Polycystic ovary syndrome (PCOS)

  • most common cause of infertility in women
  • PCOS encompasses a spectrum of variably associated clinical features that are not otherwise explained:

●Cutaneous signs of hyperandrogenism (eg, hirsutism, moderate-severe acne)

●Menstrual irregularity (eg, oligo- or amenorrhea, or irregular bleeding)

●Polycystic ovaries (one or both)

●Obesity and insulin resistance

  • originally was described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries
  • diagnostic criteria – Rotterdam consensus criteria 
    • hyperandrogenism, anovulation, and a polycystic ovary
  • Hirsutism- graded according to the Ferriman-Gallwey system

Women with PCOS have multiple abnormalities that require attention, including oligomenorrhea, hyperandrogenism, anovulatory infertility, and metabolic risk factors such as obesity, insulin resistance, dyslipidemia, and impaired glucose tolerance. Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the first-line intervention for most women.

Our overall approach à Endocrine Society Clinical Guidelines

Goals — The overall goals of therapy of women with PCOS include:

●Amelioration of hyperandrogenic features (hirsutism, acne, scalp hair loss)

●Management of underlying metabolic abnormalities and reduction of risk factors for type 2 diabetes and cardiovascular disease

Prevention of endometrial hyperplasia and carcinoma, which may occur as a result of chronic anovulation

Contraception for those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur

Ovulation induction for those pursuing pregnancy

Lifestyle changes — 

  • diet and exercise for weight reduction as the first step for overweight and obese women with PCOS.

Women not pursuing pregnancy

Menstrual dysfunction

Endometrial protection — 

The chronic anovulation seen in PCOS is associated with an increased risk of endometrial hyperplasia and possibly endometrial cancer

  • combined estrogen-progestin oral contraceptives (COCs) as first-line therapy for menstrual dysfunction and endometrial protection
  • COCs provide a number of benefits in women with PCOS, including:

●Daily exposure to progestin, which antagonizes the endometrial proliferative effect of estrogen

●Contraception in those not pursuing pregnancy, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur

●Cutaneous benefits for hyperandrogenic manifestations

Choice of oral contraceptive — COC containing 20 mcg of ethinyl estradiol combined with a progestin such as norethindrone or norethindrone acetate, progestins that have lower androgenicity, but similar VTE risk compared with levonorgestrel-containing COCs

  • COCs affect insulin sensitivity, carbohydrate metabolism, and lipid metabolism; the effects depend upon the estrogen dose and androgenicity of the progestin.
  • Absence of pregnancy should be documented before COCs are begun.
  • COCs are associated with an increased risk of venous thromboembolism (VTE) in all users but particularly in obese women.
  • Alternatives to COCs à cyclic progestin therapy, continuous progestin therapy (progestin-only pills [the “mini-pill”]), or a progestin-releasing intrauterine device (IUD).
  • Alternative à medroxyprogesterone acetate (5 to 10 mg) for 10 to 14 days every one to two months.
  • Both continuous progestin therapy (eg, a progestin-only pill such as norethindrone 0.35 mg/day)and the progestin-releasing IUD provide contraception and reduce the risk of endometrial hyperplasia.
  • Metformin is a potential alternative to restore menstrual cyclicity as it restores ovulatory menses in approximately 30 to 50 percent of women with PCOS
  • Its ability to provide endometrial protection is less well established, and we therefore consider it to be second-line therapy

Androgen excess

Hirsutism — 

  • COC as first-line pharmacologic therapy for most women
  • An antiandrogen is then added after six months if the cosmetic response is suboptimal
  • COCs and an antiandrogen may sometimes be started simultaneously at the outset, particularly when the cutaneous manifestations are bothersome to the patient.
  • Progestins with lower androgenicity include desogestrel, cyproterone acetate, and drospirenone, but all have been associated with a possible higher risk of venous thromboembolism (VTE).
  • Norgestimate is a progestin with low androgenicity and similar VTE risk to norethindrone and levonorgestrel. However, there are currently no COCs containing 20 mcg of ethinyl estradiol with norgestimate.

