Polycystic Ovarian Syndrome

Epidemiology and Pathophysiology

Epidemiology

• Prevalence: 5%–10% of reproductive-age women in the United States
• One of the most common causes of:
  • Oligomenorrhea 
  • Secondary amenorrhea Secondary Amenorrhea Secondary amenorrhea is defined as the absence of menses for 3 months in a woman with previously regular menstrual cycles or for 6 months in a woman with previously irregular cycles. Etiologies involve either disruptions to the hypothalamic-pituitary-ovarian (HPO) axis or acquired obstructions in the uterus or outflow tract. Secondary Amenorrhea 
  • Infertility
  • Hirsutism (abnormal facial and body hair growth)
• 50%–65% of patients are obese.

Pathophysiology

The exact mechanisms are unknown, but thought to be complex and include both genetic and environmental factors. Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity are often, but not always, present and likely contribute to the pathophysiology in some individuals.

• Polycystic ovarian syndrome (PCOS) includes:
  • ↑ Androgens
  • Chronic anovulation
  • Polycystic-appearing ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
  • Metabolic dysfunction (commonly known as metabolic syndrome):
    • Insulin resistance
    • Dyslipidemia
    • Hypertension
    • Associated with obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • ↑ Risk for diabetes and cardiovascular disease
• Dysfunction in the hypothalamic-pituitary-ovarian axis:
  • ↑ Luteinizing hormone (LH) level:
    • Stimulates testosterone production in ovarian theca cells
    • LH receptors tend to be over-expressed in polycystic ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries.
    • Cause of ↑ LH: ↑ Estrogen from adipocytes and chronically anovulatory ovarian follicles → alters gonadotropin-releasing hormone (GnRH) pulse → ↑ LH secretion
  • Follicle-stimulating hormone (FSH):
    • FSH stimulation is insufficient for ovulation → abnormal follicle development
    • Evidence of FSH resistance at the follicular level
  • Chronic unopposed estrogen:
    • No ovulation → no progesterone 
    • Results in endometrial proliferation without menses
    • ↑ Risk for endometrial hyperplasia Endometrial Hyperplasia Endometrial hyperplasia (EH) is the abnormal growth of the uterine endometrium. This abnormal growth may be due to estrogen stimulation or genetic mutations leading to uncontrolled proliferation. Endometrial Hyperplasia and Endometrial Cancer or carcinoma
• Hyperandrogenism:
  • ↑ LH → ↑ testosterone:
    • ↑ Insulin → sensitizes the ovary to LH
    • Theca cells overexpress steroidogenic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes → ↑ testosterone
  • Likely involves a genetic predisposition
  • Androgens secreted primarily from the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries and adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands
• Insulin resistance and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity:
  • ↑ Insulin → ↑ free testosterone due to:
    • ↑ Androgen production in ovarian theca cells
    • ↓ Hepatic production of sex hormone-binding globulin (SHBG) 
  • Obesity:
    • Adipocytes convert androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens → estrogens → ↓ FSH → worsening ovulatory dysfunction
    • ↑ Insulin resistance → ↑ free testosterone → ↑ hyperandrogenism
    • ↑ Prevalence of metabolic syndrome
    • Unclear whether obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity itself is causative in PCOS

Clinical Presentation

Polycystic ovarian syndrome (PCOS) should be suspected in any reproductive-age female with irregular menses and/or symptoms of hyperandrogenism, especially if obese or presenting with infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility.

