REVIEW
Catagen: hair growth ceases in this stage and the follicle
Hirsutism prepares to enter the resting (telogen) phase.
Telogen: this is the resting stage where the hair is loosely
Mostafa Metwally
attached and will ultimately fall to be followed by a new
hair cycle.
Abstract Androgen metabolism in the female
Hirsutism can be one of the most distressing conditions for women. It is In the female androgens originate from the ovaries and the
a symptom that is occasionally underlined by serious pathology, hence adrenal glands. The different types of androgens produced
the importance of thorough history, examination and investigation. This include (Table 1):
article first examines the underlying physiology associated with human Testosterone: produced mainly by the ovarian theca cells
hair growth and relevant to the understanding of the causes and treat- under the control of LH and insulin acting through insulin
ment of hirsutism. Causes of hirsutism are discussed, the most common like growth factor 1 (IGF-1). Testosterone is then converted
being polycystic ovarian syndrome. Other causes of disordered androgen by aromatase enzyme in the granulosa cells to oestradiol.
metabolism are also discussed. Treatment of hirsutism includes treatment Disturbance of this process in women with polycystic
of the underlying cause and often lifestyle modifications such as weight ovarian syndrome (PCOS) leads to failure of transition from
loss are needed. Cosmetic measures are needed for existing hair while an androgen to oestrogen dominant microenvironment and
prevention of new hair growth often requires pharmacological interven- therefore relative increase in ovarian androgen production.
tion. This is most commonly achieved using the combined oral contracep- Furthermore testosterone is also produced from peripheral
tive pill, while anti-androgens and GnRH agonists are reserved for more conversion of adrenal androgens.
severe and resistant cases. Androstendione: produced by both the ovary and the
adrenals.
Keywords androgens; hirsutism; hyperandrogenism; PCOS Dehydroepiandrosterone (DHEA) and Dehydroepian-
drosterone sulphate (DHEAS): produced by the adrenals.
The majority of circulating androgens are bound in an inactive
form to sex hormone-binding globulin (SHBG) and a smaller free
Definition unbound fraction is metabolically active and able to stimulate
hair growth but only after further metabolism by hair follicle 5a
Hirsutism is a condition where a female develops a male pattern reductase into dihydrotestosterone (DHT).
growth of thick, pigmented androgen dependant terminal hair.
This is to be differentiated from overgrowth of non-sexual
Aetiology of hirsutism
(vellus) hair, which is the fine, lightly pigmented hair covering
most areas of the body during the prepubertal years and is Based on the understanding of androgen metabolism in the female,
known as hypertrichosis. Although hirsutism is generally hirsutism can be caused by any of the following (Table 2):
thought to affect 5e10% of women of reproductive age, it is Increased production:
important to bear in mind that the incidence is highly affected by The commonest cause of hyperandrogenaemia in clin-
location and ethnicity being higher in those of African or Medi- ical practice is PCOS, mainly as a result of increased
terranean descent. ovarian and to a lesser extent adrenal androgen
production.
The hair growth cycle Adrenal disorders: including Cushing syndrome and
adult onset congenital adrenal hyperplasia (CAH).
The hair cycle can be divided into three separate phases; Anagen,
Cushing’s syndrome may result from a primary adrenal
Catagen and Telogen. The physical characteristics of hair such as
disorder leading to an increased release of cortisol or
length and appearance are dictated by the relative durations of
secondary over-secretion of ACTH from the pituitary
these phases:
gland (Cushing’s disease). CAH is most commonly due to
Anagen: in this stage active cellular mitosis occurs in the
basal matrix of the follicle and leads to hair growth. This
stage is the target of pharmacological agents used for
treatment of hirsutism. The duration of the Anagen stage
varies from one area to the other. Facial hair for example Androgen production in the female
has a long anagen phase and therefore for any treatment to
be effective, 6e9 months of therapy is needed to ensure this Androgen Source
stage is targeted adequately and an effect can then be seen.
Testosterone Ovaries and adrenal glands
Dihydrotestosterone Conversion from testosterone
by 5a reductase in the hair follicle
Mostafa Metwally MD MRCOG is a Consultant Gynaecologist and Androstendione Ovaries and adrenals
Subspecialist in Reproductive Medicine at Ninewells Hospital and DHEA Adrenal
Medical School, Dundee, Scotland, UK. Conflicts of interest: none
declared. Table 1
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 22:8 211 Ó 2012 Elsevier Ltd. All rights reserved.
