Hirsutism Pre M Guide 2018

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CLINICAL PRACTICE GUIDELINE

Evaluation and Treatment of Hirsutism in

Premenopausal Women: An Endocrine Society*

Clinical Practice Guideline

Kathryn A. Martin,

R. Rox Anderson,

R. Jeffrey Chang,

David A. Ehrmann,

Rogerio A. Lobo,

M. Hassan Murad,

Michel M. Pugeat,

and Robert L. Rosenfield

Massachusetts General Hospital, Boston, Massachusetts 02114;

University of California, San Diego, La

Jolla, California 92037;

University of Chicago, Chicago, Illinois 60637;

Columbia University, New York,

New York 10032;

Mayo Clinic Evidence-Based Practice Center, Rochester, Minnesota 55905; and

Hospices Civils de Lyon, Bron, France F-69677

*Co-Sponsoring Associations: Androgen Excess and Polycystic Ovary

Syndrome Society and European Society of Endocrinology.

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 un-

wanted 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. (J Clin Endocrinol Metab 103: 1–25,

2018)

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in USA

Received 29 January 2018. Accepted 29 January 2018.

First Published Online 7 March 2018

Abbreviations: CI, confidence interval; CPA, cyproterone acetate; DHEA, dehy-

droepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DSP, drospirenone; EE,

ethinyl estradiol; FDA, Food and Drug Administration; GnRH, gonadotropin-

releasing hormone; IPL, intense pulsed light; NCCAH, nonclassical congenital adrenal

hyperplasia; OC, oral contraceptive; PCOS, polycystic ovary syndrome; PH, paradoxical

hypertrichosis; RCT, randomized controlled trial; SHBG, sex hormone–binding globulin;

VTE, venous thromboembolism.

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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 tes-

tosterone levels are normal, if sexual hair growth is

moderate/severe or sexual hair growth is mild but

there is clinical evidence of a hyperandrogenic en-

docrine disorder (such as menstrual disturbance or

progression in spite of therapy), we suggest mea-

suring an early morning serum total and free tes-

tosterone 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.,intheabsenceofanab-

normal hirsutism score) because of the low like-

lihood 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 rec-

ommend 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 ade-

quate 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 anti-

androgens as initial therapy (2 |OOO). The

choice between these options depends on pa-

tient 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 ef-

fective 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 (usu-

ally 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 contra-

ceptive, we suggest adding an antiandrogen.

(2 |OO)

3.6. We do not suggest one antiandrogen over an-

other (2 |OO). However, we recommend

against the use of flutamide because of its po-

tential 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 emo-

tional 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 con-

traceptive 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

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with severe forms of hyperandrogenemia (such

as ovarian hyperthecosis) who have a subopti-

mal response to oral contraceptives and anti-

androgens. (2 |OOO)

3.11. We suggest against the use of topical anti-

androgen 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 un-

wanted 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 de-

veloping 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 Hirsut-

ism 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. Im-

portant 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-hydroxy-

progesterone 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 phar-

macological 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 hirsut-

ism in premenopausal women a priority area for revision

and appointed a task force to formulate evidence-based

recommendations. The task force followed the ap-

proach recommended by the Grading of Recommendations,

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Assessment, Development, and Evaluation group, an in-

ternational group with expertise in the development and

implementation of evidence-based guidelines (1). A detailed

description of the grading scheme has been published else-

where (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 de-

notes 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 recommen-

dations 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 de-

scription of the evidence and the values that the task force

considered in making the recommendation. In some in-

stances, 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 observa-

tions 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’sde-

velopment 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 di-

rectors; 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 re-

muneration from commercial or other entities.

The Endocrine Society’s clinical practice guidelines are

developed to be of assistance to endocrinologists by pro-

viding 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’sindi-

vidual circumstances.

The Endocrine Society makes no warranty, express or

implied, regarding the guidelines and specifically ex-

cludes 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 ap-

proach 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 con-

taining levonorgestrel (the most androgenic pro-

gestin) vs other OCs.

The results of the network analysis were consistent

with the previous meta-analyses, showing that OCs, anti-

androgens, 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. Met-

formin therapy was not superior to placebo. OCs containing

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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 per-

centile 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, $9to10(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).

Lower Ferriman–Gallwey scores can be clinically im-

portant. In one study of 633 unselected white and black

women, ;70% with scores $3and

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 as-

sociated with hyperandrogenemia when

menstrual irregularity is present (14).

Hirsutism must be distinguished

from hypertrichosis—generalized ex-

cessive hair growth that may be hered-

itary or result from certain medications

(e.g., phenytoin, cyclosporine). Hyper-

trichosis 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

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).

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;9 months for these effects to become maximal. Hir-

sutism 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 de-

termined in part by the local metabolism of androgens,

particularly by conversion of testosterone to dihy-

drotestosterone by the enzyme 5a-reductase and sub-

sequent 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.

Etiology of hirsutism

The majority of hirsutism is due to androgen excess

($80%), and the majority of women with hirsutism (70%

to 80%) have PCOS (18, 19). PCOS is defined by the

presence of a combination of two of three symptoms or

findings: otherwise unexplained chronic hyperandrogenism,

oligoovulation, and ultrasonographic polycystic ovarian

morphology (20). Gonadotropin-dependent functional

ovarian hyperandrogenism is the source of the hyper-

androgenemia in the majority of PCOS cases (18, 20). This

may be accompanied by a related mild adrenocorticotropic

hormone–dependent functional adrenal hyperandrogenism,

and in a minority of instances this form of adrenal hyper-

androgenism may occur in isolation (20, 21). PCOS is

frequently associated with a metabolic syndrome that results

from insulin resistance and/or central obesity and that re-

quires considerations distinct from those for hirsutism itself.

Obesity may worsen or cause features of PCOS (20, 22, 23).

Many women have hirsutism without hyperandro-

genemia. We term this “idiopathic hirsutism”in

eumenorrheic women who have no other clinical evidence

suggesting PCOS or other hyperandrogenic endocrine

disorder (19), although some may have polycystic ovary

morphology on ultrasound and thus meet a Rotterdam

criterion for “ovulatory PCOS”(24). Idiopathic hirsut-

ism constitutes 5% to 20% of hirsute women (19, 24).

Available data suggest that among eumenorrheic women

with mild hirsutism (a Ferriman–Gallwey hirsutism score

of 8 to 15 in the United States), approximately half have

idiopathic hirsutism (16). However, the percentage of

women with idiopathic hirsutism who meet Rotterdam

criteria for “ovulatory PCOS”remains unclear, as studies

using transvaginal ultrasound and/or high-quality andro-

gen assay technologies in this population have not yet been

performed.

It is unclear whether idiopathic hirsutism is due to al-

tered androgen mechanism of action within the hair follicle

(referred to as cutaneous hyperandrogenism) or to other

alterations in hair biology (15, 17, 25). The routine assay

of androgenic steroids other than testosterone has proven

to be of little further diagnostic utility in most, but not

all, populations (16, 26–30) (Section 5, Androgen Test-

ing Remarks). Serum total testosterone is similar to and

correlates well with serum androgenic bioactivity in young

women with and without PCOS (r= 0.7 to 0.8) (31). Thus,

hirsutism cannot currently be considered synonymous

with “clinical evidence of hyperandrogenism”if serum

total and free testosterone are normal. However, the

possibility exists that previously unsuspected circulating

androgens contribute to idiopathic hirsutism (21, 30, 32)

(Section 5, Androgen Testing Remarks).

Further workup of the eumenorrheic patient for mild

hirsutism and a normal serum total testosterone is only

clinically indicated if there is other clinical evidence

to suggest the etiology is a hyperandrogenic endocrine

disorder.

As noted, among women with mild hirsutism, ap-

proximately half have idiopathic hirsutism. Plasma total

and/or free testosterone levels are elevated in the re-

mainder of cases of mild hirsutism and in most cases of

more severe hirsutism (16, 26, 27) (Section 5, Androgen

Testing Remarks). Most women with a twofold or greater

elevation of serum androgen levels have some degree of

hirsutism or an alternative pilosebaceous response, such

as excessive acne vulgaris, seborrhea, or female- or male-

pattern alopecia.

Other causes of androgen overproduction are in-

frequent (24, 26). NCCAH, the most common of these

disorders, is present in 4.2% of hyperandrogenic women

worldwide, although specific ethnic groups are at lower or

higher risk (Section 5, Androgen Testing Remarks) (33).

