Hirsutism Pre M Guide 2018

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CL IN IC A L

P RA CT I CE

G UI DE L I NE

Evaluation and Treatment of Hirsutism in
Premenopausal Women: An Endocrine Society*
Clinical Practice Guideline
Kathryn A. Martin,1 R. Rox Anderson,1 R. Jeffrey Chang,2 David A. Ehrmann,3
Rogerio A. Lobo,4 M. Hassan Murad,5 Michel M. Pugeat,6 and Robert L. Rosenfield3
1

Massachusetts General Hospital, Boston, Massachusetts 02114; 2University of California, San Diego, La
Jolla, California 92037; 3University of Chicago, Chicago, Illinois 60637; 4Columbia University, New York,
New York 10032; 5Mayo Clinic Evidence-Based Practice Center, Rochester, Minnesota 55905; and
6
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 unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with
patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest
starting with pharmacological therapy and adding direct hair removal methods (electrolysis,
photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism
and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair
removal methods. For pharmacological therapy, we suggest oral combined estrogen–progestin
contraceptives for the majority of women, adding an antiandrogen after 6 months if the
response is suboptimal. We recommend against antiandrogen monotherapy unless adequate
contraception is used. We suggest against using insulin-lowering drugs. For most women who
choose hair removal therapy, we suggest laser/photoepilation. (J Clin Endocrinol Metab 103: 1–25,
2018)

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2018 Endocrine Society
Received 29 January 2018. Accepted 29 January 2018.
First Published Online 7 March 2018

doi: 10.1210/jc.2018-00241

Abbreviations: CI, confidence interval; CPA, cyproterone acetate; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DSP, drospirenone; EE,
ethinyl estradiol; FDA, Food and Drug Administration; GnRH, gonadotropinreleasing 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.

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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Guidelines on Hirsutism

Summary of Recommendations
1.0 Diagnosis of hirsutism
1.1. We suggest testing for elevated androgen levels
in all women with an abnormal hirsutism score
(2 |OO). In those cases where serum total testosterone levels are normal, if sexual hair growth is
moderate/severe or sexual hair growth is mild but
there is clinical evidence of a hyperandrogenic endocrine disorder (such as menstrual disturbance or
progression in spite of therapy), we suggest measuring an early morning serum total and free testosterone by a reliable specialty assay. (2 |OO)
1.2. We suggest screening hyperandrogenemic women
for NCCAH due to 21-hydroxylase deficiency by
measuring early morning 17-hydroxyprogesterone
levels in the follicular phase or on a random day
for those with amenorrhea or infrequent menses
(2 |OO). In hirsute patients with a high risk of
congenital adrenal hyperplasia (positive family
history, member of a high-risk ethnic group), we
suggest this screening even if serum total and free
testosterone are normal. (2 |OO)
1.3. We suggest against testing for elevated androgen
levels in eumenorrheic women with unwanted
local hair growth (i.e., in the absence of an abnormal hirsutism score) because of the low likelihood of identifying a medical disorder that would
change management or outcome. (2 |OO)

2.0 Treatment of hirsutism in
premenopausal women
2.1. For most women with patient-important hirsutism
despite cosmetic measures, we suggest starting with
pharmacological therapy (2 |OOO). For women
who then desire additional cosmetic benefit, we
suggest adding direct hair removal methods.
However, for women with mild hirsutism and no
evidence of an endocrine disorder, we suggest either
approach. (2 |OOO)
2.2. For hirsute women with obesity, including those
with polycystic ovary syndrome, we also recommend lifestyle changes. (1 |OO)
3.0 Pharmacological treatments
Initial therapies
3.1. For the majority of women with hirsutism who are
not seeking fertility, we suggest oral contraceptives
as initial therapy for treating patient-important
hirsutism. (2 |OO)

