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Гирсутизм у женщин в пременопаузе
Abstract

Objective

To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2008.

Participants

The participants include an Endocrine Society–appointed task force of seven medical experts and a methodologist.

Evidence

This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process

Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines.

Conclusion

We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen–progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.

Summary of Recommendations

1.0 Diagnosis of hirsutism

  • 1.1. We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score (2 |⊕⊕OO). In those cases where serum total testosterone levels are normal, if sexual hair growth is moderate/severe or sexual hair growth is mild but there is clinical evidence of a hyperandrogenic endocrine disorder (such as menstrual disturbance or progression in spite of therapy), we suggest measuring an early morning serum total and free testosterone by a reliable specialty assay. (2 |⊕⊕OO)

  • 1.2. We suggest screening hyperandrogenemic women for NCCAH due to 21-hydroxylase deficiency by measuring early morning 17-hydroxyprogesterone levels in the follicular phase or on a random day for those with amenorrhea or infrequent menses (2 |⊕⊕OO). In hirsute patients with a high risk of congenital adrenal hyperplasia (positive family history, member of a high-risk ethnic group), we suggest this screening even if serum total and free testosterone are normal. (2 |⊕⊕OO)

  • 1.3. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score) because of the low likelihood of identifying a medical disorder that would change management or outcome. (2 |⊕⊕OO)

2.0 Treatment of hirsutism in premenopausal women

  • 2.1. For most women with patient-important hirsutism despite cosmetic measures, we suggest starting with pharmacological therapy (2 |⊕OOO). For women who then desire additional cosmetic benefit, we suggest adding direct hair removal methods. However, for women with mild hirsutism and no evidence of an endocrine disorder, we suggest either approach. (2 |⊕OOO)

  • 2.2. For hirsute women with obesity, including those with polycystic ovary syndrome, we also recommend lifestyle changes. (1 |⊕⊕OO)

3.0 Pharmacological treatments

Initial therapies

  • 3.1. For the majority of women with hirsutism who are not seeking fertility, we suggest oral contraceptives as initial therapy for treating patient-important hirsutism. (2 |⊕⊕OO)

  • 3.2. For most women with hirsutism, we suggest against antiandrogen monotherapy as initial therapy (because of the teratogenic potential of these medications) unless these women use adequate contraception (2 |⊕OOO). However, for women who are not sexually active, have undergone permanent sterilization, or who are using long-acting reversible contraception, we suggest using either oral contraceptives or antiandrogens as initial therapy (2 |⊕OOO). The choice between these options depends on patient preferences regarding efficacy, side effects, and cost.

  • 3.3. For most women, we do not suggest one oral contraceptive over another as initial therapy, as all oral contraceptives appear to be equally effective for hirsutism, and the risk of side effects is low. (2 |⊕⊕OO)

  • 3.4. For women with hirsutism at higher risk for venous thromboembolism (e.g., those who are obese or over age 39 years), we suggest initial therapy with an oral contraceptive containing the lowest effective dose of ethinyl estradiol (usually 20 mcg) and a low-risk progestin (Table 2). (2 |⊕OOO)

  • 3.5. If patient-important hirsutism remains despite 6 months of monotherapy with an oral contraceptive, we suggest adding an antiandrogen. (2 |⊕⊕OO)

  • 3.6. We do not suggest one antiandrogen over another (2 |⊕⊕OO). However, we recommend against the use of flutamide because of its potential hepatotoxicity. (1 |⊕⊕OO)

  • 3.7. For all pharmacologic therapies for hirsutism, we suggest a trial of at least 6 months before making changes in dose, switching to a new medication, or adding medication. (2 |⊕OOO)

  • 3.8. In patients with severe hirsutism causing emotional distress and/or in those women who have used oral contraceptives in the past and have not experienced sufficient improvement, we suggest initiating combination therapy with an oral contraceptive and antiandrogen (2 |⊕⊕OO). However, we suggest against combination therapy as a standard first-line approach. (2 |⊕⊕OO)

Other drug therapies

  • 3.9. We suggest against using insulin-lowering drugs for the sole indication of treating hirsutism. (2 |⊕⊕OO)