Androgen-secreting tumors are present in ;0.2% of

hyperandrogenic women; over half are malignant (34).

Clinicians must consider Cushing syndrome, acromegaly,

hypothyroidism, and (rarely) hyperprolactinemia in the

differential diagnosis of hirsutism, but patients typically

will present with the features specific to these disorders.

Clinicians must consider topical androgen use by a partner

(35), exogenous androgens or anabolic steroids (36), or

valproic acid when evaluating patients with hirsutism.

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 tes-

tosterone levels are normal, if sexual hair growth is

moderate/severe or sexual hair growth is mild but

there is clinical evidence of a hyperandrogenic en-

docrine disorder (such as menstrual disturbance or

progression in spite of therapy), we suggest mea-

suring an early morning serum total and free tes-

tosterone by a reliable specialty assay. (2 |OO)

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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 an-

drogen 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)

Evidence

Hirsutism is a clinical diagnosis. The management of

hirsutism is to a considerable extent independent of the

etiology. However, hirsutism is a potential indication of

an underlying hyperandrogenic disorder that may require

specific treatment and may have distinct implications for

fertility, medical risks, and genetic counseling. There is a

wide variety of approaches specialists use to diagnose the

disorder; however, there is uncertainty regarding the cost

effectiveness, acceptability to patients, and the impact on

outcomes of these approaches (3).

The goal in assessing hirsutism is to attempt to de-

termine the specific etiology and to provide a baseline in

case it becomes necessary to reassess the patient. Figure 2

provides an approach to assessing hyperandrogenemia

that depends on both determining the presence and degree

of hirsutism and assessing whether there is clinical evidence

of PCOS, other hyperandrogenic endocrinopathies, viril-

izing disorders, or androgenic medication use.

When testing for elevated androgen levels, we suggest

first measuring serum total testosterone levels using a re-

liable specialty assay (Fig. 2). 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.

Menstrual irregularity, infertility, galactorrhea, central

obesity, acanthosis nigricans, clitoromegaly, sudden-onset

or rapid-progression hirsutism, or hirsutism progression in

spite of therapy suggests the presence of a hyperandrogenic

endocrine disorder.

The decision to test for androgen excess depends

both on the pretest likelihood that an abnormal value

may be found and upon whether a detected abnor-

mality will determine the approach to treatment. Most

women with local hair growth and regular menses who

have no evidence to suggest an endocrine cause have a

very low likelihood of excess androgen production.

Conversely, patients with hirsutism or with clinical

features suggesting an underlying endocrine disor-

der, including failure to respond to therapy over time

(Fig. 2), are more likely to have excess androgen

production (3). A rapid pace of development or pro-

gression of hirsutism, progression in spite of ther-

apy, or evidence of virilization (such as clitoromegaly,

deepening of the voice, or increasing muscularity)

points to a greater likelihood of an androgen-secreting

neoplasm. However, some tumors producing only mod-

erately excessive androgen have indolent presenta-

tions (3).

Because standard assays fail to detect androgenic

drugs, clinicians should be diligent in their effort

to obtain a history of anabolic or androgenic steroid

use, particularly among athletes and patients who have

endometriosis, sexual dysfunction, or partners who

may use testosterone gel. Valproic acid is the only

anticonvulsant medication that raises plasma testos-

terone levels.

Because of the high frequency of PCOS, clinicians

should check all hirsute women for evidence of anov-

ulation (menstrual irregularity) or more subtle ovarian

dysfunction that may present as infertility (37), central

obesity, abnormal carbohydrate and lipid metabolism,

acanthosis nigricans, or a family history of type 2 di-

abetes mellitus. Clinicians can make a diagnosis of

ovulatory PCOS in eumenorrheic women with hirsut-

ism, polycystic ovary morphology, and normal levels of

testosterone (39, 40). It is unclear whether pelvic ul-

trasonography is cost effective in the management of

idiopathic hirsutism (i.e., eumenorrheic hirsute women

with normal testosterone levels and no other clinical

evidence of PCOS).

While PCOS is the most likely diagnosis in a woman

with menstrual dysfunction, hirsutism, and an elevated

testosterone level, clinicians need to exclude conditions

other than PCOS that are: sufficiently common, associ-

ated with adverse natural histories, and treatable (e.g.,

pregnancy, nonclassic congenital adrenal hyperplasia,

ovarian or adrenal neoplasm, or other endocrinopathies).

The most common of these is nonclassic congenital ad-

renal hyperplasia due to 21-hydroxylase deficiency (as

noted in Section 1, Etiology and Section 5, Andro-

gen Testing Remarks). This is particularly important

to detect because of its genetic implications for those

women desiring fertility (33). We suggest screening

hyperandrogenemic women for nonclassic congenital

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adrenal hyperplasia 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 hirsute patients

with a high risk of congenital adrenal hyperplasia (pos-

itive family history, member of a high-risk ethnic group),

we suggest this screening even if serum total and free

testosterone are normal.

A separate Endocrine Society clinical guideline de-

scribes the approach to the diagnosis of PCOS in detail

(40). Different subspecialists use different strategies for

evaluating the patient with hirsutism (24, 41–43). The

evaluation of hyperandrogenemic women may include

the following: pregnancy tests in patients with amenor-

rhea; measuring dehydroepiandrosterone (DHEA) sul-

fate (DHEAS) to screen for adrenal hyperandrogenism;

Figure 2. Evaluation and treatment of hirsutism in premenopausal women. Figure note: Local sexual hair growth (i.e., in the absence of an

abnormal hirsutism score) that is not accompanied by clinical evidence of a hyperandrogenic endocrine disorder does not require an endocrine

workup before embarking on dermatologic therapy (cosmetic or direct hair removal measures). Elevated androgen levels should be ruled out in

women with hirsutism or any degree of sexual hair growth who also have clinical evidence of a hyperandrogenic endocrine disorder. Clinical

evidence of menstrual irregularity, infertility, galactorrhea, signs or symptoms of hypothyroidism, Cushing syndrome, acromegaly, central obesity,

acanthosis nigricans, clitoromegaly, or sudden-onset or rapid-progression hirsutism suggests the presence of a hyperandrogenic endocrine

disorder. PCOS is the most common hyperandrogenic disorder associated with hirsutism. However, androgen-secreting tumors and nonclassic

congenital adrenal hyperplasia are other major causes that clinicians should consider. Drugs that cause hirsutism include anabolic or androgenic

steroids (a consideration in athletes, users of dietary supplements, patients with sexual dysfunction, or in patients with a partner who uses

testosterone gel) and valproic acid (a consideration in patient with neurologic disorders). An accurate and specific assay, such as mass

spectrometry, is the best choice for assessing serum total testosterone concentrations. Norms are standardized for early morning, when levels are

the highest, and for days 4 to 10 of the menstrual cycle (see Section 5, Androgen Testing Remarks) when ovarian follicle development is the

most comparable to that of women with hyperandrogenic anovulation; clinicians should interpret marginal values obtained at other times

accordingly. Women with mild hirsutism, a normal total testosterone level, a pelvic ultrasound showing normal ovarian morphology (if

performed), and no clinical evidence of other hyperandrogenic endocrine disorders have idiopathic hirsutism, which may be responsive to OC

therapy. However, if the serum total testosterone is normal in the presence of moderate or severe hirsutism or if there is clinical evidence of

PCOS or other endocrine disorder, clinicians should test serum-free testosterone levels. Assessing free testosterone levels using high-quality

testosterone and SHBG or equilibrium dialysis assays with well-defined reference intervals is the single most useful, clinically sensitive marker of

androgen excess in women. A simultaneous assay of early-morning 17-hydroxyprogesterone is indicated in subjects at high risk for nonclassic

congenital adrenal hyperplasia (see text and Section 5, Androgen Testing Remarks). Progression of hyperandrogenism in the presence of a normal

serum-free testosterone is very unusual, and clinicians should thoroughly reevaluate these patients (3). Unless fertility is an issue (37),

demonstrating polycystic ovary morphology to diagnose ovulatory PCOS is unlikely to affect management. Adapted from Martin et al. (38).

