Hyperandrogenism − approach and management

Adrenals

The adrenal glands are predominantly responsible for the synthesis and secretion of dehydroepiandosterone (DHEA) and DHEA-sulfate (DHEA-S) 90%, androstenedione 50% and testosterone 25%.

Ovaries

Ovaries produce 50% of androstenedione, 25% of circulating testosterone and about 10% to 20% of DHEA. Rest of the testosterone (50%) is produced in extra-glandular tissue by circulating DHEA and androstenedione.

Idiopathic

Idiopathic hirsutism occurs more frequently in certain ethnic population, due to skewing of X chromosome carrying the androgen receptor gene. This causes increased androgen receptor-mediated sensitivity of the hair follicle.^[6]

Polycystic ovarian syndrome

PCOS is a syndrome complex that comprises of anovulation and raised androgen levels. It is manifested by hirsutism, menstrual abnormality like oligomenorrhoea, amenorrhoea, dysfunctional uterine bleeding or obesity. It affects around 10% to 20% of the reproductive age population. The basic pathology lies in dysregulation of enzyme cytochrome P450-17-∝ which is present in ovaries and adrenals and catalyses the activities of two enzyme systems that is 17-hydroxylase and 17,20 lyase resulting in hyperandrogenism.^[7] PCOS is also associated with hyperinsulinemia and insulin resistance that leads to an increase in ovarian androgen production. In the liver, it reduces the production of insulin growth factor-binding protein-I and SHBG, which further increases free androgen levels.

Stromal hyperthecosis

Hyperthecosis is a result of the differentiation of ovarian interstitial cells into testosterone producing luteinised stromal cells.^[8] These patients generally have normal LH and DHEAS levels but a higher serum insulin and testosterone level than those with PCOS. Patients with hyperthecosis present with signs of virilisation and decreased feminisation. The diagnosis can be confirmed only by histologic examination of the ovaries, which reveal nests of luteinised cells in ovarian stroma.

Congenital adrenal hyperplasia (CAH)

It can present in three forms^[9]:

1. Autosomal recessive: It is severe, presents soon after birth with evidence of adrenal insufficiency and ambiguous genitalia. There is deficiency of 21-hydroxylase leading to accumulation of 17-hydroxy progesterone which converts to excess androgens and deficiency of cortisol and aldosterone [Figure 2].

   

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   Figure 2

   Androgen synthesis pathway.

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2. Late onset: Slowly progressive, detected in early adulthood with short stature, irregular menstruation and positive family history. Onset of hirsutism is at puberty and occurs due to partial deficiency in the activity of 21-hydroxylase.

3. Cryptic form: Generally detected by biochemistry with the patient presenting with history similar to PCOS and have hyperandrogenic chronic anovulation.

The diagnosis of late-onset 21-hydroxylase deficiency requires an elevation of early morning 17-hydroxy progesterone in the follicular phase.

Hyperinsulinemia

Insulin resistance can also lead to hyperandrogenism, although it is not a mandatory outcome. Various practical criteria have been suggested for the diagnosis of insulin resistance such as body mass index >27 kg/m², a waist/hip ratio >0.85, the presence of acanthosis nigricans, impaired glucose tolerance, an elevated fasting or postprandial insulin concentration and fasting glucose/insulin ratio <4.5. Hyperandrogenism associated with insulin resistance and acanthosis nigricans come under the entity of hyperandrogenism insulin resistance and acanthosis nigricans (HAIR-AN) syndrome.^[10,11]

Rare causes

Rare causes of hyperandrogenism include virilising ovarian tumours and adrenal tumours. They are associated with rapid virilisation and progression of symptoms. Other rare causes include hyperprolactinoma that leads to hirsutism secondary to chronic anovulation. Cushing’s syndrome and gonadal dysgenesis may also present with signs of hyperandrogenism.

Acne

Persistence of acne into later teens should alert the endocrinologist to the possibility of hyperandrogenism especially if it is associated with hirsutism or menstrual irregularity.^[12,13] Excess sebum production due to androgens leads to blockage of glands or pores, wherein bacteria grow and multiply leading to inflammation.