REVIEW
History
Causes of hirsutism Particular points of significance in the patient’s history include
the presence of associated menstrual disturbances and infertility
Increased androgen production that may point to PCOS as the cause. The duration and severity of
symptoms are particularly relevant since rapidly progressive or
C PCOS severe hirsutism may be associated with more ominous causes
C Adrenal disorders: Cushing’s syndrome and CAH such as androgenic tumours, particularly when associated with
C Androgen-producing ovarian and adrenal tumours virilism. Furthermore any history of associated endocrine disor-
C XY females ders such as Cushing’s syndrome; thyroid disorders or relevant
Increased free androgens medications should be examined.
C Insulin resistance Examination
C Obesity A thorough general examination should be conducted and may
C PCOS reveal other manifestations of hyperandrogenism such as acne or
Increased local activity of 5a reductase signs of virilism such as clitoromegaly. Velvety, pigmented skin
Iatrogenic hirsutism patches (acanthosis nigricans) may be observed in the groin,
neck or axilla in women with insulin resistance. A hereditary
C Androgen therapy condition known as HAIR-AN syndrome includes the association
C Danazol of Acanthosis nigricans, insulin resistance and severe hirsutism.
C Sodium valproate To evaluate the severity of hirsutism, the FerrimaneGallwey
C Anabolic steroids scoring system first developed in 1961, is the most commonly used
scoring system. The original scoring system evaluated hair growth
Table 2
in 11 areas, namely the lip, chin, chest, upper abdomen, lower
abdomen, upper arm, forearm, thigh, lower leg, upper back, and
lower back. Later modification of the system led to the exclusion
21-hydroxylase deficiency, and consequently blockage of of the forearm and lower leg, as they were found to have poor
the production of 11-deoxycortisol from 17 OH proges- correlation with androgen excess. A score of 0e4 is given to each
terone. Steroidogenesis is consequently diverted to the site depending on the presence/absence of abnormal hair growth
androgen pathway. and its severity. A score of 8 is necessary for diagnosis. Despite
XY females with functioning testicles: these phonotyp- providing an objective method for assessment and follow up, this
ical females present mainly with primary amenorrhoea. scoring system does not account for some other relevant areas
The diagnosis can be confirmed with karyotyping. such as the buttocks and side burns. A more recent simplified
Androgen-producing ovarian and adrenal tumours. B, C scoring system has been suggested that evaluates hair growth at
and D may also present with rapidly progressive, severe only three sites, upper abdomen, lower abdomen and chin. This
hirsutism and other signs of masculinization such as system was found to be as effective as a full body evaluation of the
clitoromegaly, in a condition known as virilism, which traditional nine sites and a score of 3, is used to establish
requires urgent investigation. a diagnosis. Finally pelvic examination particularly in severe cases
Increased free androgens: high insulin concentrations is necessary to exclude pelvic masses such as in cases of androgen-
subsequent to insulin resistance such as in association with producing ovarian tumours.
obesity or PCOS can lead to decreased SHBG and conse-
quently an increase in the free fraction of testosterone. Investigations
Increased local activity of 5a reductase in the sebaceous Testosterone concentrations: free androgen index should
gland or hair follicle: can lead to acne, hirsutism or both. be measured as it reflects the active form of circulating
There are two different forms of this enzyme; type 1 is testosterone. It is important to remember that testosterone
mainly present in the sebaceous gland and type 2 in the concentrations correlate poorly with the severity of
hair follicle. Difference in the relative activity of these two hirsutism due to individual variations in hair follicle
forms can explain why some women suffer from hirsutism response. Exceedingly high testosterone concentrations
more than acne and vice versa. Enzyme activity can be (>5 mmol/l) however should prompt further investiga-
increased by high insulin concentrations and insulin like tions such as pelvic imaging (CT and MRI) to exclude the
growth factor (IGF) in conditions associated with insulin possibility of ovarian or adrenal androgen-producing
resistance such as PCOS. tumour.
Iatrogenic hirsutism caused by androgen therapy or the Baseline 17 OH progesterone measurements should be
administration of medications such as danazol, sodium performed as a screening test for late onset congenital
valproate or anabolic steroids. adrenal hyperplasia. Equivocal results need to be
confirmed using a short Synacthen test, where 17 OH
Diagnosis progesterone concentrations are measured at baseline and
A diagnosis should be made after detailed consideration of the 1-h after intramuscular injection of 250 mg of Synacthen.
patients’ history, examination and arranging appropriate A significant rise in 17 OH progesterone concentrations is
investigations: diagnostic of CAH.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 22:8 212 Ó 2012 Elsevier Ltd. All rights reserved.
