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Management of hirsutism in premenopausal women

Management of hirsutism in premenopausal women
Literature review current through: Jan 2024.
This topic last updated: Sep 12, 2023.

INTRODUCTION — Hirsutism, defined as excessive growth of terminal hair in a female, is common (affects between 5 and 10 percent of females of reproductive age) and is associated with significant emotional distress and depression [1-3]. It is usually an indication of an underlying endocrine disorder (most commonly polycystic ovary syndrome [PCOS]) (table 1) [4-7].

Hirsutism is a clinical diagnosis defined by the presence of excess terminal hair growth (dark, coarse hairs) in androgen-dependent areas (eg, upper lip, chin, midsternum, upper abdomen, back, and buttocks) [4,8]. There are several conditions characterized by generalized or "excess" hair growth that do not represent hirsutism and do not require biochemical evaluation with serum androgens, including hypertrichosis and "unwanted hair" (any hair growth [usually light, unpigmented facial hair] that the patient finds bothersome). This type of hair is not a sign of androgen excess, and it does not respond to androgen suppression therapies.

The treatment of hirsutism in women with the two most common causes of hirsutism (PCOS and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [NCCAH]) will be reviewed here. The pathogenesis, causes, and evaluation of hirsutism, and the removal of unwanted hair are discussed separately. Direct methods of hair removal are reviewed briefly here and in greater detail elsewhere. Other uncommon disorders that cause hirsutism such as classic congenital adrenal hyperplasia (CAH), androgen-secreting tumors, and ovarian hyperthecosis are associated with more severe hyperandrogenism and are also reviewed separately.

(See "Pathophysiology and causes of hirsutism".)

(See "Evaluation of premenopausal women with hirsutism".)

(See "Removal of unwanted hair".)

(See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

(See "Evaluation and management of postmenopausal hyperandrogenism".)

INITIAL VISIT

What is the patient's underlying diagnosis? — The first step before starting therapy in hirsute females is to establish or confirm the underlying diagnosis (see "Evaluation of premenopausal women with hirsutism"). Most females (80 to 85 percent) have polycystic ovary syndrome (PCOS), defined by the presence of two of the following three criteria (oligomenorrhea, hyperandrogenism, and polycystic ovaries on pelvic ultrasound) (see "Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis'). The two main pharmacologic options for hirsutism (combined estrogen-progestin oral contraceptives [COCs] and antiandrogens) can only be used in females not seeking fertility.

A much lower percentage of females with hirsutism have nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH). Their clinical presentation is very similar and often indistinguishable from PCOS. Although NCCAH is an adrenal disorder, the management of hirsutism is largely the same as for females with PCOS. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Baseline Ferriman-Gallwey score — We use the modified scale of Ferriman and Gallwey (F-G) to grade the severity of hair growth objectively. We perform an assessment at baseline and at follow-up visits. We do not use these scores to identify candidates for pharmacologic treatment, but we do use them to monitor response to therapy.

Nine androgen-sensitive sites are graded from 0 to 4 (figure 1) [9]. The criteria for identifying hirsutism using the F-G score are variable because the expression of hair growth varies considerably among racial/ethnic groups. Based on population studies, an F-G score >8 is considered abnormal for Black or White females. For Mediterranean, Hispanic, and Middle Eastern females, an F-G score ≥9 to 10 is considered abnormal, and for Asian females, a score of ≥2 qualifies.

There are a number of limitations of the F-G score including lack of clinician familiarity with its use, patient use of cosmetic hair removal methods (shaving, plucking, waxing) before the initial evaluation and while receiving therapy, and the variable scores based on ethnicity. This issue is reviewed in more detail separately.