Symptoms of hyperandrogenism

• Hirsutism:
  • Excess terminal body hair
  • Male distribution:
    • Upper lip
    • Chin
    • Periareolar
    • Linea alba
• Acne vulgaris Acne vulgaris Acne vulgaris, also known as acne, is a common disorder of the pilosebaceous units in adolescents and young adults. The condition occurs due to follicular hyperkeratinization, excess sebum production, follicular colonization by Cutibacterium acnes, and inflammation. Acne Vulgaris
• Male-pattern alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
• Early adrenarche (development of pubic hair, apocrine glands, and sebaceous glands)

Menstrual cycle irregularities

• Oligomenorrhea (cycle length > 35 days) 
• Amenorrhea (cycles absent)
• Symptoms present for 3–6 months or 3 cycle lengths
• Due to chronic anovulation

Associated conditions

• Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome:
  • Obesity (especially with ↑ waist:hip ratio)
  • Hypertension
  • Impaired glucose tolerance:
    • Type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Acanthosis nigricans (marker of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance)
  • Dyslipidemia
• Infertility
• Cardiovascular disease
• Endometrial hyperplasia and carcinoma

Diagnosis

Polycystic ovarian syndrome (PCOS) is a diagnosis of exclusion, so other causes of oligo- or amenorrhea and hyperandrogenism must be ruled out. The Rotterdam criteria are commonly used to make the diagnosis once other causes are excluded.

Rotterdam criteria

Diagnosis requires 2 of the 3 following criteria:

• Clinical and/or biochemical signs of hyperandrogenism
• Oligo- or anovulation
• Polycystic ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries on ultrasound

Physical exam

• Hirsutism:
  • Male-pattern facial and body hair growth
  • Ferriman-Gallwey score:
    • An objective evaluation of hirsutism
    • Often not helpful as some women remove unwanted hair
  • Consider normal ethnic variations in hair: Mediterranean, Middle Eastern, and South Asian (most hair) > Caucasian and Black > East Asian and Native American (least hair)
• Pelvic exam:
  • Mild ovarian enlargement
  • Rule out structural causes of abnormal bleeding.
• Signs of Cushing’s syndrome (alternate diagnosis):
  • Moon face
  • Buffalo hump
  • Abdominal striae

Laboratory and imaging evaluation

• Urine human chorionic gonadotropin (HCG): rule out pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
• Assess other potential causes of abnormal bleeding:
  • Thyroid-stimulating hormone (TSH)
    • ↑ → hypothyroid
    • ↓ → hyperthyroid
  • ↑ Prolactin → hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
• Assess for biochemical hyperandrogenism (and other potential causes of hirsutism):
  • Free testosterone: ↑ in PCOS
  • Dehydroepiandrosterone sulfate (DHEA-S): ↑ in certain androgen-secreting adrenal tumors
  • 17-hydroxyprogesterone: ↑ in non-classic congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia (NCCAH)
• Assess for metabolic syndrome:
  • 2-hour glucose tolerance test 
  • Fasting lipid panel:
    • ↑ Triglycerides and low-density lipoproteins (LDLs)
    • ↓ High-density lipoproteins (HDLs)
• Other laboratory tests to consider:
  • Cycle day 3 LH:FSH ratio → often > 2 in PCOS (normal is < 1)
  • 24-hour urinary free cortisol → screen for Cushing’s syndrome
• Transvaginal ultrasonography:
  • “Pearls on a string” (also known as the pearl necklace sign): multiple antral follicles at the periphery of the ovary
  • ↑ Ovarian volume
  • Not required if a woman already meets the Rotterdam criteria

Management

General management

• Weight loss:
  • Goal of 5%–10% weight reduction
  • ↓ Estrogen production in adipocytes → ↓ FSH inhibition by estrogen → resumption of normal ovulation
  • ↓ Risk of metabolic syndrome
• Regular screening and treatment for:
  • Diabetes
  • Dyslipidemia
  • Hypertension
  • Cardiovascular disease
• Endometrial protection:
  • Goal is to ↓ risk of endometrial hyperplasia Endometrial Hyperplasia Endometrial hyperplasia (EH) is the abnormal growth of the uterine endometrium. This abnormal growth may be due to estrogen stimulation or genetic mutations leading to uncontrolled proliferation. Endometrial Hyperplasia and Endometrial Cancer or cancer.
  • Combined oral contraceptive pills (OCPs) → allows regular withdrawal bleeding.
  • Levonorgestrel-containing intrauterine device (IUD) → endometrial suppression
  • Intermittent or continuous progestin therapy