Antiandrogens — After six months, if the patient is not satisfied with the clinical response to COC monotherapy (for hyperandrogenic symptoms), we typically add spironolactone 50 to 100 mg twice daily

Other à

  • finasteride, which inhibits 5-alpha-reductase type 2, the enzyme that converts testosterone to dihydrotestosterone (DHT), and 
  • dutasteride, an inhibitor of both 5-alpha-reductase types 1 and 2. No clinical trial data are available for dutasteride use in hirsute women.
  • Cyproterone acetate 
  • Gonadotropin-releasing hormone (GnRH) agonists are also sometimes used à “add-back” estrogen-progestin therapy is necessary to avoid bone loss and estrogen deficiency symptoms.
  • Although some clinicians use metformin to treat hirsutism, the Endocrine Society Clinical Practice Guidelines suggest against its routine use as it is associated with minimal or no benefit and is less effective than treatment with COCs and/or antiandrogens
  • Hirsutism can also be treated by removal of hair by mechanical means such as shaving, waxing, depilatories, electrolysis, or laser treatment.
  • In addition, eflornithine hydrochloride cream (13.9%) is a topical drug that inhibits hair growth. It is not a depilatory and must be used indefinitely to prevent regrowth.

Acne and androgenetic alopecia — management of acne and scalp hair loss (androgenetic alopecia) in women with PCOS

Metabolic abnormalities

Obesity — 

  • Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the first-line intervention for most women.
  • approach àstarting with lifestyle changes (diet and exercise) à followed by pharmacotherapy, and, when necessary, bariatric surgery

Even modest weight loss (5 to 10 percent reduction in body weight) in women with PCOS may result in restoration of normal ovulatory cycles and improved pregnancy rates

Bariatric surgery — Bariatric surgery is another strategy for weight loss in women with PCOS.

Insulin resistance/type 2 diabetes — 

Several drugs, including biguanides (metformin) and thiazolidinediones (pioglitazonerosiglitazone), can reduce insulin levels in women with PCOS.

These drugs may also reduce ovarian androgen production (and serum free testosterone concentrations) and restore normal menstrual cyclicity

Though not specifically approved for PCOS, liraglutide is approved for individuals with a BMI of 30 kg/m2 or greater. Limited data in women with PCOS suggest that liraglutide results in greater weight loss than placebo

Dyslipidemia — The approach to treatment of dyslipidemia in women with PCOS is the same as for other patients with dyslipidemia. Exercise and weight loss are the first-line approach, followed by pharmacotherapy, if needed.

Statins — Statins are effective for dyslipidemia in women with PCOS but do not appear to have other clinically important metabolic or endocrine effects.

Obstructive sleep apnea — Sleep apnea, a common disorder in women with PCOS, is an important determinant of insulin resistance, glucose intolerance, and type 2 diabetes

treatment with continuous positive airway pressure (CPAP) improved insulin sensitivity and reduced diastolic blood pressure

Nonalcoholic steatohepatitis — 

The prevalence of nonalcoholic steatohepatitis (NASH) appears to be increased in women with PCOS. Both weight loss and metformin use appear to improve metabolic and hepatic function in these women

Women pursuing pregnancy

Weight loss — 

For anovulatory women with PCOS who are overweight or obese, we suggest weight loss prior to initiating ovulation induction therapy.

Ovulation induction medications

●For oligoovulatory women with PCOS undergoing ovulation induction,

letrozole as first-line therapy over clomiphene citrate, regardless of the patient’s BMI.

Before starting letrozole, the clinician must discuss that this use of the drug is not approved by the US Food and Drug Administration (FDA) for this purpose and that there is an available alternative (clomiphene citrate).

Clomiphene citrate had been the first-line drug for this population for many years, with metformin used as an alternative.

However, both clomiphene and metformin appear to be less effective for live birth rates than letrozole 

Metformin –

has been used to promote ovulation either alone or in combination with clomiphene,

clomiphene or letrozole monotherapy appears to be superior to metformin monotherapy on live birth rates.

Current guidelines recommend against the routine use of metformin in obese women with PCOS (including ovulation induction), except in women with glucose intolerance who have failed lifestyle interventions

Gonadotropin therapy –

Another method to induce ovulation is administration of exogenous gonadotropins

pulsatile GnRH may be a reasonable option, particularly for lean women with PCOS.

Women with PCOS and anovulatory infertility treated with gonadotropins are at high risk for ovarian hyperstimulation syndrome (OHSS).

Laparoscopic surgery — 

In the past, wedge resection of the ovaries was a standard treatment for infertility in women with PCOS. However, this approach has been abandoned, both because of the efficacy of clomiphene and because of the high incidence of pelvic adhesions seen with wedge resection.

In vitro fertilization — If weight loss, ovulation induction with medications, and/or laparoscopic ovarian laser electrocautery are unsuccessful, the next step is in vitro fertilization

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