As an isolated clinical condition, excessive hair growth can significantly detract from a woman’s quality of life. Hirsutism that occurs along with certain other clinical findings may also signal significant endocrine disease. For example, hirsutism in the presence of oligomenorrhea is often caused by polycystic ovary syndrome (PCOS) and may be associated with infertility, en-dometrial hyperplasia, and diabetes mellitus. Hirsutism in the presence of virilization may be caused by androgen secretion from an adrenal or ovarian tumor. Fortunately, almost all cases of hirsutism can be effectively treated with a combination of hormonal and nonhormonal therapies.
Definition
Hirsutism is the presence, in a woman, of coarse, dark terminal hair in a male pattern, often involving the upper lip, chin, sideburns, and chest. Terminal hairs are thick, stiff, and pig-mented. In men, they are normally found on the face, chest, abdomen, and back. From a practice perspective, a woman who complains of hirsutism has hirsutism. Clinically, hirsutism is present if the patient’s Ferriman-Gallwey score is greater than 8 [see Figure 1].1,2
Hirsutism must also be defined in the context of cultural, ethnic, and racial norms. Most Asian and Native American women have less body hair than white women; women from Mediterranean backgrounds have greater numbers of terminal hairs. In some southern European cultures, significant terminal hair on a woman’s upper lip is considered normal. In other cultures, a similar amount of terminal hair might be viewed as abnormal.
Hirsutism must be distinguished from hypertrichosis, which is an increase in total body hair, including sites where terminal hair is not usually found, such as the forehead. Most cases of hypertrichosis are associated with the use of drugs such as phenytoin, penicillamine, diazoxide, minoxidil, and cyclosporine. Systemic diseases such as anorexia nervosa, malnutrition, por-phyria, and hypothyroidism can also cause hypertrichosis. Treatment of hypertrichosis consists of discontinuance of the inciting drug or treatment of the systemic disease. If these approaches are not successful, treatment with an antiandrogen such as spironolactone (200 mg daily) has been reported to be moderately effective.3
Epidemiology
On the basis of a Ferriman-Gallwey score of more than 8, approximately 4% of women have hirsutism; only 1% of women have a Ferriman-Gallwey score above 10.1,2 Approximately 10% of a population-based cohort of women in Finland self-reported having hirsutism.4 In this study about 2.5 % of the women reported having both hirsutism and oligomenorrhea, indicating that in the general population, the prevalence of PCOS is lower than the prevalence of hirsutism. However, a greater proportion of women with PCOS seek medical care for their condition than women with hirsutism. Consequently, in a specialty endocrine practice, women with PCOS are overrepre-sented compared with women with self-reported hirsutism.
Pathogenesis
Hirsutism is caused by an excess of androgen production, androgen action, or both.5,6 Androgen overproduction can take place in the ovary, the adrenal gland, or the skin itself (specifically, in the hair follicle). In many hirsute women, all three organs overproduce androgens.
There are three types of hair: lanugo, vellus, and terminal. Lanugo is the soft, unmedullated hair seen in the fetus; it is shed in utero in the third trimester or shortly after birth. Vellus hairs are the thin, soft, unpigmented hairs that cover many areas of the body, such as the forehead. Terminal hairs are thick, coarse, and pigmented. Terminal hair is composed of an inner sheath of pigment with an outer sheath of keratin. Androgens stimulate the conversion of vellus hairs to terminal hairs in areas of the body sensitive to androgens, including the face and chest. Paradoxically, androgens cause the loss of terminal hairs in certain areas of the body, such as the frontal and parietal regions of the scalp.