  • 3.10. We suggest against using gonadotropin-releasing hormone agonists except in women with severe forms of hyperandrogenemia (such as ovarian hyperthecosis) who have a suboptimal response to oral contraceptives and antiandrogens. (2 |⊕OOO)

  • 3.11. We suggest against the use of topical antiandrogen therapy for hirsutism. (2 |⊕OOO)

4.0 Direct hair removal methods

  • 4.1. For women who choose hair removal therapy, we suggest photoepilation for those whose unwanted hair is auburn, brown, or black, and we suggest electrolysis for those with white or blonde hair. (2 |⊕⊕OO)

  • 4.2. For women of color who choose photoepilation treatment, we suggest using a long-wavelength, long pulse-duration light source such as Nd:YAG or diode laser delivered with appropriate skin cooling (2 |⊕OOO). Clinicians should warn Mediterranean and Middle Eastern women with facial hirsutism about the increased risk of developing paradoxical hypertrichosis (PH) with photoepilation therapy. We suggest topical treatment or electrolysis over photoepilation with these patients. (2 |⊕⊕OO)

  • 4.3. For women who desire more rapid response to photoepilation, we suggest adding eflornithine topical cream during treatment. (2 |⊕⊕OO)

  • 4.4. For women with known hyperandrogenemia who choose hair removal therapy, we suggest pharmacologic therapy to minimize hair regrowth. (2 |⊕⊕OO)

Changes Since the Previous Guideline

In 2008, the Endocrine Society published the clinical practice guideline "Evaluation and Treatment of Hirsutism in Premenopausal Women.” As hirsutism is common, often associated with an underlying endocrine disorder, and associated with significant personal distress, treatment is appropriate for most women who present with this problem. In this current version, we have attempted to address several issues, as well as incorporate insights from relevant studies published since the 2008 guideline. Important modifications in this version are as follows.

Evaluation

We have broadened the suggestion for determining the serum total testosterone concentration to include all women with hirsutism and have broadened the suggestion for determining the serum-free testosterone concentration to include hirsute women whose serum total testosterone is normal in the presence of moderate to severe hirsutism or other clinical evidence of hyperandrogenemia, such as progressive growth of hair in androgen-dependent areas (sexual hair). We have added a recommendation to screen hyperandrogenemic women for nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency by measuring early morning 17-hydroxyprogesterone levels in the follicular phase or on a random day for those with amenorrhea or infrequent menses. In women with hirsutism who are at high risk for NCCAH (positive family history, member of a high-risk ethnic group), we suggest screening even if serum total and free testosterone are normal.

Treatment

For treatment, we have made the following revisions to the new guideline:

  • We now suggest either pharmacologic therapy or direct hair removal methods as initial therapy for women with mild hirsutism and no evidence of an endocrine disorder. For other women with patient-important hirsutism, we suggest starting with pharmacological therapy and adding direct hair removal methods if needed.

  • We added a recommendation that it is reasonable to start with combined pharmacological therapy [oral contraceptives (OCs) and antiandrogens] in select women with severe hirsutism that is causing distress.

  • We added a recommendation to use lower estrogen-dose OCs with low-risk progestins in women at higher risk for venous thromboembolism (VTE) (e.g., obese, age >39 years). For other women, our approach is the same as in the original guideline: we do not suggest one OC formulation over another.

  • We made a stronger recommendation against the use of flutamide for hirsutism.

  • We added a suggestion for electrolysis rather than photoepilation in women with blond or white hair who choose direct hair removal methods. We also provide guidance for the use of photoepilation (and its potential complications) in women of color.

  • We added a lifestyle recommendation for women with polycystic ovary syndrome (PCOS).

