%20Notes/Fall%202007/chapter_22%20Fall%202007.htm

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