J Clin Endocrinol Metab, April 2018, 103(4):1–25

3.2. For most women with hirsutism, we suggest
against antiandrogen monotherapy as initial
therapy (because of the teratogenic potential of
these medications) unless these women use adequate contraception (2 |OOO). However, for
women who are not sexually active, have
undergone permanent sterilization, or who are
using long-acting reversible contraception, we
suggest using either oral contraceptives or antiandrogens as initial therapy (2 |OOO). The
choice between these options depends on patient preferences regarding efficacy, side effects,
and cost.
3.3. For most women, we do not suggest one oral
contraceptive over another as initial therapy, as
all oral contraceptives appear to be equally effective for hirsutism, and the risk of side effects is
low. (2 |OO)
3.4. For women with hirsutism at higher risk for
venous thromboembolism (e.g., those who are
obese or over age 39 years), we suggest initial
therapy with an oral contraceptive containing the
lowest effective dose of ethinyl estradiol (usually 20 mcg) and a low-risk progestin (Table 2).
(2 |OOO)
3.5. If patient-important hirsutism remains despite
6 months of monotherapy with an oral contraceptive, we suggest adding an antiandrogen.
(2 |OO)
3.6. We do not suggest one antiandrogen over another (2 |OO). However, we recommend
against the use of flutamide because of its potential hepatotoxicity. (1 |OO)
3.7. For all pharmacologic therapies for hirsutism, we
suggest a trial of at least 6 months before making
changes in dose, switching to a new medication,
or adding medication. (2 |OOO)
3.8. In patients with severe hirsutism causing emotional distress and/or in those women who have
used oral contraceptives in the past and have not
experienced sufficient improvement, we suggest
initiating combination therapy with an oral contraceptive and antiandrogen (2 |OO). However,
we suggest against combination therapy as a
standard first-line approach. (2 |OO)
Other drug therapies
3.9. We suggest against using insulin-lowering drugs
for the sole indication of treating hirsutism.
(2 |OO)
3.10. We suggest against using gonadotropinreleasing hormone agonists except in women

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with severe forms of hyperandrogenemia (such
as ovarian hyperthecosis) who have a suboptimal response to oral contraceptives and antiandrogens. (2 |OOO)
3.11. We suggest against the use of topical antiandrogen therapy for hirsutism. (2 |OOO)
4.0 Direct hair removal methods
4.1. For women who choose hair removal therapy,
we suggest photoepilation for those whose unwanted hair is auburn, brown, or black, and we
suggest electrolysis for those with white or blonde
hair. (2 |OO)
4.2. For women of color who choose photoepilation
treatment, we suggest using a long-wavelength,
long pulse-duration light source such as Nd:YAG
or diode laser delivered with appropriate skin
cooling (2 |OOO). Clinicians should warn
Mediterranean and Middle Eastern women with
facial hirsutism about the increased risk of developing paradoxical hypertrichosis (PH) with
photoepilation therapy. We suggest topical
treatment or electrolysis over photoepilation with
these patients. (2 |OO)
4.3. For women who desire more rapid response to
photoepilation, we suggest adding eflornithine
topical cream during treatment. (2 |OO)
4.4. For women with known hyperandrogenemia
who choose hair removal therapy, we suggest
pharmacologic therapy to minimize hair regrowth.
(2 |OO)

Changes Since the Previous Guideline
In 2008, the Endocrine Society published the clinical
practice guideline “Evaluation and Treatment of Hirsutism in Premenopausal Women.” As hirsutism is common,
often associated with an underlying endocrine disorder,
and associated with significant personal distress, treatment
is appropriate for most women who present with this
problem. In this current version, we have attempted to
address several issues, as well as incorporate insights from
relevant studies published since the 2008 guideline. Important modifications in this version are as follows.
Evaluation
We have broadened the suggestion for determining the
serum total testosterone concentration to include all
women with hirsutism and have broadened the suggestion
for determining the serum-free testosterone concentration
to include hirsute women whose serum total testosterone is
normal in the presence of moderate to severe hirsutism or

