Hirsutism : Diagnosis and Treatment

INTRODUCTION

Hirsutism, or excessive growth of facial and body hair, is an androgen excess-related condition
that often causes significant emotional distress in women who are affected by it. Because it is a
cutaneous manifestation of androgen excess, hirsutism is a symptom and may or may not be a
disease.

Aetiology

Hirsutism has a variety of causes; however, approximately 95% of hirsute women are believed to
suffer from persistent anovulation, also known as polycystic ovary syndrome . Hirsutism can also
be an adverse effect of certain medications. Idiopathic hirsutism may actually be a mild form of
persistent anovulation or may indicate hypersensitivity to androgens.

Less common but potentially serious causes include Cushing’s syndrome, congenital adrenal
hyperplasia, adrenal or ovarian tumors, a luteoma (a pregnancy- related benign tumor), anorexia
nervosa, hypothyroidism, porphyria, and hyperpro-lactinaemia, as well as ovarian hyperthecosis
in post-menopausal women.

Patho-physiology

Regardless of the specific cause, hirsutism results from excessive activity of androgens
(testosterone and androstenedione), leading to abnormal hair growth.

Hair grows in long cycles over many months, beginning with an active phase (anagen) that is
followed by a resting phase (telogen); during the telogen phase, the shaft separates from the
follicle base and falls out. Both the biology of normal hair growth and the pathophysiology of
abnormal hair growth are influenced by several hormonal factors.

Among the androgens, testosterone stimulates growth, increasing size and intensifying
pigmentation of the hair follicle. Hair follicle sensitivity to androgens is determined by 5a-
reductase activity, which converts testosterone to its follicle-active form, dihydrotestosterone.
Because of the variation in levels of 5a-reductase activity, it is possible for women with similar
androgen levels to have varied degrees and patterns of hair growth.

Oestrogens act in the opposite manner to androgens, slowing growth and producing finer, less
highly pigmented hair; progesterone has little effect on hair
Evaluation of the Hirsute Patient

The diagnostic goal of the hirsutism evaluation is to identify the most likely cause and to exclude
rare pathology.

Persistent anovulation is characterised by onset of hirsutism during a woman’s teens or in her

early 20s, with a gradual worsening of the condition over many years. This process is
accompanied by a long history of irregular menses, usually since menarche. Most of these women
are obese. So common is this presentation that the history alone may be sufficient to establish an
accurate clinical diagnosis.

As many as 70% of women with a history of persistent anovulation develop hirsutism. Hirsutism
is an early symptom of androgen excess; later symptoms include acne, increasingly oily skin,
increased libido, and masculinisation.

Masculinisation and virilism are terms used to describe the most extreme androgen-excess state.
This is characterised by male hair pattern (balding), clitoral enlargement of greater than 1 cm,
deepening of the voice, increased muscle mass, and general male body habitus.

History and Physical Examination

The hirsutism evaluation requires a thorough history of the present illness or complaint. This
includes time and rapidity of onset, associated symptoms (e.g., obesity, acne), progression of
symptoms, age at menarche, and subsequent menstrual history –especially oligomenorrhoea,
amenorrhoea, and sporadic episodes of abnormal vaginal bleeding. All of these are commonly
associated with persistent anovulation.

To help identify less common causes of hirsutism, a review of systems and of past medical,
social, family, and medication history are also obtained.

Medications that may cause hirsutism include methyltestosterone (topical or oral), danazol, and
anabolic drugs . Medications that may cause hypertrichosis (i.e., non-androgen-dependent and
non-endocrine-related hirsutism) include metronidazole, corticosteroids, and cyclosporine.

Phenytoin, diazoxide, and minoxidil may cause increased growth of fine hair (referred to as vellus
growth)

A complete physical examination is also helpful in identifying the likely cause of hirsutism.
Special attention should be to the following factors: height and weight (including body mass
index exceeding 27 kg/m2); elevated blood pressure; stigmata of Cushing’s syndrome (central
obesity, bruising, high blood pressure); or enlargement of the thyroid; and abdominal and pelvic
masses suggestive of unilateral or bilateral ovarian enlargement.

