How does PCOS affect reproductive health? 

According to the World Health Organization, PCOS is the most common cause of anovulation and therefore the leading cause of infertility. 

Polycystic ovarian syndrome (PCOS) is one of the most common, most profound and most overlooked health conditions affecting individuals assigned female at birth.  It is a multi-system disorder which impacts hormonal, menstrual, reproductive/maternal, cardio-metabolic, oncological, mental/neurological, sexual and immune system health.  In this article we explore the link between PCOS and Reproductive Health. 

At its core, PCOS is associated with abnormal functioning of the system of hormones that connects the hypothalamus, the pituitary and the ovaries (the HPO-axis).[1] 

In individuals with PCOS, the activity level (pulse frequency) of one of the hormones produced in the hypothalamus, the Gonadotrophin Releasing Hormone (GnRH), is over-active.[2] 

• An elevated level of GnRH triggers an elevated level of Luteinizing Hormone (LH) in the pituitary, LH and Follicle Stimulating Hormone (FSH) being the two hormones responsible for stimulating growth of follicles, the part of the ovary that contains eggs, and synchronize the release of eggs from the ovaries;[3] 

• An elevated LH levels leads to increased stimulation of theca cells, a type of cell within the ovary that plays an essential role in fertility;[4] 

• The increased stimulation of these theca cells increases the rate of conversion of cholesterol, a fat-like substance that is found in all cells in the body and needed to make hormones,[5] to two androgens or sex hormones (androstenedione and testosterone);[6][7] 

• A portion of these androgens then travel to neighboring granulosa cells, a type of cell within the ovary that is important for the production of reproductive hormones;[8] 

• Within granulosa cells, some of these androgens are converted to estrogen, a sex hormone responsible for triggering egg release and thickening the lining of the uterus;[9] and 

Some of these excess androgens are not converted and therefore lead to an androgen-rich environment within the ovary[10] and an elevated level of circulating androgens. 

As a result, PCOS is associated with hyperandrogenism (HA) or androgen excess (AE), an elevated level of androgens in individuals assigned female at birth. 

Elevated androgens in girls trigger the early development of pubic (pubarche) and/or armpit hair, body odor and acne in what is known as premature adrenarche.[11]  Girls with PCOS may experience breast development (thelarche) and the onset of menstruation (menarche) either earlier or later than typical puberty progression.[12][13][14]  In general premature thelarche and menarche are linked to higher body mass index (BMI).[15]  Girls with PCOS experience a wider age range than usual for the onset of puberty, sometimes exhibiting physical signs at or before the age of 9 and sometimes with delayed onset of menstruation beyond 16.[16]  Elevated androgens also result in a growth spurt and bone maturation during puberty.[17] 

A typical menstrual cycle relies on a complex interplay of chemicals over a cycle of around 28 days and comprised of four key phases:[18] 

• Menses: the uterus sheds its lining if pregnancy hasn’t occurred from day 1 of the cycle for a typical period of 3-7 days; 

• Follicular: overlapping with menses and lasting for 10-14 days, the lining of the uterus is restored and follicles in the ovaries grow to produce (usually) a single mature egg or ovum; 

• Ovulation: at roughly day 14, an eggs is released; and 

• Luteal: from day 15-28 the egg travels to the uterus and, if fertilized by a sperm, implants into the uterine wall. 

The hormonal imbalances associated with PCOS can interfere with the follicular phase, resulting in no one single dominant mature egg or ovum developing:[19][20] 

• The hypothalamus (a region of your brain) releases gonadotrophin-releasing hormone (GnRH), a chemical messenger that is vital to puberty, sex drive and fertility;[21] 

• In individuals with PCOS, the activity level (pulse frequency) of one of the hormones produced in the hypothalamus, the GnRH, is over-active;[22] 

• The GnRH triggers the pituitary gland (a gland at the base of the brain) to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH); 

• Between day 6 and 14 of the menstrual cycle, FSH causes follicles, small sacs of fluid in your ovaries that contain a developing egg or oocyte, in one ovary to begin to mature; 

• Between day 10 and 14, a dominant follicle emerges that out-competes the other follicles for FSH; 

• This dominant follicle then secretes inhibin that reduces FSH production in effect “turning off” neighboring follicles;[23] 

• This mature follicle develops into a fully mature egg, within what is now known as a Graafian follicle[24] and reaches up to 2.5 cm in diameter;[25] 