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other clinical evidence of hyperandrogenemia, such as
progressive growth of hair in androgen-dependent areas
(sexual hair). We have added a recommendation to screen
hyperandrogenemic women for nonclassic congenital
adrenal hyperplasia (NCCAH) due to 21-hydroxylase
deficiency by measuring early morning 17-hydroxyprogesterone levels in the follicular phase or on a random
day for those with amenorrhea or infrequent menses. In
women with hirsutism who are at high risk for NCCAH
(positive family history, member of a high-risk ethnic
group), we suggest screening even if serum total and free
testosterone are normal.
Treatment
For treatment, we have made the following revisions to
the new guideline:
• We now suggest either pharmacologic therapy or
direct hair removal methods as initial therapy for
women with mild hirsutism and no evidence of an
endocrine disorder. For other women with patientimportant hirsutism, we suggest starting with pharmacological therapy and adding direct hair removal
methods if needed.
• We added a recommendation that it is reasonable to
start with combined pharmacological therapy [oral
contraceptives (OCs) and antiandrogens] in select
women with severe hirsutism that is causing distress.
• We added a recommendation to use lower estrogendose OCs with low-risk progestins in women at
higher risk for venous thromboembolism (VTE)
(e.g., obese, age .39 years). For other women, our
approach is the same as in the original guideline: we
do not suggest one OC formulation over another.
• We made a stronger recommendation against the
use of flutamide for hirsutism.
• We added a suggestion for electrolysis rather than
photoepilation in women with blond or white hair
who choose direct hair removal methods. We also
provide guidance for the use of photoepilation (and
its potential complications) in women of color.
• We added a lifestyle recommendation for women
with polycystic ovary syndrome (PCOS).

Method of Development of Evidence-Based
Clinical Practice Guidelines
The Clinical Guidelines Subcommittee of the Endocrine
Society deemed the evaluation and treatment of hirsutism in premenopausal women a priority area for revision
and appointed a task force to formulate evidence-based
recommendations. The task force followed the approach recommended by the Grading of Recommendations,

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Assessment, Development, and Evaluation group, an international group with expertise in the development and
implementation of evidence-based guidelines (1). A detailed
description of the grading scheme has been published elsewhere (2). The task force used the best available research
evidence to develop the recommendations. The task force
also used consistent language and graphical descriptions of
both the strength of a recommendation and the quality of
evidence. In terms of the strength of a recommendation,
strong recommendations use the phrase “we recommend”
and the number 1, and conditional recommendations use the
phrase “we suggest” and the number 2. Cross-filled circles
indicate the quality of the evidence, such that OOO denotes very low-quality evidence; OO, low quality;
O, moderate quality; and , high quality. The
task force has confidence that persons who receive care
according to the strong recommendations will derive, on
average, more good than harm. Conditional recommendations require more careful consideration of the person’s
circumstances, values, and preferences to determine the best
course of action. Linked to each recommendation is a description of the evidence and the values that the task force
considered in making the recommendation. In some instances, there are remarks in which the task force offers
technical suggestions for testing conditions, dosing, and
monitoring. These technical comments reflect the best
available evidence applied to a typical person being treated.
Often this evidence comes from the unsystematic observations of the task force and their preferences; therefore, one
should consider these remarks as suggestions.
The Endocrine Society maintains a rigorous conflictof-interest review process for developing clinical practice
guidelines. All task force members must declare any
potential conflicts of interest by completing a conflict-ofinterest form. The Clinical Guidelines Subcommittee
reviews all conflicts of interest before the Society’s
Council approves the members to participate on the task
force and periodically during the development of the
guideline. All others participating in the guideline’s development must also disclose any conflicts of interest in
the matter under study, and most of these participants
must be without any conflicts of interest. The Clinical
Guidelines Subcommittee and the task force have
reviewed all disclosures for this guideline and resolved or
managed all identified conflicts of interest.
Conflicts of interest are defined as remuneration in any
amount from commercial interests; grants; research
support; consulting fees; salary; ownership interests [e.g.,
stocks and stock options (excluding diversified mutual
funds)]; honoraria and other payments for participation
in speakers’ bureaus, advisory boards, or boards of directors; and all other financial benefits. Completed forms
are available through the Endocrine Society office.

