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Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are androgen excess disorders requiring the determination of classic androgen levels for diagnosis. 11-oxygenated androgens have high androgenic potential, yet their clinical value in those disorders is not clear. Additionally, the role of endocrine disruptors (EDs), particularly in IH, remains understudied. We analyzed 25 steroids and 18 EDs in plasma samples from women with IH, PCOS, and controls using LC-MS/MS. Cytokine levels and metabolic parameters were assessed. Comparisons included non-obese women with PCOS (n = 10), women with IH (n = 12) and controls (n = 20), and non-obese versus obese women with PCOS (n = 9). Higher levels of 11-oxygenated androgens were observed in women with PCOS compared to those with IH, but not controls. Conversely, 11-oxygenated androgen levels were lower in women with IH compared to controls. Cytokine levels did not differ between women with IH and controls. Bisphenol A (BPA) levels were higher in obese women with PCOS compared to non-obese women with PCOS. Bisphenol S occurrence was higher in women with PCOS (90%) compared to controls (65%) and IH (50%). Significant correlations were found between androgens (11-ketotestosterone, androstenedione, testosterone) and insulin and HOMA-IR, as well as between immunomodulatory 7-oxygenated metabolites of DHEA and nine interleukins. Our data confirms that PCOS is a multiendocrine gland disorder. Higher BPA levels in obese women might exacerbate metabolic abnormalities. IH was not confirmed as an inflammatory state, and no differences in BPA levels suggest BPA does not play a role in IH pathogenesis.

Background & Aim: The objective of this study was to investigate the effect of vitamin D treatment on androgen levels and hirsutism scores in overweight women with PCOS., Methods: A prospective, randomized, double-blind, placebo-controlled clinical study was conducted at King Abdullah University Hospital in Irbid, Jordan. Overweight Jordanian females aged 18-49 years with vitamin D deficiency and PCOS (n = 60) were assigned to two groups: the treatment group (n = 30) who received 50,000 IU per week of vitamin D 3 and the control group (n = 30) who received a placebo., Results: After receiving the treatment for 12 consecutive weeks, the levels of total testosterone, parathyroid hormone, free androgen index, and hirsutism score were significantly decreased (P < 0.001), and the levels of 25-hydroxyvitamin D (25(OH)D), sex hormone binding globulin, and phosphorus were significantly increased (P < 0.05). Furthermore, significant changes were observed in ovarian volume and follicle numbers and size ultrasonography, and in the regularity of the menstrual cycle (P < 0.001). In the placebo group, no significant changes were observed in either androgen levels, hirsutism score, or menstrual regularity., Conclusion: Vitamin D 3 at a treatment dose of 50,000 IU per week improved 25(OH)D levels and decreased the hirsutism scores and androgen levels of overweight women with PCOS. These results could mean increased fertility and better reproductive health for overweight women with PCOS; the use of vitamin D 3 as a treatment for these patients should be further investigated. CLINICALTRIALS., Gov Regestration Number: NCT02328404., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Androgens are produced throughout the body in steroid-producing organs, such as the adrenal glands and ovaries, and in other tissues, like the skin. Several androgens are found normally in women, including dehydroepiandrosterone, dehydroepiandrosterone-sulfate, testosterone, dihydrotestosterone, and androstenedione. These androgens are essential in the development of several common cutaneous conditions in women, including acne, hirsutism, and female pattern hair loss (FPHL)-androgen-mediated cutaneous disorders (AMCDs). However, the role of androgens in the pathophysiology of these diseases is complicated and incompletely understood. In the first article in this Continuing Medical Education series, we discuss the role of the skin in androgen production and the impact of androgens on the skin in women. Specifically, we review the necessary but insufficient role that androgens play in the development of acne, hirsutism, and FPHL in women. Dermatologists face the challenge of differentiating physiologic from pathologic presentations of AMCDs in women. There are currently no dermatology guidelines outlining the indications for endocrinologic evaluation in women presenting with acne, hirsutism, or FPHL. We review the available evidence regarding when to consider an endocrinologic workup in women presenting with AMCDs, including the appropriate type and timing of testing., (Published by Elsevier Inc.)

Hirsutism is present in up to 25% reproductive aged women and is most often caused by polycystic ovary syndrome. Less than 5% of patients with hirsutism are diagnosed with rare endocrine diseases including ovarian or adrenal androgen-producing tumours, but these tumours may be malignant and need surgery. Terminal hair growth on lip and chin gradually increases after menopause, which complicates distinction from normal physiological variation. Precise testosterone assays have just recently become available in the daily clinic. We present three women diagnosed with testosterone-producing tumours. Gold standard techniques were used to measure testosterone levels. All tumours originated from the ovaries. Based on the present cases and the existing literature, we suggest that androgen-producing tumours should be suspected in patients with rapid progression of hyperandrogen symptoms, particularly when total testosterone levels are above three times the upper reference limit., (2015 BMJ Publishing Group Ltd.)

