Hirsutism: Common Clinical Problem or Index of Serious Disease?

Oğuz Tekin, MD; Zekai Avcı, MD; Bünyamin Işık, MD; Adem Özkara, MD; Cem Uraldı, MD; Ferhat Çatal, MD; Elife Eraslan, MD; Tuncay Delibaşı, MD

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In This Article

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.[] 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]

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]

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.

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