History
Detailed history taking from the patient is the cornerstone in patients with hirsutism. Most of the patients with hirsutism will develop excess hair around puberty or a few years thereafter. Onset of mild hirsutism with a slowly progressive course is usually associated with a functional disturbance. On the other hand, rapid progression of hair growth suggests an androgen secreting tumor. [29]
Location and rate of hair growth
Patients with hirsutism are often most concerned with unwanted hair in their face. However, areas covered by clothes may be less of a concern. Hence, it is important to ask about increased hair growth in other areas, including the upper chest, abdomen, inner aspects of the thighs, and the upper and lower back. The frequency and the method used to remove unwanted hair should be elicited because this often gives some idea of the extent of hair growth.
Rapid virilization associated with hirsutism is suggestive of androgen secreting neoplasm or exogenous androgenic drug use. History should include acne, alopecia, clitoromegaly, deepening of voice, masculinization, breast atrophy, and amenorrhea.
Menstrual abnormalities
Hirsutism is almost always a manifestation of other disease (more than 90% of the time). Because PCOS represents 80% of the etiology, it is important to ask about symptoms of this disorder. Oligomenorrhea or amenorrhea with hirsutism is sufficient to diagnose PCOS according to the revised Rotterdam criteria [30] after exclusion of other causes.
A study by Willis et al found that self-reported hirsutism in women, as measured using the modified Ferriman-Gallwey score, was associated with menstrual irregularity, bleed lengths of 7 days or more, and heavy menstrual bleeding. [31]
Regular menses, however, do not predict normal androgen status in hirsute women. Although 40% of women with hirsute have regular menses, half of them will be found to have elevated levels of one or more androgens. [32] Other cutaneous manifestations of PCOS like acne, oily skin, androgenic alopecia, seborrhea, and obesity may be present with hirsutism.
Family history
An increased prevalence of hirsutism, acne, and male pattern baldness have been found to run in some families. [33] PCOS often presents with familial clustering. However, it is unclear if this is due to genetic pattern alone or due to environmental factors such as diet. [34] Congenital adrenal hyperplasia also presents with familial clustering. The ethnic differences in hair quantity and distribution should be kept in mind.
Physical
Focused physical examination is essential for the evaluation of women with hirsutism. The clinician should determine whether hirsutism is truly present, as many women who complain of excess hair growth might not actually have hirsutism, especially those with ethnic and genetic predisposition (South European, and Middle East). Excess hair should be established as villus or terminal. Also, hirsutism should be distinguished from hypertrichosis, where hair growth is not mediated by androgens and hairs are not distributed in an androgen sensitive (male) pattern. [35]
Height, weight, body mass index (BMI), and waist-to-hip ratio (WHR) should be determined. Increased BMI and WHR are associated with PCOS, insulin resistance, and increased risk of coronary artery disease. [36]
Hirsutism
Ferriman and Gallwey [37] published a hirsutism rating scale that is illustrated in the table below. This scale allows the physician to measure a response to therapy objectively. This system is the most widely used and evaluates body areas for absent-to-severe hirsutism with scores of 0-4, respectively. Scores of 8 and higher are consistent with a diagnosis of hirsutism. This scale does not measure the thickness of the hair, which is another way of objectively assessing excess hair.
Scoring systems are a useful aid in quantifying hirsutism and in evaluating treatment response. However, they are somewhat subjective, so the absolute score is not used to define hirsutism. Even with scores >8, the patient determines if she is hirsute. When evaluating treatment response, the patient can determine if he or she notices a difference. Photographs are helpful for documentation and for following the progress of therapy.
Table. Ferriman-Gallwey Scoring System (Open Table in a new window)
Body Area Evaluated |
Score (Graded from 0-4*) |
Upper lip |
|
Chin |
|
Upper abdomen |
|
Lower abdomen |
|
Upper arm |
|
Thighs |
|
Upper back |
|
Lower back/buttocks |
|
*0 = No hirsutism, 4 = Severe hirsutism |
|
Other signs of androgen excess
Acne and oily skin are both associated with hirsutism. Androgen acts on the PSU to increase sebum production and has an important role in acne development. However, many cases of acne are not associated with hyperandrogenism.
Androgenic alopecia is another distressing condition associated with androgen excess. It is characterized by hair loss from the crown of the scalp sparing the frontal and occipital hairline (male pattern baldness). [38]
Acanthosis nigricans is a mucocutaneous condition where velvety hyperpigmentation patches appear mainly in the skin of the base of the neck, axilla, antecubital fossae, and groin. Acanthosis nigricans is a marker of insulin resistance. [39] In contrast, acanthosis nigricans is rarely seen with androgen secreting tumors. [40]
Virilization
Virilization suggests an androgen secreting tumors. Features of virilization include temporal male pattern balding, laryngeal hypertrophy, loss of feminine body contour and clitoral hypertrophy. [41] Clitoromegaly is diagnosed when the clitoral length times diameter is >35 mm2.