Method of Development of Evidence-Based Clinical Practice Guidelines

The Clinical Guidelines Subcommittee of the Endocrine Society deemed the evaluation and treatment of hirsutism in premenopausal women a priority area for revision and appointed a task force to formulate evidence-based recommendations. The task force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation group, an international group with expertise in the development and implementation of evidence-based guidelines (1). A detailed description of the grading scheme has been published elsewhere (2). The task force used the best available research evidence to develop the recommendations. The task force also used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence. In terms of the strength of a recommendation, strong recommendations use the phrase "we recommend” and the number 1, and conditional recommendations use the phrase "we suggest” and the number 2. Cross-filled circles indicate the quality of the evidence, such that ⊕OOO denotes very low-quality evidence; ⊕⊕OO, low quality; ⊕⊕⊕O, moderate quality; and ⊕⊕⊕⊕, high quality. The task force has confidence that persons who receive care according to the strong recommendations will derive, on average, more good than harm. Conditional recommendations require more careful consideration of the person’s circumstances, values, and preferences to determine the best course of action. Linked to each recommendation is a description of the evidence and the values that the task force considered in making the recommendation. In some instances, there are remarks in which the task force offers technical suggestions for testing conditions, dosing, and monitoring. These technical comments reflect the best available evidence applied to a typical person being treated. Often this evidence comes from the unsystematic observations of the task force and their preferences; therefore, one should consider these remarks as suggestions.

The Endocrine Society maintains a rigorous conflict-of-interest review process for developing clinical practice guidelines. All task force members must declare any potential conflicts of interest by completing a conflict-of-interest form. The Clinical Guidelines Subcommittee reviews all conflicts of interest before the Society’s Council approves the members to participate on the task force and periodically during the development of the guideline. All others participating in the guideline’s development must also disclose any conflicts of interest in the matter under study, and most of these participants must be without any conflicts of interest. The Clinical Guidelines Subcommittee and the task force have reviewed all disclosures for this guideline and resolved or managed all identified conflicts of interest.

Conflicts of interest are defined as remuneration in any amount from commercial interests; grants; research support; consulting fees; salary; ownership interests [e.g., stocks and stock options (excluding diversified mutual funds)]; honoraria and other payments for participation in speakers’ bureaus, advisory boards, or boards of directors; and all other financial benefits. Completed forms are available through the Endocrine Society office.

The Endocrine Society provided the funding for this guideline; the Task Force received no funding or remuneration from commercial or other entities.

The Endocrine Society’s clinical practice guidelines are developed to be of assistance to endocrinologists by providing guidance and recommendations for particular areas of practice. The guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of health care providers and each patient’s individual circumstances.

The Endocrine Society makes no warranty, express or implied, regarding the guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained in this work.

Commissioned Systematic Review

The Endocrine Society Task Force commissioned two systematic reviews in 2008 that were updated to support the current guideline. The updated review included a network meta-analysis that compared the available 37 randomized controlled trials (RCTs) of pharmacologic therapy for hirsutism. This network meta-analysis approach facilitated simultaneous comparison of multiple agents and allowed indirect comparison of interventions (that have not been evaluated in head-to-head trials) based on their effect on a common comparator.

The goals of the systematic reviews and meta-analyses were to:

  • Update the analyses of the efficacy and safety of OCs, antiandrogens, and metformin vs placebo, and OCs plus antiandrogens vs OCs, for the treatment of hirsutism; and

  • Compare the impact on hirsutism of OCs containing antiandrogens [cyproterone acetate (CPA) and drospirenone (DSP)] vs other OCs, and OCs containing levonorgestrel (the most androgenic progestin) vs other OCs.

The results of the network analysis were consistent with the previous meta-analyses, showing that OCs, antiandrogens, and the combination of OCs plus antiandrogens were all more effective than placebo and led to reduction in hirsutism scores. The addition of antiandrogens to OCs was slightly more effective than OCs alone for hirsutism. Metformin therapy was not superior to placebo. OCs containing antiandrogens were no more effective than other OCs, and OCs containing levonorgestrel were equally effective as other OCs for the treatment of hirsutism. The results of the review serve as the evidence base for the recommendations about pharmacologic therapy.