Assess degree of emotional distress — Regardless of the baseline F-G score, the impact of the hirsutism on the patient's quality of life should be assessed [1-3]. Females with scores below those that are considered to be abnormal can experience significant distress from the presence of excess terminal hair, particularly on the face and neck (figure 1). We therefore treat any female with "patient-important" hirsutism, defined in the Endocrine Society guidelines as "unwanted sexual hair growth of any degree that causes sufficient distress for females to seek additional treatment" [10]. If not done previously, screening for depression should be performed. (See 'Management' below and "Evaluation of premenopausal women with hirsutism", section on 'Emotional distress/depression' and "Diagnosis of polycystic ovary syndrome in adults", section on 'Depression and anxiety disorders'.)

MANAGEMENT

Review strategies and expectations — We review the available pharmacologic options and methods of direct hair removal (photoepilation [laser and intense pulsed light] and electrolysis).

For all pharmacologic therapies for hirsutism, we suggest a trial of at least six months before making any changes in dose, adding a medication, or switching to a new medication [10]. (See 'Six-month assessment' below.)

Our approach is similar to that outlined in the 2018 Endocrine Society clinical guidelines [10]. We suggest that most females with hirsutism start with pharmacologic therapy, and we consider combined estrogen-progestin oral contraceptives (COCs) to be the first-line drug (algorithm 1). Exceptions would include females with contraindications to COC use or those who choose not to take COCs. (See 'Combined estrogen-progestin oral contraceptives' below.)

An antiandrogen (spironolactone) is then added if the clinical response is suboptimal after six months of therapy (algorithm 1) [10]. We try to avoid antiandrogen monotherapy unless the patient has adequate contraception (such as an intrauterine device [IUD]), because of the potential risk that a developing male fetus could be undervirilized. (See 'Antiandrogens' below.)

We do not typically start with combination therapy (both a COC and an antiandrogen) as initial treatment. However, in occasional patients with severe hirsutism causing significant distress or in females who have not had a good response to COC monotherapy in the past, it is reasonable to initiate combination therapy with a COC and antiandrogen [10]. (See 'Combined with COCs' below.)

Reasonable expectations should be discussed; females should be counseled that drug therapy is unlikely to completely eliminate already existing hair growth, but that hair may become less coarse, grow more slowly, and/or require less frequent use of cosmetic methods (shaving, plucking, waxing).

For females with overweight or obesity, we also recommend lifestyle interventions with a goal of weight loss, in addition to the specific therapy they choose for hirsutism. Weight loss results in improved insulin sensitivity, a decrease in serum androgens, and, in some cases, a return of ovulatory cycles (see 'Obesity' below). The impact on hirsutism is less clear. The majority of females with hirsutism have polycystic ovary syndrome (PCOS). Additional metabolic evaluation for them is reviewed separately. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)

Insulin-lowering agents are not an effective therapy for hirsutism, and we do not suggest their use [9,11]. (See 'Treatments not routinely recommended' below.)

Direct methods of hair removal such as photoepilation (laser and intense pulsed light), are also referred to as "permanent" hair reduction techniques. Females may choose to start these options at any point; some choose this as their initial therapy. However, hyperandrogenic females are likely to experience hair regrowth because of the continued stimulation of hair follicles by endogenous androgens. Females who decide to pursue laser/intense pulsed light should also be on pharmacologic therapy to suppress androgens and prevent new hair growth. (See 'Role of direct hair removal methods' below.)

Combined estrogen-progestin oral contraceptives — For most females, COCs are our first-line drug; an antiandrogen can then be added if the clinical response is suboptimal after six months of therapy (algorithm 1). Females should be aware that COCs and antiandrogens do not have US Food and Drug Administration (FDA) approval for the indication of hirsutism. Therefore, these therapies represent "off-label" use. These preparations also provide additional non-hirsutism benefits such as contraception, cycle management, and reduction of other hyperandrogenic symptoms such as acne. It is assumed that transdermal and vaginal estrogen-progestin contraceptive preparations are also effective for hirsutism, but data are limited.

