Hirsutism: Common Clinical Problem or Index of Serious Disease?

Abstract

Hirsutism is a clinical condition commonly encountered in the practice of primary care medicine. The etiology and the age of the patient when it occurs vary widely. Causes range from a basic illness or condition (drug exposure, smoking, idiopathic, and obesity) to complex and serious diseases (Cushing's syndrome, neoplasms, congenital adrenal hyperplasia, insulin-resistance syndromes, hyperprolactinemia, polycystic ovary syndrome, and hyperthecosis).

Hirsutism may appear in childhood as well as in older persons. Some drugs (oral contraceptives, L-thyroxine, danazol, and diazoxide), tobacco smoke, some syndromes (polycystic ovary syndrome, obesity, insulin resistance, hyperprolactinemia, hyperthecosis, congenital adrenal hyperplasia, and idiopathic), and some neoplasms (adrenal or ovarian) may lead to hirsutism. The most frequently defined "causes" of hirsutism are polycystic ovary syndrome and idiopathic hirsutism. In hirsutism of gradual onset, hyperprolactinemia, insulin-resistance syndromes, hyperthecosis, polycystic ovary syndrome, and idiopathic hirsutism may be responsible. Cushing's syndrome, neoplasms, and congenital adrenal hyperplasia should be suspected if there has been rapid onset.

Introduction

Hirsutism is an excessive growth of body hair in women at androgen-dependent areas. These areas include the lips, chin, chest, abdomen, back, and femoral region, where normally very few hairs are found. Hirsutism must be distinguished from hypertrichosis, which is an increase of body hair that is not limited to androgen-dependent areas. Hypertrichosis, on the other hand, may be a side effect of certain drugs, including phenytoin, penicillamine, L-thyroxine, and others, or it may be the result of systemic diseases, such as hypothyroidism and malnutrition. Hirsutism may be classified from I (hirsutism) to IV (virilization), depending on the amount of hair.[1] The most important determinant in making the diagnosis is a change in the form and rate of hair growth. Recently, a technique has been developed for assessing hirsutism with video equipment and computer software. Digital imaging of hair development is recorded, which demonstrates a significant difference in hair form and growth rate between hirsute and nonhirsute women.[2]

Worldwide, hirsutism is one of the most frequent complaints among women. The majority of complaints are for cosmetic reasons; however, ethnic differences must be kept in mind when evaluating the disorder, as most American and Asian women have very little hair, whereas Mediterranean women have a moderate amount of hair. This article discusses the diagnosis, etiology, and evaluation of hirsutism, and examines important causes of the condition.

The Pathogenesis of Hirsutism

Hirsutism is commonly due to the effect of androgens on hair follicles. The quantity of secreted androgens, peripheral conversion of androgens to end products, the amount of free androgens in circulating blood, the metabolic clearance rate, and the sensitivity of the hair follicles all affect the pathology.

Androgens are produced from both ovary and adrenal glands. Testosterone secretion is usually of ovarian origin, whereas dehydroepiandrosterone (DHEA)-sulfate is secreted by the adrenal glands and androstenedione secretion originates both in the ovarian and adrenal glands. DHEA-sulfate has little clinical importance, as it converts to androstenedione and later to testosterone. Thus, to a large extent, the pathology of hirsutism depends on androstenedione and testosterone levels. Large quantities of androgens bind to specific plasma proteins, including sex hormone-binding globulin (SHBG), cortisol-binding globulin, and albumin. Increased levels of oestrogens result in an increase in SHBG. In hirsutism, SHBG decreases and free androgens reach levels comparable to those seen in men. Peripheral conversion of testosterone to 5-alpha-dihydrotestosterone (DHT), which is controlled by 5-alpha-reductase, may increase. This phenomenon helps to clarify the increased sensitivity of hair follicles to androgens.[3] DHT is finally converted to 3-alpha- and 3-beta-androstenediol and similar glucuronides in target cells. This has led to several clinical studies measuring levels of 3-alpha-androstanediol glucuronide in hirsute and nonhirsute women; significant differences have been found between these 2 groups.[4]

Hirsutism also may be caused by an overproduction of androgens from ovarian and adrenal tumors. Assessing hyperandrogenism is now more accurate owing to the hormonal hirsutism score.[5] Serum concentrations of testosterone, androstenedione, DHEA, DHEA-sufate, and SHBG are used to calculate the hormonal hirsutism score (T/SHBG + A/100 and T/SHBG + A/100 + DHEAS/100).[6] This index shows the optimal correlation with hirsutism, especially in cases in which levels of hormones are minimally elevated.[7] Sometimes, an overproduction of testosterone occurs in target organs despite the presence of serum androgen levels in the normal range.