REVIEW
Adrenal androgens such as DHEA may be measured in their oestrogen dominant effect, while those containing
women where an adrenal cause is suspected. levonorgestrel or norethisterone should be avoided. The
Dexamethasone suppression test or 24 h urinary free former can antagonize the beneficial effect of oestrogen
cortisol for suspected cases of Cushing’s syndrome. on SHBG whilst the latter is an androgen derivative.
In cases where androgen-secreting tumours are suspected DianetteÒ is a preparation in which the progestagen
but pelvic imaging is negative selective venous sampling component is the androgen antagonist; cyproterone
from the ovarian and adrenal veins may be performed. acetate (2 mg) that acts by inhibiting gonadotropin
induced androgen production as well as increasing
Treatment androgen clearance by the liver.
Another progestagen; drospirenone which is an
Treatment of hirsutism focuses on the following points, treat-
analogue of spironolactone, also has an anti androgen
ment of the underlying cause, cosmetic measures for existing
effect by inhibiting androgen production and blocking
hair and pharmacological therapy to decrease new hair growth.
androgen receptors. Drospirenone is found in the OCP
Treatment of the cause: apart from appropriate treatment for
YasminÒ that combines 3 mg drospirenone with 0.03
any obvious underlying cause for increased androgen
mg of ethinyl oestradiol. In clinical studies YasminÒ has
production, lifestyle changes are often necessary particularly
been found to have comparable results to Dianette as
to achieve weight loss in obese women. Weight loss can lead
well as better outcomes regarding the lipid and endo-
to a decrease in insulin resistance and an increase in SHBG,
crine profile in women with PCOS compared to des-
ultimately leading to a decrease in androgen production.
ogestrel containing pills.
Cosmetic measures: it is important for the patient to be
Androgen antagonists: these are mainly used as
aware that any treatment for hirsutism will not treat
a second line treatment in more severe and resistant
existing hair. This will need to be manually removed by
cases. These medications can have serious conse-
several possible methods including laser therapy, elec-
quences for pregnancy in the form of feminization of
trolysis, waxing, plucking or shaving.
a male fetus and therefore their use needs to be
Pharmacological agents (Table 3): a number of pharma-
combined with a reliable contraceptive.
cological agents are available and aim at decreasing
- Cyproterone acetate can be used alone in higher
circulating concentrations of free androgens, blocking the
doses than those found in DianetteÒ (50e100 mg/
effect of androgens at the receptor level or decreasing the
day). Due to its long half-life, Cyproterone acetate
activity of 5a reductase. It is important to warn the patient
can be combined with ethinyl oestradiol in a reverse
that the effect of such treatment is not immediate and
sequential regimen. Cyproterone acetate is given
several months of treatment may be necessary before an
from day 5 to day 15 of the cycle and ethinyl oes-
effect can be observed.
tradiol (25e50 mg/day) from day 5 to day 25. The
The combined oral contraceptive pill (COCP): this is
dose of cyproterone acetate can later be decreased to
usually the first line of treatment. As well as the additional
5 mg/day. Compared to placebo, this regimen has
advantage of providing contraception if required, in
shown proven efficacy in clinical studies.
women with irregular periods it provides the advantage of
- Spironolactone acts by blocking androgen receptors
cycle regulation. Combined oral contraceptive pills act by
as well as by inhibition of 5a reductase. Due to its
decreasing free testosterone through an increase in sex
relatively favourable safety profile, spironolactone is
hormone-binding globulin as well as directly inhibiting LH
the commonest used anti androgen. Potential side
stimulated androgen production by the theca cells. They
effects however include diuresis, postural hypoten-
also lead to a mild decrease in adrenal androgen
sion in early stages, menstrual irregularities and
production.
rarely hyperkalaemia.
Regarding the choice of the pill, those containing des-
- Flutamide: this is a potent antagonist of the androgen
ogestrel, gestodene or norgestimate are preferred due to
receptor and has been shown to be as effective as
a combination of spironolactone and Dianette. Its
most serious side effect is hepatotoxicity and there-
Pharmacological treatment of hirsutism
fore should only be used under specialist care. The
Combined oral contraceptive pills dose varies from 250 to 500 mg/day.