Clinical trial data on the impact of COCs on hirsutism have been somewhat limited. However, in a network meta-analysis that included trials of COC therapy, the pool-weighted mean difference in Ferriman-Gallwey (F-G) score versus placebo was -7.20 (95% CI -11.96 to -2.52) [11]. Although there is no established minimally important difference established for the F-G score, virtually all females would consider these reductions to be clinically important [10]. COCs are also effective for the treatment of acne that often accompanies hirsutism, especially in females with PCOS. These data are reviewed separately. (See "Acne vulgaris: Management of moderate to severe acne in adolescents and adults", section on 'Oral contraceptives'.)

For females with PCOS, COCs provide the additional benefit of preventing the development of endometrial hyperplasia and restoring regular menstrual cyclicity. The treatment of PCOS, including the use of COCs for hirsutism, is reviewed in greater detail separately. (See "Treatment of polycystic ovary syndrome in adults".)

Mechanisms of action in hyperandrogenism/hirsutism — The contraceptive mechanisms of COC action are well known and are discussed separately. COC therapy reduces hyperandrogenism and hirsutism by the following mechanisms (see "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Noncontraceptive uses'):

Inhibition of gonadotropin secretion – Inhibition of ovarian androgen production through suppression of luteinizing hormone (LH) secretion. COC therapy decreases LH and, to a lesser extent, follicle-stimulating hormone (FSH) secretion in hyperandrogenic females [12-15]. In studies of gonadotropin secretion in females with PCOS, serum FSH concentrations fell more rapidly than did serum LH concentrations, but the fall in serum LH was greater (70 versus 50 percent) [12,13]. The result was decreased ovarian secretion of testosterone and other androgens by the ovaries.

Increased SHBG – Stimulation of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing androgen binding in serum and reducing serum free androgen concentrations. In the circulation, testosterone (and estradiol) are bound with high affinity to SHBG and, with lesser affinity but greater extent, to albumin. In females, only approximately 1.0 to 1.5 percent of the testosterone in serum is in the physiologically active free form [16,17]. Androgens and insulin both decrease the hepatic production of SHBG. Since both are often increased in hyperandrogenic females, these females have lower serum SHBG concentrations than normal [18,19]. (See "Steroid hormone metabolism in polycystic ovary syndrome", section on 'Control of androgen production' and "Steroid hormone metabolism in polycystic ovary syndrome", section on 'Role of insulin'.)

Estrogen (and COCs) causes a dose-dependent increase in serum SHBG concentrations over three to four weeks in hyperandrogenic females [15,20,21]. As serum SHBG concentrations increase, serum free testosterone concentration decreases. This increase is smaller in females treated with a COC containing a progestin that has significant androgenic properties (eg, levonorgestrel) [22].

When hormonally evaluating females who have been on a COC, it is best to discontinue the medications for at least 8, if not 12, weeks as it takes at least this length of time for measured androgens and SHBG levels to return to basal values [23].

Reduction in serum total and free testosterone concentrations – As a result of both inhibition of LH secretion and increase in SHBG production, serum free testosterone concentrations decrease by approximately 50 percent in hyperandrogenic females treated with a COC (figure 2) [12-14,24,25]. Serum total testosterone concentrations also fall, but not as much as free testosterone, because of the increase in serum SHBG concentrations. (See "Steroid hormone metabolism in polycystic ovary syndrome", section on 'Control of androgen production'.)

Secondary mechanisms – COCs may also ameliorate hyperandrogenism by decreasing adrenal androgen secretion [26-29], inhibiting the peripheral conversion of testosterone to dihydrotestosterone (DHT), and inhibiting the binding of DHT to androgen receptors. However, the evidence that COCs have any of these actions is not strong, and it is unlikely that these mechanisms contribute importantly to their benefit in hyperandrogenic females.