Causes of Hirsutism

General

The general causes of hirsutism are hyperandrogenemia (exogenous or endogenous), increased sensitivity of the hair follicles to androgens,[6] and idiopathic. In adolescents, hyperandrogenemia may cause precocious puberty, with or without hirsutism. In idiopathic hirsutism, however, the androgen levels are normal and certain pathology is still obscure. Epidemiologic studies have shown that the most common causes of hirsutism are polycystic ovary syndrome and idiopathic hirsutism.[7]

Other causes include obesity, insulin resistance, hyperprolactinemia, adrenal hyperplasia (sometimes late-onset), certain drugs (danazol and oral contraceptives), smoking, hyperthecosis, and ovarian or adrenal tumors (Table 1).

Table 1.

Etiology of Hirsutism

Drugs
Cigarette smoking*
Syndromes	Polycystic ovary syndrome**
	Idiopathic hirsutism**
	Obesity**
	Insulin resistance***
	Hyperprolactinemia****
	Hyperthecosis*****
Tumors	Adrenal tumors Ovarian tumors

*Data from Medina E, Arteaga P, Pizarro L, Ahumada M. Effects of cigarette smoking in women. Rev Med Chil. 1990; 118:253-258

**Data from Moran C, Tapia MC, Hernandez E, Vazquez G, Garcia-Hernandez E, Bermudez JA. Etiological review of hirsutism in 250 patients. Arch Med Res. 1994;25:311-314.

***Data from Hrnciar J. [Clinical manifestations of the insulin resistance syndrome. The hormonal-metabolic syndrome X, the 5H syndrome and their etiopathogenesis]. Vnitr Lek. 1995;41:92-98.

****Data from Glasow A, Breidert M, Haidan A, Anderegg U, Kelly PA, Bornstein SR. Functional aspects of the effect of prolactin (PRL) on adrenal steroidogenesis and distribution of the PRL receptor in the human adrenal gland. J Clin Endocrinol Metab. 1996;81:3103-3111.

*****Data from Nagamani M, Lingold JC, Gomez LG, Garza JR. Clinical and hormonal studies in hyperthecosis of the ovaries. Fertil Steril. 1981;36:326-332.

Virilism is a syndrome characterized by the presence of android-type obesity, acne, frontal balding, and hoarseness with or without menstrual abnormalities.

Smoking

The frequency of abortions, the incidence of early menopause, obesity, hoarseness, hormonal disturbances,[8] and the incidence of hirsutism have been compared between smokers and nonsmokers (Table 1).

Syndromes and Metabolic Disturbances Causing Endogenous Hyperandrogenemia

Adrenal androgen excess, insulin resistance,[9] acne, infertility, dysfunctional uterine bleeding, and hirsutism are characteristic findings in polycystic ovary syndrome. Obesity is present in only 40% of these patients. Elevated serum luteinizing hormone (LH) concentrations and an increased serum LH:follicle-stimulating hormone (FSH) ratio result either from an increased gonadotropin-releasing hormone (GnRH) hypothalamic secretion or less likely from a primary pituitary abnormality. This results in a dysregulation of androgen secretion and increased intraovarian androgen, the effect of which in the ovary are follicular atresia, maturation arrest, polycystic ovaries, and anovulation. Hyperinsulinemia is a contributing factor to ovarian hyperandrogenism, independent of LH excess.