Causes
A specific underlying cause can be identified in most patients with androgen excess. [42]
Polycystic ovary syndrome (PCOS)
Approximately 80-90% of women with excess androgens have PCOS. [43, 42] PCOS is the most common endocrinological disorder affecting women in their reproductive years. [44] The prevalence in the United States has been estimated at 5-7% [45] and appears to be rising. Approximately 70% of women with PCOS are found to have mildly elevated free testosterone, and 20-30% have mildly elevated dehydroepiandrosterone sulphate (DHEAS). [46, 47]
Evidence suggests that hyperandrogenemia may be associated with chronic inflammation in PCOS by affecting adipocyte attributes and morphology. [48] Further, a study by Rudnicka et al indicated that increased androgen concentration is related to white blood cell (WBC) count in PCOS and therefore contributes to the mediation of chronic inflammation in this condition. [49]
A literature review by Escobar-Morreale and Roldán-Martín suggested that in women with type 1 diabetes mellitus, the prevalences of PCOS and associated traits, including hyperandrogenemia, are greater than in the general population without diabetes. The investigators found that out of 475 adolescent or adult women with type 1 diabetes, the prevalences of PCOS and hyperandrogenemia were 24% and 25%, respectively, while those for hirsutism, menstrual dysfunction, and polycystic ovarian morphology were 25%, 24%, and 33%, respectively. [50]
Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome
HAIR-AN syndrome is a subset of women with PCOS who present with hyperandrogenism, insulin resistance, acanthosis nigricans, and obesity in the absence of insulin receptor defect. [51] This syndrome is found in 1-3% of hyperandrogenic women. [52] HAIR-AN syndrome is characterized by high levels of post-glucose challenge insulin levels that may reach 300-500 µU/mL. [53]
Ovarian hyperthecosis
Ovarian hyperthecosis is another condition related to PCOS that most often presents in the perimenopausal period. This condition accounts for less than 1% of women with elevated androgens in their reproductive years, but most of the cases of hyperandrogenemia in postmenopausal women. [54]
Ovarian hyperthecosis is described when luteinized theca cell nests are present in the ovarian stroma. Although there is a considerable overlap between hyperthecosis and PCOS, hyperthecosis is associated with a more severe form of hyperandrogenism and virilization. Testosterone levels are much higher than PCOS and may reach levels greater than 200 ng/dL. [55]
Congenital adrenal hyperplasia
Approximately 2% of women with androgen excess are found to have late-onset, nonclassical, congenital adrenal hyperplasia. [43] Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from mutations in the genes coding for steroidogenic enzymes. In these disorders, a block in cortisol biosynthesis leads to loss of negative feedback inhibition, increased ACTH secretion, and subsequent excessive adrenal androgen production. [56]
The most common cause of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which accounts for 90-95% of patients with this condition. [56] The remaining patients with congenital adrenal hyperplasia have either 11 β-hydroxylase deficiency or 3 β-hydroxysteroid deficiency. [57, 58]
Cushing syndrome
Cushing syndrome is a rare but important cause of androgen excess, and hirsutism is present in approximately 81% of these patients. [59] Cushing syndrome (also called hypercorticism) is primarily the result of increasing levels of circulating cortisol or exogenous glucocorticoids. This syndrome can present insidiously with a spectrum of classic symptoms including rapid central weight gain (central obesity and “moon face”), abdominal striae, and signs of hyperandrogenemia including hirsutism, acne, and baldness.
Glucocorticoid therapy is currently the most common cause of Cushing syndrome but is unlikely to be associated with signs of increased androgens. In contrast, endogenous Cushing syndrome is often associated with hirsutism. Cushing syndrome can be secondary to an ACTH secreting pituitary tumor, which is called Cushing disease. Other cases of Cushing syndrome are related to autonomous cortisol secretion by the adrenal glands. [60] Adrenal tumors are associated with rapid onset of Cushing syndrome symptoms, often with hirsutism. [61] Rarely, Cushing syndrome is caused by ACTH secretion by other types of tumors such as small cell lung cancer.
Androgen secreting tumors
Androgen secreting tumors of the ovaries or adrenal glands are rare causes of hyperandrogenism that often mimic PCOS. Women with these tumors tend to have sudden onset of symptoms, rapid progression of hyperandrogenism and early development of frank virilization.
The most common virilizing ovarian tumors are Sertoli Leydig cell tumors and account for 0.5% of all ovarian neoplasms. [55] However, any type of ovarian tumor can present with signs of hyperandrogenism.
Androgen-secreting adrenal neoplasms are less common than ovarian neoplasms. [62] Patients with these tumors usually present with mixed picture of Cushing syndrome and virilization. [63]
Hyperprolactinemia
Elevated prolactin levels are found in as many as 6% of women with hirsutism. [64] The exact relationship between elevated prolactin levels and androgen excess is still unclear. Elevated prolactin levels might directly stimulate the adrenal cortex. [65]
Pregnancy
Testosterone rises throughout the normal pregnancy, reaching values around 600-800 ng/dL by term. The increase in SHBG and the placental aromatization of androgens to estrogens protect the mother and her fetus. Placental aromatase enzyme deficiency can cause hyperandrogenemia in both mother and fetus and result in virilization. [66]
Exogenous androgens
Ingestion of androgens or agents with androgenlike activity can result in hirsutism, acne, and virilization. Various anabolic steroids are used by professional athletes, both men and women, to attain a competitive edge or to assist in recovery from injury. These drugs are also used by a large number of noncompetitive body builders for cosmetic purposes and by women to increase libido.
-
Androgen secretion pathway in adrenal glands and ovaries.
-
Chemical structures of spironolactone and drospirenone. The testosterone core is in black.
Tables
Body Area Evaluated |
Score (Graded from 0-4*) |
Upper lip |
|
Chin |
|
Upper abdomen |
|
Lower abdomen |
|
Upper arm |
|
Thighs |
|
Upper back |
|
Lower back/buttocks |
|
*0 = No hirsutism, 4 = Severe hirsutism |
|
