Hirsutism

Hirsutism is defined as the excessive growth of terminal hair on the face and body of a female in a typical male pattern distribution. Hirsutism is a common clinical problem in women and the treatment depends on the cause of hirsutism. Untreated hirsutism can be associated with considerable loss of self-esteem and psychological morbidity. Hyperandrogenemia is the key trigger for excess hair growth. Polycystic ovary syndrome and idiopathic hirsutism are the most common cause of hirsutism. As with all medical problems, investigation begins with a careful history, examination and then investigation directed at the possible cause. A raised serum testosterone level of > 150 ng/dl (5.2 nmol/l) should prompt further investigations to exclude an underlying androgen-secreting tumour. The treatment of hirsutism is most effective using combination therapy, including lifestyle therapies, androgen suppression, peripheral androgen blockage and cosmetic treatments. Women should be warned not to expect improvement or at least 3-6 months after therapy is begun and lifelong therapy may be needed to prevent recurrence. The current review discusses definition, pathogenesis, differential diagnosis, diagnostic strategies, management, guidelines and the authors' recommendations about hirsutism.     

Hirsutism in women

Hirsutism is excess terminal hair that commonly appears in a male pattern in women. Although hirsutism is generally associated with hyperandrogenemia, one-half of women with mild symptoms have normal androgen levels. The most common cause of hirsutism is polycystic ovary syndrome, accounting for three out of every four cases. Many medications can also cause hirsutism. In patients whose hirsutism is not related to medication use, evaluation is focused on testing for endocrinopathies and neoplasms, such as polycystic ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and androgen-secreting tumors. Symptoms and findings suggestive of neoplasm include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass. Patients without these findings who have mild symptoms and normal menses can be treated empirically. For patients with moderate or severe symptoms, an early morning total testosterone level should be obtained, and if moderately elevated, it should be followed by a plasma free testosterone level. A total testosterone level greater than 200 ng per dL (6.94 nmol per L) should prompt evaluation for an androgen-secreting tumor. Further workup is guided by history and physical examination, and may include thyroid function tests, prolactin level, 17-hydroxyprogesterone level, and corticotropin stimulation test. Treatment includes hair removal and pharmacologic measures. Shaving is effective but needs to be repeated often. Evidence for the effectiveness of electrolysis and laser therapy is limited. In patients who are not planning a pregnancy, first-line pharmacologic treatment should include oral contraceptives. Topical agents, such as eflornithine, may also be used. Treatment response should be monitored for at least six months before making adjustments.     

Comparison of the clinical efficacy of flutamide and spironolactone plus ethinyloestradiol/cyproterone acetate in the treatment of hirsutism: A randomised controlled study

Introduction: Hirsutism is commonly a consequence of ovarian androgen over-production. Polycystic ovary syndrome (PCOS) or peripheral hypersensitivity to normal androgen circulating levels (idiopathic hirsutism) can be the underlying cause. Several drugs with anti-androgenic properties, such as cyproterone acetate (CPA), spironolactone and flutamide have been used to treat hirsutism, but the efficacy of these drugs has yet to be fully elucidated. The objective of this study was to compare the effectiveness of flutamide, and spironolactone plus a combination tablet of 2 mg CPA/35 mug ethinyloestradiol (EE) in the treatment of hirsutism. Methods: A prospective randomised clinical study was conducted in a tertiary care hospital setting. Twenty-nine women with hirsutism as a consequence of PCOS or idiopathic hirsutism were randomly assigned to receive 250 mg/day flutamide alone or 100 mg/day spironolactone plus a combination tablet of 2 mg CPA/35 mug EE, for 6 months. Patients' hormonal and lipid profiles were evaluated. Hirsutism was graded according to the modified Ferriman-Gallwey (mF-G) score, and side effects were monitored. Results: A significant decrease in mF-G scores was observed in the flutamide (from 11.2+/-3.3 to 7.6+/-4.0) and spironolactone plus CPA/EE (from 9.9+/-1.9 to 7.1+/-2.0) groups. However, there was no statistically significant difference between the two groups. After flutamide therapy, total cholesterol levels decreased significantly but no significant change was observed in any other lipid parameters or in the patients' hormone profiles. After spironolactone plus CPA/EE therapy, levels of luteinising hormone, total testosterone and free testosterone significantly decreased and triglyceride levels increased. No patients were found to have abnormal liver function test results. Conclusion: Flutamide and spironolactone plus CPA/EE are effective drugs in the treatment of hirsutism.     