Choice of pill — Although data suggest that COCs have similar efficacy for hirsutism [10,11], we typically choose one that contains a progestin with low or neutral androgenicity, such as norethindrone or norgestimate (table 2 and algorithm 1). Some clinicians prefer to start with a COC containing an antiandrogenic progestin, drospirenone, or cyproterone acetate (CPA). Drospirenone is structurally related to spironolactone, and it is a very weak antiandrogen at the dose employed in many contraceptives (3 mg). [30]. Data comparing COCs containing drospirenone or CPA with COCs containing other progestins are limited but do not suggest a clinically important advantage for hirsutism [10,11,31-33]. In addition, there have been concerns about a possible excess risk of venous thromboembolism (VTE) with both of these newer progestins compared with other progestins such as norethindrone and levonorgestrel. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

We typically avoid COC preparations containing the most androgenic progestin, levonorgestrel. Although limited clinical trial data suggest that levonorgestrel-containing COCs have similar benefits for hirsutism as other less androgenic COCs [10,11,34], they may have adverse metabolic effects. In one study, a COC containing desogestrel, a third-generation progestin with low androgenicity, had more favorable effects on lipid profiles when compared with a COC containing levonorgestrel [10,35], a potential concern in females with PCOS who have metabolic concerns at baseline. (See "Treatment of polycystic ovary syndrome in adults", section on 'Metabolic effects of COCs in PCOS'.)

COCs containing desogestrel or gestodene are sometimes used. While they are among the least androgenic progestins, there have been concerns about a higher risk of venous thromboembolism (table 3). (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

We start most patients on a COC formulation that contains 20 mcg of ethinyl estradiol, particularly females with obesity or over age 39 (risk factors for VTE). However, some clinicians may start with 30 to 35 mcg if the hirsutism is more significant and the patient has no VTE risk factors. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

There had been concerns that the COCs with lower doses of ethinyl estradiol (20 mcg) would be less effective for ovarian androgen suppression. However, in a meta-analysis of 42 studies, suppression of serum total and free testosterone concentrations was similar with 20 mcg versus 30 to 35 mcg dose pills [36]. The transdermal contraceptive patch and vaginal ring suppress serum androgens to a similar degree; limited data suggest that they are beneficial for hirsutism, but their impact on hirsutism has not been studied [37]. (See "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)

Six-month assessment — We suggest a trial of at least six months before making any changes in dose, adding a medication, or switching to a new medication. This is because the growth phase of a hair follicle is approximately six months; a significant reduction in hair growth may not occur before then.

In addition, we do try to obtain an F-G score at baseline and at each follow-up visit (figure 1). Although we make therapeutic changes primarily based upon the patient's assessment of her response to therapy, the F-G score may help to confirm a good response or suboptimal response (algorithm 1).

We do not suggest routine monitoring of serum androgens to assess the response to drug therapy. However, if there is progression of hirsutism during therapy, repeat biochemical evaluation is warranted. (See "Evaluation of premenopausal women with hirsutism".)

Clinical improvement — For females who are satisfied with the degree of improvement in their hirsutism after six months of COC therapy, we suggest continuing the COC based upon the patient's priorities (stop if she decides to pursue fertility). (See 'Duration of drug therapy' below.)

Suboptimal response: Add antiandrogen — If the patient is not satisfied with the degree of improvement in her hirsutism after six months of monotherapy with a COC, we suggest adding an antiandrogen (algorithm 1) [10,38].

Antiandrogens

Combined with COCs — As noted above, we most commonly add an antiandrogen to a COC when the initial response to six months of COC monotherapy has been inadequate. Monitoring of females on combination COC-antiandrogen therapy is the same as that described for COC monotherapy (algorithm 1). (See 'Six-month assessment' above.)

We suggest against combination therapy as the initial therapy for most females. However, in occasional patients with severe hirsutism causing significant distress or in females who have not had a good response to COC monotherapy in the past, it is reasonable to initiate combination therapy with a COC and antiandrogen [10,38].