The adrenal gland produces large quantities of the major an-drogens dehydroepiandrosterone sulfate (DHEAS), dehydro-epiandrosterone (DHEA), and androstenedione. The ovary produces androstenedione and testosterone. In end organs, such as the pilosebaceous unit (hair follicle), androstenedione and testosterone can be converted to the potent androgen dihy-drotestosterone (DHT) by the enzyme 5-a-reductase type 2. DHT and testosterone are the most potent androgens in humans; both bind with high affinity to the androgen receptor and initiate gene transcription that stimulates the growth of the pi-losebaceous units on the face and chest and decreases the growth of pilosebaceous units on the frontal and parietal scalp. DHEA and DHEAS have no inherent androgen activity but can be metabolized to the active androgens testosterone and DHT. In research studies, nearly all hirsute women have been found to have increased production of testosterone, but standard clinical assays may not be sensitive enough to reliably detect the elevations in serum testosterone levels in these patients.5,7
Many women with hirsutism have several hormonal defects, including the following: (1) overproduction of adrenal andro-gens, (2) overproduction of ovarian androgens,8 (3) increased conversion of androstenedione and testosterone to DHT in the hair follicle, and (4) increased sensitivity of the hair follicle to an-drogen action. Androgen overproduction in many hirsute women probably arises from multiple pathophysiologic defects, including (1) increased pituitary secretion of luteinizing hormone (LH), which stimulates ovarian production of testosterone and androstenedione; (2) elevated insulin levels, because of insulin resistance, which decrease the production of sex-hormone-binding globulin (SHBG) and thus increase free testosterone levels; (3) mild biochemical defects in the adrenal steroid enzymes that produce cortisol, which increase the ratio of androgen-to-cortisol secretion and result in adrenal androgen overproduction; and (4) increased activity of 5-a-reductase in the hair follicle, which increases the conversion of androgens to DHT in the follicle.
Etiology
The two most common causes of hirsutism are idiopathic hir-sutism and PCOS. Idiopathic hirsutism is defined as hirsutism(patient self-report or a Ferriman-Gallwey score above 8) in a woman with regular ovulatory menses. PCOS is the combination of oligomenorrhea (oligo-ovulation) and hyperandrogen-ism, as manifested by hirsutism or elevation in levels of a serum androgen such as androstenedione, testosterone, or DHEA. In many cases, idiopathic hirsutism may be a mild form of PCOS, in which androgen levels are elevated enough to cause hir-sutism but not elevated enough to produce oligo-ovulation and oligomenorrhea.9 In a very small number of women, hirsutism (usually severe hirsutism, the so-called bearded-lady phenomenon) is a manifestation of serious diseases such as adrenal or ovarian tumors. One study of 350 British women who presented with hirsutism or androgenic alopecia found that 68% had idiopathic hirsutism, 30% had PCOS, and 2% had serious underlying disease, including congenital adrenal hyperplasia, ovarian tumors, adrenal tumors, prolactinoma, and acromegaly.10 Controversy exists as to a possible relationship between hy-perprolactinemia, excess production of adrenal androgens, and hirsutism. Several investigators have reported a relationship between hyperprolactinemia and excess production of DHEAS,11 but others have not confirmed these observations.12,13 In one of the most detailed studies, Schiebinger and colleagues13 found that in women with hyperprolactinemia, successful treatment decreased the DHEAS production rate from 27 mg to 17 mg a day and increased the metabolic clearance rate from 16 L to 21 L a day. Along with these changes, serum DHEAS decreased from 2.5 ^g/ml to 1.8 ^g/ml. These results suggest that hyper-prolactinemia may play a modest role in stimulating adrenal androgen production and may occasionally contribute to the development of hirsutism.
Figure 1 Ferriman-Gallwey system for clinical scoring of hirsutism.1,58 Each of the 11 designated body areas is assigned a score of 0 (absence of coarse dark terminal hairs) to 4 (extensive terminal hair growth). A score higher than 8 indicates hirsutism. Hair scores over the forearms and lower leg do not contribute significantly to the distinction of hirsutism from nonhirsutism.
