Treatment of polycystic ovary syndrome in adolescents

INTRODUCTION — Polycystic ovary syndrome (PCOS) should be considered in any adolescent girl with a chief complaint of hirsutism, menstrual irregularity, or obesity. Acanthosis nigricans, treatment-resistant acne, scalp hair loss, or hyperhidrosis may alternatively be the chief complaint, although these features are not always present. PCOS is diagnosed in adolescents with otherwise unexplained persistent hyperandrogenic anovulatory symptoms that are inappropriate for age and stage of adolescence [1]. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents", section on 'Clinical features'.)

The diagnosis of PCOS has lifelong implications, with increased risk for infertility, metabolic syndrome, type 2 diabetes mellitus, cardiovascular events, and endometrial carcinoma [2-7].

Treatment for PCOS in adolescents is primarily symptomatic and directed at the major clinical manifestations, which are:

●Abnormal uterine bleeding – Menstrual irregularity or excessive bleeding

●Cutaneous hyperandrogenism – Primarily hirsutism and persistent acne

●Obesity and insulin resistance

Several treatment options have been developed for each of these in adults, and some options address more than one symptom [1,3,8]. Few clinical trials focus on treatment of PCOS in adolescents. Recommendations for the management of PCOS in adolescents were presented by two international expert groups representing diverse professional stakeholder organizations in 2017 and 2018 [9-12]. Strategies for managing PCOS and associated symptoms in adolescents are discussed in this topic review.

Other aspects of PCOS in adolescents are discussed in separate topic reviews:

●(See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)

●(See "Diagnostic evaluation of polycystic ovary syndrome in adolescents".)

●(See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)

MANAGEMENT STRATEGY

Overview — The choice of therapy for PCOS depends on the individual adolescent's symptoms and her goals and preferences [10]:

●First-line treatment for PCOS is ordinarily estrogen-progestin combination oral contraceptives (COCs) since these correct both menstrual abnormalities and hyperandrogenemia (table 1) [10,13,14].

●If hirsutism is not controlled satisfactorily by cosmetic and COC treatment, antiandrogen and/or direct hair reduction therapy are then added [13].

●For the overweight and obesity that may be associated with PCOS, lifestyle modification is first-line treatment [9,15].

●If the abnormal glucose tolerance or lipid abnormalities of the metabolic syndrome cannot be normalized by weight loss, if ovulation is the primary goal, or if personal preferences preclude the use of COCs, treatment with metformin may be helpful.

In most cases, treatment is initiated only after documenting persistent hyperandrogenism and anovulation, which are required to confirm the diagnosis of PCOS [1,16]. In some cases, the symptoms are sufficiently severe (eg, hirsutism) or acute (eg, excessive uterine bleeding) to require prompt empiric treatment with COCs before persistent hyperandrogenic anovulation can be documented. Because this treatment masks the hyperandrogenism and anovulatory symptoms, it also precludes a firm diagnosis of PCOS. In such cases, pretreatment diagnostic screening should be initiated to the extent possible (see "Diagnostic evaluation of polycystic ovary syndrome in adolescents"). In this way, a provisional diagnosis of PCOS can be made. After the patient reaches gynecologic maturity, the diagnosis of PCOS can be confirmed by demonstrating persistence of PCOS manifestations during a trial off COC treatment for a few months. If a trial off of COC is attempted, it should be coupled with contraceptive counseling because the infertility of PCOS is relative, not absolute.

The optimal duration of treatment has not been determined. Whereas PCOS ordinarily persists, little is known about the natural history of PCOS diagnosed in adolescence, particularly in mild cases. We advise continuing treatment until the patient is gynecologically mature (five years postmenarcheal) or has lost a substantial amount of excess weight if obesity is a coexisting condition.

Management of PCOS in adolescents also includes evaluation of first-degree relatives because the hyperandrogenism and metabolic components of the syndrome have familial elements. (See 'Family evaluation' below.)

Goals of treatment include addressing each of the following major symptoms:

Abnormal uterine bleeding — PCOS in adolescents is characterized by anovulatory symptoms, which can manifest as menstrual irregularity and/or excessive menstrual bleeding. The thresholds for defining these abnormal uterine bleeding patterns in adolescents are discussed separately (table 2). (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents", section on 'Anovulation'.)

Menstrual irregularity — Menstrual irregularity should be treated in adolescents with PCOS, not only for psychosocial reasons, but because chronic anovulation increases the risk of developing endometrial hyperplasia, which is associated with endometrial carcinoma. Progestin is the critical ingredient in COCs that inhibits endometrial proliferation; it prevents the hyperplasia that results from unopposed estrogen action. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis" and "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)

Excessive menstrual bleeding — Excessive irregular menstrual bleeding due to ovulatory dysfunction is a common manifestation of PCOS and often is the initial presenting complaint (table 2). Heavy uterine bleeding can cause anemia of a critical degree. COCs or progestin-only regimens are usually effective in managing this symptom. However, transfusion, antifibrinolytic, or invasive treatment occasionally may be required [17]. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents", section on 'Anovulation' and "Abnormal uterine bleeding in adolescents: Management".)