Monotherapy — Although antiandrogens appear to be as effective as COCs for hirsutism [39], we suggest not using them as monotherapy, because of the potential adverse effects on a developing male fetus in utero. However, in females who cannot conceive or who are using a reliable contraceptive method, either a COC or an antiandrogen can be used as initial therapy as they appear to have similar efficacy (algorithm 1) [10].

Antiandrogen therapy is also effective for those with acne in addition to hirsutism [40,41].

The approach for females with contraindications to COC use are reviewed below. (See 'Females with contraindications to COCs' below.)

Available antiandrogens: Efficacy — In a network meta-analysis of pharmacologic therapies for hirsutism [11], analyses of seven trials of individual antiandrogens versus placebo (two spironolactone trials 100 mg/day; three finasteride 2.5 to 5 mg/day; two flutamide 500 mg/day), each antiandrogen showed a significant reduction in hirsutism scores. The effects of the three drugs were similar. Of note, we suggest not using flutamide because of its potential hepatotoxicity. When results of the seven trials of the three antiandrogens were pooled, antiandrogens were significantly more effective than placebo at reducing F-G scores, with a pooled weighted mean difference of -7.02 (95% CI -11.51 to -2.52).

Available antiandrogens that are commonly used for hirsutism include the following:

Spironolactone Spironolactone, our first choice of antiandrogen, is an aldosterone and androgen receptor antagonist that is structurally similar to progestin. It competes with DHT for binding to the androgen receptor and inhibits enzymes involved in androgen biosynthesis. (See 'Suggested drug: spironolactone' below.)

Finasteride Finasteride inhibits 5-alpha-reductase type 2, the enzyme that converts testosterone to DHT. Only a partial inhibitory effect occurs when used for excess hair growth because the enhanced 5-alpha-reductase activity in hirsutism involves both the type 1 and type 2 enzymes. It is used by some clinicians at doses of 1 to 5 mg/day, but there are particular concerns about its inadvertent use in early pregnancy, given the essential role of DHT in the development of male external genitalia. Dutasteride, an inhibitor of both 5-alpha-reductase types 1 and 2, would theoretically be a more effective therapy than finasteride for hirsutism. It is used for the treatment of benign prostatic hyperplasia, but we suggest against its use for females with hirsutism as there is a substantial risk of preventing the development of normal male external genitalia during early pregnancy [10]. In addition, there are no clinical trial data demonstrating its efficacy for hirsutism.

Flutamide Flutamide is a nonsteroidal androgen receptor antagonist. It is used primarily in the management of prostate cancer, but it has been used off-label for managing hirsutism. The efficacy of flutamide (250 to 750 mg/day) is similar to that of spironolactone (100 to 200 mg/day) and finasteride (5 mg/day) [42-46]. However, we suggest against the use of flutamide for hirsutism since it has been associated with hepatotoxicity [47-49], even at doses as low as 62.5 mg (a dose that has not been shown to be effective for hirsutism in randomized clinical trials) [10,50]. While some studies have reported that low-dose flutamide (≤250 mg) is not hepatotoxic [51-54], others have identified adverse hepatic effects:

In a 10-year surveillance study of 203 females receiving flutamide (62.5 to 125 mg/day), 22 (11 percent) experienced elevated serum concentrations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) [50].

In a retrospective study of 414 females taking flutamide (125 to 250 mg/day) alone or with COCs, 6 percent stopped therapy in the first year due to elevated transaminases [55].

In a series of seven females with acne or hirsutism who developed hepatoxicity while taking flutamide (150 to 250 mg/day), five required urgent liver transplantation (four of the five survived) [49].

Other Two weak antiandrogens, CPA (a 17-hydroxyprogesterone derivative) and drospirenone, are the progestin component in some COCs:

Drospirenone, a progestin used in some COCs, is a very weak antiandrogen. The dose used with ethinyl estradiol in COCs (3 mg) is equivalent to approximately 25 mg of spironolactone [10]. Drospirenone-containing COCs have been associated with a higher risk of VTE than COCs containing second-generation progestins. A progestin-only contraceptive pill containing drospirenone is available, but no data are available for its possible efficacy for treating hirsutism. (See 'Choice of pill' above and "Contraception: Progestin-only pills (POPs)", section on 'Formulations'.)

