Hyperandrogenism

Hyperandrogenism is the most common endocrinopathy seen in women and may result from ovarian or adrenal overproduction of androgens, altered peripheral metabolism and/or end-organ hypersensitivity. Androgen excess can have profound effects on human skin, especially the skin appendages, sebaceous glands and hair follicles, which are strongly dependent on biologically active androgens. 

This chapters focuses on hyperandrogenism in the skin, and is set out as follows:

• The most common cause of clinical hyperandrogenism is the Polycystic Ovarian syndrome (PCOS) - 72%
• Idiopathic hyperandrogenism - 23%
• Non-classical adrenal hyperplasia - 4.3%
• Androgen secreting tumours - 0.2%

• The dermatological manifestations of hyperandrogenism in women include hirsutism, acne, female (or male) pattern alopecia and acanthosis nigricans. Symptoms vary within a patient population as a result of the complex interplay between genetics, end-organ susceptibility and hormonal variations
   
• Non-dermatological manifestations include obesity, irregular menses, a deepening voice, clitoromegaly, increased muscle mass and a decreased breast size

1. General notes

• Measurement of total testosterone even using modern immunoassays has a low sensitivity for diagnosing some conditions such as the PCOS. This is because high concentrations of sex hormone binding globulin (SHBG) eg with the use of oral contraceptive pills, or low concentrations of SHBG eg in insulin resistance or obesity, can affect total testosterone values
   
• The most useful measurement is the free androgen index (FAI), which can be calculated by the total testosterone concentration divided by the SHBG concentration and this figure multiplied by 100  

2. Biochemical tests for patients with suspected hyperandrogenism, except for PCOS (refer to section 3)

• Measure early morning testosterone and SHBG levels and manage as follows:
  • Testosterone levels in the lower range of normal - no further evaluation
  • Testosterone in the higher range of normal or slightly raised - calculate the FAI (see above) and refer to section 3 (PCOS)
  • Testosterone levels > 4.8 - repeat, preferably in the first 5 days of the menstrual cycle, if remain above this level refer to section 4 

Patients who also have oligomenorrhoea / amenorrhoea / fertility problems 

• Check TFT, prolactin levels (hyperprolactinaemia), and FSH (to exclude primary ovarian failure)  

3. Suspected PCOS

• The assessment of biochemical hyperandrogenism is of greatest value in patients with minimal or no clinical signs of hyperandrogenism (i.e. no hirsutism)
   
• The diagnosis of PCOS partly relates to the presence of irregular menstrual cycles defined as:
  • Normal in the first year post menarche as part of the pubertal transition
  • > 1 to < 3 years post menarche: < 21 or > 45 days
  • > 3 years post menarche to perimenopause: < 21 or > 35 days or < 8 cycles per year
  • > 1 year post menarche > 90 days for any one cycle
     
• Investigations - PCOS is to some extent a diagnosis of exclusion, first making sure there is no other cause of hyperandrogenism. Be alert to oligomenorrhoea (refer to section 2), virilisation (refer to section 4) and other conditions such as Cushing's (refer to section 5), if there are no such features then investigate as follows:
  • Step a) irregular periods + evidence of clinical hyperandrogenism (hirsutism, not just acne) = PCOS (blood tests not needed)
  • Step b) if no clinical hyperandrogenism (eg hirsutism) test for biochemical hyperandrogenism, if above normal proceed to step c, unless significantly above normal in which case refer to section 4
  • Step c) if only irregular cycles or biochemical hyperandrogenism:
    • Adults: one of either anti-müllerian hormone (AMH) or ultrasound (ideally transvaginal) needs to be positive to make a diagnosis of PCOS
    • Adolescents: AMH or ultrasound not indicated, consider at risk of PCOS and reassess later   
       
• Patients without PCOS, who have recalcitrant acne should be checked for late onset (non-classical) congenital adrenal hyperplasia (refer to section 5)
   

4. Suspected androgen secreting tumours 

Either of the following can suggest an androgen secreting tumour:

• Early morning total testosterone levels > 4.8 on repeat testing (preferably in the first 5 days of the menstrual cycle)
• New onset and progressive features of virilisation (extreme hirsutism, male pattern alopecia, deepening voice, clitoromegaly, increased muscle mass, a decreased breast size, acanthosis nigricans) - some androgen-secreting neoplasms may only induce mild to moderate biochemical hyperandrogenism

Patients should be referred urgently to an endocrinologist or gynaecologist depending on likely aetiology - check dehydroepiandrosterone sulfate (DHEA) levels, which is the androgen produced in the adrenal glands. Normal levels of DHEA suggest an ovarian disorder, elevated levels suggest an adrenal disorder. Refer below for other possible investigations.