Polycystic ovary syndrome: a review for primary providers

PCOS is a metabolic syndrome that exists throughout the world with much clinical heterogeneity. PCOS is now appreciated as encompassing two interrelated metabolic phenomena--insulin resistance and hyperandrogenism. Patients present with oligo-amenorrhea and clinical hyperandrogenism, and the diagnosis is based on clinical grounds with few laboratory tests necessary. Because patients are at higher than normal risk for diabetes, glucose intolerance, and hyperlipidemia, and perhaps at higher risk for coronary heart disease, newly diagnosed patients with PCOS should be evaluated for glucose intolerance and hyperlipidemia. The cornerstone of therapy today includes weight management, and further therapeutic intervention is focused on reproductive and cardiovascular health and treatment of insulin resistance. Clinical case continued The 17-year-old mentioned in the beginning of this article probably does have PCOS. She fits the clinical criteria: oligo-ovulation and hyper-androgenism (the acne and hirsutism). In addition, she is obese, which is also associated with PCOS. Her TSH and prolactin were normal, and as her presentation was not suggestive of an adrenal tumor or congenital adrenal hyperplasia (she had mild hirsutism, and those diagnoses are associated with more severe hyperandrogenism), no further laboratory evaluation was deemed necessary. Once the diagnosis was made, she was screened for lipid abnormalities and for glucose intolerance. Her LDL was 150, HDL 35; oral glucose tolerance test (OGTT) was normal. A pregnancy test was negative, and she was started on OCPs. Devoting herself to exercise and dietary change, she lost 10 pounds in her first 3 months after diagnosis. Her hirsutism and acne have improved with the OCPs and weight loss, and her menses are regular. She has elected to defer oral insulin sensitizers until her weight loss has stabilized. Findings PCOS is common in reproductive-aged women. Diagnosis is clinical and is supported by lab findings; there is significant clinical heterogeneity. Insulin resistance is likely central to the pathophysiology along with androgen excess. Health implications include infertility, diabetes, endometrial cancer, hyperlipidemia, and possibly coronary heart disease. Treatment is evolving and includes weight loss, OCPs, and insulin sensitizers.     

运动对多囊卵巢综合征患者的胰岛素抵抗和性激素的影响

目的：多囊卵巢综合征(PCOS)是造成生育期妇女不孕的原因之一，临床多表现为月经稀少或闭经、不孕、多毛和肥胖等一组征候群，胰岛素抵抗和高雄激素血症是其基本特征：本研究旨在探讨耐力运动对PCOS患者的高胰岛素和高雄激素血症的调节作用，为临床康复治疗开拓新的应用领域。方法：20例PCOS患者根据干预方法的不同分为运动组(n=11)和药物组(n=9)。运动组在低热卡饮食的基础上，实施每次60min以上中等强度运动，慢跑总路程6—8kin，每周运动5天以上，连续3个月。药物组服用达因-35(Diane-35，Cyproteroneacetate)，每日1片，连用21天，停药7天后再服第2个周期，依此类推，共服3个周期。结果：BMI、血清胰岛素、胰岛素敏感性在运动前后均显著降低，药物组则无变化；血清睾酮、黄体生成素以及黄体生成素／卵泡刺激素比值在运动组和治疗组治疗前后均见有显著降低，两组之间无统计学差异。结论：低热卡饮食加运动治疗有利于改善胰岛素抵抗，降低高黄体生成素和高睾酮血症作用，提示运动是治疗PCOS经济、安全、有效的辅助手段之一。     

Complete response to combination therapy with an LHRH agonist and flutamide in metastatic male breast cancer: a case report