Hirsutism management

• Mechanical hair removal (e.g., waxing, laser hair removal)
• Combined OCPs:
  • ↓ LH → ↓ testosterone production in the ovary
  • ↑ SHGB → ↑ binding of testosterone → ↓ free testosterone
  • ↓ DHEA-S in the adrenals
  • ↓ 5-α-reductase activity in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
• Antiandrogens Antiandrogens Antiandrogenic drugs decrease the effect of androgens. Classes include androgen receptor blockers, 5-alpha-reductase inhibitors, and androgen synthesis inhibitors. Both men and women may use antiandrogens, which treat advanced prostate cancer, benign prostatic hyperplasia (BPH), alopecia, and hirsutism. Androgens and Antiandrogens:
  • Spironolactone
  • Finasteride
• Metformin: 
  • No longer 1st line treatment for any PCOS indication
  • Still considered 1st line in patients with type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
  • Insulin sensitizing agent: ↓ hepatic glucose production → ↓ insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin → ↓ testosterone 
  • Despite ↓ testosterone, there is limited reduction in hirsutism.

Infertility management

• Letrozole:
  • Aromatase inhibitor
  • More effective at ovulation induction and safer than clomiphene citrate
  • Not approved by the Food and Drug Administration (FDA) for fertility indications, though considered 1st line by many experts
  • ↓ Estrogen → ↓ inhibition of FSH → ↑ FSH → ↑ follicular development → ovulation
• Clomiphene citrate: 
  • A selective estrogen receptor modulator (SERM) 
  • FDA approved to treat infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
  • ↑ FSH → ↑ follicular development → ovulation

Differential Diagnosis

• Non-classical congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia (NCCAH): a less severe form of an inherited enzyme deficiency (usually 21-hydroxylase) resulting in decreased production of aldosterone and cortisol. Instead, precursors are shunted down the sex steroid pathways, leading to increased androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens. Patients will develop hirsutism, oligomenorrhea, and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility. Elevated 17-hydroxyprogesterone is diagnostic for congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia (CAH), but will be normal in PCOS. Management involves antiandrogens and glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids. 
• Cushing’s syndrome: elevated cortisol due to excess adrenocorticotropic hormone (ACTH) secretion, adrenal tumors, or exogenous steroids. Presentation is similar to PCOS with menstrual irregularities and hirsutism, as well as abdominal purple striae, truncal obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and moon face. Patients can be screened with a 24-hour urine free cortisol test or a dexamethasone suppression test. Management depends on the cause and includes withdrawal of exogenous steroids, adrenal inhibitors, or surgery for tumors. 
• Exogenous testosterone exposure: occurs when a man’s testosterone cream is transmitted to a woman through contact exposure. Patients may develop hirsutism; diagnosis is based on history and elevated testosterone levels.
• Ovarian tumors: sex-cord stromal tumors arising from the theca or granulosa cells within the ovary secreting androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens or estrogens, respectively. Patients may have signs of virilization, irregular menstrual cycles, or abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding. Androgen and estrogen levels tend to be more elevated than typically seen in PCOS. Initial treatment is surgical and based on the stage of malignancy.
• Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: a thyroid hormone deficiency resulting in either oligo- or amenorrhea, which may negatively impact fertility. Effects are likely due to structural similarities between TSH, FSH, and LH, as well as associated decreases in SHBG. Other symptoms include thinning of the hair, dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, brittle nails, periorbital edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, and fatigue. Thyroid-stimulating hormone (TSH) is increased due to low thyroxine. Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism is treated with levothyroxine. 
• Pregnancy: results in amenorrhea, though typically not causing hirsutism symptoms. Pregnancy should be ruled out with a urine pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care test when evaluating amenorrhea. Treatment is obstetric care.