A thorough skin assessment should be performed. Note the distribution of hair and areas of coarse
hair: the upper lip, chin, chest, upper arms, upper and lower abdomen, thighs, and back. Hirsutism
is graded according to the distribution, quantity, and quality of hair.

Rapidity of Onset

Determining the speed of hirsutism onset is key to establishing an accurate diagnosis. Gradual
onset of symptoms over a number of years since adolescence (often since menarche) is most
likely indicative of persistent anovulation. Women believed to have persistent anovulation do not
require further diagnostic testing unless other causes are suspected; this is because results of
diagnostic tests for this condition are often within normal range and do not help clarify the
diagnosis. In addition, enlarged ovaries are not required for a diagnosis of persistent anovulation,
nor do enlarged ovaries indicate it; many normal women have asymptomatic cystic ovaries.

When persistent anovulation is suspected, current recommendations advise testing for insulin
resistance and diabetes mellitus.

In contrast to hirsutism of gradual onset, rapid-onset hirsutism (i.e., over a matter of months) in a
woman older than 25 years suggests a more aggressive underlying cause (e.g., an androgen-
producing tumour or other adrenal condition).

Table 1 - Diagnostic Tests in the Hirsutism Workup

• Fasting glucose-to-insulin ratio: A calculation of less than 4.5 suggests insulin
resistance.

• 2-Hour glucose level after a 75-g glucose load: A measurement below 140
mg/dL is normal, levels of 140 to 199 mg/dL indicate impaired glucose
tolerance; and of 200 mg/dL or higher, type 2 diabetes mellitus.

• Serum thyroid-stimulating hormone (TSH): This test is performed to rule out

thyroid disease. Normal range is 0.32 to 5 µIU/L.

• Serum testosterone: Normal level is 90 ng/dL or less. Levels are normal or

slightly elevated in persistent anovulation or benign adrenal conditions. A level
exceeding 200 ng/dL suggests an adrenal tumour.

• 17a-Hydroxyprogesterone (17-OHP) in the morning: Levels below 200 mg/dL

are considered normal; those between 200 and 800 mg/dL require
adrenocorticotropic hormone testing. A 17-OHP level higher than 800 mg/dL is
diagnostic of late-onset adrenal hyperplasia.

• 24-Hour urinary free cortisol excretion: Normal excretion is 10 to 90 µg/dL. A

late-evening plasma cortisol level of less than 15 µg/dL rules out Cushing’s
syndrome.

• Prolactin should be measured in patients with amenorrhoea, especially those

who also experience galactorrhoea. Levels of 10 to 25 ng/mL are normal.

• Pelvic ultrasonography should be performed if an ovarian tumour or a luteoma

is suspected, or if the pelvic examination is hindered by obesity.
Treatment

The most important goal in treating women with persistent anovulation-related hirsutism is to
prevent potentially serious complications of infertility, diabetes, hypertension, and heart disease.
Hirsutism treatment is directed at interrupting the steady state of persistent anovulation
characterised by tonic luteinising hormone (LH) elevations, excess androgen production, and low
levels of sex hormone-binding globulin (SHBG). Cosmetic improvement is an important but
secondary goal.

Patients with a clinical diagnosis of persistent anovulation who wish to become pregnant should
be referred to a gynaecologic specialist for ovulation induction, combined with an insulin-
sensitising agent (metformin or troglitazone) and weight loss.

Those with persistent anovulation or idiopathic hirsutism should be advised to lose weight and
may also be started on low-dose combination OCs (oral contraceptives). OCs suppress ovarian
steroid production, which in turn curbs LH levels. Low-dose OCs, especially those containing
new-generation, low-androgen progestins (norgestimate and desogestrel), raise levels of SHBG
for greater androgen-binding capacity, thus reducing circulating testosterone levels. In addition,
5a-reductase (at the skin level) is inhibited by the progestin component in OCs.