Twelve months after modified radical mastectomy with axillary dissection (4 out of 13 nodes found positive) in a 66-year old man, bone scintigraphy showed multiple bone metastases. Treatment was started with the combined administration of an LHRH agonist and the pure antiandrogen Flutamide. Six and a half months later, bone scintigraphy was normal while serum testosterone was reduced to 10% of control and the serum concentration of the adrenal steroids was decreased by 23 to 45%. Following relapse of the disease at 12 months, more complete blockade of adrenal steroid secretion was achieved with aminoglutethimide and hydrocortisone. Stability of the disease was then observed up to the last evaluation performed in January 1990 (5 years of stable disease). Since the adrenal steroids are converted into active androgens and estrogens in peripheral tissues, including the breast, the combined therapy has the advantage of reducing the source of potentially active estrogens and androgens while blocking the action of androgens in target tissues. No side-effects other than those due to hypoandrogenicity, namely hot flushes and loss of libido and potency were observed. This well-tolerated treatment achieves complete medical castration, partial medical adrenalectomy, and neutralization of peripheral androgen action.     

Hypoandrogen-metabolic syndrome: a potentially common and underdiagnosed condition in men

Recently, it has been proposed that hypoandrogenaemia (hypogonadism, hypotestosteronaemia) may be a common accompanying factor in men with the metabolic syndrome (insulin resistance, Reaven's syndrome or syndrome X). When they are present together they may be considered as a specific entity, the hypoandrogen-metabolic (HAM) syndrome. The metabolic syndrome is common and its prevalence is predicted to increase in coming years. Hypoandrogenaemia, often unrecognised, is also common and may be an aetiological factor in the development of the metabolic syndrome in men. The prevalence of both hypoandrogenaemia and the metabolic syndrome increases with age and the clinician will frequently attend to men in their middle to advanced years with obesity, low androgen levels and metabolic syndrome. These conditions place men at an increased risk of cardiovascular and coronary heart disease and type 2 diabetes and can be simply investigated with weight, waist and blood pressure measurement and blood sample analyses. Men with HAM and symptoms of androgen deficiency may be managed by, in the absence of contraindications, testosterone replacement therapy along with weight reduction and other measures to normalise glucose, lipid and blood pressure control.     

Evaluation and treatment of women with hirsutism

Hirsutism is a common disorder, often resulting from conditions that are not life-threatening. It may signal more serious clinical pathology, and clinical evaluation should differentiate benign causes from tumors or other conditions such as polycystic ovary syndrome, late-onset adrenal hyperplasia, and Cushing's syndrome. Laboratory testing should be based on the patient's history and physical findings, but screening for levels of serum testosterone and 17alpha-hydroxyprogesterone is sufficient in most cases. Women with irregular menses and hirsutism should be screened for thyroid dysfunction and prolactin disorders. Pharmacologic and/or nonpharmacologic treatments may be used. Advances in laser hair removal methods and topical hair growth retardants offer new options. The use of insulin-sensitizing agents may be useful in women with polycystic ovary syndrome.     

黄芪多糖联合达英-35对多囊卵巢综合征患者胰岛素抵抗、雄激素及脂代谢的影响

目的：探讨黄芪多糖和达英-35联合应用对多囊卵巢综合征（PCOS）胰岛素抵抗、雄激素水平及脂代谢的影响。方法：对32例PCOS患者联合应用黄芪多糖和达英-35共3个月,观察治疗前后血性激素、胰岛素敏感性及血脂的改变。结果：治疗后患者血清空腹胰岛素水平、LH／FsH比值、T、A、DHEAS均显著降低（P〈0．01）,胰岛素敏感指数显著升高,血T—CHO、Lp（a）降低（P〈0．01）,HDL—C显著升高,TG也有轻度降低,差异具有统计学意义（P〈0．05）。结论：黄芪多糖联合达英-35可有效改善PCOS患者胰岛素抵抗和高雄激素状态及血脂代谢,可为PCOS治疗的又一选择。     

HAIR-AN syndrome: a multisystem challenge.