J Clin Endocrinol Metab, April 2018, 103(4):1–25

The Endocrine Society provided the funding for this
guideline; the Task Force received no funding or remuneration from commercial or other entities.
The Endocrine Society’s clinical practice guidelines are
developed to be of assistance to endocrinologists by providing guidance and recommendations for particular areas
of practice. The guidelines should not be considered inclusive
of all proper approaches or methods, or exclusive of others.
The guidelines cannot guarantee any specific outcome, nor
do they establish a standard of care. The guidelines are not
intended to dictate the treatment of a particular patient.
Treatment decisions must be made based on the independent
judgment of health care providers and each patient’s individual circumstances.
The Endocrine Society makes no warranty, express or
implied, regarding the guidelines and specifically excludes any warranties of merchantability and fitness for a
particular use or purpose. The Society shall not be liable
for direct, indirect, special, incidental, or consequential
damages related to the use of the information contained
in this work.

Commissioned Systematic Review
The Endocrine Society Task Force commissioned two
systematic reviews in 2008 that were updated to support
the current guideline. The updated review included a
network meta-analysis that compared the available 37
randomized controlled trials (RCTs) of pharmacologic
therapy for hirsutism. This network meta-analysis approach facilitated simultaneous comparison of multiple
agents and allowed indirect comparison of interventions
(that have not been evaluated in head-to-head trials)
based on their effect on a common comparator.
The goals of the systematic reviews and meta-analyses
were to:
• Update the analyses of the efficacy and safety of
OCs, antiandrogens, and metformin vs placebo, and
OCs plus antiandrogens vs OCs, for the treatment of
hirsutism; and
• Compare the impact on hirsutism of OCs containing
antiandrogens [cyproterone acetate (CPA) and
drospirenone (DSP)] vs other OCs, and OCs containing levonorgestrel (the most androgenic progestin) vs other OCs.

The results of the network analysis were consistent
with the previous meta-analyses, showing that OCs, antiandrogens, and the combination of OCs plus antiandrogens
were all more effective than placebo and led to reduction in
hirsutism scores. The addition of antiandrogens to OCs was
slightly more effective than OCs alone for hirsutism. Metformin therapy was not superior to placebo. OCs containing

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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

Table 1.

5

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
The modified Ferriman–Gallwey score is
score
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
Unwanted sexual hair growth of any
hirsutism
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.

Hirsutism is excessive terminal hair that appears in a male
pattern in women (3) (Table 1). Some sexual hair growth
is normal, but clinicians commonly diagnose hirsutism
as a Ferriman–Gallwey score (4) above the 95th percentile for the population (Fig. 1) (5, 6). Ferriman–
Gallwey total scores that define hirsutism in women of
reproductive age are as follows: United States and United
Kingdom black or white women, $8 (6); Mediterranean,
Hispanic, and Middle Eastern women, $9 to 10 (6);
South American women, $6 (7); and Asian women, a
range of $2 for Han Chinese women (6) to $7 for
Southern Chinese women (8, 9). Although widely used,
this scoring system has its limitations, which include its
subjective nature, the failure to account for a locally high
score that does not raise the total score to an abnormal
extent, and the lack of consideration of such androgen(3, 15). Androgens appear to induce vellus follicles in sexsensitive areas such as the sides of the face from the
specific areas to develop into terminal hairs, which are
hairline to below the ear (sideburns) and the buttocks.
larger and more heavily pigmented. Hairs grow in
Self-scoring can be clinically useful, but correlates only
nonsynchronous cycles, and the growth (anagen) phase
modestly with scoring by a trained observer (10–12).
(which varies with body area) is ;4 months for facial
Lower Ferriman–Gallwey scores can be clinically imhair. Due to the long hair growth cycle, it takes
portant. In one study of 633 unselected white and black
;6 months to detect the effects of hormonal therapy and
women, ;70% with scores $3 and
many with lower scores considered
themselves to be hirsute, and most used
some form of cosmetic treatment (13). It
has also been shown that even minimal
degrees of unwanted hair are often associated with hyperandrogenemia when
menstrual irregularity is present (14).
Hirsutism must be distinguished
from hypertrichosis—generalized excessive hair growth that may be hereditary or result from certain medications
(e.g., phenytoin, cyclosporine). Hypertrichosis is distributed in a generalized,
nonsexual pattern (i.e., predominantly
on forearms or lower legs) and is not
caused by excess androgen (although
hyperandrogenemia may aggravate it).
Figure 1. Ferriman–Gallwey hirsutism scoring system (4). Each of the nine body areas most
Pathogenesis of hirsutism
The growth of sexual hair is entirely
dependent on the presence of androgen

