Endocrinology and Acne Quiz

Polycystic Ovary Syndrome (PCOS)

• PCOS is the most common endocrine disorder in reproductive-age people with a uterus/ovaries.
• It's characterized by irregular menstrual periods, high androgen levels, and polycystic ovaries.
• Prevalence is 5-15%, closer to 20% in overweight and obese populations.
• Diagnosis and management are challenging due to variability in clinical presentation.

Pathophysiology

• PCOS pathophysiology includes hyperandrogenism, ovulatory dysfunction, polycystic ovaries, and insulin resistance.
• Inappropriate gonadotropin secretion is a key mechanism.
• Insulin resistance with hyperinsulinemia is another key mechanism.
• Excessive androgen production is a contributing factor.

Hormonal Imbalances

• Altered gonadotropin-releasing hormone (GnRH) secretion contributes to increased LH hormone secretion compared to FSH hormone secretion.
• Normally, GnRH leads to pulsatile secretion of FSH and LH every 60-90 minutes
• The increase in LH pulse frequency and amplitude in PCOS results in a higher LH:FSH ratio (above 2:1).
• Elevated LH stimulates ovarian androgen production.
• Low FSH leads to reduced conversion of testosterone to estrogen in granulosa cells.
• The lack of a dominant follicle with subsequent difficulty ovulating is linked to early LH secretion or high LH.
• Consequently, progesterone is not produced.

Causes and Contributing Factors

• A definitive cause of PCOS has not yet been established.
• Genetic and environmental interactions play a role.
• Exposure to high androgen levels in the fetus may be a factor.

Insulin Resistance

• People with PCOS tend to have greater insulin resistance and compensatory hyperinsulinemia.
• There's a reduced uptake of glucose from target cells (primarily muscle)
• Insulin hypersecretion attempts to maintain normal blood sugar levels.
• Insulin resistance leads to hypersecretion of insulin, causing mildly elevated blood glucose.
• High insulin levels in turn increase androgen production by the ovaries, worsen insulin resistance, and impair ovulation
• Therapies targeting insulin resistance can improve menstrual dysfunction, androgen levels, and metabolic profiles.
• Insulin stimulates release of FSH and LH from the pituitary and increases the release of androgens.
• Insulin resistance leads to reduced production of SHBG by the liver, leading to increased circulating androgens.

Androgens

• Androgens are primarily produced in the ovarian theca cells (testosterone and androstenedione).
• Elevated free testosterone levels are common (70-80%) in people with PCOS.
• Also, there is an elevated DHEAS levels (an androgen) in 25-65% of cases.

Sex-Hormone Binding Globulin (SHBG)

• SHBG, produced in the liver, binds most sex hormones, making them biologically inactive.
• Insulin production suppresses SHBG production.
• Reduced SHBG causes more unbound androgens to circulate, leading to clinical hyperandrogenism.
• Low SHBG levels have been associated with impaired glucose tolerance and a higher risk of developing type 2 diabetes mellitus (T2DM).

Anovulation

• Anovulation, the absence of ovulation, is a multifactorial process not fully understood.
• Insulin resistance plays a role as evidenced by resumption of regular ovulation in PCOS patients treated with insulin sensitizers (e.g., metformin).
• High levels of androgens produced by antral follicles also contribute to oligo-ovulation.

Signs, Symptoms, and Long-Term Health Consequences

• Short-term consequences include obesity, infertility, irregular menses, depression/anxiety, abnormal lipid levels, non-alcoholic fatty liver disease, hirsutism, acne, and androgenic alopecia.
• Long-term consequences include type 2 diabetes mellitus, endometrial cancer, and cardiovascular disease.

Obesity

• Women with PCOS are more likely to be obese (elevated BMI and waist-to-hip ratio).
• Android (central) or upper body obesity; is common in PCOS patients and is an independent risk factor for insulin resistance and cardiovascular disease.
• Obesity exacerbates PCOS by worsening hyperandrogenism, acanthosis nigricans, and menstrual dysfunction.

Infertility

• PCOS is a common cause of infertility due to anovulatory cycles.

