Infertility, type 2 diabetes and endometrial cancer are related to Polycystic Ovary Sx.(PCOS)?

Public Health

By Jorge A Cevallos, MD

06/02/2022

Introduction

How many women live in the world? Approximately 3,904,727,342 (that is 3,905 million or 3.905 billion!), which represents 49.6% of the world population (1). Then, in a very, very rough estimation, that would make 7.81 billion ovaries in the world! Now, since ovaries are on your mind, let us take a moment to appreciate that women must go through a recurring painful, emotionally distressing, monthly experience men do not (and not just once) for a significant portion of their lives. This fact does not only deserve empathy, but also deserves understanding, respect, and appreciation. Whether we are women or men, we all have some notions of what ovaries are and what they do. But what are they? I mean, really, what are they?

In this post, we will start by understanding what makes up an ovary, to then understand their purpose, to then understand what polycystic ovary syndrome (PCOS) is. Spoiler alert, it affects around 6-26% (changes depending on the criteria used) of women worldwide (2), and is a very common if not the pervasive cause of infertility worldwide. PCOS is the most common cause of infertility in the United States and carries an increased risk for type 2 diabetes mellitus, and endometrial cancer. PCOS also places women at risk for metabolic syndrome: insulin resistance, atherogenic dyslipidemia (elevated levels of triglycerides, and low levels of high-density lipoprotein HDL "good cholesterol"), and hypertension.

What is an ovary?

So, what´s an ovary? It is the female reproductive organ. Its functional unit or most basic element is what is known as a follicle. The ovary is made up of many follicles and a capsule containing these, all embedded in connective tissue.

Ok, but what is a follicle then? A follicle is a structure made up of three kinds of cells: the oocyte (the egg) which is surrounded by granulosa cells, and outside the latter, we can find what are known as theca cells. Therefore, a follicle is made up of the egg (oocyte), theca cells, and granulosa cells (3).

Before we proceed, we must also have some knowledge of what the pituitary gland is. So, what is it? The pituitary gland is a tiny, bean-shaped gland found at the base of our brains, and despite it being so tiny, the pituitary gland can influence nearly every part of our body! In this post we will focus on the reproductive role related to the ovary and will cover the pituitary in greater depth in a future post (4).

Considering this; in normal functioning/physiology, the pituitary gland secretes two hormones known as Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). These hormones have key roles as regulators of the menstrual cycle in women (3,5).

LH reaches the theca cells and induces the production of androgen (group of sex hormones – both men and women make them- but men make more of). At the same time, FSH reaches the granulosa cells and allows these cells to take the androgen made by the theca cells and convert it into estrogen. Subsequently, this estrogen bathes the egg (oocyte) and this allows it to mature. Estrogen also goes out into the blood and reaches the endometrium (or inner layer -lining- of the uterus) to induce the proliferative phase of the menstrual cycle. This is the phase in which the lining that was shed in the previous period is being rebuilt, and the endometrium becomes thicker and thicker (3,5).

The maturation of the egg secondary to estrogen stimulation will eventually result in ovulation or break off and release an egg (oocyte) from the ovary and into the fallopian tubes. Once this occurs, the secretory phase of the menstrual cycle begins. It is known as the secretory phase because the lining of the uterus secretes many molecules during the phase. This phase comprehends the period between ovulation and the menstrual or bleeding phase. In this secretory phase, the residual cells of the follicle (granulosa and theca cells) begin to produce progesterone (sex hormone involved in the menstrual cycle, pregnancy, and the formation of the embryo). Progesterone, in turn, influences the endometrium and prepares it for the implantation of a fertilized egg (in the hopes of) (3).

These residual cells of the follicle that produce progesterone enlarge and collectively start turning yellow secondary to the increased hormone production role and are collectively known as the corpus luteum. This “yellow body” enlarges to almost the size of the ovary in this process! Hereby, in the secretory phase, the Corpus Luteum calls the shots and drives what the ovary does while this “yellow body” exists (3,5).

And that is the big picture of the workings of the ovary! It is important to note that the follicles in the ovaries can degenerate, and when this happens, they become cystic (filled with liquid). Most women can have around 1 to 3 follicular cysts within the ovary, and this is considered normal (3,5).

What is polycystic ovary syndrome (PCOS)?

Now that we have a general understanding of the function of the ovary, let us focus our attention on PCOS. About 8% of women of reproductive age in the United States are affected by PCOS. This syndrome is also the most common cause of infertility in women and carries an increased risk of endometrial cancer, and increased risk for insulin resistance and diabetes mellitus type 2. In addition, PCOS also places women at increased risk for metabolic syndrome: insulin resistance, atherogenic dyslipidemia (elevated levels of triglycerides and small-dense-low-density lipoprotein (LDL or bad cholesterol) that can “clog” arteries), and hypertension (3,5).