Cutaneous hyperandrogenism — Over one-half of PCOS adolescents have hirsutism or moderate to severe acne vulgaris. Medical endocrine therapy improves these manifestations, decreasing the effect of excess androgens by:

●Reducing androgen production

●Reducing serum free androgen levels by increasing androgen binding to serum sex hormone-binding globulin (SHBG)

●Blocking androgen action at the level of target organs (eg, hair follicle)

COCs accomplish the first two of these goals. They lower serum free testosterone levels mainly by decreasing ovarian production via suppression of serum gonadotropin levels, and the estrogenic component increases serum SHBG levels. They also modestly lower dehydroepiandrosterone sulfate (DHEAS) levels. Reducing androgen levels hinders the further transformation of vellus to terminal hairs, which occurs with androgen exposure. In most patients with PCOS, treatment with COCs can be expected to arrest progression of hirsutism, reduce the need for shaving by approximately one-half, and improve acne within three months.

Antiandrogenic therapy, which inhibits binding of androgen to its receptor, is indicated for patients with hirsutism that does not respond sufficiently to COC treatment and physical measures. (See 'Antiandrogens' below.)

Obesity and insulin resistance — Insulin-resistant hyperinsulinism is an important factor in the pathogenesis of PCOS and its complications. Treatments that reduce insulin resistance improve ovulation moderately and hyperandrogenemia slightly. Obesity is an important contributor to the insulin resistance of PCOS, although the insulin resistance is disproportionately greater than can be explained simply by the degree of adiposity. Insulin resistance is commonly manifested as acanthosis nigricans and metabolic syndrome, although it may exist in the absence of these clinical findings. Diet and exercise are first-line treatment to address obesity in adolescents with PCOS. Metformin is appropriate for patients with impaired glucose tolerance as an adjunct to lifestyle management and, usually, COCs. (See 'Obesity and insulin resistance' below.)

THERAPEUTIC MODALITIES — First-line treatment of PCOS is ordinarily estrogen-progestin combination oral contraceptives (COCs) since these treat both menstrual abnormalities and the cutaneous manifestations of hyperandrogenemia [8,13]. It is combined with weight management for patients with obesity [10]. Additional strategies can be offered to patients with cutaneous hyperandrogenism or abnormal glucose tolerance that is not adequately controlled by these hormonal treatments (table 1). (See 'Hirsutism' below and 'Insulin resistance' below.)

Combination oral contraceptives

Indications — COCs, which contain estrogen and progestin, usually are the first-line treatment for adolescents with PCOS and abnormal menstrual bleeding or cutaneous signs of androgen excess. The estrogen-progestin combination suppresses the hypothalamic-pituitary-ovarian axis and reduces excess androgen production by the ovary, which improves menstrual regularity and decreases anovulatory uterine bleeding, hirsutism, and acne. The progestin component also inhibits endometrial proliferation, preventing hyperplasia and the associated risk of carcinoma. COCs are packaged such that the active ingredients are ordinarily taken once daily for 21 successive days, and withdrawal bleeding is expected during the following week when inert ingredients are taken as a spacer. COCs regulate menstrual periods with a higher degree of reliability than other forms of treatment. International and Endocrine Society guidelines suggest COCs as first-line pharmacologic therapy of menstrual irregularity [8,10] and hirsutism [10,13].

Drug selection — In general, we suggest selecting a COC that contains at least 30 mcg ethinyl estradiol, unless the adolescent is at risk for COC side effects (see 'Limitations' below). This is because COCs containing ≤20 mcg ethinyl estradiol, though posing little cardiovascular risk, may inadequately promote normal accrual of bone mass [18] and may be less effective in controlling irregular menstrual bleeding, particularly in obese hyperandrogenic girls, than those containing 30 to 35 mcg ethinyl estradiol.

COCs may carry a more deleterious metabolic risk profile in obese women with PCOS than those without PCOS [19-22]. For this reason, we ordinarily use a COC that has a progestin with antiandrogenic or minimal androgenic activity, as illustrated in the list below. However, consistent clinically significant differences in androgenic and metabolic effects have not been found among commonly used COCs [23,24]. All COCs are efficacious for treating hirsutism and acne [13,25]. Those listed below may be the most advantageous. The choice of agent depends mainly upon the clinical manifestation(s) of the individual patient and cost/insurance considerations. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Hormone components' and "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Dosing regimens'.)

●Drospirenone – Drospirenone is a progestational analog of spironolactone with antiandrogenic and antimineralocorticoid properties; it is combined with ethinyl estradiol: 20 mcg for 24/28 days (in Yaz) or 30 mcg for 21/28 days (in Yasmin) [26]. Its unique properties seem particularly well suited for patients with PCOS because its natriuretic effect minimizes the fluid retention that occurs with other COCs [27,28]. Drospirenone-containing COCs have approximately a 50 percent higher risk of venous thromboembolism (VTE) than norgestimate-containing COCs (table 3) [13]. However, the overall risk is still very low.

●Norgestimate – Norgestimate is a potent progestin with marginal androgenic effect; it is combined with ethinyl estradiol 35 mcg (as in Ortho-Cyclen or Ortho-Tri-Cyclen). There is variable absorption of this medication. The US Food and Drug Administration (FDA) has approved this combination for the treatment of acne. Other approved combinations include drospirenone (Yaz, above) or the more androgenic progestin norethisterone (also called norethindrone). Norethisterone is available as Estrostep (in a 1 mg dose, combined with graduated doses of ethinyl estradiol 20 to 35 mcg). Norethisterone is also the active progestin metabolite of ethynodiol diacetate in Zovia 1/35 and 1/50, which contains 1 mg ethynodiol diacetate with 35 or 50 mcg ethinyl estradiol, respectively [29]. The 1/50 preparation is useful for patients who require a large dose of estrogen, such as those with obesity or heavy uterine bleeding [30]; after control is achieved, maintenance should be attempted at the lower estrogen dose.

