And It's About Time There Was Some Support For Cushing's!
The extent of normal hair growth varies between individuals, families and races, being more extensive in the Mediterranean and some Asian subcontinent populations. These variations in body hair in the normal population, and the more extensive hair growth seen in patients complaining of hirsutism appear to represent a continuum from no visible hair to extensive cover with thick dark hair. It is therefore impossible to draw an absolute dividing line between 'normal' and 'abnormal' degrees of facial and body hair in the female. Soft vellous hair is normally present all over the body and this type of hair on the face and elsewhere is 'normal' and is not sex-hormone dependant. Any excess in the latter regions is thus usually a mark of increased ovarian or adrenal androgen production.
It has been traditional to divide patients with hirsutism into those with no elevation of serum androgen levels and no other clinical features (usually labeled 'idiopathic hirsutism') and those with an identifiable endocrine imbalance (most commonly polycystic ovary syndrome (PCOS) or rarely other causes). However in recent years it has become apparent that most patients with 'idiopathic hirsutism' have some radiological or biochemical evidence of PCOS on more detailed investigation.
Familial or idiopathic hirsutism does occur, but usually involves a distribution of hair growth which is not typically androgenic. Similarly, non-androgen-dependant hair growth occurs with drugs such as phenytoin, diazoxide, minoxidil and cyclosporin. Iatrogenic hirsutism also occurs after treatment with androgens, or more weakly androgenic drugs such as progestagens or danazol.
Rarer, and more serious, endocrine causes of hirsutism and virilization include congenital adrenal hyperplasia, Cushing's syndrome and virilization tumors of the ovary and adrenal. All these should be considered in any patients with hirsutism.
A wide variety of ovarian and adrenal steroid hormone products and precursors are androgenic and hypersecretion of androgens from one or both of these endocrine organs is usually found in patients with hirsutism. In addition, estrogens are converted to androgens in adipose tissue, which represents a further source of androgen excess in obese patients. The response of the hair follicle to circulating androgens also seems to vary between individuals with otherwise identical clinical and biochemical features, and the reason for this variation in end-organ response remains poorly understood. Whatever the underlying pathology, hair has a long growing cycle with spontaneous variations and clinical changes are therefore slow, both as hair develops and as it responds to therapy.
The complaint of hirsutism is common and often accompanied by severe anxiety and social stress. The following are important issues to consider.
This should be recorded objectively, ideally using a scoring system, to document the problem and to monitor treatment. The method and frequency of physical removal (e.g. shaving, plucking) should also be recorded. Most patients who complain of hirsutism will have an objective excess of hair on examination, but occasionally a normal pattern of hair will be found (and appropriate counseling is then indicated).
Hirsutism related to PCOS usually begins around the time of the menarche and increases slowly and steadily in the teens and twenties. Rapid progression and prepubertal or late onset suggests a more serious cause.
Hirsutism due to PCOS may be severe and effect all androgen-dependant areas on the face and body. However, more severe virilization (clitoromegaly, frontal balding, male phenotype) implies substantial androgen excess, usually indicates a rarer cause other than PCOS.
Most patients with hirsutism will have some disturbance of menstruation. The greater the disruption the more likely it is that there is a serious cause.
Many patients with hirsutism are also overwieght or obese. This worsens the underlying androgen excess and insulin resistance and inhibits the response to treatment, and is an indication for appropiate advice on diet and exercise. In severe cases the insulin resistance may have a visible manifestation as acanthosis nigricans on the neck and in the axillae.
A variety of investigations may aid the diagnosis of patients with hirsutism:
Serum testosterone may be elevated in PCOS and is invariably substantially raised in virilization tumors. Patients with hirsutism and normal testosterone level frequently have low levels of sex hormone binding globulin (SHBG), leading to high free androgen levels. SHBG can be measured in some centers.
17-x-Hydroxyprogesterone is elevated in classical CAH (congenital adrenal hyperplasia), but may be apparent in late-onset CAH only after stimulation.
Gonadotrophin levels. LH hypersecretion is a consistent feature of PCOS, but the pulsatile nature of secretion of this hormone means that an increased LH/FSH ratio is not always observed on a random sample.
Estrogen levels. Estradiol is usually normal in PCOS, but estrone levels (which are rarely measured) are elevated due to peripheral conversion. Levels are variable in other causes.
Ovarian ultrasound. The most consistent investigation in PCOS is ovarian ultrasound, although a skilled observer is necessary. The typical ultrasonic features are those of a thickened capsule, multiple 3-5mm cysts and hyperechogenic stroma. It should also be noted that prolonged hyperandrogenization from any cause may lead to polycystic changes in the ovary. Ultrasound may also reveal virilization ovarian tumors, although these are often small.
Serum prolactin. Mild hyperprolactinaemia is common in PCOS but rarely exceeds 1500mUL-1.
If a virilization tumor is suspected clinically or after investigation, then more complex tests may include dexamethosone suppression tests, CT or MRI of adrenals, and selective venous sampling catheters.
Most patients presenting with a combination of hirsutism and menstrual disturbances will be shown to have polycystic ovary syndrome, but the rarer alternative diagnoses should always be born in mind, and excluded with appropriate investigations if suspected. This includes late-onset CAH (early-onset, raised serum 17-x-OH-progesterone), Cushing's syndrome (look for other clinical features) and virilization tumors of the ovary or adrenals. (severe virilization, markedly elevated serum testosterone).
The extent of investigation will depend on clinical context. In many cases a single serum testosterone may be sufficient to exclude rare causes. Urine free cortisol should be measured if Cushing's syndrome is a clinical possibility and 17-x-OH-progesterone if early onset or family history suggests congenital adrenal hyperplasia.
The underlying cause should be removed in the rare instances where this is possible (e.g. drugs, adrenal or ovarian tumors). Other therapy depends upon whether the aim is to reduce hirsutism, regularize periods or produce fertility.
Plucking, bleaching, depilatory cream or wax and shaving may all help and are often underused. Waxing is of especial value where the "bikini area is causing the concern. Electrolysis is slow and expensive.
This always requires a year or more of treatment for maximal benefit, and long-term treatment is frequently required as the problem tens to recur when treatment is stopped. The patient must therefore be an active participant in the decision to use systemic therapy and must understand the rare risks as well as benefits.
Estrogens (e.g.. oral contraceptives) suppress ovarian androgen production and reduce free androgens by increasing SHBG levels when these are low. Combined pills, which contain a non-androgenic progestogen (e.g. Dianette or Marvelon) have a theoretical advantage over older combined pills, and will result in a slow improvement in hirsutism in a majority of cases and should normally be used first unless there is a contraindication.
Cyproterone acetate (50 -200mg daily) is an anti-androgen but is also teratogenic and a weak glucocorticoid and progestogen. Given continuously it produces amenorrhoea, and so is normally given for days 1-14 of each cycle. In women of child bearing age, contraception is essential.
Spironalactone (200mg daily) also has anti-androgen activity and can cause useful improvements in hirsutism in selected cases.
Other agents of doubtful efficacy include bromocriptine and cimetidine.
New agents which remain to be fully evaluated include finasteride and flutamide.
Eflornithine Cream is the first topical prescription treatment for women with unwanted facial hair. Eflornithine works by inhibiting the growth of facial hair and was shown in controlled clinical trials to provide clinically meaningful and statistically significant improvement in the reduction of facial hair growth in women.
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