Definition, Pathogenesis, and Etiology of Hirsutism

Hirsutism is excessive terminal hair that appears in a male pattern in women (3) (Table 1). Some sexual hair growth is normal, but clinicians commonly diagnose hirsutism as a Ferriman–Gallwey score (4) above the 95th percentile for the population (Fig. 1) (5, 6). Ferriman–Gallwey total scores that define hirsutism in women of reproductive age are as follows: United States and United Kingdom black or white women, ≥8 (6); Mediterranean, Hispanic, and Middle Eastern women, ≥9 to 10 (6); South American women, ≥6 (7); and Asian women, a range of ≥2 for Han Chinese women (6) to ≥7 for Southern Chinese women (8, 9). Although widely used, this scoring system has its limitations, which include its subjective nature, the failure to account for a locally high score that does not raise the total score to an abnormal extent, and the lack of consideration of such androgen-sensitive areas such as the sides of the face from the hairline to below the ear (sideburns) and the buttocks. Self-scoring can be clinically useful, but correlates only modestly with scoring by a trained observer (10–12).

Table 1.

Definition of Terms

Term Definition 
Hirsutism Hirsutism is excessive terminal hair that appears in a male pattern (excessive hair in androgen-dependent areas; i.e., sexual hair) in women. 
Ferriman–Gallwey score The modified Ferriman–Gallwey score is the gold standard for evaluating hirsutism. Nine body areas most sensitive to androgen are assigned a score from 0 (no hair) to 4 (frankly virile), and these separate scores are summed to provide a hormonal hirsutism score (Fig. 1). 
Local hair growth This is unwanted localized hair growth in the absence of an abnormal hirsutism score. 
Patient-important hirsutism Unwanted sexual hair growth of any degree that causes sufficient distress for women to seek additional treatment. 
Hyperandrogenism Hyperandrogenism (for the purposes of this guideline) is defined as clinical features that result from increased androgen production and/or action. 
Idiopathic hirsutism This is hirsutism without hyperandrogenemia or other signs or symptoms indicative of a hyperandrogenic endocrine disorder. 
Figure 1.

Ferriman–Gallwey hirsutism scoring system (4). Each of the nine body areas most sensitive to androgen is assigned a score from 0 (no hair) to 4 (frankly virile). These separate scores are summed to provide a total hormonal hirsutism score. Generalized hirsutism (score ≥8) is abnormal in the general US population, whereas locally excessive hair growth (score <8) is a common normal variant. The normal score is lower in some Asian populations and higher in Mediterranean populations (see text). Reproduced from Hatch et al. (5).

Lower Ferriman–Gallwey scores can be clinically important. In one study of 633 unselected white and black women, ∼70% with scores ≥3 and many with lower scores considered themselves to be hirsute, and most used some form of cosmetic treatment (13). It has also been shown that even minimal degrees of unwanted hair are often associated with hyperandrogenemia when menstrual irregularity is present (14).

Hirsutism must be distinguished from hypertrichosis—generalized excessive hair growth that may be hereditary or result from certain medications (e.g., phenytoin, cyclosporine). Hypertrichosis is distributed in a generalized, nonsexual pattern (i.e., predominantly on forearms or lower legs) and is not caused by excess androgen (although hyperandrogenemia may aggravate it).

Pathogenesis of hirsutism

The growth of sexual hair is entirely dependent on the presence of androgen (3, 15). Androgens appear to induce vellus follicles in sex-specific areas to develop into terminal hairs, which are larger and more heavily pigmented. Hairs grow in nonsynchronous cycles, and the growth (anagen) phase (which varies with body area) is ∼4 months for facial hair. Due to the long hair growth cycle, it takes ∼6 months to detect the effects of hormonal therapy and ∼9 months for these effects to become maximal. Hirsutism results from an interaction between the plasma androgens and the apparent sensitivity of the hair follicle to androgen. The sensitivity of the hair follicle is determined in part by the local metabolism of androgens, particularly by conversion of testosterone to dihydrotestosterone by the enzyme 5α-reductase and subsequent binding of these molecules to the androgen receptor. The hirsutism score does not correlate well with the androgen level (16, 17), apparently because the androgen-dependent pilosebaceous follicle response to androgen varies considerably.

https://academic.oup.com/jcem/article/103/4/1233/4924418

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