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. Hirsutism results from an interaction between the plasma
androgens and the apparent sensitivity of the hair follicle
to androgen. The sensitivity of the hair follicle is determined in part by the local metabolism of androgens,
particularly by conversion of testosterone to dihydrotestosterone by the enzyme 5a-reductase and subsequent binding of these molecules to the androgen
receptor. The hirsutism score does not correlate well with
the androgen level (16, 17), apparently because the
androgen-dependent pilosebaceous follicle response to
androgen varies considerably.
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 hyperandrogenemia 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 hyperandrogenism 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 requires considerations distinct from those for hirsutism itself.
Obesity may worsen or cause features of PCOS (20, 22, 23).
Many women have hirsutism without hyperandrogenemia. 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 hirsutism 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 androgen assay technologies in this population have not yet been
performed.
It is unclear whether idiopathic hirsutism is due to altered 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

J Clin Endocrinol Metab, April 2018, 103(4):1–25

to be of little further diagnostic utility in most, but not
all, populations (16, 26–30) (Section 5, Androgen Testing 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, approximately half have idiopathic hirsutism. Plasma total
and/or free testosterone levels are elevated in the remainder 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 malepattern alopecia.
Other causes of androgen overproduction are infrequent (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 testosterone levels are normal, if sexual hair growth is
moderate/severe or sexual hair growth is mild but
there is clinical evidence of a hyperandrogenic endocrine disorder (such as menstrual disturbance or
progression in spite of therapy), we suggest measuring an early morning serum total and free testosterone by a reliable specialty assay. (2 |OO)

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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 androgen levels in eumenorrheic women with
unwanted local hair growth (i.e., in the absence
of an abnormal hirsutism score) because of
the low likelihood of identifying a medical
disorder that would change management or
outcome. (2 |OO)
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 determine 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, virilizing disorders, or androgenic medication use.
When testing for elevated androgen levels, we suggest
first measuring serum total testosterone levels using a reliable 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

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may be found and upon whether a detected abnormality 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 disorder, 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 progression of hirsutism, progression in spite of therapy, 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 moderately excessive androgen have indolent presentations (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 testosterone levels.
Because of the high frequency of PCOS, clinicians
should check all hirsute women for evidence of anovulation (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 diabetes mellitus. Clinicians can make a diagnosis of
ovulatory PCOS in eumenorrheic women with hirsutism, polycystic ovary morphology, and normal levels of
testosterone (39, 40). It is unclear whether pelvic ultrasonography 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, associated 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 adrenal hyperplasia due to 21-hydroxylase deficiency (as
noted in Section 1, Etiology and Section 5, Androgen 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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Guidelines on Hirsutism

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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).

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 (positive 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 describes 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 amenorrhea; measuring dehydroepiandrosterone (DHEA) sulfate (DHEAS) to screen for adrenal hyperandrogenism;

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assessing for Cushing syndrome, thyroid dysfunction, acromegaly, and hyperprolactinemia if features of
these conditions are present (however, all are uncommon causes of hirsutism); and pelvic ultrasonography (preferably transvaginal) to detect an ovarian
neoplasm in women with severe or progressive hyperandrogenism. Of note, some androgen-secreting ovarian 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 following: (1) measuring serum androstenedione (the immediate precursor for testosterone) (28) or other steroid
intermediates [that have on occasion provided additional information (Section 5, Androgen Testing Remarks)]; (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 spectrometry to exclude apparent cortisone reductase deficiency (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) agonist (46). Lastly, transvaginal ultrasound is also helpful
if ovarian hyperthecosis is suspected; absence of follicles and or the polycystic ovarian morphology supports
the diagnosis of hyperthecosis. This approach to evaluation 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 Society (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 hyperandrogenic 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 management and outcome.