Menstrual abnormalities usually can be controlled within one to two months of starting COC treatment, in our experience. COC therapy will normalize androgen levels within 18 to 21 days. We suggest rechecking serum free testosterone late in the third cycle of COC treatment. Because of escape from ovarian suppression during the pill-free interval, exceptional patients require an extended cycle COC to control severe hyperandrogenemia [31]. If treatment is not successful in reducing androgen levels, the patient either has an unusually prominent component of functional adrenal hyperandrogenism to the PCOS or the diagnosis of PCOS should be questioned. For such patients, we suggest referral to an endocrinologist for further evaluation. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Further evaluation by endocrinology subspecialists for rare disorders mimicking PCOS'.)

Treatment of heavy menstrual bleeding is similar in adolescents with or without PCOS. The estrogen doses required to treat excessive abnormal uterine bleeding may be three- to fourfold higher than the doses needed to treat irregular menses [32]. Once active bleeding is controlled, therapy with cyclic COC or progestin should be started to prevent recurrence of abnormal uterine bleeding. (See "Abnormal uterine bleeding in adolescents: Management".)

For adolescents who respond to and tolerate COC treatment, we suggest continuing for a few years, then withholding treatment for three months to allow recovery of suppression of pituitary-gonadal function and to check for persistence of PCOS features [10]. In doing so, however, one must provide contraceptive counseling since patients with PCOS may conceive despite their tendency for anovulatory cycles and relative infertility.

Gynecologic referral is indicated for patients who have uncontrollable menstrual irregularity despite COC therapy or whose bleeding cannot be controlled medically.

Limitations — The role of COCs in the management of PCOS in adolescents may be limited for several reasons:

●Overall, COCs carry approximately a fourfold increased risk of VTE compared with patients who are not using COCs (table 3) [33-35]. The risk is primarily related to the dose and duration of estrogen use and the use of recent-generation progestins (eg, drospirenone, desogestrel), which confer approximately a 50 to 100 percent independent risk over first-generation progestins (table 3). This risk is less than that of pregnancy [36]. PCOS and obesity independently appear to pose a slightly increased risk for VTE; while population studies are unclear as to whether COCs further increase this risk [37,38], a desogestrel-containing COC has been reported to significantly increase thrombin generation, a VTE risk factor, in PCOS [39] (see "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Venous thromboembolism'). For most women with PCOS, the benefits of oral contraceptives outweigh the potential risks of VTE. A detailed discussion of the risks and side effects of COCs is presented separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)

●Overall, COCs containing 30 to 40 mcg ethinyl estradiol carry a small increased risk (approximately 1.5 to 2-fold) of thrombotic stroke and myocardial infarction in 15- to 49-year-old women compared with those who are not taking COCs [40]. The overall risks of these disorders in this population are low: approximately 20 and 10 events per 100,000 person years, respectively. This risk is not influenced by type of progestin.

●In perimenarcheal girls with short stature for whom growth potential is important, the risk of growth inhibition by the COC estrogen must be considered.

●Estrogen promotes salt and water retention [41]. Thus, COCs may impede weight loss measures, though generally not significantly [42]. Ethinyl estradiol-containing contraceptives raise blood pressure significantly unless they contain an antimineralocorticoid progestin [28]. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Weight gain' and "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Hypertension'.)

●The patient may believe the treatment is curative and defer follow-up.

●The contraceptive effect of COCs is inappropriate for those desiring pregnancy.

Concerns have been raised that the incompletely mature adolescent neuroendocrine system may have heightened risk for post-pill amenorrhea and infertility [43]. However, this hypothetical concern is based on observations in other patient groups undergoing treatment with high-dose estrogens during adolescence. Most post-pill amenorrhea is thought to reflect the presence of an undiagnosed preexisting condition, such as PCOS or hyperprolactinemia.

Progestin

●Cyclic oral progestin – Menstrual irregularities in sexually mature adolescents often can be controlled with cyclic progestin alone. Cyclic progestin is particularly useful in younger patients with menstrual irregularity but without clinical evidence of hyperandrogenism, before the diagnosis of PCOS can be established. It is also useful when there are contraindications or patient objections to estrogen-containing COCs. Progestin therapy in a six-week cycle can also permit the detection of the emergence of normal menstrual cyclicity. As an example, the perimenarcheal girl who responds well to progestin therapy can be maintained on six-week cycles, permitting the detection of spontaneous menses.

Micronized progesterone (Prometrium, 100 to 200 mg given orally at bedtime), medroxyprogesterone acetate (DMPA; Provera, 10 mg given orally at bedtime), or norethisterone/norethindrone (Aygestin, 2.5 to 10 mg given orally daily) can be used for 7 to 10 days out of each month or cycle. Anovulatory menstrual flow can be expected to cease during progestin administration, and withdrawal bleeding can be expected to occur within a few days of cessation of the course of progestin administration. Patients must be informed that oral progestin prescribed to regulate menstrual cyclicity (ie, 7 to 10 days each month) is not a means of contraception.