CPA competes with DHT for binding to the androgen receptor and reduces serum LH and ovarian androgen concentrations. It is used in a low dose (2 mg) as the progestin component of COCs, or as a higher dose (12.5 to 100 mg) as monotherapy or with estrogen. It is available in almost all countries but the United States. 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 [56,57].

Suggested drug: spironolactone — There are few comparative studies of different antiandrogens in females with hirsutism. Since they all appear to be effective for hirsutism, the choice of drug depends upon its availability, cost, side effects, and potential toxicity (algorithm 1).

We suggest spironolactone, as clinical trials have shown consistent benefit, and it is considered to be safe [10,58,59]. We start with 50 mg twice daily and increase to 100 mg twice daily as needed. The side effects of spironolactone include hyperkalemia (a rare problem in females with normal renal function and aldosterone secretion). However, we measure a serum potassium level in all patients after one month of spironolactone administration. Females with renal insufficiency should not be prescribed spironolactone, because of the high risk of hyperkalemia.

Other side effects include gastrointestinal discomfort and irregular menstrual bleeding. In females taking spironolactone (200 mg daily) who develop irregular uterine bleeding, decreasing the spironolactone dose to 100 mg daily may reduce or resolve the bleeding. As noted above, we suggest against spironolactone monotherapy because of the potential risk that a developing male fetus could be undervirilized. An exception is that females with an IUD or subdermal progestin implant can use an antiandrogen monotherapy because they are at a low risk of unintended pregnancy.

Duration of drug therapy — Pharmacologic therapy is usually continued during the reproductive years as the underlying condition typically persists during this window, and hirsutism recurs when treatment is discontinued [60,61].

When pregnancy is desired, all pharmacologic treatments for hirsutism must be discontinued. Antiandrogens, in particular, are contraindicated in females trying to conceive because of potential adverse effects on male sexual development.

Role of direct hair removal methods — Direct or mechanical methods of hair removal, including electrolysis and photoepilation (laser and intense pulsed light), are also referred to as "permanent" hair reduction techniques. However, females with underlying hyperandrogenemia are likely to experience hair regrowth because of the continued stimulation of hair follicles by endogenous androgens. This can be prevented by suppressing endogenous androgens with pharmacologic therapy.

Melanin pigment is necessary for photoepilation; therefore, hair that is naturally white or blonde is not amenable to treatment. We therefore suggest electrolysis for these patients. Patients with tanned or darkly pigmented skin are at higher risk for unintended thermal injury to the epidermis during photoepilation. Other adverse effects that occur more commonly in females with dark skin include inflammation, blistering, hyperpigmentation, hypopigmentation, and/or rarely, scarring [62]. In females with fair skin, the risk of side effects other than temporary perifollicular inflammation is low.

Direct methods of hair removal, including laser and intense pulsed light, are reviewed in more detail separately. (See "Removal of unwanted hair", section on 'Laser and intense pulsed light'.)

Topical therapy — Females who desire a more rapid response to laser therapy can add eflornithine cream. Vaniqa (eflornithine hydrochloride cream 13.9%) is a topical drug that is available for the treatment of unwanted facial hair in females. It is an inhibitor of hair growth, not a depilatory, and it must be used indefinitely to prevent regrowth [63,64]. In two clinical trials of combined eflornithine and laser therapy, a more rapid response was observed when compared with laser treatments alone [65,66]. Use of this drug is limited by its high cost.

TREATMENTS NOT ROUTINELY RECOMMENDED

Metformin — Insulin-lowering drugs, which have been used for a number of indications, do not appear to be effective for hirsutism. Metformin is used primarily for blood glucose control in patients with type 2 diabetes but has also been used for some indications in females with polycystic ovary syndrome (PCOS). However, it is no longer suggested for treating hirsutism [10].