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assessing for Cushing syndrome, thyroid dysfunc-

tion, acromegaly, and hyperprolactinemia if features of

these conditions are present (however, all are uncom-

mon causes of hirsutism); and pelvic ultrasonogra-

phy (preferably transvaginal) to detect an ovarian

neoplasm in women with severe or progressive hyper-

androgenism. Of note, some androgen-secreting ovar-

ian tumors are too small to be detected by transvaginal

ultrasound.

Further workup to identify the origin of androgen

excess may be clinically indicated because of atypical

clinical or laboratory findings and may include the fol-

lowing: (1) measuring serum androstenedione (the im-

mediate precursor for testosterone)(28)orothersteroid

intermediates [that have on occasion provided addi-

tional information (Section 5, Androgen Testing Re-

marks)]; (2) assessing the response to cosyntropin of

17-hydroxyprogesterone, DHEA, 17-hydroxypregnenolone,

and 11-deoxycortisol, and/or genotyping to exclude

rare forms of congenital adrenal hyperplasia; (3)

assessing urinary corticoid metabolites by mass spec-

trometry to exclude apparent cortisone reductase de-

ficiency (44); (4) dexamethasone suppression testing to

suppress androgens arising from a functional adrenal

source; (5) adrenal computed tomography, ovarian

ultrasound, or more specialized imaging studies (45) if

there is reason to suspect an androgen-secreting tumor;

and (6) assessing the suppressive response to combined

OC or gonadotropin-releasing hormone (GnRH) ago-

nist (46). Lastly, transvaginal ultrasound is also helpful

if ovarian hyperthecosis is suspected; absence of folli-

cles and or the polycystic ovarian morphology supports

the diagnosis of hyperthecosis. This approach to eval-

uation is similar to that recommended by other groups,

including the following: the American Association of

Clinical Endocrinologists (43), the American Society for

Reproductive Medicine (47), the French Endocrine

Society (48), and the Androgen Excess and PCOS So-

ciety (6).

Values and preferences

Our suggestion for testing for hyperandrogenemia in

all women with hirsutism places a relatively high value

on the identification of treatable underlying hyper-

androgenic diseases. Our suggestion for not testing

for hyperandrogenemia in patients with normal variant

unwanted hair, for whom hormonal treatment is not

contemplated, places a relatively high value on avoiding

the risk of false positives and the resulting increase in

medical tests and procedures. It places a relatively low

value on the potential benefits of early detection of mild

hyperandrogenemia that will not affect initial man-

agement and outcome.

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 hir-

sutism and no evidence of an endocrine disorder,

we suggest either approach. (2 |OOO)

2.2. For hirsute women with obesity, including those

with PCOS, we also recommend lifestyle changes.

(1 |OO)

Evidence

The development of hirsutism is mostly dependent on

circulating androgen concentrations and the response of

the hair follicle to the local androgen milieu. Thus, there

are two main approaches to the management of hirsutism

that may be used either individually or in combination:

(1) pharmacologic therapies that target androgen pro-

duction and action, and (2) direct hair removal methods

(electrolysis and photoepilation). Most women also use

cosmetic measures (shaving, plucking, waxing) before

their first medical consultation and continue to use them

during pharmacotherapy. We suggest pharmacotherapy

as initial therapy for most women with patient-important

hirsutism (adding direct hair removal methods later if

needed); however, some women may choose to start both

therapies simultaneously.

Although experts have often made treatment recom-

mendations based on the severity of hirsutism using

Ferriman–Gallwey scores [mild (score 8 to 15) or severe

(score .15)], this approach has several limitations: (1)

many clinicians are unfamiliar with calculating

Ferriman–Gallwey scores; (2) most women use cosmetic

measures before seeking consultation, making it impos-

sible to accurately determine a Ferriman–Gallwey score;

and (3) treatment decisions need to be proportionate to

the extent that excessive hair affects patient well-being

(i.e., some women with low scores may be more distressed

and desire more aggressive management of their hirsut-

ism than other women who may be less bothered, despite

having higher hirsutism scores). We use the term patient-

important hirsutism to refer to unwanted sexual hair

growth of any degree that causes sufficient distress for

women to seek additional treatment.

Cosmetic measures to manage hirsutism include

methods that remove hair shafts from the skin surface

(depilation) and those that extract hairs to above the bulb

(epilation). Shaving is a popular depilation method that

removes hair down to just below the surface of the skin.

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Shaving does not affect the rate or duration of the anagen

phase or diameter of hair. However, it yields a blunt tip

rather than the tapered tip of uncut hair, which gives the

illusion of thicker hair. Chemical depilatory agents are

also commonly used to dissolve the hair. Most de-

pilatories contain sulfur and have an unpleasant odor.

In addition, irritant dermatitis can occur. Epilation

methods, such as plucking or waxing, are relatively safe

and inexpensive, but cause some discomfort. These methods

do not cause an increase in hair diameter. Scarring, follic-

ulitis, and hyperpigmentation (particularly in women of

color) may occur. Although not a method of hair removal,

bleaching with products containing hydrogen peroxide and

sulfates is a method for masking the presence of undesired

hair, particularly facial hair. Side effects include irritation,

pruritus, and possible skin discoloration.

In addition to cosmetic and/or pharmacologic therapy,

lifestyle changes for obese women with PCOS may im-

prove their hirsutism. In a meta-analysis of four studies

that included 132 subjects, lifestyle changes (diet, exer-

cise, behavioral, or combination therapy) resulted in

weight loss, a decrease in serum testosterone and fasting

insulin concentrations, and a small improvement in

Ferriman–Gallwey scores when compared with minimal

or no treatment—mean difference, 21.19 [95% confidence

interval (CI) (22.35 to 20.03)] (49). However, lifestyle

changes should not be considered a primary therapy for

hirsutism, as their impact is not clinically significant, par-

ticularly when compared with OCs (50). Our approach is

consistent with the Endocrine Society clinical guidelines on

the diagnosis and treatment of PCOS (40).

3.0 Pharmacological Treatments

Initial therapies

3.1. For the majority of women with hirsutism who

are not seeking fertility, we suggest OCs 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 ade-

quate contraception (2 |OOO). However, for

women who are not sexually active, have un-

dergone permanent sterilization, or who are us-

ing long-acting reversible contraception, we

suggest using either OCs 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 OC over

another as initial therapy, as all OCs 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 VTE

(e.g., those who are obese or over age 39 years),

we suggest initial therapy with an OC containing

the lowest effective dose of ethinyl estradiol

(EE) (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 OC, we suggest

adding an antiandrogen. (2 |OO)

3.6. We do not suggest one antiandrogen over an-

other (2 |OO). However, we recommend

against the use of flutamide because of its po-

tential 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 emo-

tional distress and/or in those women who have

used OCs in the past and have not experienced

Table 2. OCs and Associated VTE Risks

Progestin

Generation

Progestin Relative

Androgenicity

Progestin Relative

VTE Risk

a,b

Progestin Absolute

VTE Risk

b,c

Progestin/Dose EE Dose (mcg)

1 Medium 2.6 7 Norethindrone 0.5–1.0 mg 20, 35

2 High 2.4 6 Levonorgestrel 0.15 mg 20, 30

2–3 Low 2.5 6 Norgestimate 0.25 mg 35

3 Low 3.6 11 Gestodene 0.075 mg 20, 30

3 Low 4.3 14 Desogestrel 0.15 mg 20, 30

4 Antiandrogen 4.1 13 DSP 3 mg 20, 30

—Antiandrogen 4.3 14 CPA 2 mg

Relative risk compared with no OC use.

Vinogradova et al. (73); Stegeman et al. (57).

Extra cases VTE per 10,000 women treated with OCs per year.

OCs containing CPA are not available in the United States.

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sufficient improvement, we suggest initiating com-

bination therapy with an OC and antiandrogen

(2 |OO). However, we suggest against combi-

nation therapy as a standard first-line approach.

(2 |OO)

Evidence

Combined oral estrogen–progestin contraceptives

Most combined estrogen–progestin OCs contain the

potent, synthetic estrogen EE in combination with a

progestin. Of note, in this guideline, OCs refers only to

combined oral estrogen–progestin contraceptives con-

taining EE and not to newer OCs that contain 17-

b-estradiol or estradiol valerate combined with highly

potent progestins, as the doses of estrogen in these pills

are unlikely to suppress ovarian androgens. The guideline

also does not refer to oral progestin-only contraceptives,

which are ineffective for hirsutism.