Cyclic treatment with oral progestins relies on their direct inhibitory effects on endometrial proliferation. Unlike COCs, cyclic therapy with oral progestins is not effective in treating hirsutism; transient reduction in androgen levels is achieved, but this is variable and generally insufficient to expect improvement in hirsutism [44,45]. Side effects of progestin include mood symptoms (eg, depression), bloating, and breast soreness. Progesterone itself confers no risk for cardiovascular disease or breast cancer and may lessen the small estrogen-related increase in risk in premenopausal women [46,47].

●Depot progestin – For patients who require long-term contraceptive effects without effects on clinical hyperandrogenism, depot progestin-only contraceptives such as DMPA (Depo-Provera) 150 mg intramuscularly every three months, or the etonogestrel implant (Nexplanon) are often a good choice.

These are generally effective contraceptives because the high and sustained doses of progestins suppress gonadotropins. However, the hyperandrogenism of PCOS variably antagonizes the gonadotropin-suppressive [48,49] and endometrium-inhibiting [50] effects of progestins, which limits their efficacy in treating hyperandrogenism [51] and warrant watchfulness in monitoring their efficacy as contraceptives in PCOS. If hyperandrogenism becomes a clinically significant problem, appropriate alternatives should be explored.

Long-term use of DMPA is associated with mild hypogonadotropic estrogen deficiency. This seems responsible for a mild, reversible reduction in bone mineral density [52], whereas the effect of COCs on bone mineral density is unclear [53]. DMPA has also been associated with increases in weight and adiposity [54], but the extent of these changes is inconsistent among studies. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Weight changes'.)

Other androgen-reducing therapies — Rarely, the following interventions are used instead of COCs or progestin-only treatment:

●Gonadotropin-releasing hormone (GnRH) agonist therapy (eg, depot leuprolide) can be used instead of COCs to suppress ovarian function in the rare patient who cannot tolerate COCs (such as PCOS secondary to autoimmune insulin resistance) or for those with severe forms of hyperandrogenemia (such as ovarian hyperthecosis) who have a suboptimal response to COCs and antiandrogens [13,55,56]. Patients who receive GnRH agonist therapy also should be treated with low-dose physiologic estradiol and cyclic progestin "add-back" therapy (eg, 50 to 100 mcg estradiol transdermal patch) to maintain vaginal lubrication and to ensure bone mineral accrual if used during adolescence. Bone mineral density should be monitored during prolonged therapy. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

●A glucocorticoid therapeutic trial may be considered in the unusual situation of the nonobese patient whose PCOS seems solely due to functional adrenal hyperandrogenism (as occurs in 5 percent of PCOS, in contrast with ovarian hyperandrogenism, which is far more common) [57]. This possibility is raised if the patient does not experience normalization of serum testosterone during treatment with COCs and confirmed if other causes of hyperandrogenism are excluded during a thorough endocrine evaluation, including a dexamethasone-androgen suppression test (see "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Further evaluation by endocrinology subspecialists for rare disorders mimicking PCOS'). Glucocorticoid effects on ovulation and hirsutism are inconsistent [13,58]. If glucocorticoids are used, they should be given under the supervision of an endocrinologist at low doses (similar to those used for nonclassic congenital adrenal hyperplasia) and should not be administered for more than a few months, unless there is an unequivocally good response.

ADDITIONAL MEASURES FOR SPECIFIC SYMPTOMS

Hirsutism — If hirsutism is not controlled satisfactorily within six months with both cosmetic measures and estrogen-progestin combination oral contraceptives (COCs), or the alternative treatments outlined above, then additional treatments can be added [14]. Options are direct hair removal measures, hormonal therapy, or both. The costs of these treatments are not covered by third-party payers. The decision among these options depends upon patient preference, including cost of the measure, tolerance of discomfort/pain, risk of complications, and outcome. The 2018 Endocrine Society clinical guideline for the treatment of hirsutism suggests first adding antiandrogen therapy and supplementing this with direct hair removal therapy if necessary in hyperandrogenic women, such as those with PCOS [13]. A summary on the treatment of hirsutism will be presented below. More detailed discussions are found separately. (See "Management of hirsutism in premenopausal women" and "Acne vulgaris: Overview of management" and "Hidradenitis suppurativa: Management".)

Acne — For acne resistant to first-line topical treatments, clascoterone, an antiandrogen, may be useful. It has been approved by the US Food and Drug Administration (FDA) as a 1% cream for the topical treatment of acne for patients 12 years of age and older [59]. Long-term safety studies are limited but have shown no systemic antiandrogenic effects. (See "Acne vulgaris: Overview of management".)

Adolescent females with acne resistant to topical treatments should be evaluated for androgen excess [1]. Hyperandrogenism would, in most cases, be due to PCOS and be an indication for COC treatment. Patients with refractory acne or hirsutism may also benefit from antiandrogens. (See 'Medical therapy' below.)

Cosmetic and direct hair removal measures — Cosmetic measures to mask and remove excess hair are the cornerstone of all treatments for hirsutism [9]. These measures consist of shaving, chemical depilatory agents, bleaching, and waxing techniques. They provide temporary improvement and can be repeated as necessary. Although they can cause skin irritation, they are essentially safe, often efficacious, and relatively inexpensive. (See "Removal of unwanted hair", section on 'Temporary methods'.)