HAIR-AN syndrome is an acronym for an unusual multisystem disorder in women that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The precipitating abnormality is thought to be insulin resistance, with a secondary increase in insulin levels and subsequent overproduction of androgens in the ovaries. Long periods of hyperinsulinism and, some suspect, hyperandrogenism can result in the cutaneous manifestation of acanthosis nigricans. Patients are often concerned about the physical manifestations of this disorder, including virilization and acanthosis nigricans, and may be less aware of systemic problems. Physicians should assess women with these problems for an underlying endocrine abnormality. Although a treatment regimen for the HAIR-AN syndrome has not been established, antiandrogen therapy and weight loss are useful.     

Hirsutism: definitions and etiology

Hirsutism as a sign of hyperandrogenism is a common endocrinological disorder in women. Its spectrum varies from mild forms with dominating psychic component to severe forms associated with virilization. The severity should be assessed by semiobjective scoring systems, the use of which also allows the systematic follow-up of the results of treatment. An increase in serum androgen levels or an increased turnover of androgens can be detected in most patients. Enhanced peripheral conversion of androgens to locally acting androgen also leads to hirsutism. The thorough investigation of the endocrinological milieu is required to rule out androgen producing neoplasms. In most patient, however, disturbances are functional, among which polycystic ovary syndrome is the commonest. It is a disorder exhibiting a complexity of changes in endocrinological interactions. Besides inappropriate gonadotropin secretion insulin and insulin like growth factor are also involved. The opioidergic system also seems to be affected. Polycystic ovary syndrome is also associated with obesity and infertility, both of which require attention.     

Sex steroids and insulin resistance

There is extensive experimental evidence that sex steroids and insulin interact in their actions on tissues. At physiological levels, testosterone and oestradiol are thought to be involved in maintaining normal insulin sensitivity. However, outside this 'physiological window' these steroids may promote insulin resistance. Considerable research has been carried out on polycystic ovarian syndrome, a common disorder associated with excessive androgen production and insulin resistance. Hyperinsulinaemia in patients with this condition is believed to stimulate ovarian androgen production, and there is also evidence that androgens act directly on peripheral tissues to promote insulin resistance. There is the potential for a vicious circle to develop with increasing androgen production and insulin resistance. The molecular basis of this insulin resistance has been reported to involve reduced insulin receptor autophosphorylation, reduced expression and translocation of insulin-responsive glucose transporters and defects of the insulin signalling pathway distal to the insulin receptor. These defects await full characterization. Insulin-sensitizing agents can reverse many of the effects of insulin resistance and may have a future place in the treatment of polycystic ovarian syndrome and other conditions associated with steroid-induced insulin resistance. Recognition and treatment of sex steroid-associated insulin resistance at an early stage in patients may reduce their risk of developing Type II (non-insulin-dependent) diabetes mellitus, hypertension and dyslipidaemia, and so may improve fertility and reduce cardiovascular risk. Here we review the interplay between sex steroids and insulin resistance, and consider the implications this has for clinical conditions.     

Polycystic ovary syndrome: a common reproductive and metabolic disorder necessitating early recognition and treatment

Patients who have polycystic ovary syndrome (PCOS) present with infertility, recurrent miscarriages, menstrual irregularities, hirsutism, and acne. Many also have metabolic and hormonal abnormalities that can significantly increase risk for coronary artery disease, type 2 diabetes mellitus, and endometrial carcinoma. PCOS patients should be screened for obstructive sleep apnea. Early recognition may reverse physical signs of the disease, while correcting the metabolic abnormalities that can pose significant health risk if untreated. Although lifestyle modification and pharmacotherapy are used to treat PCOS, there are few long-term outcome data regarding benefits of metabolic interventional strategies. Insulin sensitizers can improve ovulatory function, lower insulin resistance, lower androgen levels, and increase the likelihood of becoming pregnant. Further studies should yield other treatment options.     

Idiopathic hirsutism: Is it really idiopathic or is it misnomer?

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, may result from various causes including polycystic ovary syndrome(PCOS), non-classic congenital adrenal hyperplasia, adrenal or ovarian tumors or it may be idiopathic. Idiopathic hirsutism is currently defined as hirsutism associated with normal ovulatory function, normal serum androgen levels and normal ovarian morphology, however, the pathogenesis of idiopathic hirsutism is not clear. The androgens are t...     

Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome.

BACKGROUND: One of the main criteria to establish a diagnosis of polycystic ovary syndrome (PCOS) is hyperandrogenemia. Recent observations suggest that total testosterone may not be a sensitive marker for the detection of androgen excess. The aim of the present study was to compare the value of different androgen determinations for diagnosis of PCOS. METHODS: Untreated PCOS patients (n=133; mean age 28 years) and healthy control women (n=54; mean age 28 years) were included in the study. Measurements of total testosterone and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstendione, dehydroepiandrosterone sulfate (DHEAS) and albumin were performed. In addition, the free androgen index (FAI), free and bioavailable testosterone were calculated. Clinical signs of hyperandrogenism were evaluated by physical examination. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the sensitivity and specificity of different androgen determinations to detect PCOS, defined as clinical hyperandrogenism and irregular cycles compatible with the National Institutes of Health criteria of chronic anovulation and clinical or biochemical hyperandrogenism. RESULTS: All biochemical parameters of hyperandrogenism were significantly higher in PCOS patients than in controls (all p<0.0001). The highest AUC-ROC was found for bioavailable testosterone (0.852) followed by FAI (0.847) and free testosterone (0.837). Lower AUC-ROC was found for SHBG, total testosterone and androstendione (0.765, 0.799 and 0.706, respectively). When FAI=4.97 was taken as a cutoff value, sensitivity was 71.4% and specificity was 85.2%. A cutoff of 0.78 nmol/L for bioavailable testosterone had even higher sensitivity of 75.9%, but slightly lower specificity of 83.3%. FAI and bioavailable testosterone correlated significantly (all p<0.05) with total testosterone, androstendione, LH/FSH ratio and DHEAS. In addition, free testosterone, bioavailable testosterone and FAI correlated significantly with hirsutism scores, and ovarian volume and follicle count. CONCLUSIONS: ROC analysis provided evidence that calculated testosterone indices (bioavailable testosterone, FAI, free testosterone) are useful parameters for the discrimination of PCOS patients and healthy controls.     

Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgen

Concentrations of triglycerides are increased and concentrations of high-density lipoprotein (HDL) cholesterol are low in women with hyperandrogenism. These alterations could be related to excessive androgen or estrogen, to hyperinsulinism, or to a combination of these abnormalities. We examined their independent influences on lipids in 21 women with hyperandrogenism, subgrouped according to apparent source of androgen excess. Results for lipid, androgen, and insulin did not differ among subgroups, so these data were pooled. Free plus albumin-bound testosterone (uT) was correlated with triglycerides (r = 0.69, P less than 0.01) and HDL cholesterol (r = -0.56, P less than 0.01). Both triglycerides (r = 0.66, P less than 0.01) and HDL cholesterol (r = -0.48, P less than 0.05) were also correlated with insulin measured during fasting. Partial correlation revealed that, after adjusting for insulin, lipids were associated with uT. This suggests that androgen excess is independently related to lipid excess. Insulin also was correlated with lipids when adjusted for uT. Free plus albumin-bound estradiol was not associated with any of the lipids. We conclude that altered lipids in women with hyperandrogenism result from the independent effects of androgen and insulin.     

Fatty liver--an additional and treatable feature of the insulin resistance syndrome

To test the hypothesis that fatty liver coexists with other metabolic abnormalities of the insulin resistance syndrome, and responds to their amelioration, we prospectively studied 48 consecutive patients with chronically elevated liver enzymes and clinical, ultrasound and histological findings consistent with fatty infiltration of the liver. Most of the patients were overweight or obese (64%) with increased waist circumference which closely relates to visceral fat. Only 10% of the patients had normal glucose tolerance: 44% had diabetes mellitus, 29% impaired glucose tolerance, and 17% were hyperinsulinaemic. The most common dyslipidaemia found was hypertriglyceridaemia and/or low HDL-C (86%). Dietary intervention and follow-up (median 24 months), supplemented by oral hypoglycaemic or lipid-lowering drugs as needed, resulted not only in weight loss (mean 3.7 kg), decreased fasting blood glucose (p < 0.005) and improvement in serum lipid profile (p < 0.02 for both triglycerides or HDL-C) but also in an improvement of serum liver enzymes in 96%, which became normal in more than half of the patients. Thus, fatty liver was strongly associated with many features of the insulin resistance syndrome, and follow-up revealed a high potential for reversibility and a benign course.     

