The evaluation of a patient with hirsutism requires knowledge of the physiology of androgens and hair growth. The polysebaceous unit is formed by the hair follicle, sebaceous gland and arrector pili muscle. The first can be classified as:

– vellus hair: fine, short, soft and non-pigmented, predominating in childhood;

– terminal hair: thick, long and pigmented, also called sexual hair.

The transformation of vellus hair into terminal hair is an androgen-dependent process. Sensitivity to this transformation derives from genetic and racial characteristics and the affected areas. The most sensitive regions of the body are the axillary and pubic regions, followed, in order, by the upper labial, lower abdominal, maxillary, thoracic and lumbar regions.

Hirsutism refers to the transformation of vellus hair into terminal hair with a male distribution, usually caused by excessive androgenic stimulation.

Virilization is a more severe form of hyperandrogenism, in which hirsutism is found along with other signs such as acne, temporal baldness, deepening of the voice, increased muscle mass and/or clitoromegaly. It should be evaluated quickly, as it may be a sign of ovarian or adrenal tumor.

Hypertrichosis is the excessive growth of vellus hair, but it must be differentiated from hirsutism. The hair is usually distributed in non-sexual areas, such as the lumbar region and arms. Generalized hypertrichosis can occur in anorexia nervosa, hypothyroidism, porphyria, certain diseases of the nervous system and with drug use (phenobarbital).

Androgens may originate from the adrenal glands, the ovaries or from peripheral conversion of precursors. The principal androgens produced and secreted into the circulation of normal women are testosterone, androstenedione, the principal androgen secreted by the ovary, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (SDHEA). In the presence of a tumor or increased ovarian stroma, testosterone becomes the principal hormone secreted.

Sex steroids represent intermediate byproducts in the synthesis of glucocorticoids and mineralocorticoids by the adrenal gland, and excessive androgen secretion occurs only in cases of neoplasia or enzyme deficiencies.

ETIOLOGY OF HIRSUTISM/HYPERANDROGENISM

OVARIAN ORIGIN:

– polycystic ovary syndrome (PCOS);

– tumors.

ADRENAL ORIGIN:

– Cushing’s syndrome;

– tumors;

– congenital adrenal hyperplasia, non-classical form: deficiency of 21-hydroxylase, 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase.

MEDICINES:

– anabolic steroids;

– danazol: used in the treatment of endometriosis;

– 19-norprogestin, used in birth control pills;

– phenytoin: anticonvulsant.

IDIOPATHIC HIRSUTISM

The most common form of hirsutism, its carriers have a genetic predisposition that produces hypersensitivity to normal levels of circulating androgens. Menstrual cycles are regular and hormone levels are normal.

CLINICAL EVALUATION

HISTORY:

– ethnicity;

– family history of hirsutism;

– age at menarche; – age of onset and progression of hirsutism;

– characterization of menstrual cycles; – use of medications.

PHYSICAL EXAMINATION:

– special attention should be paid to the quantification of hirsutism and, mainly, to the presence of virilization. We use the Ferriman-Gallwey index, in which hirsute patients can be classified as mild (values ​​between 8 and 12), moderate (between 13 and 18) and severe (above 19);

– investigate clinical signs of Cushing’s syndrome: centripetal obesity, violet striae and arterial hypertension;

– gynecological examination: evaluate annexes, in addition to morphology and signs of virilization of the external genitalia.

DIAGNOSTIC APPROACH

POLYCYSTIC OVARY SYNDROME (PCOS)

Laboratory findings:

– high ratio of luteinizing and follicle-stimulating hormones (LH/FSH) (>3:1);

– slight elevation of testosterone and androstenedione; – normal or slightly elevated DHEA-SD;

– pelvic ultrasound: enlarged ovaries, with elevated stroma and presence of several microcysts (2 to 6 mm). A normal ultrasound does not rule out the diagnosis of PCOS.