Each of the following treatments results in approximately a 30 to 70 percent reduction of hirsutism. While these treatments are efficacious alone, they are most effective when combined with medical therapy to minimize hair regrowth [13]:

●Eflornithine hydrochloride cream (Vaniqa) is a topical agent available by prescription that is FDA approved for the reduction of unwanted facial hair in women [13]. It inhibits the rate of hair growth and takes approximately six to eight weeks to see clinical effect. It needs to be used repeatedly and indefinitely to prevent regrowth. It is a useful adjunct to photoepilation, providing a more rapid response. It may be preferable to photoepilation in Mediterranean and Middle Eastern women with facial hirsutism because of their increased risk of developing paradoxical hypertrichosis [13]. (See "Removal of unwanted hair", section on 'Pharmacologic options'.)

●Photoepilation (laser and intense pulsed light) therapy reduces hair permanently by thermal destruction of the dermal papilla [13]. FDA-approved devices will permanently reduce hair density by 30 percent or more with three to four treatments of a site. This treatment can only be applied to a limited area but is nevertheless a more efficient means of hair removal than electrolysis. It is not efficacious in blond- or white-haired individuals because melanin pigment is essential for photoepilation. In some individuals, especially heavily tanned or darker-skinned patients, burns with residual pigment changes and scarring may occur. For this reason, a long-wavelength, long pulse-duration laser delivered with appropriate skin cooling is the preferable photoepilation mode for women of color. The costliness of the therapy limits its use. (See "Removal of unwanted hair", section on 'Laser and intense pulsed light'.)

●Electrolysis can remove hair permanently because it destroys the dermal papilla. It is a slow, expensive therapy that can be uncomfortable and occasionally causes scarring. Because of the expense and discomfort, electrolysis is generally only practical for treating limited areas of the body. It is the preferred method for direct hair reduction in blond- or white-haired women. It is preferable to photoepilation in Mediterranean and Middle Eastern women with facial hirsutism because of their increased risk of developing paradoxical hypertrichosis [13]. (See "Removal of unwanted hair", section on 'Electrolysis'.)

Medical therapy — Medical endocrinologic treatment of hirsutism is another treatment option. All hormonal treatment for hirsutism is off-label in the United States [13,60].

Combination oral contraceptives — COCs are the usual first-line medical therapy for hirsutism, as discussed above. Although their use for hirsutism is off-label, their use for acne is a labeled indication. (See 'Combination oral contraceptives' above.)

Antiandrogens — The decision to add an antiandrogen to a COC depends on the severity of the hirsutism and considerations of efficacy, side effects, and costs. (See "Management of hirsutism in premenopausal women".)

Antiandrogenic therapy in combination with a COC reduces hirsutism by one-third on average, although there is considerable individual variation [61]. Antiandrogens act by inhibiting the androgen-induced transformation of vellus to terminal hairs. Thus, the maximum effects of these agents usually are not appreciated for 9 to 12 months, because of the long growth cycles of sexual hair follicles.

Antiandrogens should be prescribed with a contraceptive measure because of their potential for teratogenic feminization of the male fetus. The optimal choice for contraception in this setting is a COC because this will also treat the menstrual disturbance that is often caused by antiandrogens. Antiandrogens have only a modest effect on the metabolic abnormalities associated with PCOS [62]. As for all patients with PCOS, we suggest selecting a nonandrogenic COC if possible, as discussed above. (See 'Combination oral contraceptives' above.)

The antiandrogens include the following (table 1):

●Spironolactone probably is the safest and most effective antiandrogen available in the United States [13]. In combination with COCs, it lowers the hirsutism score (figure 1) by approximately one-third, although there is considerable individual variation. The randomized control trials and meta-analysis demonstrating the benefit of spironolactone are discussed separately. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

Guidelines recommend starting with a dose at the upper end of the therapeutic range, ie, 100 to 200 mg given in two divided doses daily [13]. Approximately 9 to 12 months of therapy is required to achieve the maximal effect because of the long hair growth cycle. After one year of therapy, the dose can be reduced gradually for maintenance therapy as efficacious. Spironolactone must be administered as long as the patient wishes to maintain her improvement in hirsutism. Spironolactone usually is well tolerated at these doses, but fatigue and hyperkalemia rarely limit its usefulness in some patients. Laboratory testing of electrolytes and liver function tests should be performed one to two weeks after initiation of spironolactone therapy to determine whether the spironolactone dose should be lowered.

●Cyproterone acetate is a progestin with antiandrogenic activity that is sometimes used for the treatment of hirsutism. It is not available in the United States but is available in Canada and Mexico as a COC containing ethinyl estradiol and low-dose cyproterone acetate (5 mg; Diane). It also is available in Europe in this form and as a high-dose (50 mg) progestin tablet that can be combined with any form of estrogen. Drug regulatory agencies in Europe have recommended limiting its use to "second-line" therapy because of a perceived increase in risk of hepatotoxicity compared with other available progestins [63,64]. In addition, high-dose cyproterone acetate is associated with a small increase in the risk of meningioma and is contraindicated in people with a history of meningioma. (See "Management of hirsutism in premenopausal women", section on 'Suggested drug: spironolactone' and "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'High-dose cyproterone'.)

●Other competitive inhibitors of androgen receptor action – Flutamide is a more specific antiandrogen with efficacy similar to that of cyproterone. Its use has been limited by expense and the rare risk of fatal hepatocellular toxicity [65]. Flutamide may permit ovulation in women with PCOS; however, its utility for women who wish to conceive is limited by the potential risk of feminization of the male fetus. The Endocrine Society hirsutism guidelines suggest against the routine use of flutamide because of its potential hepatotoxicity, expense, and the availability of other effective antiandrogens [13]. While it has been argued that low-dose flutamide is safe [66], the population studied is too small to be certain. There is less experience with newer more potent and selective antiandrogens [67,68]. (See "Management of hirsutism in premenopausal women".)