• Instead, in individuals with PCOS, an elevated level of GnRH in individuals with PCOS can result in over-production of LH,[26] so that follicle development stalls at the antral phase (2-9 mm in diameter)[27] and no dominant follicle emerges; 

• In some individuals with PCOS these immature follicles can accumulate and remain as several small follicles often referred to as a “string of pearls”,[28] hence the naming of the condition as polycystic ovarian syndrome (PCOS).[29] 

The hormonal imbalances associated with PCOS can therefore interfere with the process of ovulation itself:[30][31] 

• In a typical cycle, the Graafian follicle moves towards the surface of the ovary and, at around day 14, the mature follicle produces sufficient estradiol to trigger an LH surge which kicks off the steps towards ovulation; 

• In an individual with PCOS none of the small immature follicles is typically capable of growing to a size that would be sufficient to trigger this LH surge.[32] 

As a result, PCOS is associated with anovulation and oligo-ovulation (sporadic ovulation).[33]  Anovulation is responsible for c.30% of cases of infertility[34] and PCOS is the primary cause of anovulation.[35] 

Due to the irregular or absent ovulation, individuals with PCOS show a slower decline in ovarian reserve (the number of follicles remaining) and therefore tend to experience menopause 2-4 years later on average.[36][37]  As a result, individuals with PCOS tend to have a longer reproductive lifespan.[38] 

In general, average antral follicle count (AFC) and anti-Müllerian hormone (AHM) level are used as indicators of ovarian reserve, the number of eggs remaining in a woman’s ovaries and therefore fertility.[39]  Individuals with PCOS have a high AFC and high AMH due to the immature follicles accumulating on the ovaries.[40][41]  These measurements should therefore be interpreted carefully as they are not an indicator of egg quality[42] and, particularly in individuals with PCOS, do not necessarily mean you will have an easier time conceiving.[43] 

Beyond challenges with conception, individuals with PCOS have increased risk of certain pregnancy and postpartum complications, including: 

• Early pregnancy loss due to implantation failure,[44] placental insufficiency,[45] increased prevalence of obesity[46][47] and increased use of assistive reproductive technology;[48] 

• Recurrent pregnancy loss (RPL);[49] 

• Gestational diabetes mellitus (GDM);[50] 

• Pre-eclampsia, a serious condition characterized by high blood pressure that can lead to organ damage and seizures;[51] 

• Pre-term birth, defined as babies born alive before 37 weeks of pregnancy;[52] 

• Small for gestational age (SGA), where baby’s birth weight is lower than expected for the number of weeks of pregnancy;[53] 

• Large for gestational age (LGA), where baby’s birth weight is higher than expected for the number of weeks of pregnancy;[54] 

• Postpartum hemorrhage (PPH), a serious condition where a woman has significant blood loss in the days or weeks following childbirth;[55]  

• Post-partum depression (also known as perinatal depression), a mood disorder which may be experienced by pregnant or postpartum women;[56] and 

• Low milk supply during early postpartum period.[57][58] 

Individuals with PCOS are also at increased risk of certain types of reproductive cancers, including: 

• Epithelial ovarian cancer (representing 90% of all ovarian cancers),[59] linked to the effect of elevated androgens on the granulosa and theca cells within the ovary;[60][61] and 

• Endometrial cancer, linked to endometrial hyperplasia, the build up of endometrial cells without regular “shedding” due to menstruation.[62][63][64] 

There is insufficient evidence to suggest an increased risk of cervical cancer,[65][66] vaginal or vulvar cancer.[67] 

Overall risk factors for reproductive health include:[68] 

• Increasing age; 

• Personal history of chronic diseases such as endometriosis, fibroids, diabetes, lupus, arthritis, hypertension and asthma; 

• Personal history of sexually transmitted diseases or Fallopian tube disease; 

• Personal history of pelvic surgery or abnormal Pap smears that were treated with cryosurgery or cone biopsy; 

• Abnormalities of the uterus that are either present from birth or caused due to injury and/or surgery; 

• Use of tabacco; 

• High alcohol consumption; 

• Use of certain medications such as long-term use of non-steroidal anti-inflammatory drugs (NSAIDS), chemotherapy drugs, antipsychotics, antidepressants and spironolactone (sometimes used to treat PCOS-related acne and hirsutism);[69] 

• Exposure to toxins such as lead, mercury, certain solvents and some pesticides;[70] 

• Exposure to ionizing radiation, loud noise or extreme heat;[71] 

• High or low BMI; 

• Poor diet;  

• Strenuous exercise (can prevent ovulation); and 

• Stress. 

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