Most progestins are derived from 19-nortestoster-

one and exhibit varying degrees of androgenicity (31,

51). Examples of progestins with low androgenicity

include norgestimate, desogestrel, and gestodene; those

with medium androgenicity include norethindrone;

and those with relatively high androgenicity include

norgestrel and levonorgestrel. CPA and DSP are

structurally unrelated to testosterone and function as

weak androgen receptor antagonists. Several OCs

contain DSP, a progestin structurally related to spi-

ronolactone that exhibits weak antiandrogenic activ-

ity. In bioassays, 3 mg DSP (the dose used in OCs) was

equivalent to only 9 to 10 mg spironolactone. For

comparison, 100 to 200 mg spironolactone is the

therapeutic dose for hirsutism. Also, 2 mg CPA (the

dose used in OCs) was equivalent to ;50 mg spi-

ronolactone (52, 53). A 12-month trial comparing OCs

containing either 3 mg DSP or 2 mg CPA showed

similar reductions in hirsutism scores, suggesting that

the efficacy is substantially related to ovarian sup-

pression (54). Although DSP is a very weak anti-

androgen, it is more potent than spironolactone in

antimineralocorticoid equivalency.

OC therapy reduces hyperandrogenism via a number

of mechanisms, including the following: suppression

of luteinizing hormone secretion (and therefore ovar-

ian androgen secretion) (55), stimulation of hepatic pro-

duction of sex hormone–binding globulin (SHBG) (thereby

increasing androgen binding in serum and reducing serum-

free androgen concentrations), and a slight reduction in

both adrenal androgen secretion and binding of androgens

to their receptor. Consequently, there is a reduction of

testosterone production. Androgenic progestins also in-

crease the metabolic clearance of testosterone (56, 57).

There may also be a small direct effect in inhibiting 5a-

reductase activity in the pilosebaceous unit.

Combination OCs carry about a threefold increased

risk of VTE in first-time users. VTE risk is significantly

but weakly related to estrogen dose and may wane with

duration of estrogen use. The use of OCs containing some

of the recent-generation low-androgenicity progestins

(desogestrel, gestodene), and androgen receptor antag-

onists (CPA, DSP) may confer a 50% to 100% increased

risk of VTE compared with OCs containing the second-

generation progestin levonorgestrel, according to reviews

of large-scale comparative analyses (58, 59). However,

the DSP risk was not found in a prospective post-

marketing study of first-time contraceptive users (60). Of

note, the absolute risk is low and far less than that seen

during pregnancy (61). There have been concerns that the

presence of PCOS may represent an additional in-

dependent risk factor for VTE, but available data are

inconclusive (62, 63). There have also been concerns

about an excess risk of VTE with OCs containing CPA,

but the Pharmacovigilance Risk Assessment Committee

of the European Medicines Agency concluded in 2013

that the benefits of the drug outweighed the risks (64).

Increased age and obesity are additional factors associ-

ated with an increased risk of VTE. The risk in women

over age 39 years taking OCs is approximately fourfold

higher than in younger women (100 vs 25 per 100,000

women years) (65). The risk in obese women taking OCs

has been estimated to be 2- to 10-fold higher than

nonobese women taking OCs (66, 67). However, the

benefits outweigh the risks based on obesity alone (68)

when using OCs for contraception. The risk-benefit ratio

for women with PCOS taking OCs simply for cycle

control and/or androgen suppression is unclear.

Updated systematic review and meta-analysis

The results of the network analysis were consistent

with our previous meta-analysis. Our 2008 review

identified only one placebo-controlled, randomized trial

(69) and a second trial that compared OCs to no therapy

in women with hirsutism (70). The updated review iden-

tified no additional trials. A combined analysis of

these trials associated OC therapy with a greater reduc-

tion in hirsutism scores, with a pooled weighted mean

difference of 27.20 [95% CI (211.96 to 22.52)]. The

extent to which this average reduction in hirsutism scores

reflects a reduction in hirsutism-associated distress

remains unclear.

The systematic review also compared OCs containing

antiandrogenic progestins (CPA and DSP) vs all other

OCs and the relatively androgenic progestin levo-

norgestrel vs all other OCs. Only four trials presented

data sufficient for meta-analysis. OCs containing

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levonorgestrel had a similar effect on hirsutism scores

compared with all other OCs. OCs containing anti-

androgenic progestins (one trial using CPA and one

trial using DSP) were associated with slightly lower

Ferriman–Gallwey scores than other OCs, with a

weighted mean difference of 22.86 [95% CI (24.96 to

20.76)], a difference that is probably not clinically im-

portant (71).

Which OCs should be used for hirsutism?

For most women, we do not suggest one particular OC

formulation over another for treating hirsutism. This

recommendation is consistent with the Endocrine Society

clinical guideline on the diagnosis and treatment of PCOS

(40). There were no clinically important advantages of

OCs containing the antiandrogen progestins CPA or DSP

in our meta-analysis. Although we were concerned that

OCs containing levonorgestrel (the most androgenic

progestin) would be less effective for hirsutism, this was

not observed in our meta-analysis. Whereas a potential

benefit of OCs containing levonorgestrel is their lower

VTE risk, an important concern is the adverse effects of

levonorgestrel on metabolic biomarkers (72). Although

there are no data to suggest that the metabolic effects are

associated with adverse clinical outcomes, we tend to

avoid this progestin in women with PCOS, a population

with metabolic concerns at baseline. As noted previously,

for women with hirsutism at higher risk for VTE (e.g.,

those who are obese or over age 39 years), we suggest

initial therapy with an OC containing the lowest effective

dose of EE (usually 20 mcg) and a low-risk progestin

(Table 2). Our approach is similar to that of the consensus

statement from the Androgen Excess and PCOS Society,

which also suggests using a low-dose OC product to

minimize VTE risk (6).

Ovarian androgen suppression may be similar with

OCs containing different doses of EE. In a meta-analysis

of 42 studies, the suppression of serum total and free

testosterone concentrations was similar with OCs con-

taining 20 vs 30/35 mcg EE (74). Limited data suggest

that OCs containing DSP with 20 or 30 mcg EE have a

similar effect on Ferriman–Gallwey scores (75). Trans-

dermal contraceptive patch and OCs suppressed serum

androgens to a similar degree in one study, but the

outcome of hirsutism was not addressed (76).

Antiandrogens

Our systematic review identified seven trials of anti-

androgens, as follows: three of finasteride, two of flutamide,

and two of spironolactone. In analyses of individual anti-

androgens compared with placebo, spironolactone 100 mg/d,

finasteride 2.5 to 5 mg/d, and flutamide 500 mg/d, each

showed a significant reduction in hirsutism scores. When all

antiandrogens were pooled together as a class, and results

were expressed in Ferriman–Gallwey units, antiandrogens

were significantly more effective than placebo, with a pooled

weighted mean difference of 27.02 [95% CI (211.51

to 22.52)]. There was no statistically significant difference

among the three antiandrogens.

Available antiandrogens and their dosing regimens are

shown in Table 3. Spironolactone, an aldosterone an-

tagonist, exhibits dose-dependent competitive inhibition

of the androgen receptor as well as inhibition of 5a-

reductase activity (77). Although there are no rigorous

dose-response trials to date, spironolactone’s effects are

known to be dose dependent (77). The drug is generally

well tolerated, but should not be used if there is renal

impairment. Spironolactone may have a dose-dependent

association with menstrual irregularity unless the pa-

tient uses an OC concomitantly. Spironolactone use may

rarely result in hyperkalemia, and it may cause increased

diuresis and occasionally postural hypotension and

dizziness early in treatment. OCs containing DSP have a

mild mineralocorticoid effect and should not be used

with a potassium-sparing diuretic. As with all anti-

androgens, if a patient inadvertently uses spironolactone

during early pregnancy, there is a danger that a male

fetus could be feminized (78) because of the exquisite

sensitivity of the fetal genitalia to exposure to maternal

synthetic sex hormone ingestion (79), although the

absolute risk of this is not known.

Clinicians worldwide use CPA to treat hirsutism and

acne, but it is not available in the United States. CPA is a

progestogenic compound with antiandrogen activity by

virtue of its effects in inhibiting the androgen receptor and

to a lesser degree in inhibiting 5a-reductase activity (80).