●Finasteride interferes with androgen action by competitively inhibiting 5-alpha-reductase type 1. It has seemed slightly less effective than spironolactone in some studies on the treatment of women with hirsutism. However, meta-analysis of the limited available data has not shown a significant difference in efficacy between these treatments [13]. The usual dose is 5 mg daily.

A more detailed discussion of these antiandrogens in the treatment of hirsutism is discussed separately. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

Obesity and insulin resistance

Obesity — For overweight and obese patients with PCOS, weight management is a major treatment goal, especially if the ovarian dysfunction is mild [9,15]. Healthy lifestyle interventions are essential and often require attention to psychosocial and behavioral factors [9,11]. There seems to be no advantage to a low-glycemic index or low-carbohydrate diet over a low-fat diet [69,70]; rather, a reduction of both carbohydrate and fat intake in the context of a high-quality diet of natural foods is indicated, as with any individual with obesity [15,71].

Patients with obesity typically experience improvement in their anovulatory symptoms roughly in proportion to the amount of weight loss [69]. Improvement in hyperandrogenism is minimal, however [13,70]. Patients with the most severe ovarian dysfunction are those least likely to experience symptomatic improvement with weight loss [72]. This is consistent with the concept that it is the patients with the atypical PCOS caused by obesity who can expect the greatest symptomatic benefits with weight loss [57].

Substantial and sustained improvements in weight or glycemic control are difficult to achieve, even when a lifestyle intervention program with family involvement is undertaken [15] or when metformin is combined with behavior modification [73,74].

Bariatric surgery has led to improvement in hirsutism, androgen levels, and menses in the vast majority of obese adults with PCOS [75]. Much of this appears to be due to the atypical form of PCOS caused by obesity [57,76] (see "Etiology and pathophysiology of polycystic ovary syndrome in adolescents"). Even eumenorrheic women with severe obesity usually have an ovulatory defect manifest as luteal dysfunction, and this defect is only partially corrected after surgically induced weight loss [77]. Bariatric surgery is suggested only for select adolescent patients with extremely high body mass index and access to centers that specialize in bariatric surgery in this age group [15]. (See "Obesity in adults: Behavioral therapy" and "Obesity in adults: Role of physical activity and exercise" and "Obesity in adults: Dietary therapy" and "Surgical management of severe obesity in adolescents".)

Insulin resistance — Patients with PCOS and insulin resistance may benefit from adjunctive treatment to improve glucose metabolism [10]. Metformin is the usual first-line choice for this purpose. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Insulin-resistant hyperinsulinism'.)

Metformin — Metformin is an option to add to COCs for the management of obesity and clinical evidence of insulin resistance (acanthosis nigricans, dyslipidemia, impaired glucose tolerance) in adolescents with PCOS, if lifestyle counseling alone (diet, exercise, psychological support) has been ineffective for weight control [9,10]. This is an off-label use; type 2 diabetes is the only indication for which metformin is approved by the FDA. In addition, metformin may be tried as a primary treatment option, together with lifestyle counseling measures, if ovulation is the primary goal or if personal preferences preclude the use of COCs [9,10].

●Mechanisms of action – Metformin is an insulin sensitizer, with many additional actions. It primarily lowers insulin levels by reducing hepatic glucose production [78-82]. The classic mechanism of action of metformin on glucose metabolism principally involves reducing liver mitochondrial energy generation so that hepatic gluconeogenesis is decreased and insulin sensitivity is increased, though the molecular basis is a matter of controversy [78,79,82]. At micromolar serum concentrations, metformin reduces both postprandial glucose and hepatic fat content by binding to a secretase subunit, PEN2, which, in turn, complexes with a lysosomal protein pump ATPase, thereby stimulating lysosomal adenosine monophosphate (AMP)-activated protein kinase [83]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Mechanism of action'.)

However, at least one-half of metformin's effects are attributable to weight loss because of its anorexic effect, which is mediated at least in part through actions in the gut [84]. Phase I and II studies of a delayed-release form of metformin that restricts its activity to the lower bowel showed that glycemic control of diabetes improves at relatively low plasma metformin levels [85]. Metformin's enhancement of entero-endocrine cell production of the incretin glucagon-like peptide 1 (GLP-1) [85] and alteration of the gut microbiome appear to contribute to these gut effects on glucose tolerance [86].

Several enteric hormones appear to mediate the anorexic action of metformin. Metformin elevates serum growth and development factor 15 (GDF15) by stimulating its release from hepatocytes [81], intestinal wall epithelium, and kidney [84,87]. In mice, GDF15 is essential to the metformin effect on appetite, weight, and serum insulin [84]. Metformin also stimulates secretion of the incretins gastric inhibitory polypeptide and gut peptide YY, which suppress appetite [87,88].

In addition, metformin exerts a myriad of effects through other mechanisms. These include suppression of inflammatory cytokines [89], stimulation of adipogenesis [90], alteration of gene expression via differential microRNA expression [91], and tumor suppression [92]. This literature must be interpreted with caution: The therapeutic serum concentration of metformin is approximately 1 micromolar or less, and many of these putative effects would require suprapharmacologic doses of metformin [82,83].

These biochemical processes have the potential to exert a broad spectrum of effects, with clinical sequelae that are both positive (direct inhibition of ovarian steroidogenesis [93-95]) and rarely negative (lactic acidosis [96]).