Serum 3-alpha-androstanediol glucuronide, as well as other C19 sulfate and glucuronide conjugates, increase, reflecting peripheral androgen action. The adrenal androgens, DHEA-sulfate, 11-beta-hydroxyandrostenedione, and fasting insulin levels are elevated.[10]

Endogenous stimulation by metyrapone results in an exaggerated response of testosterone.[11] Another study demonstrates an increase in ovarian secretion of 17-OH progesterone and adrenal delta-4-17,20-lyase activity, suggesting mild ovarian and adrenal hyperandrogenic activity.[12]

In women with obesity, the production of testosteronee, DHT, and 3-alpha-androstanediol (3-alpha-diol) increases approximately 2-fold; SHBG decreases and metabolic clearance rates increase 2- to 3-fold as compared with women who are not obese. Plasma androgen levels are not increased in obese nonhirsute women, and thus, menstrual abnormalities, hirsutism, and virilism are not seen. In hirsute obese persons, however, increased metabolic clearance rates are seen and plasma androgen levels are high.[13] Insulin resistance is generally associated with obese, hirsute, and hyperandrogenic women. Darkening of skinfold areas, acanthosis nigricans, is a manifestation of this condition.[14]

Insulin-resistance conditions may be divided into prereceptor, receptor, and postreceptor steps. Metabolic syndrome X is characterized by hyperinsulinism, hyperglycemia, hyperlipoproteinemia, hypertension, hirsutism, and polycystic ovary syndrome. Therefore, it may be called the 5H syndrome. This is a postreceptor disorder. Impaired insulin use (liver and muscles) and impaired primary secretory response due to a disorder of blood sugar control (glucokinase and GLUT-2) are associated with hyperinsulinism.[15]

Hyperinsulinism causes ovarian hyperandrogenism by acting on theca-cell receptors via insulin-like growth factor-1 and decreases serum SHBG levels, causing a subsequent increase of free testosterone levels in plasma.

In severe insulin-resistance syndromes, such as hyperinsulinemia type A (a rare disease), too much insulin directly stimulates the ovaries and causes androgen hyperproduction and the formation of polycystic ovaries.[16]

Hyperprolactinemia is one of the most common endocrinologic disorders. Prolactin has receptors in all 3 layers of the adrenal cortex. Stimulation by prolactin causes increases in serum levels of cortisol, aldosterone, and DHEA-sulfate.[17] The effect of DHEA-sulfate on hirsutism is very weak. Hirsutism appears to be particularly related to polycystic ovary syndrome and is frequently seen together with hyperprolactinemia.[18]

Congenital adrenal hyperplasia is a strange cause of hirsutism. This is generally a childhood disorder; however, late-onset forms are also seen. Severe hirsutism, virilism, short stature, family occurrence, and regular menses are characteristic findings. Among hirsute women, the incidence of this condition has been reported to be 0% to 30%. The pathology is often a 21-hydroxylase deficiency.[19] 17-Hydroxyprogesterone and androstenedione levels are increased in classic forms, but adrenocorticotropic hormone (ACTH) stimulation requires determining the pathology in late-onset forms. Exaggerated response to ACTH has been demonstrated in several studies.[20]

Virilization and hirsutism caused by ovarian stromal hyperthecosis are rarely seen. Hyperthecotic ovarian theca cells secrete large amounts of testosterone and DHT. Peripheral progesterone and 17-alpha-hydroxyprogesterone levels are also increased. FSH and LH levels are normal or low, with a lack of response of LH to a hormonal stimulus.[21] However, bioactive LH secretion is increased.[22] Hyperinsulinemia and insulin resistance are significantly seen in the pathology, and this phenomenon plays an important role in the stimulation of ovarian adrenal synthesis.[23] The mechanism of this stimulation is most likely via insulin-like growth factor-1 receptors in the ovary.[24]

Androgen-secreting ovarian tumors cause rapidly progressive virilization and hirsutism. These are rare and are generally seen in older women. Sometimes, however, they may appear in younger persons.[25] Tumors are frequently a sex-cord stromal type; the most common of these are Sertoli-Leydig cell tumors and lipid cell tumors, but granulosa cell tumors also are seen.[26] Serum testosterone levels exceed 1.5 ng/mL in all cases.[26] However, higher levels of serum testosterone are not pathognomonic findings for ovarian neoplasms, and catheterization of ovarian veins shows significant elevation of unilateral testosterone. If ovarian venous testosteronee exceeds 20 ng/mL, this generally accompanies a tumor.[27]

Adrenal tumors, those that lead to hirsutism and virilization, are rare. Adrenal adenomas secrete testosterone, whereas adrenal carcinomas secrete testosterone, DHEA-sulfate, and cortisol. These findings are strongly significant for tumoral events, especially in the case of detecting unilateral, high blood levels of previous hormones during venous procedures. Dexamethasone tests show no suppression of androgen and cortisol levels at neoplastic events.[28]