OVARIAN TUMORS

Features that suggest ovarian tumor:

– testosterone > 200ng/ml or 2.5 times the upper limit of normal for any assay;

– normal DHEA-S;

– rapidly progressive hirsutism (months);

– evidence of virilization.

Ovarian tumors associated with increased androgens include lipoid cells, Leydig cells, arrhenoblastomas, dysgerminomas, teratomas, cystadenomas, cystadenocarcinomas, and luteomas.

Although some of these tumors can reach large dimensions, others are very small, making diagnosis difficult. Initial evaluation should include bimanual pelvic palpation and pelvic ultrasonography. If there is no evidence of tumor and the patient has a strong clinical suspicion, laparoscopy should be requested to evaluate both ovaries.

CUSHING’S SYNDROME

Laboratory diagnosis:

– urinary free cortisol: normal values ​​range from 25 to 75 µg/m2 / 24 hours;

– nocturnal dexamethasone suppression test: administer 1 mg of dexamethasone at 11 pm and measure plasma cortisol at 8 am the following day. A cortisol level above 5 µg/dL confirms the hypothesis of hypercortisolism. For the differential diagnosis between adrenal or pituitary causes, tests with higher doses of dexamethasone should be performed;

– computed tomography or nuclear magnetic resonance of the adrenal or pituitary glands.

Adrenal carcinomas may predominantly present with signs of virilization. The following suggest an adrenal tumor:

– SDHEA > 700 µg /dL or 2.5 times greater than the upper limit of normal for any test;

– rapidly progressive hirsutism;

– evidence of virilization;

– testosterone > 200ng/dl: can be found in rare cases of testosterone-producing adrenal tumors.

CONGENITAL ADRENAL HYPERPLASIA

Laboratory diagnosis

Adrenocorticotropic hormone (ACTH) test in the follicular phase of the menstrual cycle: measure basal 17OH-progesterone (usually normal in these patients); administer 0.25 mg of ACTH intravenously (IV) in a bolus; collect blood to measure 17OH-progesterone 30 and 60 minutes later; if it is above 10 ng/ml, the diagnosis is confirmed.

TREATMENT

Whenever possible, it should be directed at the etiological factor.

DRUGS THAT SUPPRESS OVARIAN FUNCTION

Oral contraceptives: block the secretion of gonadotropins (FSH and LH) and increase sex hormone binding globulin (SHBG), reducing the free fraction of testosterone. Used in idiopathic hirsutism and PCOS. We frequently use them in combination with cyproterone acetate.
Antiandrogens: These compounds selectively inhibit the binding of free testosterone [dihydrotestosterone (DHT)] to its receptor. For this reason, they have the potential to feminize the genitalia of a male fetus when administered to a pregnant woman.

– Spironolactone: is an aldosterone antagonist that inhibits the binding of DHT to its receptor. Usual dose: 75 to 200 mg/day, orally. Undesirable effects: headache, hypercalcemia, nausea, hypotension and menstrual irregularity. These effects generally improve after a few months of treatment.

– Cyproterone acetate: is a synthetic progestogen that inhibits the binding of DHT to its receptor, in addition to preventing the secretion of gonadotropins. Usual dose: 50 to 200 mg/day in combination with ethinylestradiol in reverse regimen (taken in the first ten days of the cycle). Side effects: nausea, weight gain, decreased libido and irregular vaginal bleeding.

– Flutamide: binds to androgen receptors, directly inhibiting hair growth. Usual dose: 500 mg in combination with hormonal contraceptives. Although rare, there are reports of severe hepatotoxicity. Serial liver function tests should therefore be performed.

COSMETIC TREATMENT

Electrolysis: adjuvant in any drug therapy regimen.
Laser.

IMPORTANT RECOMMENDATIONS

Clinical improvement may be evident only after the first six to nine months of continuous treatment.
A combination of drugs may be more effective than single-drug therapy.
Patients should be warned about the risks to the fetus in the event of pregnancy, since adherence to the use of oral contraceptives is not satisfactory in this age group.