This syndrome (sum of signs and symptoms) is characterized by menstrual cycle disturbances, infertility, acne, androgenic alopecia (thinning hair due to androgens), and hirsutism (excess hair in a male distribution pattern such as excess facial hair) secondary to hyperandrogenism (excess androgens) (5).

A key characteristic of PCOS is the presence of more than 11 tiny (2-9 mm) follicles within the capsule that surrounds the ovary and are seen in around 67% of women with this condition. These are the result of degenerated follicles that turn into fluid-filled cysts secondary to a hormonal imbalance (3,5).

The fundamental principles that characterize PCOS are an excess of testosterone and estrogen (3,5). PCOS is characterized by increased LH and low FSH. As we learned previously, LH is involved in androgen production which induces very high levels of androgens in the blood, which in turn cause hirsutism. Some of these androgens go on and into the peripheral adipose tissue (fat tissue). Here, the androgens are converted to estrogen by an enzyme known as aromatase. This makes up the excess of peripheral estrogens (3,5).

Hyperandrogenism and an increased LH/FSH ratio causes inhibition of the maturation and release of a single dominant ovarian follicle or egg (ovulation) from the ovary and into the fallopian tube as we learned above.

PCOS can also present with the characteristic insulin resistance. This causes an increase in the levels of insulin in the blood, and further sensitizes ovarian hyper responsiveness to LH, and consequently more androgen production (3,5).

Patients with PCOS have increased risk for obesity or are obese, which leads to a large amount of peripheral estrogen production as we just saw. These large quantities of peripheral estrogen go back through the blood into the pituitary gland and consequently signal the gland to stop producing FSH. This reduction of FSH levels impede the granulosa cells (which normally turn androgens produced by theca cells into ovarian estrogens) from producing ovarian estrogen (3,5).

Consequently, since the eggs do not receive the necessary estrogen to properly mature, the follicle arrests its development and degenerates into fluid-filled cysts. This is where the classic presence of more than 11 tiny (2-9 mm), follicles within the ovarian capsule is seen in around 67% of women with PCOS (3,5).

PCOS is the primary cause of infertility in the US which makes sense since hyperandrogenism and an increased LH/FSH ratio inhibits the maturation and release of a single dominant ovarian follicle (ovulation) (3,5).

The consequent anovulatory periods lead to chronic persistently low progesterone levels since there is no yellow body (corpus luteum) formation. Then in a synergetic fashion, hyperandrogenism and low progesterone cause unregulated endometrial proliferation which increases the risk for endometrial hyperplasia and endometrial cancer. The more estrogen the endometrium sees in a lifetime, the higher the risk becomes for endometrial cancer (3,5).

Concluding remarks

Women experience recurrent, painful, and mood-disturbing monthly episodes that call not only for out empathy, but for our respect and understanding. PCOS is an important topic to be aware of due to its implications including infertility and increased risk for type 2 diabetes mellitus, metabolic syndrome (insulin resistance, atherogenic dyslipidemia (elevated levels of triglycerides, and low levels of high-density lipoprotein HDL "good cholesterol"), and hypertension), and the increased risk for endometrial cancer. It is important to seek prompt attention for this condition.

References

1. World sex ratio 2021 - StatisticsTimes.com [Internet]. [cited 2022 Feb 4]. Available from: https://statisticstimes.com/demographics/world-sex-ratio.php

2. Rao M, Broughton KS, LeMieux MJ. Cross-sectional Study on the Knowledge and Prevalence of PCOS at a Multiethnic University. Progress in Preventive Medicine [Internet]. 2020 Jun [cited 2022 Feb 5];5(2):e0028. Available from: https://journals.lww.com/progprevmed/Fulltext/2020/06000/Cross_sectional_Study_on_the_Knowledge_and.1.aspx

3. Sattar HA. Fundamentals of Pathology. 2021st ed. Chicago.

4. Chapman PR, Singhal A, Gaddamanugu S, Prattipati V. Neuroimaging of the Pituitary Gland: Practical Anatomy and Pathology. Radiologic clinics of North America [Internet]. 2020 Nov 1 [cited 2022 Feb 5];58(6):1115–33. Available from: https://pubmed.ncbi.nlm.nih.gov/33040852/

5. Meier RK. Polycystic Ovary Syndrome. The Nursing clinics of North America [Internet]. 2018 Sep 1 [cited 2022 Feb 5];53(3):407–20. Available from: https://pubmed.ncbi.nlm.nih.gov/30100006/