It also suppresses serum gonadotropin and androgen

levels. In one systematic review, the OC CPA (2 mg) with

35 mcg EE was similar to antiandrogen therapy and more

effective than placebo (81).

Finasteride inhibits type 2 5a-reductase activity.

Because enhanced 5a-reductase activity in hirsutism

Table 3. Antiandrogens Used for the Treatment

of Hirsutism

Antiandrogens Dosing

CPA

50–100 mg/d on menstrual cycle days

5–15, with EE 20–35 mg on days 5–25

Spironolactone 100–200 mg/d [given in divided doses

(twice daily)]

Finasteride 2.5–5 mg/d

Flutamide

250–500 mg/d (high dose)

62.5 to #250 mg/d (low dose)

Not available in the United States; also prescribed as an OC (2 mg CPA +

35 mcg EE).

Flutamide not recommended because of hepatotoxicity.

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probably involves both type 1 and 2 5a-reductase en-

zymes, only a partial inhibitory effect may be expected

with finasteride. One review of available trials reported

that finasteride reduced hirsutism scores by 30% to 60%

and reduced hair shaft diameters as well (82). This effect

was found to be similar to that with the use of other

antiandrogens with no major adverse effects. Although

5 mg finasteride is the most commonly used dose, some

data suggest that 7.5 mg is more effective (83), and that

doses of 2.5 and 5 mg appear to be equally effective (84).

Our systematic reviews also demonstrated a significant

reduction in hirsutism scores with finasteride compared

with placebo (85). Dutasteride has been approved for the

treatment of men with prostate cancer, and it inhibits both

type 1 and 2 isoenzymes. Although this would seem-

ingly be an attractive option for the treatment of hir-

sutism, there are no clinical data to support its use at

this time.

Flutamide is a “pure”antiandrogen with a dose-

response inhibition of the androgen receptor (86).

Whereas the most frequently used dose in RCTs is 500

mg/d, some experts have suggested equal efficacy with

250 and 500 mg/d (87). Retrospective studies, trials of

combination therapy (low-dose flutamide with other

drugs) (88, 89), and nonrandomized studies of low-dose

flutamide (as low as 62.5 mg) (90) suggest that flutamide

doses of 62.5 to 250 mg may be effective for hirsutism

(91), but there is no evidence from RCTs of low-dose

flutamide monotherapy vs placebo to support this.

The major concern with flutamide is its propensity for

hepatic toxicity. This is not trivial, as numerous studies

have associated flutamide with liver failure and even death

(92–94). Although some studies have reported that low

doses of flutamide are not hepatotoxic (88, 95, 96), others

have raised important concerns. A 10-year surveillance

study of 203 women receiving flutamide at doses of 62.5 or

125 mg identified 22 (11%) who experienced elevated

serum concentrations of alanine aminotransferase and/or

aspartate aminotransferase (97). In a retrospective study of

414 women with hirsutism receiving low-dose flutamide

alone or with OCs, 6% stopped therapy due to elevated

transaminases (all were taking 125 to 250 mg and all

occurred in the first year of therapy) (91). Lastly, one

center reported a series of seven women who developed

hepatoxicity while taking flutamide (150 to 250 mg/d) for

acne or hirsutism; five required urgent liver trans-

plantation and four of five survived (98).

In our 2008 guideline, we suggested against standard

dose flutamide (.250 mg). Based upon emerging evi-

dence of hepatotoxicity, unproven efficacy for hirsutism,

and the availability of alternative antiandrogens, we

also recommend against the use of low-dose flutamide

(#250 mg).

Addition of antiandrogens to OCs

If hirsutism has not improved despite 6 or more

months of monotherapy with an OC, we suggest adding

an antiandrogen. Our 2008 updated systematic reviews

identified five RCTs of antiandrogens combined with

OCs vs OCs alone. The addition of antiandrogen therapy

to OCs was slightly more effective for hirsutism than OC

therapy alone (five trials) and was associated with in-

cremental reduction of hirsutism scores—weighted mean

difference, 21.73 [95% CI (23.32 to 20.13)].

OCs vs antiandrogens

IntheonlyRCTcomparinganOCtoananti-

androgen (finasteride), the OC contained a low-dose

antiandrogen (2 mg CPA) (99). After 9 months of

treatment, there was no significant difference in hir-

sutism score between the finasteride group and the

group receiving this OC.

Glucocorticoid therapy

Clinicians administer glucocorticoids long-term to

suppress adrenal androgens in women with classic con-

genital adrenal hyperplasia due to 21-hydroxylase de-

ficiency. In these patients, glucocorticoids help prevent or

manage hirsutism, and they are effective for maintaining

normal ovulatory cycles. In women with the nonclassic

form of 21-hydroxylase deficiency, glucocorticoids are

effective for ovulation induction, but their role in the

management of hirsutism is less clear.

In patients with pure adrenal hyperandrogenism, even

in those who are very sensitive to glucocorticoids, sup-

pressing adrenal androgens results in only minor im-

provements in hirsutism, although these patients can

achieve prolonged remission after therapy withdrawal

(100, 101).

Women with NCCAH

Our approach to treating hirsutism in women with

NCCAH is the same as for women with PCOS. We suggest

starting with an OC and adding an antiandrogen after

6 months if necessary. Clinicians can administer an anti-

androgen as initial therapy if the woman is not pursuing

pregnancy and has a reliable form of contraception. We

only suggest glucocorticoids for the management of

hirsutism in women who have a suboptimal response to

OCs and/or antiandrogens, or cannot tolerate them. For

hirsutism, we use prednisone 4 to 6 mg daily or dexa-

methasone 0.25 mg/d. Clinicians should counsel women

that are considering pregnancy about the teratogenic

risks of antiandrogens. For ovulation induction, we

suggest glucocorticoid therapy. We typically start with

prednisone 5 mg daily (102). If ovulation has not oc-

curred, the dose can be increased to 7.5 mg. Clomiphene

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citrate is then added if ovulation does not occur

with prednisone alone. We do not suggest dexametha-

sone because it is not inactivated by placental 11-

b-hydroxysteroid dehydrogenase type 2 (i.e.,fetal

exposure occurs).

In women with adrenal hyperandrogenism, although

glucocorticoids may improve hirsutism, both OCs and

antiandrogens may be more effective. In a study of

women with hirsutism of adrenal origin or enzyme de-

ficiency randomized to receive an OC (CPA plus EE) or

dexamethasone (103), serum DHEA and DHEAS con-

centrations decreased in the dexamethasone group, but

not the OC group. However, more women in the OC

group experienced a significant reduction in hirsutism (10

of 15 patients; 66%) than in the dexamethasone group (4

of 13 patients; 31%).

In a trial of women with NCCAH receiving CPA or

hydrocortisone (104), CPA-treated patients experi-

enced a significantly greater decrease in hirsutism

scores (54%) after 1 year than hydrocortisone-treated

women (26%); in contrast, androgen levels normalized

only in the hydrocortisone-treated subgroup, sug-

gesting that half of the cutaneous expression of

hyperandrogenism is dependent on the peripheral re-

ceptivity to androgens.

Adverse effects associated with

glucocorticoid therapy

Slight overdosing can occur even at recommended

doses and is independent of daily or alternate-day ad-

ministration. Slight overdosing may be associated with

side effects, such as adrenal atrophy, increased blood

pressure, weight gain, Cushingoid striae (particularly with

dexamethasone), and decreased bone mineral density.

DHEAS levels indicate the degree of adrenal suppression;

the target level is ;70 mcg/dL (25).

Values and preferences

Our recommendation not to use flutamide for the

routine management of hirsutism places a high value on

avoiding potential hepatotoxicity and medication costs in

women with a relatively benign disorder and a relatively

lower value on foregoing a potentially useful intervention.

The suggestion not to offer glucocorticoid therapy as first-

line therapy to hirsute women with NCCAH places a

relatively higher value on avoiding the potential for ad-

verse effects of glucocorticoids and a relatively lower value

on the potential benefits of suppressing endogenous an-

drogens and inducing a more prolonged remission of

hirsutism and hyperandrogenism after therapy with-

drawal (100, 101). Our approach does recognize the

importance of glucocorticoid therapy for ovulation in-

duction in NCCAH.