We agree with the 2018 Endocrine Society guidelines and suggest against its routine use for hirsutism as metformin has minimal or no benefit [9-11,67].

GnRH agonist or antagonist therapy — We suggest against the routine use of gonadotropin-releasing hormone (GnRH) analog therapy (agonist or antagonist) for hirsutism. However, GnRH agonists are sometimes considered for females with severe hyperandrogenemia, menstrual disturbances, and signs of virilization in addition to hirsutism (for example, ovarian hyperthecosis). It should only rarely be used in females with PCOS [68-72]. (See "Ovarian hyperthecosis", section on 'Management' and "Evaluation and management of postmenopausal hyperandrogenism", section on 'Ovarian hyperthecosis'.)

The role of "add-back" estrogen and progestin therapy to prevent bone loss and hot flashes is discussed separately. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

Other

Multidrug therapy – European investigators have studied the following combinations for the treatment of hirsutism:

A combined estrogen-progestin oral contraceptive (COC) plus metformin and low-dose flutamide [51-53]

Metformin plus flutamide [54,73]

A COC plus metformin in adolescents and females with hirsutism and oligomenorrhea [74]

The combinations in these trials were effective in the treatment of hirsutism. In addition, flutamide reduced the accumulation of visceral fat, and metformin improved insulin sensitivity.

In the absence of additional clinical trial data for these regimens, we suggest against their routine use. In addition, as noted above, we do not recommend treating hirsutism with flutamide, because of potential hepatotoxicity and because there are other effective and safer antiandrogens. (See 'Suggested drug: spironolactone' above.)

Topical antiandrogens – Limited data suggest that topical canrenone (the active metabolite of spironolactone) and finasteride provide little or no benefit for hirsutism [75,76]. Thus, we suggest against their use. One topical antiandrogen, clascoterone, has been approved for the treatment of acne, but it has not yet been studied for hirsutism [77].

SPECIAL POPULATIONS

Females with NCCAH — Given their relative lack of benefit for hirsutism and their potential side effects, we suggest against glucocorticoid therapy for the routine treatment of hirsutism. Like other females with hirsutism, we suggest combined estrogen-progestin oral contraceptives (COCs) as first-line therapy. An exception is in females with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH) who do not respond to or cannot tolerate COC and antiandrogen therapies [10]. Glucocorticoids are also indicated for ovulation induction in females with NCCAH. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Women'.)

Exogenous glucocorticoids are used long term to manage hirsutism and maintain ovulatory cycles in females with classic CYP21A2 deficiency but have also been used to treat hirsutism in females with the nonclassic form of CYP21A2 deficiency (NCCAH). In two trials of glucocorticoid therapy in females with NCCAH (one randomized, one nonrandomized), glucocorticoids were more effective than COCs or antiandrogens for suppressing serum adrenal androgen concentrations (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone sulfate [DHEAS]) but less effective for decreasing hirsutism scores [78,79]. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Obesity — For hirsute females with obesity, including those with polycystic ovary syndrome (PCOS), we recommend lifestyle changes in addition to starting pharmacologic therapy. We avoid COCs in females who are obese and over age 40 years because of an excess risk of venous thromboembolism (VTE) and other cardiovascular complications. A list of relative and absolute contraindications to COCs is found separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Eligibility criteria (WHO and CDC)'.)

Coexisting depression — Depression and anxiety symptoms are common in females with hirsutism, but the optimal management of the mood disorder is unclear. It is important to monitor the patient's mood symptoms during treatment. If they do not improve (or worsen), the patient should be referred for further evaluation and treatment. Some studies suggest that treatment of the hirsutism can improve quality of life and reduce depression and anxiety symptoms [1,80]. (See "Treatment of polycystic ovary syndrome in adults".)