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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 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 production 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 recommendations 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 impossible 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 hirsutism than other women who may be less bothered, despite
having higher hirsutism scores). We use the term patientimportant 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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Guidelines on Hirsutism

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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 depilatories 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, folliculitis, 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 improve their hirsutism. In a meta-analysis of four studies
that included 132 subjects, lifestyle changes (diet, exercise, 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, particularly when compared with OCs (50). Our approach is
consistent with the Endocrine Society clinical guidelines on
the diagnosis and treatment of PCOS (40).

3.2.

3.3.

3.4.

3.5.

3.6.

3.7.

3.0 Pharmacological Treatments
Initial therapies

3.8.

3.1. For the majority of women with hirsutism who
are not seeking fertility, we suggest OCs as initial
Table 2.
Progestin
Generation
1
2
2–3
3
3
4
—
a

OCs and Associated VTE Risks
Progestin Relative
Androgenicity

Progestin Relative
VTE Riska,b

Progestin Absolute
VTE Riskb,c

Progestin/Dose

EE Dose (mcg)

Medium
High
Low
Low
Low
Antiandrogen
Antiandrogen

2.6
2.4
2.5
3.6
4.3
4.1
4.3

7
6
6
11
14
13
14

Norethindrone 0.5–1.0 mg
Levonorgestrel 0.15 mg
Norgestimate 0.25 mg
Gestodene 0.075 mg
Desogestrel 0.15 mg
DSP 3 mg
CPA 2 mgd

20, 35
20, 30
35
20, 30
20, 30
20, 30
35

Relative risk compared with no OC use.

b
c

therapy for treating patient-important hirsutism.
(2 |OO)
For most women with hirsutism, we suggest
against antiandrogen monotherapy as initial
therapy (because of the teratogenic potential of
these medications) unless these women use adequate contraception (2 |OOO). However, for
women who are not sexually active, have undergone permanent sterilization, or who are using long-acting reversible contraception, we
suggest using either OCs or antiandrogens as
initial therapy (2 |OOO). The choice between
these options depends on patient preferences
regarding efficacy, side effects, and cost.
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)
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)
If patient-important hirsutism remains despite
6 months of monotherapy with an OC, we suggest
adding an antiandrogen. (2 |OO)
We do not suggest one antiandrogen over another (2 |OO). However, we recommend
against the use of flutamide because of its potential hepatotoxicity. (1 |OO)
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)
In patients with severe hirsutism causing emotional distress and/or in those women who have
used OCs in the past and have not experienced

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

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

d

OCs containing CPA are not available in the United States.

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sufficient improvement, we suggest initiating combination therapy with an OC and antiandrogen
(2 |OO). However, we suggest against combination 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 containing EE and not to newer OCs that contain 17b-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-nortestosterone 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 spironolactone that exhibits weak antiandrogenic activity. 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 spironolactone (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 suppression (54). Although DSP is a very weak antiandrogen, 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 ovarian androgen secretion) (55), stimulation of hepatic production of sex hormone–binding globulin (SHBG) (thereby
increasing androgen binding in serum and reducing serumfree 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 increase the metabolic clearance of testosterone (56, 57).

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There may also be a small direct effect in inhibiting 5areductase 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 antagonists (CPA, DSP) may confer a 50% to 100% increased
risk of VTE compared with OCs containing the secondgeneration progestin levonorgestrel, according to reviews
of large-scale comparative analyses (58, 59). However,
the DSP risk was not found in a prospective postmarketing 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 independent 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 associated 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 identified no additional trials. A combined analysis of
these trials associated OC therapy with a greater reduction 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 levonorgestrel 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 antiandrogenic 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 important (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 containing 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). Transdermal 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 antiandrogens, as follows: three of finasteride, two of flutamide,
and two of spironolactone. In analyses of individual antiandrogens 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