Drugs Causing Exogenous Hyperandrogenemia

Some drugs are thought to lead to hirsutism. Oral contraceptives and danazol have been known etiologic agents for a long time.[29,30] Oral contraceptives are used frequently by women all over the world. Adverse effects of oral contraceptives, such as hirsutism and hypertension, have been observed, especially among middle-aged women.[29] Danazol has been used for endometriosis since 1976, and adverse effects have been reported in 85% of patients. Major adverse effects are weight gain, edema, a decrease in breast size, oily skin, hirsutism, and deepening of the voice.[30] L-Thyroxin therapy, which is used broadly in endemic goiter lesions, may lead to hirsutism, causing a decrease in SHBG, transcortin, and estradiol levels, and an elevation in the level of DHEA-sulfate.[31] Diazoxide also can cause hirsutism by inducing 5-alpha-reductase activity (Table 2).[32]

Table 2.

Drugs Leading to Hirsutism

Oral Contraceptives

Danazol

L-thyroxine

Diazoxide

Idiopathic Hyperandrogenemia

Regular ovulation and normal androgen levels are found with idiopathic hirsutism, but some ovarian and adrenal steroidogenetic abnormalities may be seen. Additionally, exogenous alpha-1-24 ACTH leads to an increase in plasma androstenedione, DHEA, and cortisol levels in hirsute persons more so than in nonhirsute persons.

Evaluating the Patient With Hirsutism

As previously discussed, the first step in diagnosis is determining the hirsutism's nature. The patient should be asked about medications (oral contraceptives, danazol, and others) and smoking. Cessation of smoking or those medications that lead to hirsutism may be a simple but appropriate management for some patients. One difficulty, naturally, is determining whether the hirsutism is actually the result of the drugs or the smoking. The diagnosis will be accurate if the hirsutism shows regression after cessation of the offending drug.

Virilization, Quick Progress, and Postmenopausal or Prepubertal Onset

Some symptoms indicate adrenal or ovarian pathology, most of which will be of tumoral origin. An abdominal mass may be palpated when the lesion is large enough. Elevated levels of serum testosterone and DHEA-sulfate concentrations strongly suggest an adrenal neoplastic process. Adrenal adenomas may produce testosterone, whereas adrenal carcinomas produce not only testosterone but also DHEA-sulfate. Dexamethasone administration usually depresses serum DHEA-sulfate and cortisol levels and urinary 17-ketosteroid excretion in nonneoplastic events, but never in neoplastic cases.[28]

Magnetic resonance imaging (MRI) or computed tomography (CT) of the adrenal region is useful for diagnosis. Adrenal adenomas are smaller than carcinomas. Four-centimeter and larger lesions should be excised owing to the risk of malignancy, especially in younger patients.[28]

Adrenal tumors vary in their endocrine functions. In one study, adrenal incidentalomas were evaluated by measuring hormonal status: 85% were nonfunctioning, 9.2% were Cushing's syndrome, 4.2% were pheochromocytomas, and 1.6% were aldosteronomas.[33]

Cushing's syndrome should be part of the differential diagnosis, and symptoms, including moon face, hyperglycemia, striae, buffalo hump, and typical dispersion of obesity to the hips, should be examined. Diagnosing Cushing's syndrome includes assessing serum ACTH levels, a dexamethasone suppression test, and ACTH response to corticotropin-releasing hormone. In Cushing's syndrome with adrenal etiology, the ACTH level is always low and ACTH response to the corticotropin-releasing hormone administration is blunted. Adminstration of 1 mg of dexamethasone provides no suppression in the serum cortisol levels.

Virilization, Quick Progress, and Adrenal Mass

Androgen-secreting ovarian tumors are rare but may be seen later in life. They are Sertoli-Leydig cell tumors, granulosa-theca cell tumors, and lipid cell tumors. Serum testosterone levels are often high, but DHEA-sulfate levels are low.

Testosterone levels are usually higher than 1.5-2 ng/mL. Patients are generally obese, and if they are in the premenopausal period, menstrual irregularities may be seen. Vaginal ultrasonography has been successfully used to detect ovarian pathologies.[36] As previously noted, ovarian venous sampling of testosterone levels may show unilateral elevation. However, certain diagnoses must be made by pathological examination of surgically resected materials.