●Clinical effects – In patients with PCOS, metformin reduces insulin concentrations, promotes ovulation, and lowers androgen levels modestly (by approximately 20 percent) but not sufficiently to improve hirsutism [13,97-100]. Some studies suggest that a patient's metabolic [101] or ovulatory [102] responsiveness to metformin is influenced by various genetic polymorphisms related to metformin transport. Although a relationship of some gene variants to glucose control in diabetic individuals is well established [92,103,104], the only randomized clinical trial to date in PCOS found no relationship of gene variants to weight or metabolic outcomes [105]. Some groups have reported that metformin improves androgen levels in the absence of insulin resistance [106-108]; these data are consistent with the concept that levels of insulin in the normal range modulate the androgenic response to luteinizing hormone (LH) [57].

Three randomized, double-blind, placebo-controlled trials compared metformin with lifestyle counseling for three to six months in adolescents with PCOS [73,74,97]. Metformin was found to significantly improve high-density lipoprotein cholesterol levels. It increased the likelihood of menses significantly in only the shortest of these studies [97], while the other two studies showed only nonsignificant tendencies toward an increase in ovulatory cycles. It did not lower testosterone levels or weight better than lifestyle/placebo. These results are less salutary than those of open-label trials [9].

●Efficacy – To date, randomized trials comparing metformin to COCs in adolescents were not blinded, which limits their quality [109]. While treatment with COCs suppresses mean free testosterone more than metformin, this is not reflected in statistical differences in these relatively small studies [74]. When metformin and COCs are used in combination, the positive effects of metformin on total cholesterol and triglyceride levels are blunted by the negative effects of COCs on these lipids [110]. Metformin has been reported to ameliorate the negative effect of a COC on thrombin generation [39].

Metformin is minimally effective for PCOS in the absence of weight control [111]; variability in weight control may explain the inconsistent effects of metformin treatment on insulin levels [97,112,113]. Metformin lowers testosterone levels modestly (averaging approximately 20 percent), so it is unlikely to normalize androgen levels that are substantially above normal, and the decrease in testosterone level is not enough to appreciably improve hirsutism [97,112-114]. Metformin provides endometrial protection only to the extent that it induces ovulatory menstrual cycles. (See "Metformin for treatment of the polycystic ovary syndrome".)

Prevention of PCOS with metformin has been attempted in two settings. One group administered metformin to a unique population of prepubertal Catalonian girls at high risk for PCOS because of a combined history of low birth weight and premature pubarche [115,116]. The treatment delayed the onset of PCOS features. Two studies evaluated the effect of metformin in pregnant women with PCOS on blood levels of anti-müllerian hormone (AMH), a marker of ovarian pre-antral and antral follicle number, in their female offspring; the results were mixed and do not permit a firm conclusion about the potential effects of this intervention on prevention of PCOS [117,118].

●Dose and monitoring – Metformin therapy for PCOS is started with 500 mg daily. It should be taken before the evening meal to minimize nausea, which is the cause of an approximate 15 percent dropout rate. The dose is gradually increased, as tolerated, to the effective dose of 1000 to 2000 mg daily. The greater doses often may be better tolerated when divided into two daily doses or when given in an extended-release form [119]. An effect on PCOS cannot be anticipated before three months or in the absence of weight control. We suggest obtaining a comprehensive metabolic panel as a baseline because of the rare complication of lactic acidosis [65]. Metformin is contraindicated in patients with impaired hepatic or renal function, alcoholism, or cardiopulmonary insufficiency because it can cause lactic acidosis in these settings.

Other treatments for obesity and insulin resistance — Other treatments for obesity or type 2 diabetes may also be beneficial for patients with PCOS by promoting weight loss, which improves insulin sensitivity. The most promising agents are GLP-1 agonists, which reduce appetite; some are approved in the United States for management of obesity (liraglutide) or type 2 diabetes (liraglutide, exenatide) in adolescents. (See "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy' and "Management of type 2 diabetes mellitus in children and adolescents", section on 'Indications for adding insulin or GLP-1 agonist'.)

The most effective of the obesity pharmacotherapies is the GLP-1 agonist semaglutide, which is only approved for adults. (See "Obesity in adults: Drug therapy".)

Myo-inositol, which, in the form of inositolphosphoglycan, is a second messenger involved in insulin signaling, is a dietary supplement that may be an insulin sensitizer [10,120]. It appears to be safe. The one randomized controlled, double-blind trial of women with PCOS found it to be significantly superior to placebo in improving ovulatory frequency (by approximately twofold) and weight loss (from mean body mass index 35.0 to 34.4 kg/m²) [121].

Dyslipidemia in adolescents with PCOS is generally as expected for the degree of obesity [122]. Dietary modification (a high-fiber, low-glycemic index, low-saturated fat, lower-calorie diet) coupled with behavioral counseling for weight loss is the foundation of dyslipidemia management. Statins worsen insulin resistance yet may slightly improve hyperandrogenism in women with PCOS [123,124]. (See "Dyslipidemia in children and adolescents: Management".)