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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 antagonist, exhibits dose-dependent competitive inhibition
of the androgen receptor as well as inhibition of 5areductase 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 patient 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 antiandrogens, 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
CPAa
Spironolactone
Finasteride
Flutamideb

Dosing
50–100 mg/d on menstrual cycle days
5–15, with EE 20–35 mg on days 5–25
100–200 mg/d [given in divided doses
(twice daily)]
2.5–5 mg/d
250–500 mg/d (high dose)
62.5 to #250 mg/d (low dose)

a

Not available in the United States; also prescribed as an OC (2 mg CPA +
35 mcg EE).

b

Flutamide not recommended because of hepatotoxicity.

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probably involves both type 1 and 2 5a-reductase enzymes, 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 seemingly be an attractive option for the treatment of hirsutism, there are no clinical data to support its use at
this time.
Flutamide is a “pure” antiandrogen with a doseresponse 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 transplantation and four of five survived (98).
In our 2008 guideline, we suggested against standard
dose flutamide (.250 mg). Based upon emerging evidence of hepatotoxicity, unproven efficacy for hirsutism,
and the availability of alternative antiandrogens, we
also recommend against the use of low-dose flutamide
(#250 mg).

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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 incremental reduction of hirsutism scores—weighted mean
difference, 21.73 [95% CI (23.32 to 20.13)].
OCs vs antiandrogens
In the only RCT comparing an OC to an antiandrogen (finasteride), the OC contained a low-dose
antiandrogen (2 mg CPA) (99). After 9 months of
treatment, there was no significant difference in hirsutism 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 congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 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, suppressing adrenal androgens results in only minor improvements 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 antiandrogen 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 dexamethasone 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 occurred, 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 dexamethasone because it is not inactivated by placental 11b-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 deficiency randomized to receive an OC (CPA plus EE) or
dexamethasone (103), serum DHEA and DHEAS concentrations 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 experienced 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, suggesting that half of the cutaneous expression of
hyperandrogenism is dependent on the peripheral receptivity to androgens.
Adverse effects associated with
glucocorticoid therapy
Slight overdosing can occur even at recommended
doses and is independent of daily or alternate-day administration. 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 firstline therapy to hirsute women with NCCAH places a
relatively higher value on avoiding the potential for adverse effects of glucocorticoids and a relatively lower value
on the potential benefits of suppressing endogenous androgens and inducing a more prolonged remission of
hirsutism and hyperandrogenism after therapy withdrawal (100, 101). Our approach does recognize the
importance of glucocorticoid therapy for ovulation induction in NCCAH.

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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 hyperandrogenemia (such as ovarian hyperthecosis) who
have a suboptimal response to OCs and antiandrogens. (2 |OOO)
3.11. We suggest against the use of topical antiandrogen 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 rosiglitazone, 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 lowdose estrogen–progestin add-back was more effective
for hirsutism than an OC in two trials—one by photographic 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 estrogen plus progestin (in women with a uterus) as addback 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 limited efficacy, with one study of a cream containing
canrenone (the active metabolite of spironolactone)
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 Treatment 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 without 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 unwanted hair is auburn, brown, or black, and we
suggest electrolysis for those with white or blonde
hair. (2 |OO)
4.2. For women of color who choose photoepilation
treatment, we suggest using a long-wavelength,
long pulse-duration light source such as Nd:
YAG or diode laser delivered with appropriate skin cooling (2 |OOO). Clinicians should
warn Mediterranean and Middle Eastern women
with facial hirsutism about the increased risk
of developing PH with photoepilation therapy.
We often suggest topical treatment or electrolysis 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)

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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) hyperpigmentation 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 reduction. 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 electrochemical 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 effective for permanent hair reduction. In one small comparative 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 melanin 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 wavelengths between 500 and 1200 nm that the melanin
absorbs. Pulse durations of milliseconds permit heat to
diffuse from the pigmented hair shaft into the surrounding 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 irreversible 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 treatment, 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 alexandrite laser treatments to the left axilla and four electrolysis
treatments to the right axilla (130). Laser treatment was