5. Other conditions causing hyperandrogenism 

• Drug causes
  • Drug-related causes include use of androgens, valproic acid, and ciclosporin
     
• Late onset (non-classical) congenital adrenal hyperplasia
  • Clinical features in childhood include precocious puberty, recalcitrant acne and accelerated bone age
  • Clinical features in adolescent and adult females include recalcitrant acne, moderate-severe hirsutism, fertility problems and short stature. Menstrual irregularities occur in approximately 50% of such cases
  • There is often a family history
  • Patients usually have biochemical evidence of hyperandrogenism (total testosterone between 3-4 and/or raised FAI)
  • Test for serum levels of 17-hydroxyprogesterone levels in the follicular phase around 9 am
     
• Cushing's syndrome
  • Clinical features include a moon face, truncal obesity, thin skin, easy bruising, striae, tiredness, hypertension, hirsutism and menstrual irregularities
  • Biochemical evidence of hyperandrogenism (total testosterone between 3-4 and/or raised FAI) is common
  • No single lab test is perfect and usually several are needed. The best screening tool is the 24-hour urinary free cortisol test. Basal 24 hour urinary cortisol excretion of more than three times the upper limit of normal (50-250 nmol/24 h) has a sensitivity of 100% and specificity of 98% in the diagnosis of Cushing’s syndrome  
     
• Acromegaly
  • Hyperandrogenism is usually absent or mild, whereas menstrual irregularities are common
  • The main clinical features are acral enlargement, coarse features and prognathism
  • Blood tests show elevated levels of IGF-1  
     
• ​Obesity
  • A diagnosis of exclusion
  • Hyperandrogenism is usually present, menstrual problems are uncommon

Step 1: general measures

• Patients with PCOS (and some other causes of hyperandrogenism) have higher prevalence rates of the metabolic syndrome than the general female population. Patients need to be checked for diabetes and have a cardiovascular risk assessment  

Step 2: non-hormonal treatments

• Refer to the related chapters Hirsutism, and Male and female pattern alopecia 

Step 3: anti-androgens for the treatment of acne, hirsutism, and female/male-pattern alopecia in women  

Medication will help some patients, irrespective of whether or not they have biochemical hyperandrogenism. From the onset it is important to give realistic expectations explaining the potential benefits and risks, that a minimum period of 6 months (and sometimes 12 months) is needed before significant improvements may be seen, and that if helpful, treatment needs to be continued.

• Combined oral contraceptive pills (COCP) - the primary driver of ovarian androgen secretion is luteinising hormone, which can be suppressed using a COCP. The effectiveness of oral contraceptives will depend on the content of ethinylestradiol and on the nature of the progestogen. COCP containing drospirenone (an analogue of spironolactone) such as Eloine ® and Yasmin ® are the logical choice. Dianette is another option, although this carries an increased risk of VTE. Pills containing levonorgestrel and norethisterone are more androgenic and could potentially exacerbate symptoms. Third generation progestogens such as desogestrel or gestodene have relatively neutral androgenic effect
   
• Spironolactone
  • Can be used in women for female/male pattern alopecia, and hirsutism. In acne it is mainly used in cases of PCOS
  • Generally very safe
  • Adverse effects include headaches, menstrual disturbance, breast tenderness, and gastro-intestinal disturbances. It is advisable to start patients on a lower dose and increase gradually, ideally every 4 weeks
  • Baseline U&E are needed to exclude hyperkalaemia, if normal, studies have shown there is no need to monitor in patients aged under 40 years of age
  • While spironolactone is not teratogenic, feminisation of the male foetus can occur in late pregnancy. While contraception is not needed, should women become pregnant then treatment needs to be discontinued  
  • Dose - start at 50 mg OD, increasing up to 100 mg OD after 4 weeks if tolerated. In terms of hirsutism, spironolactone 100 mg OD appears more effective than finasteride. In patients with a high BMI the dose can be increased gradually up to 200 mg OD if tolerated
     
• 5-alpha reductase inhibitors
  • Can be used for both female/male pattern alopecia and hirsutism
  • The primary aim of treatment of alopecia in women is to stop / reduce hair loss. In some women the hair volume may increase, this is compared to men where some 90% of patients experience new hair growth
  • Finasteride 2.5 mg every 3 days appears as effective as once daily
  • Dutasteride blocks type 1 and type 2 5AR (α-adrenergic receptors) whereas finasteride only blocks type 2 receptors. The recommended dose is 0.5 mg OD. In terms of alopecia, dutasteride is more effective than finasteride in men, further evidence is needed in women
  • 5-alpha reductase inhibitors appear safe post-menopausal, pre-menopausal women need careful counselling and contraception as pregnancy can cause external genital abnormalities in the male foetus. Treatment needs to be stopped should pregnancy occur
  • Adverse effects include:
    • Reduced libido, erectile dysfuction, depression, headache, nausea, and hot flushes
    • A single-center, randomized, controlled study that evaluated 200 men has highlighted that the long-term use of dutasteride may lead to male infertility by persistently impairing semen volume and sperm motility
    • 5-alpha reductase inhibitors decrease the conversion of testosterone to DHT causing a build-up of testosterone, which subsequently converts to oestradiol creating a relative oestrogen excess that in theory could increase the risk of breast cancer -although no formal link has been established, long-term safety data is lacking and as such it is recommended to avoid 5-alpha-reductase inhibitors in those with a family history of breast cancer affecting a first degree relative
       
• Flutamide (125-250 mg per day) is generally avoided because of a higher risk of liver toxicity. A new treatment, bicalutamide 50 mg OD (contraception required), is showing early promise  
   
• Metformin can be used in PCOS. The dose should be increased weekly up to 500 mg tds if tolerated. In terms of hirsutism, metformin appears less benifical in patients with a BMI > 25