Novel treatment strategies on the horizon — In some individuals with PCOS, the gonadotropin-releasing hormone (GnRH) pulse generator operates at an abnormally fast frequency, which favors LH over follicle-stimulating hormone secretion. This faster frequency occurs, in part, due to androgen interference with progesterone negative feedback. GnRH pulse frequency is controlled by a set of neurons in the arcuate nucleus of the hypothalamus called KNDy neurons, so-named because they co-express the hormones kisspeptin, neurokinin B, and dynorphin. Neurokinin B acts in an autocrine manner to stimulate pulsatile kisspeptin secretion (through its receptor, NK3R), whereas dynorphin is an antagonist (via the kappa opioid receptor).

It has been hypothesized that pharmacologic interventions to slow the GnRH pulse generator (using an NK3R antagonist or kappa receptor agonist) could be a useful treatment strategy in PCOS. A double-blind, placebo-controlled trial of the NK3R antagonist fezolinetant in 64 women with PCOS indeed demonstrated an 8 to 10 IU/L decrease in LH and 20 to 30 percent decrease in testosterone levels but saw no effect on ovulation (which may relate to the relatively short study duration of 12 weeks) [125]. A study in a murine model of PCOS similarly demonstrated a reduction in LH and testosterone levels as well as normalization of estrous cycles using a kappa receptor agonist [126].

OTHER CONSIDERATIONS — Obese adolescents with PCOS are also at risk for metabolic syndrome and associated risks, such as sleep-disordered breathing, and should therefore be screened accordingly [127-129]. Their quality of life and mental health should also be evaluated. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Additional evaluation of PCOS patients'.)

FAMILY EVALUATION — Because of the high frequency of PCOS and metabolic syndrome among immediate relatives of individuals with PCOS, we recommend screening for features of metabolic syndrome and for diabetes mellitus in first-degree relatives, particularly in those with obesity, and for features of PCOS in those females who are premenopausal. In particular, we suggest screening the overweight or obese parents of women with PCOS for diabetes because only approximately one-half of the parents with diabetes are symptomatic at the time their daughter is diagnosed with PCOS. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Evaluation of family members'.)

OTHER RESOURCES — The following online resources are available to patients with PCOS and their families:

●PCOS Resources for a Healthier You – From the Center for Young Women's Health of Boston Children's Hospital [130]

●Polycystic Ovary Syndrome: A Guide for Families – From the Pediatric Endocrine Society and the American Academy of Pediatrics [131]

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Hirsutism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Polycystic ovary syndrome (The Basics)")

●Beyond the Basics topic (see "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Several treatment options are available for adolescents with polycystic ovary syndrome (PCOS) (table 1). The choice of therapy depends on the individual adolescent's symptoms, her goal for treatment, and her preferences (eg, cost).

●First-line options

•We suggest the use of estrogen-progestin combination oral contraceptives (COCs) as first-line treatment for adolescents who suffer the menstrual and cutaneous symptoms of PCOS, rather than other therapies (Grade 2B). The progestin component inhibits endometrial proliferation, preventing hyperplasia and the associated risk of carcinoma. The estrogen component reduces excess androgen, which corrects menstrual abnormalities promptly and improves hirsutism and acne. An effect of COCs on hirsutism can be seen after three to six months of therapy. We prefer the use of a COC that has antiandrogenic or minimal androgenic activity. As a general rule, COCs should be continued until the patient is gynecologically mature (five years postmenarcheal) or has lost a substantial amount of excess weight. At this time, a trial off of therapy is reasonable to document the persistence of the syndrome. (See 'Combination oral contraceptives' above.)

•If the adolescent patient is unable or unwilling to take COCs, the main other therapeutic option for menstrual irregularities is progestin. (See 'Progestin' above and 'Other androgen-reducing therapies' above.)

●Additional measures for specific symptoms

•Hirsutism – For patients with substantial hirsutism who have an unsatisfactory response to initial treatment by cosmetic measures (such as shaving, bleaching, depilatory agents) in combination with COCs, we suggest either physical hair reduction and/or antiandrogen therapy. The decision among these options involves patient preference, including cost of the measure, tolerance of discomfort/pain, risk of complications, and outcome.

-For patients who choose physical hair reduction, the choice of technique is dependent on the extensiveness of the area affected by hirsutism and patient preference and includes eflornithine hydrochloride cream, electrolysis, and/or laser therapy. (See 'Cosmetic and direct hair removal measures' above and "Removal of unwanted hair".)

-For patients who choose antiandrogen therapy, we suggest adding spironolactone rather than other antiandrogens (Grade 2C). Spironolactone should only be used in combination with COCs because of potential teratogenic effects. Cyproterone acetate is a reasonable alternative, where available. The effects of hormone treatments on hirsutism are maximal after 9 to 12 months of therapy. (See 'Medical therapy' above and "Management of hirsutism in premenopausal women".)

•Acne – The treatment of acne is the same as in patients without PCOS and is discussed separately. (See "Acne vulgaris: Overview of management".)

•Obesity and insulin resistance

-For adolescents with PCOS and obesity, weight loss improves menstrual regularity, acanthosis nigricans, and hyperandrogenemia. Weight-reduction measures (eg, exercise and diet) are the same as in patients with obesity but without PCOS. (See 'Obesity and insulin resistance' above.)

-Insulin-lowering agents improve ovulation in approximately one-half of cases and modestly reduce androgen levels. They are not as effective as COCs in controlling menstrual cyclicity or hirsutism. Metformin is the only one of these agents widely used in adolescents with PCOS, in whom it is used to treat coexistent insulin-resistant metabolic abnormalities and as an adjunct to weight-control measures. (See 'Insulin resistance' above and "Metformin for treatment of the polycystic ovary syndrome".)