Postmenopausal females — In postmenopausal females with new hirsutism that is severe or rapidly progressive, the possibility of an androgen-secreting tumor or ovarian hyperthecosis must be excluded before initiating treatment. If there is no evidence of a tumor, treatment options include antiandrogens or direct hair removal. In menopausal females with ovarian stromal hyperthecosis and severe hirsutism, bilateral oophorectomy may be considered. (See "Evaluation and management of postmenopausal hyperandrogenism" and "Ovarian hyperthecosis".)

Females with contraindications to COCs — For females with contraindications to COC use, antiandrogens may be given as initial therapy, as long as the individual is using some form of reliable contraception. For example, in a female with a thrombophilia who cannot take an estrogen-containing contraceptive, an approach to management of hirsutism could include a long-acting reversible contraceptive such as a levonorgestrel-releasing IUD and an antiandrogen such as spironolactone. (See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

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".)

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Basics topics (see "Patient education: Hirsutism (excess hair growth in women) (The Basics)")

Beyond the Basics topics (see "Patient education: Hirsutism (excess hair growth in females) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition Hirsutism, defined as excessive male-pattern hair growth in a female, is common (affects between 5 and 10 percent of females of reproductive age) and is associated with significant emotional distress and depression. It is usually an indication of an underlying endocrine disorder (most commonly polycystic ovary syndrome [PCOS]) (table 1). (See 'Initial visit' above.)

Candidates for treatment We consider any female with patient-important hirsutism to be a candidate for treatment (pharmacologic, direct hair removal, or both). (See 'Baseline Ferriman-Gallwey score' above and 'Assess degree of emotional distress' above and 'Initial visit' above.)

Pharmacotherapy

COCs For the majority of females with hirsutism who choose pharmacologic therapy, we suggest combined estrogen-progestin oral contraceptives (COCs) as initial therapy (algorithm 1) (Grade 2C). COCs and antiandrogens have similar efficacy, but we prefer COCs because antiandrogen monotherapy has potential adverse effects on a developing male fetus. (See 'Combined estrogen-progestin oral contraceptives' above and 'Monotherapy' above.)

Although we do not suggest one particular COC over another, it is reasonable to avoid preparations with the most androgenic progestin, levonorgestrel, which has less desirable metabolic effects. (See 'Combined estrogen-progestin oral contraceptives' above.)

Adding an antiandrogen For females with a suboptimal cosmetic result after six months of COC monotherapy, we typically add an antiandrogen. We suggest spironolactone as the antiandrogen of choice (algorithm 1) (Grade 2C). (See 'Antiandrogens' above.)

it is important to wait at least six months before making any changes in dose, adding a medication, or switching to a new medication. This is because the growth phase of a hair follicle is approximately six months; a significant reduction in hair growth may not occur before then. (See 'Six-month assessment' above.)

Combination COC-antiandrogen therapy In occasional females with either severe hirsutism or hirsutism causing severe emotional distress, we start with combination therapy (a COC and an antiandrogen). However, we do not use combination therapy as a standard approach. (See 'Combined with COCs' above.)

Treatments we do not recommend

-We suggest against the use of flutamide for hirsutism because of its potential hepatotoxicity (Grade 2C). (See 'Suggested drug: spironolactone' above.)

-We suggest not using metformin for hirsutism (Grade 2B). (See 'Treatments not routinely recommended' above.)

Special populations

For females with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCCAH), we suggest COCs rather than glucocorticoids as initial therapy for hirsutism. (Grade 2C). (See 'Females with NCCAH' above.)

For females with hyperandrogenism undergoing direct hair removal methods, we suggest that pharmacologic therapy be added or continued to minimize hair regrowth (Grade 2C). (See 'Role of direct hair removal methods' above.)

The approach to other patients, including those with obesity, depression, contraindications to COC use and postmenopausal females with new-onset hirsutism are reviewed above. (See 'Special populations' above.)

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