J Clin Endocrinol Metab, April 2018, 103(4):1–25

60 times faster (30 seconds vs 30 minutes). Six months
following the initial treatment, there was a 74% reduction 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, controlled studies with objective quantitative endpoints that
compared lasers or IPL devices for photoepilation generally 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, comparison 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 comparison 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-thecounter 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 photoepilation devices makes them slower than medical photoepilation 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 photoepilation, 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 regions 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 application 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 pigmentation (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 consecutive patients treated with ruby laser, the overall frequency
of pigmentary side effects was 9%, but it was 24% in

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17

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 facilities 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 apparently 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 background, 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 irreversible 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 irreversibly inhibiting ornithine decarboxylase, which catalyzes the rate-limiting step for follicular polyamine
synthesis. A topical preparation, eflornithine hydrochloride cream 13.9%, is FDA approved for the treatment 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 results 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, particularly 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 photoepilation 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 laserinduced 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

J Clin Endocrinol Metab, April 2018, 103(4):1–25

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 testosterone 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 populations of apparently normal women with unrecognized
androgen excess (22) further complicate the interpretation of testosterone levels in women. Some direct
radioimmunoassays and chemiluminescence assays
available in specialty laboratories provide results comparable 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. Salivary 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 glucuronide), as it is not a unique metabolite of serum testosterone 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 testosterone 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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Appendix.

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19

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

Task Force Member
Kathryn A. Martin, MD,
Chair

Employment

Massachusetts General Hospital,
Senior Deputy Editor,
Endocrinology, UpToDate
Richard R. Anderson, MD Massachusetts General Hospital,
Director, Wellman Center for
Photomedicine Harvard
Medical School, Professor,
Dermatology
R. Jeffrey Chang, MD
University of California San
Diego, Professor Emeritus of
Reproductive Medicine
David Ehrmann, MD
University of Chicago, Professor
of Medicine
Rogerio Lobo, MD
Columbia University Medical
Center, Professor of Obstetrics
& Gynecology
M. Hassan Murad, MD,
The Mayo Clinic, Professor of
MPH
Medicine
Michel Pugeat, MD
Hospices Civils de Lyon, Professor
of Endocrinology
Robert L. Rosenfield, MD University of Chicago, Professor
Emeritus of Pediatrics &
Medicine

Uncompensated Uncompensated
Memberships
Leadership

Personal
Financial

Industry
Relationship/
Organizational
Spousal/
Financial
Family Info Relevant Conflict

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

NIH – research
support
None

None

None

None

None

None

None

None

None

None

None

None

None

None

None

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.

the free testosterone concentration from total testosterone and SHBG concentrations or as the product of the
total testosterone concentration and the fraction of testosterone 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 steroids or precursors (e.g., the intermediate 17-hydroxyprogesterone, 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 elevated DHEAS level in the setting of normal free testosterone is unlikely to affect management. The magnitude
of the androgen level is of poor predictive value for tumors (26, 42), although a very high testosterone (adultmale 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 prevalence 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 Hispanics 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 follicular phase or on a random day for those with amenorrhea 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 approximately 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 analysis of the CYP21A2 gene (33, 191).

Acknowledgments
Financial Support: This guideline was supported by the Endocrine Society. No other entity provided financial or other
support.

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20

Martin et al

Guidelines on Hirsutism

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 guidelines are developed to be of assistance to endocrinologists by
providing guidance and recommendations for particular areas
of practice. The guidelines should not be considered inclusive of
all proper approaches or methods, or exclusive of others. The
guidelines cannot guarantee any specific outcome, nor do they
establish a standard of care. The guidelines are not intended
to dictate the treatment of a particular patient. Treatment
decisions must be made based on the independent judgement of healthcare providers and each patient’s individual
circumstances.
The Endocrine Society makes no warranty, express or implied, regarding the guidelines and specifically excludes any
warranties of merchantability and fitness for a particular use
or purpose. The Society shall not be liable for direct, indirect,
special, incidental, or consequential damages related to the use
of the information contained herein.

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