Diagnosis
The main goal in the evaluation of women with hirsutism is to determine whether idiopathic hirsutism or PCOS is present and to exclude rare, medically serious causes of hyperandro-genism, such as ovarian and adrenal tumors.14 This can best be done on the basis of the history and physical examination, along with limited laboratory testing [see Table 1].
Clinical Features
The differentiation between the two most common causes of hirsutism can be made by menstrual history. Women with idio-pathic hirsutism have normal menstrual cycles lasting 23 to 35 days. Women with PCOS have oligomenorrhea, with some menstrual cycles lasting longer than 35 days. Many women with PCOS have fewer than six spontaneous menstrual cycles a year.
Table 1 Differential Diagnosis of Hirsutism in Women of Reproductive Age
|
Associated Finding |
Most Likely Diagnosis |
|
Oligomenorrhea |
Polycystic ovary syndrome (PCOS) |
|
Regular ovulatory cycles |
Idiopathic hirsutism |
|
Fasting 17-hydroxyprogesterone level > 4 ng/ml |
Nonclassic adrenal hyperplasia |
|
Virilization |
Ovarian or adrenal androgen-secreting tumor, or ovarian stromal hyperthecosis |
|
Acanthosis nigricans |
Severe insulin resistance syndrome, often associated with PCOS or ovarian stromal hyperthecosis |
|
Galactorrhea and elevated serum prolactin level |
Hyperprolactinemia |
Serious causes of hyperandrogenism (e.g., ovarian or adrenal tumors) typically manifest themselves clinically as virilization, with frontal balding, acne, clitoromegaly, increased upper body muscle mass, and deepening of the voice. Almost all women with signs of virilization are amenorrheic; none have regular ovulatory menstrual cycles. In addition, most women who present with virilization from an ovarian or adrenal tumor report recent onset (within the past year) of their hirsutism and rapid progression of their condition. In contrast, most women with id-iopathic hirsutism or PCOS notice the onset of hirsutism many years before presenting for medical care, often during puberty.
When taking the history, the clinician should ask whether the patient has been using androgenic medications such as danazol or testosterone and its derivatives, which is a rare cause of hirsutism. Some female athletes may use anabolic steroids.
Laboratory Testing
Serum Androgen Assays
Patients with clinical evidence of hirsutism should undergo measurement of serum testosterone (total or free) and serum 17-hydroxyprogesterone levels. Unfortunately, most of the an-drogen assays available in clinical practice are designed to differentiate between levels found in normal women and men, and these assays are neither sensitive enough nor specific enough for detecting differences between normal and hirsute women. For example, the mean circulating total testosterone level is approximately 25 ng/dl in normal women, 50 ng/dl in hirsute women, and 600 ng/dl in men. Clinical assays are excellent at differentiating between 25 ng/dl and 600 ng/dl but are poor at differentiating between 25 ng/dl and 50 ng/dl.
Another problem with clinical assays is that testosterone circulates in both free and SHBG-bound forms. Testosterone bound to SHBG is not able to stimulate end organs, such as the pilosebaceous unit. The amount of free testosterone depends on both testosterone production rates and the concentration of SHBG. To complicate the situation, an increase in testosterone production causes a decrease in SHBG production, which results in a decrease in total testosterone (the form of testosterone that is most often measured in practice) and an increase in free testosterone (a form that is not typically measured in clinical practice).
In most clinical assays, the upper limit of normal for serum testosterone is 80 ng/dl. Almost all women with virilization have serum testosterone levels greater than 150 ng/dl.15-17 It is probably wise for primary care physicians to seek the help of an endocrinologist if they identify a virilized woman or a woman with a serum testosterone concentration above 150 ng/dl.
Other Tests
In a hirsute woman who has amenorrhea, the serum pro-lactin level should be measured. Women with PCOS, especially those who are obese, should be screened for diabetes mellitus. This is particularly true of patients in whom physical examination reveals acanthosis nigricans, which suggests significant insulin resistance.