Anti-androgens (Adequate contraception is needed) - Finasteride an inhibitor of 5a reductase used at dose
of 5 mg/day. Additional emphasis needs to be given
C Cyproterone acetate to the use of an effective contraceptive since finas-
C Spironolactone teride can result in teratogenicity. In addition it can
C Finasteride (teratogenic) cause mild gastrointestinal disturbances, dry skin
C Flutamide (hepatotoxic) and decreased libido.
Insulin sensitizing agents: metformin Eflornithine (VaniqaÒ): a topical antiprotozoal drug that
Eflornithine (may worsen acne) inhibits hair follicle ornithine decarboxylase enzyme,
GnRH agonists essential for hair growth. The main problem associated
with its use is the potential to worsen any associated
Table 3 acne due to obstruction of the sebaceous glands.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 22:8 213 Ó 2012 Elsevier Ltd. All rights reserved.
REVIEW
Insulin sensitizing agents: metformin may improve contraceptive vs. ethinyl estradiol and drospirenone 21/7 combined
hirsutism through an improvement in insulin resistance. oral contraceptive in the treatment of hirsutism. Contraception 2011;
Effectiveness however is controversial where some 84: 508e11.
studies have shown it to be as effective as an OCP 7 Van der Spuy ZM, le Roux PA. Cyproterone acetate for hirsutism.
containing 2 mg cyproterone acetate together and 35 mg Cochrane Database Syst Rev 2003. Issue 4. Art. No.:CD001125.
of ethinyl oestradiol while others have shown little 8 Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone
benefit. versus placebo or in combination with steroids for hirsutism and/or
GnRH agonists: in severe cases resistant to treatment, acne. Cochrane Database Syst Rev 2009. Issue 2. Art. No.:
GnRH agonists can be used to suppress ovarian activity. CD000194.
It is not normally advised for long-term treatment due to 9 Inal MM, Yildirim Y, Taner CE. Comparison of the clinical efficacy of
the negative impact on bone density as well as the flutamide and spironolactone plus Diane 35 in the treatment of idio-
associated menopausal symptoms. pathic hirsutism: a randomized controlled study. Fertil Steril 2005; 84:
1693e7.
A 10 Karakurt F, Sahin I, Guler S, et al. Comparison of the clinical efficacy
of flutamide and spironolactone plus ethinyloestradiol/cyproterone
acetate in the treatment of hirsutism: a randomised controlled study.
FURTHER READING Adv Ther 2008; 25: 321e8.
1 Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of
hirsutism in premenopausal women: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab 2008; 93: 1105e20.
2 Somani N, Harrison S, Bergfeld WF. The clinical evaluation of hirsutism. Practice points
Dermatol Ther 2008; 21: 376e91.
3 Cook H, Brennan K, Azziz R. Reanalyzing the modified FerrimaneGallwey C The commonest cause of hirsutism in clinical practice is poly-
score: is there a simpler method for assessing the extent of hirsutism? cystic ovarian syndrome.
Fertil Steril 2011; 96: 1266e70. C Signs of virilism, rapidly progressive severe hirsutism or
4 van Vloten WA, van Haselen CW, van Zuuren EJ, Gerlinger C, exceedingly high testosterone concentrations should prompt
Heithecker R. The effect of 2 combined oral contraceptives containing urgent detailed investigations including abdominal and pelvic
either drospirenone or cyproterone acetate on acne and seborrhea. imaging to exclude androgen-secreting tumours.
Cutis 2002; 69(4 suppl): 2e15. C Weight loss is of paramount importance in obese women
5 Kriplani A, Periyasamy AJ, Agarwal N, Kulshrestha V, Kumar A, suffering from hirsutism.
Ammini AC. Effect of oral contraceptive containing ethinyl estradiol C Patients should be warned that several months of treatment
combined with drospirenone vs. desogestrel on clinical and may be necessary before a noticeable effect is seen
biochemical parameters in patients with polycystic ovary syndrome. C The combined oral contraceptive pill is the commonest used
Contraception 2010; 82: 139e46. treatment for hirsutism provided pregnancy is not
6 Oner G, Muderris II. A prospective randomized trial comparing low- a requirement.
dose ethinyl estradiol and drospirenone 24/4 combined oral
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 22:8 214 Ó 2012 Elsevier Ltd. All rights reserved.