Virilization, Quick Progress, and Infancy

Hirsutism and virilism, which begin in early infancy, strongly suggest congenital adrenal hyperplasia. Sometimes, clinical symptoms may be delayed; this is called late-onset congenital adrenal hyperplasia.[35]

Serum testosterone and DHEA-sulfate levels are low. The pathology is most commonly a 21-hydroxylase deficiency. Although the pathology of the steroidogenetic pathway decreases the corticosteroid synthesis and increases 17-hydroxyprogesterone and androstenedione synthesis, ACTH administration results in an exaggerated response of serum 17-alpha-hydroxyprogesterone.[36]

Hirsutism, Gradual Course, and Galactorrhea

Cases of hirsutism with galactorrhea are generally associated with hyperprolactinemia and irregular menses. If the serum level of prolactin is high, hyperprolactinemia, which is commonly seen in the disorder, should be considered in the pathology.

Hyperprolactinemia may be associated with various conditions, either physiological or nonphysiological. Some drugs (phenothiazines, benzodiazepines, and others) as well as prolactinoma, hypothyroidism, or idiopathic hyperprolactinemia are nonphysiological, whereas lactation and stress represent physiological causes.

Hirsutism, Gradual Course, Obesity, and LH Excess

Gradual-onset hirsutism associated with obesity and family history suggests polycystic ovary syndrome. This is a very common disorder. In this scenario, the serum LH:FSH ratio is generally above 2. Pelvic ultrasonography shows polycystic ovarian pathology. Nonobservable conditions may be explained by microcystic changes on ovarian tissue.

Hirsutism, Gradual Course, Obesity, Acantosis Nigricans, Hyperlipidemia, and Glucose Intolerance

Insulin-resistance conditions are generally associated with obesity, and acanthosis nigricans may be demonstrable on skin examination. Severe congenital syndromes are very rare.

Insulin resistance and polycystic ovary syndrome frequently occur together. Other laboratory and clinical features help diagnose the 5H syndrome, which is also called syndrome X or metabolic syndrome. In these, serum insulin levels are high, leading to pathology.[37]

Hirsutism, Gradual Course, Testosterone Excess, Progesterone Excess, and Normal LH

Ovarian stromal hyperthecosis is a rare syndrome, characterized by the synthesis of large amounts of testosterone, DHT, and progesterone by ovarian theca cells. Serum LH levels are normal or low, whereas the bioactive fraction of total LH is high. The lack of an LH response to a hormonal stimulus is another feature of this condition.

Hirsutism, Gradual Course, Regular Menses, and Normal Laboratory Findings

Idiopathic hirsutism is a very frequent syndrome leading to hirsutism among women. Although results of most laboratory tests appear normal, some analyses will indicate pathology. Metyrapone tests, for example, show very high serum testosterone results. 17-OH progesterone and adrenal delta-4-17,20-lyase activity are high, suggesting mild ovarian and adrenal hyperandrogenic activity.

Table 3.

Clinical Course and Laboratory Features of Various Conditions Leading to Hirsutism

Rapid onset	Cushing's syndrome	Serum cortisol -- high Dexamethasone suppression test -- negative Surrenal CT/MRI --diagnostic
	Adrenal tumors	Serum testosterone -- high DHEA-sulfate level -- high Surrenal CT/MRI -- diagnostic
	Ovarian tumors	Serum testosterone -- high Serum DHEA-Sulfate -- low Pelvic CT/USG --diagnostic
	Congenital adrenal hyperplasia	Serum testosterone -- low Serum DHEA-sulfate -- low Serum 17-hydroxyprogesterone -- high
Gradual course	Hyperprolactinemia	Serum prolactin -- high Hypophysis MRI for adenoma -- diagnostic
	Insulin-resistance syndromes	Serum glucose -- high Serum lipids -- high Serum Insulin – high Acanthosis nigricans on skin examination
	Polycystic ovary syndrome	Serum LH:FSH ratio above 2 Pelvic USG -- sometimes diagnostic
	Idiopathic hirsutism	All routine laboratory results normal Exaggerated response of testosterone with metyrapone test
	Hypertechosis ovary	Serum testosterone -- high Serum progesterone -- high Serum LH low -- normal Lack of LH response to hormonal stimulus

CT = computed tomography; DHEA = dehydroepiandrosterone; USH = ultrasonography; MRI = magnetic resonance imaging; LH = luteinizing hormone; FSH = follicle-stimulating hormone