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 GnRH agonists except

in women with severe forms of hyperandro-

genemia (such as ovarian hyperthecosis) who

have a suboptimal response to OCs and anti-

androgens. (2 |OOO)

3.11. We suggest against the use of topical anti-

androgen therapy for hirsutism. (2 |OOO)

Evidence

Insulin-lowering drugs—updated systematic review

and meta-analysis

Reducing insulin levels pharmacologically attenuates

hyperandrogenemia. Metformin, an insulin-lowering

drug, has been used for a number of indications in

women with PCOS, including hirsutism. In our 2008

meta-analysis of eight RCTs, metformin was no more

effective than placebo for hirsutism treatment (105),

and we suggested against its use (38). Similar results

were seen in our updated systematic review of nine

trials; in a pooled analysis, metformin was no more

effective than placebo for lowering hirsutism scores.

Other insulin sensitizers, troglitazone and rosiglita-

zone, had no significant effect on hirsutism. Our results

are consistent with other meta-analyses of metformin

therapy for hirsutism (106).

GnRH agonists

Uncontrolled trials of GnRH agonist therapy in

women with ovarian hyperandrogenism have reported

significant reductions in luteinizing hormone, ovarian

androgens, and Ferriman–Gallwey scores (107–110).

When compared with OC therapy, GnRH agonist

therapy alone seems to have similar benefit for reducing

hirsutism scores (111–113). GnRH agonist with low-

dose estrogen–progestin add-back was more effective

for hirsutism than an OC in two trials—one by pho-

tographic hair density (114) and one by Ferriman–

Gallwey scores (115). Because GnRH agonists alone

result in severe hypoestrogenism and eventual bone loss

(116), clinicians prescribe low doses of estrogen or es-

trogen plus progestin (in women with a uterus) as add-

back therapy (117, 118).

Although GnRH agonist therapy is more effective than

placebo or no therapy for hirsutism, it appears to have no

advantages when compared with other available agents

(such as OCs and antiandrogens). In addition, GnRH

agonist therapy is expensive, requires injections, and,

unless clinicians add some form of estrogen, results in

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severe estrogen deficiency with menopausal symptoms

(such as hot flashes and bone loss). We therefore suggest

against using GnRH agonists except in women with

severe forms of hyperandrogenemia (such as ovarian

hyperthecosis) who have a suboptimal response to OCs

and antiandrogens.

Topical antiandrogens

Creams with antiandrogens appear to have lim-

ited efficacy, with one study of a cream containing

canrenone(theactivemetaboliteofspironolactone)

reporting both benefit and no benefit (119). Similarly,

trials of finasteride have yielded inconsistent results,

with local applications of preparations with 0.25%

showing benefit (120) and 0.5% showing no benefit

(121). We therefore suggest against their use. Note that

eflornithine (which has been approved as a topical

treatment) is not an antiandrogen (see Topical Treat-

ment below).

Values and preferences

Our suggestion against the use of GnRH agonists

for the routine management of hirsutism places a high

value on avoiding an expensive, inconvenient therapy

that requires the addition of estrogen (with or with-

out progestin) to avoid side effects and bone loss and a

relatively lower value on foregoing a potentially useful

intervention.

4.0 Direct Hair Removal Methods

4.1. For women who choose hair removal therapy, we

suggest photoepilation for those whose un-

wanted 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 appropri-

ateskincooling(2|

OOO). Clinicians should

warn Mediterranean and Middle Eastern women

with facial hirsutism about the increased risk

of developing PH with photoepilation therapy.

We often suggest topical treatment or electrol-

ysis over photoepilation with these patients.

(2 |OOO)

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)

Evidence

Temporary methods of hair removal

(cosmetic methods)

Depilation is the removal of the hair shaft from the skin

surface, for example by shaving. Depilation in humans has

no known biological effect on the hair follicle, producing

no change in hair growth, hair diameter, or hair color.

Shaving yields a sharply cut hair tip, which upon regrowth

feels coarse and gives the illusion of thicker hair compared

with a naturally tapered hair tip. Plucking, waxing, or

mechanical devices that extract hairs are relatively safe

and inexpensive, but cause some discomfort. Scarring,

folliculitis, and (particularly in women of color) hyper-

pigmentation may occur.

Chemical depilatory agents dissolve the hair. Most are

thioglycolates, which disrupt disulfide bonds in the hair.

Side effects include emission of a sulfurous odor and

irritant dermatitis (especially on the face), which may be

followed by hyperpigmentation.

Although not a method of hair removal, bleaching

with products containing hydrogen peroxide and sulfates

is a method for masking the appearance of pigmented

hair. Side effects include irritation, pruritus, and possible

skin discoloration.

Permanent methods of hair reduction: electrolysis

and photoepilation

The Food and Drug Administration (FDA) has

approved a large number of photoepilation devices [laser

and intense pulsed light (IPL)] for permanent hair re-

duction. They define permanent hair reduction as

attaining at least a 30% reduction of terminal hairs and

sustaining this reduction for a period longer than the

complete growth cycle of hair follicles (4 to 12 months,

depending on body site). Photoepilation is a method

capable of rapidly treating large areas; it requires the

presence of pigmented, terminal hair. Electrolysis is

generally limited to small treatment areas, and it does not

depend on hair pigmentation.

Electrolysis

Despite being available as a hair reduction method

for well over a century, prospective clinical trials have

rarely studied electrolysis. Electrical current is passed

through a fine wire electrode, which is manually inserted

sequentially into individual hair follicles. The galvanic

electrolysis technique uses direct current, causing elec-

trochemical reactions that locally release toxic products

within the hair follicle. The thermolysis technique uses a

higher level of alternating current to produce heat in the

hair follicle immediately surrounding the wire electrode.

Some claim a combination of these (“The Blend”) is more

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effective (122). Electrolysis is generally regarded as ef-

fective for permanent hair reduction. In one small com-

parative study, electrolysis was more effective than

plucking for permanent reduction of axillary hair (123).

The thermolysis and blend techniques are painful; topical

anesthetic applications prior to treatment can reduce this

discomfort (124).

Photoepilation

Permanent hair reduction by photoepilation appeared

,20 years ago (125) and is now the third most prevalent

nonsurgical aesthetic procedure in the United States after

botulinum toxin and hyaluronic acid injections, with

;890,000 procedures performed during 2012 (126).

Photoepilation uses pulses of light absorbed by mel-

anin in the hair shaft and follicle to cause selective

photothermolysis of pigmented terminal hair follicles

(127): it selectively injures pigmented tissues based upon

wavelength, pulse duration, and fluence (energy applied

per area of skin surface). Photoepilation sources include

four types of laser (ruby, alexandrite, diode, and Nd:

YAG) and various IPL sources emitting specific wave-

lengths between 500 and 1200 nm that the melanin

absorbs. Pulse durations of milliseconds permit heat to

diffuse from the pigmented hair shaft into the sur-

rounding epithelium of a terminal hair follicle (128).

Clinicians can adjust fluence and pulse duration

according to a particular patient’s hair and skin type.

Effective and safe treatment requires producing irre-

versible thermal damage to hair follicles, and not to the

surrounding skin. Some photoepilation devices are able

to rapidly treat very large areas (e.g., the lower face, neck,

chest, and both axillae) within 20 minutes. The FDA has

cleared less powerful, home-use versions of diode laser

IPLs for over-the-counter sale, which do not necessarily

meet the efficacy criteria for permanent hair reduction.

Photoepilation vs electrolysis

The advantages of electrolysis over photoepilation are

its ability to permanently reduce hair of any color in any

skin type and the lack of reported PH (the rare occurrence

of paradoxical hair growth instead of hair removal after

laser epilation). The disadvantage of electrolysis is longer

treatment time. Both electrolysis and photoepilation are

somewhat painful, and both treatments often include a

topical anesthetic. A small prospective, split-face study

compared a series of six treatments with the blend

method of electrolysis vs IPL. Nine months after treat-

ment, there was significantly greater efficacy of IPL, and

24 of 25 patients preferred IPL to electrolysis (129). In a

similar study design, 12 women received three alexan-

drite laser treatments to the left axilla and four electrolysis

treatments to the right axilla (130). Laser treatment was

60 times faster (30 seconds vs 30 minutes). Six months

following the initial treatment, there was a 74% re-

duction in terminal hair count after laser and 35% after

electrolysis.