These actions gradually correct hirsutism, acne, and amenorrhoea – in addition to preventing the
complications previously mentioned. Low-dose and multiphasic OCs are as effective as higher-
dose preparations.

Therapy must continue for 6 to 12 months and may be required for many years, especially if
obesity is not corrected. Therefore, weight loss is a key component of therapeutic regimens
intended to resolve symptoms and prevent complications. Significant weight loss, is the only
long-term solution to obesity-related hirsutism.

When OCs are contraindicated (e.g., in extremely obese patients) or not desired, good cosmetic
effects may be obtained with medroxyprogesterone acetate (MPA), either as a 150-mg
intramuscular injection every 3 months, or orally by 10 to 20 mg/day. In contrast with OCs, MPA
reduces testosterone levels by inducing liver enzyme activity, mild LH suppression, and reduction
of total testosterone production. Surprisingly, this is accomplished without raising SHBG levels.

Treatment with either OCs or progesterone may be continued for 1 to 2 years, then discontinued
to observe the patient for spontaneous (though unlikely) return of ovulatory cycles. If anovulation
recurs, hirsutism will as well, and treatment must be resumed.

Various other antiandrogen medications may also be used to treat hirsutism. Spironolactone, an
aldosterone-antagonist diuretic (50 to 200 mg/day), inhibits ovarian and adrenal production of
androgens. Flutamide (250 mg/day, given in divided doses) acts by competing with androgen
receptors; however, hepatotoxicity is a concern. Finasteride (1 to 5 mg/day), by contrast, blocks
the conversion of testosterone to dihydrotestosterone by inhibiting 5a-reductase, however,
because this agent is highly teratogenic, effective contraception is required.

To maximise their therapeutic effect and to prevent pregnancy, these antiandrogen medications
may be given in combination with OCs.
Gonadotropin-releasing hormone analogs include leuprolide (a 3.75-mg intramuscular injection,
given monthly) and nafarelin (400 µg bid intranasally).

Cyproterone acetate (CPA) is a potent, long-acting progestin that blocks androgen action and
inhibits gonadotropin production (not yet approved in the United States, CPA is used extensively
in the United Kingdom to treat hirsutism ); it combines low-dose CPA with ethinyl oestradiol for
the effectiveness of standard-dose CPA with a significant reduction in adverse effects.

Glucocorticoids offer only a modest effect by suppressing adrenal androgen production. These
include dexamethasone (0.25 to 0.5 mg), prednisolone (5.0 to 7.5 mg), and hydrocortisone (10 to
20 mg) – each administered in a single nightly dose.

Great optimism surrounds the insulin-sensitising agents : Rosiglitazone / Pioglitazone and

Metformin [850 mg/day, then bid even upto 2.5 gm per day], which reduce ovarian androgen
production by suppressing levels of LH and follicle-stimulating hormone; they also lower plasma
insulin levels. According to current data, they may be effective not only to treat, but to prevent
persistent anovulation-associated and/or idiopathic hirsutism. Though a good option for women
who must avoid oestrogens, insulin-sensitising agents are expensive and may be associated with
some adverse effects.

All the medications described may be associated with adverse effects, high cost, and possible
teratogenic risk (especially finasteride). They must be prescribed carefully and only after a
thorough review of relevant prescribing information.

The only permanent or semipermanent treatments for previously established coarse hair are
electrolysis, thermolysis, and various laser systems. Recent research indicates the most promising
effects from long-pulsed ruby laser. These cosmetic modalities should be considered only after 6-
12 months of medical management, whether with monotherapy or combination treatment.

Because hirsutism is often very distressing to patients and because of the complications
associated with persistent anovulation, supportive counseling and comprehensive education are
essential.

Conclusion

Female hirsutism is a common endocrine problem, which is very distressing to most patients and
is generally caused by one of several underlying conditions. The most common cause, persistent
anovulation, may be diagnosed by a detailed history and a thorough physical examination.
Carefully selected diagnostic tests are useful to rule out less common and rare causes and to
clarify cases in which speed of hirsutism onset is unclear.