Plasma thiols and androgen levels in polycystic ovary syndrome.

Homocysteine is a risk factor for ischemic heart disease; similarly as is hyperlipidemia or insulin resistance, which frequently occur in women with polycystic ovary syndrome. We examined the relationships between thiols and hormonal status or insulin resistance in 40 women (aged 25.8 +/- 7 years) with polycystic ovary syndrome and in 11 controls (33 +/- 5 years). Blood levels of homocysteine, glutathione, total and high density lipoprotein (HDL)-cholesterol, triglycerides, insulin, sex hormone-binding globulin, testosterone, androstenedione, dehydroepiandrosterone sulfate, and estradiol were determined. Student's t test and Spearman correlations were computed after adjustment for body mass index (BMI) and age. Homocysteine was significantly higher in polycystic ovary syndrome patients than in the control group (10.3 +/- 2.87 vs. 8.78 +/- 2.75 micromol/l; p < 0.05). In women with polycystic ovary syndrome, there were significant positive correlations between homocysteine and androstenedione (r = 0.329; p < 0.05) and glutathione and dehydroepiandrosterone sulfate (DHEA-S) (r = 0.469; p < 0.05). We conclude that homocysteine is increased in women with polycystic ovary syndrome and is probably linked to androgen levels but not to markers of insulin resistance or with lipid metabolism.     

Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells

Antioxidants, such as vitamin E, are being investigated for efficacy in prostate cancer prevention. In this study, we show that the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), has antiandrogen activity in prostate carcinoma cells. In the presence of PMCol, the androgen-stimulated biphasic growth curve of LNCaP human prostate carcinoma cells was shifted to the right. The PMCol-induced growth shift was similar to that produced by treatment with the pure antiandrogen bicalutamide (i.e., Casodex), indicative of androgen receptor (AR) antagonist activity. The concentration of PMCol used was below the concentration required to affect cell growth or viability in the absence of androgen. Using an AR binding competition assay, PMCol was found to be a potent antiandrogen in both LNCaP and LAPC4 cells, with an IC(50) of approximately 10 micro M against 1 nM R1881 (methyltrienolone; a stable, synthetic androgen). Prostate-specific antigen release from LNCaP cells produced by androgen exposure with either 0.05 or 1.0 nM R1881 was inhibited 100% and 80%, respectively, by 30 micro M PMCol. Also, PMCol inhibited androgen-induced promoter activation in both LNCaP and LAPC4 cells. However, PMCol did not affect AR protein levels, suggesting that the inhibitory effects of PMCol on androgenic pathways were not due to decreased expression of the AR. Therefore, growth modulation by the antioxidant moiety of vitamin E in androgen-sensitive prostate carcinoma cells is due, at least in part, to its potent antiandrogenic activity.     

The evolving role of hormone therapy in advanced prostate cancer

Earlier diagnosis and treatment of prostate cancer has changed the face of late-stage disease, and the use of mainstay hormonal therapies--orchiectomy, luteinizing hormone releasing-hormone analogs, and combined androgen ablation--are evolving rapidly. New approaches such as antiandrogen monotherapy and intermittent therapy are being evaluated. In addition, palliative treatments for patients with androgen-independent tumors have expanded. The most common clinical presentation of advanced prostate cancer is a rising prostate-specific antigen level following primary therapy (radical prostatectomy or radiotherapy or both). Due to the negative psychological implications of orchiectomy, many patients are opting for treatment with luteinizing hormone-releasing hormone analogs. Because studies of combined androgen ablation have not provided conclusive results, it is reasonable to forego antiandrogen therapy for patients who undergo bilateral orchiectomy. Management options for patients with androgen-independent prostate cancer are expanding and include antiandrogen removal, antiandrogen therapy, and glucocorticoids.