Efficacy of photoepilation

All FDA-approved photoepilation devices have met

the FDA hair removal criteria after a single treatment in at

least one prospective study. This includes most of the

commercially available photoepilation lasers and many

IPL devices. Complete or nearly complete alopecia occurs

for 4 to 6 weeks after each photoepilation treatment,

followed by gradual regrowth of terminal hair that is

typically reduced in number compared with baseline.

A meta-analysis of 24 prospective trials published

between 1998 and 2003 found that hair reduction at least

6 months after the last treatment averaged 57.5%,

54.0%, 52.8%, and 42.3% for diode, alexandrite, ruby,

and Nd:YAG lasers, respectively. Although diode had the

highest percentage reduction rate, the differences among

all four lasers were not statistically significant (131). An

earlier systematic review of 11 RCTs involving 444

people reported a similar 50% reduction in hair growth

for up to 6 months with alexandrite and diode lasers

(132). The review did not perform a meta-analysis for

IPL, ruby, or Nd:YAG lasers because of heterogeneous

interventions and outcome measures. Prospective, con-

trolled studies with objective quantitative endpoints that

compared lasers or IPL devices for photoepilation gen-

erally support these conclusions. Efficacy increases with

the number of treatments (133), but rarely achieves

100% hair removal (134). In a retrospective report

on .2000 consecutive patients treated with alexandrite

laser, average hair reduction was ;80% at 6 months after

the final treatment (135).

Photoepilation laser vs IPL

All prospective RCTs comparing two or more of the

various FDA-approved photoepilation lasers and IPL

devices have found that both are effective for long-term

reduction of pigmented terminal hair. In general, com-

parison studies have assessed relative device efficacy in

Fitzpatrick skin prototypes I to IV (fair to moderately

pigmented skin) and/or relative device safety in treating

prototypes V to VI (moderate to darkly pigmented skin).

Results of studies comparing the efficacy of laser

compared with IPL have been variable, and the com-

parison of devices is of limited generalizability, because

efficacy is dependent upon fluence. In three studies that

objectively counted hair before and 6 months after four to

six photoepilation treatments, the mean hair reduction

was similar for lasers and IPL: 27% to 40% for IPL; 34%

for diode laser; and 46% for alexandrite laser (136–138).

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One of these studies found significantly greater efficacy of

an alexandrite laser vs an IPL device in women with

PCOS (138), whereas others did not (136, 137).

Home-use lasers

Home-use diode lasers and IPLs cleared for over-the-

counter sale have not been studied in RCTs. Reported

hair count reductions range from 6% to 72% at 3 to

6 months after multiple treatments given to various body

sites (139). The limited power of home-use photo-

epilation devices makes them slower than medical pho-

toepilation devices. Despite safety concerns, there are no

reports of injury from home-use photoepilation.

Side effects and risks of photoepilation

Because melanin pigment is necessary for photo-

epilation, unwanted hair that is naturally white or blonde

is not amenable to treatment. Light must also pass

through melanin present in the epidermis [in epithelial

stem cells (;1 mm deep in the outer root sheath) and in

dermal papillae (;2 to 5 mm deep)] to reach target re-

gions of hair follicles. Patients with tanned or darkly

pigmented skin are at higher risk for unintended thermal

injury to the epidermis during photoepilation, resulting

in inflammation, burns, blistering, hyperpigmentation,

hypopigmentation, and/or scarring (rarely). However,

in fair skin the risk of side effects, other than temporary

perifollicular inflammation, is low (140). Skin cooling,

lower fluence, longer pulse duration, and/or longer

wavelength can reduce the relative risk of skin injury

during photoepilation. Light sources with integrated

skin-cooling devices, cryogen spray, and the applica-

tion of cold air or cold transparent gels help with skin

cooling.

Mild to moderate pain during treatment and transient

perifollicular erythema and/or edema are side effects

directly related to thermal destruction of hair follicles.

Clinicians often use these acute responses as therapeutic

endpoints. Side effects related to unintentional epidermal

injury are more likely to occur with darker skin pig-

mentation (141), higher treatment fluence (142), and/or

inadequate skin-cooling techniques. These side effects

include strong pain, blisters, erosions, crusting, transient

or prolonged pigmentary changes (in up to ;10% of

patients), and scarring (very rare).

The risk of side effects appears to be greater after IPL

and ruby laser (694 nm) treatments. In a retrospective

series of 2541 Middle Eastern patients treated for at least

eight sessions with IPL, pigmentary changes occurred in

;5%, blistering or erosions in ;4%, and scarring in

;0.01% (143). In a retrospective series of 346 consec-

utive patients treated with ruby laser, the overall frequency

of pigmentary side effects was 9%, but it was 24% in

individuals with the darkest skin types (Fitzpatrick skin

types V to VI) (134).

Nd:YAG (1064 nm) lasers (which have the same cost

of efficacy) are effective for photoepilation in darkly

pigmented skin because of the lower risk of epidermal

injury and pigmentary side effects (144, 145). A legal

database review found that injury from photoepilation

is the most common cause of litigation associated with

laser/IPL esthetic treatments, with a high proportion of

cases in which physicians delegate administration of

treatment to nonphysician practitioners (146). We

therefore suggest that women seek laser therapy in fa-

cilities that are either physician operated or supervised.

Paradoxical hypertrichosis after photoepilation in

women with facial hirsutism

PH is an infrequent, but psychologically profound,

long-lasting, and potentially permanent side effect of

photoepilation. PH is the paradoxical occurrence of hair

growth after laser epilation (instead of the expected hair

removal). Women with hyperandrogenism are appar-

ently at higher risk for unclear reasons (147). Studies have

not reported PH in men. It occurs most commonly on the

face and neck and is apparently more likely to occur in

patients with a Mediterranean or Middle Eastern back-

ground, although data from large prospective trials are

not available. The reported prevalence ranges from 0.6%

to 10% (148, 149). Although further photoepilation can

potentially reduce PH (150), a repeated cycle of partial

removal followed by more PH can occur.

Eye injury

Because the highest concentration of melanin in the

body exists in retina and uvea, they can be damaged by

light passing through a closed eyelid or soft tissues

around the eye. Six reports of nine patients with irre-

versible anterior uvea, iris, and/or lens damage after

photoepilation near the eyes have appeared (151). Proper

placement of fully occlusive, opaque scleral shields can

prevent this injury.

Topical treatment

Eflornithine reduces the rate of hair growth by irre-

versibly inhibiting ornithine decarboxylase, which cata-

lyzes the rate-limiting step for follicular polyamine

synthesis. A topical preparation, eflornithine hydro-

chloride cream 13.9%, is FDA approved for the treat-

ment of unwanted facial hair in women. Open-label (148,

152–155) and randomized studies (156) suggest that

eflornithine reduces the growth and appearance of facial

hair and helps to improve quality of life. Noticeable re-

sults take ;6 to 8 weeks; after discontinuation of

treatment, hair returns to pretreatment levels after

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;8 weeks. Systemic absorption is extremely low (155).

Skin irritation has been reported only with experimental

overuse (153). With clinical use, side effects include

itching and dry skin.

Eflornithine can be used alone or in conjunction with

other therapies, including lasers and IPL. Two RCTs have

compared laser of the upper lip combined with either

eflornithine cream (randomly assigned to be applied to

one half of the lip) or placebo cream (applied to the other

half) (157, 158). Both trials reported a more significant

reduction in hair with the addition of eflornithine, par-

ticularly early in the trial (using hair counts and subjective

scoring). In one trial, the difference was significant until

week 22, but no significant differences were seen by week

34. In the second trial, a greater percentage of subjects in

the eflornithine group had a complete response at the end

of the trial. Both trials had methodological limitations

(unclear concealment of allocation in one and lack of

intention-to-treat analysis in both).

Values and preferences

Our suggestion to use photoepilation over electrolysis

for most women with unwanted pigmented hair is based

on higher efficacy and convenience, less pain, and overall

lower cost for the number of treatments necessary in most

women. Our suggestion to use electrolysis over photo-

epilation for women with white or blonde unwanted hair

is based on IPL’s lack of efficacy for this group. Our

suggestion to use long-wavelength, long pulse-duration

lasers with skin cooling over other lasers or IPLs for

photoepilation in women of color is based on relative

avoidance of skin burns and pigmentation changes. Our

suggestion to consider electrolysis (or shaving, waxing,

topical therapy) over photoepilation for women of

Mediterranean or Middle Eastern background with facial

hirsutism is based on higher risk of developing laser-

induced PH.

