endocrine: polycystic ovary syndrome

clinical pearls about PCOS

• the most common endocrinopathy in reproductive-age women, with an estimated prevalence of 6-10%

• associated with a high risk of infertility (75%) and is the most common pathologic cause of anovulation

• associated with a higher risk of endometrial hyperplasia and cancer compared with age-matched women without the disease

• because of insulin resistance, it is associated with higher risks of metabolic syndrome, T2DM, HTN, dyslipidemia, cardiovascular disease, sleep apnea, anxiety, and depression compared to women without it

• the economic burden is estimated to be $8 billion annually

pathophysiology of PCOS

1. hypothalamus-pituitary-ovarian abnormality

   • ovarian-induced increase in gonadotropin-releasing hormone (GnRH) results in abnormal increase in the LH/FSH ratio, with a resulting increase in ovarian testosterone production

2. insulin resistance

   • due to increases in insulin exposure

     • for example, T1 diabetics taking insulin

   • increases in endogenous insulin levels caused by insulin resistance in muscle and adipose tissues results in excess androgen production by the ovaries (which remains sensitive to insulin), causing increased testosterone production

   • excess insulin also decreases hepatic synthesis of sex-hormone binding globulin (SHBG) which normally binds to free testosterone, resulting in increased hirsutism

     • these mechanisms exacerbate the effects of LH on theca cells’ testosterone production

clinical presentation of PCOS

• chronic anovulation (no release of egg) most often manifesting as oligomenorrhea (fewer than 9 periods per year) or amenorrhea (no periods)

  • anovulatory cycles may lead to dysfunctional uterine bleeding, decreased fertility, and a higher prevalence of endometrial hyperplasia and carcinoma

• cutaneous manifestations of hyperandrogenism include:

  • hirsutism: hair growth on the sternum, upper abdomen, or upper back

  • acne

  • male pattern baldness (aka androgenic alopecia)

  • other virilizing factors such as clitormegaly and increased muscle bulk suggests an alternative diagnosis

• hyperandrogenemia (eg. elevated levels of total or free testosterone or androstenedione)

• characteristics of insulin resistance

• abdominal (visceral) obesity

• symptoms typically begin around menarche

characteristics of insulin resistance

• acanthosis nigricans

  • raised velvety brown discoloration on the nape of the neck, armpit, knuckles, elbow

• overweight or obese

• 40% with impaired glucose tolerance, 10% with T2DM by age 40

  • an oral glucose tolerance test (OGTT) is recommended for all women with PCOS and a BMI > 27

• non-alcoholic steatohepatitis (NASH)

• higher risk of coronary artery disease, HTN, low HDL-C, high triglycerides, and obstructive sleep apnea

diagnosis

• typically via exclusion

• at least two of the following:

  1. oligoovulation or anovulation

     • usually manifested as amenorrhea or oligomenorrhea

  2. elevated levels of circulating androgens (hyperandrogenemia) or clinical manifestations of androgen excess (hyperandrogenism)

  3. polycystic ovaries

     • defined as ovation ultrasonography (transvaginal) ≥ 12 2-9 mm diameter follicles in each ovary or increased ovarian volume (>10 cm³)

• other causes must be ruled out:

  • hyperprolactinemia

  • non-classical congenital adrenal hyperplasia

  • Cushing’s syndrome

  • androgen-secreting neoplasm

  • acromegaly

  • hypothyroidism (HoTR)

  • pregnancy

PCOS phenotypes

• A

  • patient has hyperandrogenism + polycystic ovaries + oligomenorrhea or anovulation

• B

  • patient has hyperandrogenism + oligomenorrhea or anovulation

• C

  • patient has hyperandrogenism + polycystic ovaries

• D

  • patient has polycystic ovaries + oligomenorrhea or anovulation

goals of therapy of PCOS

• must be tailored to the specific needs of each patient

• improve (hyperandronergic) symptoms and quality of life

• increase fertility (for most women)

  • assess if the patient wants to be pregnant

• regulation menstruation

• preventing cardio-metabolic complications

• prevent concomitant morbidity

• treatment is rarely monotherapeutic

pharmacologic targets for PCOS

1. must consider patient preferences prior to treatment!

   1. ovulatory dysfunction

   2. infertility

   3. hyperandrogenism

2. remember that there is no single drug class that treats PCOS

3. treatment focuses on the management of the complication/concern and should be individualized

   1. determine whether the patients seeks pregnancy or not, and proceed from there

non-pharmacologic treatment for PCOS

• lifestyle modifications are the cornerstone of PCOS management → improves all PCOS-specific complications:

  • weight loss: modest reductions in body weight (5-7%) have been associated with reductions in androgen levels and improved ovulatory function

  • exercise: aerobic exercise decreases insulin resistance (regardless of weight loss)

pharmacologic options for PCOS-related infertility

• aromatase inhibitor therapy

• clomiphene (Clomid, Serophene)

• GnRH agonists

• metformin

• clomiphene is generally the first-line agent for induction of ovulation in women with PCOS

MOA of aromatase inhibitors

• increases ovulation by blocking estrogen production, leading to increases in FSH release

MOA of clomiphene in PCOS treatment

• an anti-estrogen that induces a rise in FSH and LH, resulting in ovulation → ovulation induction

  • recommended for women who want to be pregnant!