Menstrual Dysfunction

• PCOS can cause amenorrhea (absence of menses), oligomenorrhea (infrequent menses), and heavy bleeding (leading to iron-deficiency anemia).
• Anovulation, which results in inadequate progesterone production, and chronic unopposed estrogen impacts the endometrium and causes thickened endometrium, which leads to unpredictable bleeding.
• Irregular cycles in adolescents at the post-menarche period is linked to hypothalamic-pituitary-ovarian axis immaturity.
• Cycles of <20 days or >45 days after menarche, or cycles longer than 90 days warrants a thorough evaluation.
• Regular cycles may resume with increasing age in some individuals due to decreased antral follicle count and decreased follicular androgen production.

Obstructive Sleep Apnea (OSA)

• OSA is related to central obesity and is more common in women with PCOS compared to age-matched controls
• Metabolic changes associated with PCOS likely contribute to OSA.

Dyslipidemia

• Women with PCOS frequently display high levels of low-density lipoprotein (LDL) and triglycerides, lowered high-density lipoprotein(HDL), and a high cholesterol:HDL ratio
• The high levels of lipids are linked to atherogenic changes and higher cardiovascular risk.
• The prevalence of dyslipidemia in PCOS is notably high.

Hyperandrogenism

• Hirsutism, acne, and alopecia symptoms result due to increased androgen levels.
• Increased muscle mass, deeper voice, or cliteromegaly (signs associated with rapid androgen increases) NOT typical of PCOS.
• In these cases, investigation for an androgen-secreting tumor is warranted.

Hirsutism

• Hirsutism, or excessive hair growth, is primarily due to elevated androgen levels and is seen disproportionately more often in women from Mediterranean, or South Asian backgrounds
• Androgen converts vellus hair into terminal hair in an irreversible process.

Alopecia

• Alopecia, or hair loss, can be, but not always, linked to high androgen activity.
• High DHT levels due to high 5 alpha reductase activity leads to hair follicle transformation from terminal hairs to vellus hairs.
• Alopecia warrants investigation for other possible causes, such as chronic illnesses or anemia.

Acne

• Increased androgen levels are strongly linked to acne formation, particularly severe acne.
• Acne vulgaris is a common finding in adolescents and women with PCOS
• Four primary factors involved in acne formation are blockage of the follicle opening (hyperkeratosis), sebum overproduction, proliferating commensal bacteria (Propionibacterium acnes), and inflammation.
• Elevated testosterone conversion to DHT in the sebaceous glands causes inflammation and sebum formation. Inflammation, in turn, leads to scarring.

Acanthosis Nigricans

• Acanthosis nigricans is a cutaneous marker of insulin resistance, characterized by thick, velvety plaques in skin folds.
• It's linked to hyperinsulinemia and high keratinocyte growth, which are common in women with PCOS and metabolic syndrome.

Impaired glucose tolerance and T2DM

• Impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are closely related to insulin resistance.
• The high prevalence continues even after adjusting for BMI.
• Patients with PCOS who do not ovulate usually have higher insulin resistance than those who ovulate
• 75 gram OGTT, HbA1C, and fasting blood glucose test can be used for diabetes screening.

Endometrial Neoplasia

• Women with PCOS have 3-4 times greater risk of endometrial neoplasia (cancer).
• The increased risk stems from anovulation and unopposed estrogen, coupled with hyperandrogenism, hyperinsulinemia, obesity, and reduced circulating SHBG that causes increased circulating estrogen.
• Most women do not develop endometrial cancer before age 40 but warrants attention.

Metabolic Syndrome (METS)

• METS, characterized by insulin resistance, obesity, dyslipidemia, and hypertension, is a notable risk factor in PCOS.
• Increased androgen levels can act as a contributing factor to METS independent of body mass index (BMI).
• The incidence of METS in women with PCOS is around 45% compared to age-matched controls.

Cardiovascular Disease (CVD)

• Metabolic syndrome (METS) is an independent risk factor for cardiovascular disease (CVD).
• Women with PCOS should have cardiovascular risk factors addressed and managed.

Complications in Pregnancy

• PCOS is associated with a higher rate of early miscarriages (30-50% compared to 15%).
• Miscarriage risk is not wholly explained, but overweight/obesity and insulin resistance are notable factors.
• PCOS is linked to a greater likelihood of hypertensive disorders, gestational diabetes, and preterm birth, which are not wholly explained.
• Increased risk of multi-fetal pregnancies due to fertility interventions may also increase risk of maternal and neonatal complications.

Psychological Complications

• Anxiety, depression, eating disorders, and negative body image are increased in women with PCOS.