5.0 Androgen Testing Remarks

Testosterone is the key androgen to measure because it is

the major circulating androgen (3, 24, 26). It is produced

as a by-product of ovarian or adrenal function, either by

secretion or by the metabolism of secreted prohormones

(mainly androstenedione) in peripheral tissues, such as fat

and skin (159–161). Testosterone levels vary episodically

and diurnally (they are highest in the early morning and

vary by ;25% around the mean); in ovulatory women,

levels reach a midcycle zenith (3).

Considerable evidence supports the free hormone

hypothesis, i.e., that the bioactive portion of serum

testosterone is the free testosterone (protein unbound),

although the albumin-bound testosterone may be

bioavailable in some vascular beds (162–166). The serum

free (or bioavailable) testosterone level is more often

elevated in hirsute women than the total testosterone level

and is more sensitive than total testosterone in detecting

excess androgen production (167, 168). The reason for

this greater diagnostic sensitivity is that hirsute women

commonly have a relatively low level of SHBG. SHBG is

the main determinant of the fraction of plasma testos-

terone that is free or bound to other plasma proteins,

principally albumin (166). SHBG levels are raised by

estrogen and suppressed by androgen, insulin-resistant

obesity, and hypothyroidism (162, 169). Although the

low SHBG in obese individuals has long been attributed

to hyperinsulinemia (170), recent evidence suggests that

monosaccharide excess and inflammatory cytokines

mediate the SHBG response to obesity (169, 171). SHBG

polymorphisms can cause abnormal SHBG levels or

binding affinity, and, rarely, mutations cause very low

levels of SHBG (166, 172).

There are many pitfalls in testosterone assays at the

low levels found in women. The diagnostic utility of

serum testosterone depends on use of an accurate, specific

assay. The automated immunometric assays that are

available in most hospital laboratories are generally not

suitable to accurately measure testosterone in women

(165, 173). Systematic differences between assays and

excessively broad normal ranges derived from pop-

ulations of apparently normal women with unrecognized

androgen excess (22) further complicate the interpreta-

tion of testosterone levels in women. Some direct

radioimmunoassays and chemiluminescence assays

available in specialty laboratories provide results com-

parable to the new generation of liquid chromatography/

mass spectrometry methods (6, 174, 175). We anticipate

that the widespread use of liquid chromatography/mass

spectrometry methods beyond specialty laboratories

will improve access to reliable testosterone assays. Sali-

vary testosterone, although not a simple ultrafiltrate

of plasma, correlates with serum-free testosterone, but

methodologic differences have led to widely divergent

values between laboratories, so we recommend against

this methodology (176–179). We also do not recommend

measurements of urinary testosterone (testosterone glu-

curonide), as it is not a unique metabolite of serum tes-

tosterone and therefore does not accurately reflect

circulating testosterone (180, 181).

There is no uniform laboratory standard for free or

bioavailable testosterone levels, and so assay-specific

results differ widely. Direct assay of serum-free testos-

terone is unreliable (165). Advances in physicochemical

methodology indicate that current models of linear

binding of testosterone to SHBG and albumin are

oversimplistic (166). The most reliable methods compute

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the free testosterone concentration from total testoster-

one and SHBG concentrations or as the product of the

total testosterone concentration and the fraction of tes-

tosterone that is free by equilibrium dialysis or not bound

to SHBG (165, 182). Low SHBG itself is a useful marker

for the insulin resistance that underlies the metabolic risks

common in PCOS.

It has long been known that testosterone is not the

only naturally circulating androgen (167). However, the

routine assay of other known serum androgenic ste-

roids or precursors (e.g., the intermediate 17-hydroxy-

progesterone, the prohormones androstenedione and

DHEA, and the androgens dihydrotestosterone and

androstenediol) has been of little further diagnostic utility

in most, but not all, populations (16, 26–30). DHEAS is

increased in #17% of hirsute women who have normal

total and free testosterone levels (16, 26). A mildly ele-

vated DHEAS level in the setting of normal free testos-

terone is unlikely to affect management. The magnitude

of the androgen level is of poor predictive value for tu-

mors (26, 42), although a very high testosterone (adult-

male range) or DHEAS level (.700 mg/dL) is suggestive.

DHEAS levels are of limited sensitivity in screening for

NCCAH (26, 183).

It has recently been recognized that atypical adrenal

androgens such as 11-oxy-C19 steroids may contribute

significantly to androgen action (32, 184, 185). Estimates

of 11-ketotestosterone potency relative to testosterone

range from 20% to 75% (32, 186).

A meta-analysis indicates that the worldwide preva-

lence of NCCAH is 4.2%; however, the prevalence of

NCCAH among hyperandrogenic women varies with the

population: it is 1% to 2% among US Whites and His-

panics and relatively unusual among African Americans,

but 3% to 6% in Spain, France, Italy, and Canada, and

5% to 10% in the Middle East (33). At particularly high

risk are those with a positive family history and certain

ethnic groups, notably Ashkenazi Jews in whom the

prevalence is 37-fold greater than in the general Caucasian

population (26, 187). Although assay of total and free

testosterone would be expected to detect the excessive

androgen underlying hirsutism in NCCAH, the variability

in these levels may miss an occasional case (188).

Therefore, in hirsute patients with a high risk of congenital

adrenal hyperplasia (positive family history, member of a

high-risk ethnic group), we suggest screening by measuring

early morning 17-hydroxyprogesterone levels in the fol-

licular phase or on a random day for those with amen-

orrhea or infrequent menses, even if serum total and

free testosterone are normal. A 17-hydroxyprogesterone

value .170 to 200 ng/dL (5.15 to 6.0 nmol/L) is ap-

proximately 95% sensitive and 90% specific for NCCAH

(189, 190). Definitive diagnosis requires demonstrating a

17-hydroxyprogesterone value $1000 to 1500 ng/dL (30

to 45 nmol/L) either basally or in response to cosyntropin

stimulation testing, with those in the 1000 to 1500 range

being subject to confirmation by molecular genetic anal-

ysis of the CYP21A2 gene (33, 191).

Acknowledgments

Financial Support: This guideline was supported by the En-

docrine Society. No other entity provided financial or other

support.

Appendix. Conflict of Interest of Hirsutism in Premenopausal Women Guideline Task Force Members

Task Force Member Employment

Uncompensated

Memberships

Uncompensated

Leadership

Personal

Financial

Organizational

Financial

Spousal/

Family Info

Industry

Relationship/

Relevant Conflict

Kathryn A. Martin, MD,

Chair

Massachusetts General Hospital,

Senior Deputy Editor,

Endocrinology, UpToDate

None None None None None None

Richard R. Anderson, MD Massachusetts General Hospital,

Director, Wellman Center for

Photomedicine Harvard

Medical School, Professor,

Dermatology

None None None None None None

R. Jeffrey Chang, MD University of California San

Diego, Professor Emeritus of

Reproductive Medicine

None None None None None None

David Ehrmann, MD University of Chicago, Professor

of Medicine

None None None NIH –research

support

None None

Rogerio Lobo, MD Columbia University Medical

Center, Professor of Obstetrics

& Gynecology

None None None None None None

M. Hassan Murad, MD,

MPH

The Mayo Clinic, Professor of

Medicine

None None None None None None

Michel Pugeat, MD Hospices Civils de Lyon, Professor

of Endocrinology

None None None None None None

Robert L. Rosenfield, MD University of Chicago, Professor

Emeritus of Pediatrics &

Medicine

None None Pfizer - speaker None None None

Note: Financial, business, and organizational disclosures of the Task Force cover the year prior to publication. Disclosures prior to this time period are

archived.

doi: 10.1210/jc.2018-00241 https://academic.oup.com/jcem 19

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on 21 March 2018

Correspondence and Reprint Requests: Kathryn A. Martin,

MD, Massachusetts General Hospital, Bartlett Hall Extension 5,

55 Fruit Street, Boston, Massachusetts 02114. E-mail: kamartin@

partners.org.

Disclosure Summary: See Appendix.

Disclaimer: The Endocrine Society’s clinical practice guide-

lines 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 judge-

ment of healthcare providers and each patient’s individual

circumstances.

The Endocrine Society makes no warranty, express or im-

plied, 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 herein.

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