• first-line for increasing fertility and ovulation!

MOA of metformin in PCOS treatment

• decreases endogenous insulin levels by inhibiting hepatic glucose production → the lower insulin concentrations results in the reduction of androgen production by ovarian theca cells with a 4-fold increased potential for ovulation

  • NOT first-line

• can be used for:

  • hirsutism or acne

  • oligomenorrhea or amenorrhea

  • ovulation induction

  • insulin lowering

aromatase inhibitors → drugs

• letrozole (Femara)

brand name for letrozole

• brand name

  • Femara

dosing for letrozole (Femara)

• 2.5 - 7.5 mg daily on cycles days 3-7

  • this increases the rate of ovulation

side effects of aromatase inhibitors

• hot flashes

• night sweats

• insomnia

• increased likelihood of multiple births

contraindications to aromatase inhibitors

• pregnancy

brand name for clomiphene

• brand names

  • Clomid

  • Serophene

dosing for clomiphene (Clomid, Serophene)

• 50-100 mg/day for 5 days, initiated on day 5 of cycle

side effects of clomiphene

• hot flashes

• breast discomfort

• ovarian hyperstimulation

• abdominal distention or bloating

• increased likelihood of multiple births

contraindications to clomiphene

• liver disease

• pregnancy

dosing for metformin

• 1-2 g/day → this helps to improve blood glucose and lipid profile and lowers the rate of spontaneous miscarriage and gestational diabetes in women who conceive while taking it

pharmacotherapy for PCOS-related menstrual irregularities

• oral contraceptives, specifically those with low androgenic progestin

pharmacotherapy for PCOS-related endometrial hyperplasia

• oral contraceptives

  • progestin challenge if ≥ 3 months of amenorrhea

  • endometrial biopsy if ≥ 1 year of amenorrhea or if endometrial thickness on ultrasound is > 14 mm

pharmacotherapy for PCOS-related hyperandrogenism/hirsutism

• oral contraceptives

• metformin (1-2 g/day)

• spironolactone

• eflornithine (Vaniqa)

• can also include local measures like shaving, waxing, plucking, etc

oral contraceptives with a non-androgenic progestin

• norgestimate

• desogestrel

• drospirenone

MOA of oral contraceptives in PCOS treatment

• estrogen-progestin combinations, ideally with a non-androgenic progestin

• controls hirsutism and acne

• is also effective treatment of oligomenorrhea and amenorrhea, and protects against unopposed estrogenic stimulation of the endometrium

side effects of oral contraceptives

• exacerbation of insulin resistance and glucose tolerance

• vascular reactivity

• venous thromboembolism

indication for metformin in patients with PCOS

• recommended for patients with PCOS with impaired glucose tolerance or T2DM that are not responding adequately to available lifestyle modifications or other therapeutic options

MOA of spironolactone in PCOS treatment

• possesses moderate anti-androgenic effects when administered in large doses (100-200 mg/day)

• decreases adrenal androgen production and blocks the androgen receptor (mineralocorticoid receptor)

  • controls hirsutism and acne

• should be used with oral contraceptives to prevent feminization of male infants (if pregnant)

  • also has synergistic effects when used together with oral contraceptives

MOA of eflornithine in PCOS treatment

• inhibits the ornithine decarboxylase, leading to decreased rate of hair growth

• use of hair removal techniques is still required

brand name for eflornithine

• brand name

  • Vaniqa

dosing for eflonithine (Vaniqa)

• 13.9% cream applied to the affected areas of face BID (8 hours apart)

  • do not wash skin for 8 hours after application

side effects of eflornithine

• pruritus

• burning/tingling skin

• dry skin

• rash

pharmacotherapy for PCOS-related insulin resistance

• metformin

• pioglitazone (Actos)

• GLP-1 agonists → weight loss

• SGLT-2 inhibitors → weight loss

MOA of pioglitazone in PCOS treatment

• an insulin sensitizer that results in the reduction of androgen production by ovarian theca cells

  • this also results in a greater likelihood of ovulation

• improves blood glucose

• increases HDL-C levels

• lowers plasminogen activator 1 levels

• double serum adiponectin levels

• concerns about its use during pregnancy, so not considered first-line

• can be used for:

  • hirsutism or acne

  • oligomenorrhea or amenorrhea

  • induction of ovulation

  • insulin lowering

dosing for pioglitazone (Actos)

• 15-45 mg orally daily

side effects of pioglitazone

• edema

• weight gain