Between 1% and 5% of women who present with hirsutism and oligomenorrhea have nonclassic congenital adrenal hyper-plasia (NCAH) from 21-hydroxylase deficiency that was too mild to be detected at birth.18 All of these women have elevated levels of 17-hydroxyprogesterone (above 4 ng/ml) in the early morning (8 A.M.) during the follicular phase of the menstrual cycle. Consequently, measurement of a follicular-phase 8 A.M. 17-hydroxyprogesterone level can help rule out NCAH. It is not clear whether all women with hirsutism and oligomenor-rhea should be screened for NCAH, because the disorder has a low prevalence in many populations. In addition, many women with NCAH respond well to the standard treatments for PCOS. Screening might be warranted in women of ethnic groups that have an increased prevalence of NCAH (e.g., Ashkenazi Jews, Inuits). One middle-of-the-road approach is to screen women for NCAH only if their serum testosterone concentration is above a clearly elevated level, such as 100 ng/dl or 150 ng/dl. This approach will detect the most clinically significant cases of NCAH.
Treatment
The goals of treatment of hirsutism include the following: (1) rule out a serious underlying medical condition such as a viril-izing tumor of the adrenal or ovary, (2) slow or stop new hair growth, (3) remove or hide existing hair, (4) evaluate and treat associated hormonal problems such as oligomenorrhea, and (5) anticipate long-term health conditions that can occur in women with hyperandrogenism, such as an increased risk of diabetes.
Hormonal treatment of hirsutism typically does not result in normalization of the Ferriman-Gallwey score (i.e., to below 8). In many studies, patients’ Ferriman-Gallwey scores are in the range of 20 to 25 at the initiation of treatment. After 12 months of treatment, the Ferriman-Gallwey scores are in the range of 10 to 15. On the basis of these general observations, clinicians can assure women that treatment is effective but should warn them that treatment is unlikely to reduce facial hair to a level similar to that in nonhirsute women. In addition, clinicians should advise women that it will take at least 6 months for treatment to reach near maximal effects. Finally, most patients report that if they discontinue hormone treatment, the hir-sutism recurs over the next 3 to 9 months.
Treatment of hirsutism should be multimodal [see Table 2]. It should include hormonal suppression of androgen production or action, along with a nonhormonal method of controlling hair growth. A common strategy is to combine an estrogen-progestin contraceptive formulation with an antiandrogen and to use electrolysis or shaving as a nonhormonal adjuvant. An alternative hormonal approach is treatment with an antiandro-gen alone. Alternative nonhormonal treatments include the use of a facial antihair cream or laser destruction of hair follicles [see Nonhormonal Approaches, below].
Weight Loss
Body mass index (BMI) is a major determinant of insulin resistance and hyperinsulinemia. Women with a BMI greater than 27 kg/m2 are often insulin resistant.19 Women with a BMI under 25 kg/m2 are seldom insulin resistant, unless they have a relatively rare genetic cause of insulin resistance, such as lipodystrophy. Hyperinsulinemia causes hyperandrogenism through several mechanisms. In combination with LH, elevated insulin levels cause the ovarian theca and stroma to produce excess quantities of androstenedione and testosterone.20 In addition, hyperinsulinemia suppresses hepatic production of SHBG, which causes an increase in free androgens. Excess ovarian production of androgens and decreased SHBG work synergistically to increase the risk of development of hirsutism.
Numerous studies have demonstrated the benefits of weight loss in hyperandrogenic, insulin-resistant women.21-25 In these studies, mean weight loss ranging from about 10 to 20 kg has been associated with decreases in insulin levels and testosterone concentration and with ovulation and pregnancy in many women.
Weight loss is difficult to achieve. A structured program that includes consultation with a nutritionist, encouragement by the physician, a low-calorie diet, and initiation of an exercise program may be the most effective nonsurgical approach in these patients. Surgical methods of weight reduction can be very effective, especially in women whose BMI is greater than 40 [see 3:X Obesity].