Androgenic alopecia

Androgenic alopecia, which is hair loss caused by male hormones, tends to affect the temples, the crown and the vertex. This is due to stimulation of hair growth elsewhere thereby retarding scalp growth. About 15% of women in reproductive age group presenting with alopecia and no other signs of hyperandrogenism have hyperandrogenaemia.^[14]

Acanthosis nigricans

This occurs in severe hyperandrogenism and hyperinsulinemia. It presents as a velvety, mossy verrucous, hyperpigmented skin change over the nape of the neck, axillae, beneath the breast and in other body folds. Histologically, it represents hyperkeratosis, epidermal papillomatosis and hyperpigmentation.

Hirsutism

Hirsutism is defined as the presence of hair in locations where hair is not commonly found in women. These hairs are of dark colour, coarse texture and occur in androgen-dependent areas particularly over the upper lip, breast, chest, intermammary region, inner thigh and lower back.^[15,16]

Depending on the effect of androgens on various types of hair, these can be divided into three groups:

1. Hair that show no androgen dependence, for example lanugo, eyebrows and eyelashes.

2. Hair dependent on adrenal androgens adrenocorticotropic hormone (ACTH) such as axillary or pubic hair.

3. Hair dependent on gonadal androgens luteinizing hormone (LH) such as midline, facial and intermammary except scalp hair.

Hypertrichosis

It is a term reserved for androgen-independent growth of hair that is seen in nonsexual areas like trunk and extremities.

Virilism

It occurs because of severe hyperandrogenism and is characterized by temporal balding, deepening of voice, decreased breast size, increased muscle mass, loss of female body contour, clitoral enlargement and amenorrhoea. It is usually seen in androgenic tumours.

History

A detailed history pertaining to the patient’s lineage needs to be taken. Other important details are as follows:

1. Age of onset: during childhood it could be due to CAH. During puberty it could be due to PCOS, CAH and Stein-Leventhal syndrome.

2. Mode of onset: it is rapid in ovarian or adrenal tumours whereas it is slow, progressive in CAH and PCOS.

3. Personal history: a stressful event in life such as change of place, occupation or marriage can cause disturbance in hypothalamic pituitary axis.

4. Menstrual disorders: generally present with oligomenorrhea in PCOS, although women with gonadal dysgenesis and virilising tumours may present with amenorrhoea.

5. Family history: history in other family members can point towards genetic predisposition, PCOS, metabolic syndrome and CAH.

6. Drugs history: intake of androgens, danazol, 19-norprogesterone and minoxidil.

Clinical evaluation

Height, weight and body mass index should be measured since a growth spurt can be seen in CAH or virilising tumours, and women with polycystic ovarian syndrome (PCOS) and metabolic syndrome can present with increased weight.

Blood pressure may be high in patients with Cushing’s syndrome, PCOS and metabolic syndrome.

An examination of the thyroid should also be carried out.

Abdomino-pelvic examination is not very reliable for ruling out neoplasms, as these tumours are small and patients are usually obese. Ovaries may be palpable in PCOS.

Clitoromegaly may be present in patients of CAH, virilising tumours and a few cases of PCOS. Skin evaluation can detect hyperpigmentation and acanthosis nigricans in case of HAIR-AN syndrome or Cushing’s syndrome.

Clinical assessment of hirsutism should be made using the Ferriman-Gallway score. A score of 7 or less is normal, 8–15 suggests mild hirsutism and more than 15 suggests severe hirsutism.

Figure 3 gives a pictorial representation of the score.

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Figure 3

Ferriman Gallway scoring

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Investigations

The algorithm of evaluation of a woman presenting with features of hyperandrogenism has been summarised in Figure 4.^{[17,18,19,20]}

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Figure 4

Algorithm of evaluation of a woman presenting with features of hyperandrogenism.

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Management revolves around identification and treatment of the underlying cause. The various modalities of treatment are summarized in Table 1.

Table 1 Treatment of hyperandrogenism

Other non-pharmacological methods for hair removal can be used such as epilation, shaving, plucking, waxing, depilation and some permanent methods such as thermolysis, electrolysis and laser treatment.

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Conflicts of interest

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