Excess male-pattern body hair in women is a very common and psychologically damaging condition. Although its cause is usually a chronic and benign disorder (most commonly polycystic ovary syndrome) it may rarely be an indication of a more serious endocrine disease such as Cushing syndrome or an androgen-secreting tumour. Investigations do not usually need to be extensive, but effective management is important, irrespective of cause, for what can be a debilitating symptom. Specific treatment of any underlying disease is important but in most cases treatment is empirical; it may simply involve physical hair removal, ideally by electrolysis or laser treatment. However, endocrine therapy to suppress androgen production and/or action is desirable in many, if not most, cases.

Background: Hyperandrogenism refers to classical androgen-dependent signs such as hirsutism, acne and androgenetic alopecia. Hirsutism is the main hyperandrogenic symptom, defined as an excess of body hair in the androgen-sensitive skin regions of the women. In this review, we attempt to focus on the pathogenesis of hirsutism related to disorders other than polycystic ovary syndrome (PCOS). Also, we will discuss their clinical and biochemical features as well as therapeutic options., Design: Several original articles, meta-analysis and reviews have been screened in the field of hirsutism and hyperandrogenic disorders., Results: Current English literature including our studies suggests that PCOS is the most common cause of hirsutism. The most important purpose for investigation is to identify those women with androgen-secreting tumours because of their life-threatening potential. In approximately 1-8% of the women with hirsutism, the underlying cause is nonclassical adrenal hyperplasia because of 21-hydroxylase deficiency. Depending on ethnicity and the geographic area, idiopathic hirsutism constitutes 5-17% of the patients with hirsutism. Approximately 3% of hyperandrogenic women were observed to suffer from hyperandrogenic-insulin-resistant acanthosis nigricans syndrome. More rare causes are glucocorticoid resistance syndrome, hyperprolactinemia, acromegaly, Cushing's syndrome and some drugs. Specific causes of hirsutism such as Cushing's syndrome and adrenal/ovarian tumours should be treated specifically. In other patients, pharmacological approach is the mainstay of therapy., Conclusions: A number of patients presenting with hirsutism and exhibiting similar features to PCOS may have other underlying diagnoses. Unlike PCOS, some of these disorders can occasionally be life threatening and require prompt diagnosis and treatment., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

--Hirsutism, defined as excessive growth of terminal hair in a male-type pattern, is prevalent in women and is most often a feature of androgen excess, associated with polycystic ovary syndrome (PCOS). Idiopathic hirsutism is the second most common cause. In a small minority of cases, hirsutism is the result of a serious adrenal or ovarian disorder. --The primary aim of diagnostic procedures is to establish or exclude underlying pathology. In the case ofhirsutism, i.e. a modified Ferriman and Gallwey score > 6, analysis of circulating androgen levels and other relevant endocrine parameters is indicated. --Adrenal or ovarian pathologies require primary therapy. --Hirsutism in women with PCOS, or without measurable changes in plasma androgen levels, can be treated with drugs either inhibiting ovarian or adrenal androgen production, blocking androgen receptors or inhibiting 5alpha-reductase in the hair follicle. --Spironolactone or cyproterone acetate combined with an oral contraceptive is the safest and most effective therapeutic approach. --Weight loss is an important part of the treatment of obese, hirsute women with PCOS.

Introduction: A Food and Drug Administration advisory group has questioned the long-term safety of testosterone administration to postmenopausal women. Although only short-term data exist on safety from the double-blind, placebo-controlled trials, testosterone has been used for more than 50 years. Therefore, some data concerning the long-term safety issues must exist in the literature., Aim: To review the published data concerning the safety of administration of testosterone to women., Methods: Review of published articles identified by a search of the Ovid databases and bibliographies from articles identified as dealing with the topics of testosterone or androgen treatment of women., Results: The major adverse reactions to exogenous androgens are the expected androgenic side effects of hirsutism and acne. High-density lipoprotein levels may be decreased with oral androgens. There are insufficient long-term safety data regarding breast, endometrium, or heart safety to draw strong conclusions, although the data available to date are reassuring., Conclusions: Testosterone administration to postmenopausal women that result in physiological to slightly supraphysiological serum-free testosterone levels is safe for at least 2 years.

Background: Measured endocrinological parameters (total testosterone [TT], free testosterone [FT], dihydrotestosterone [DHT], dehydroepiandrosterone sulfate [DHEAS], and sex hormone binding globulin [SHBG]) and calculated parameters (calculated FT (cFT), calculated bioavailable testosterone (cBT), and the free androgen index [FAI]) in women with hirsutism were compared to the values of a control group. The question remains if cFT or cBT are more appropriate markers for assessment of hyperandrogenemia in clinical situations such as hirsutism in women., Methods: Sixty-six women showed an modified Ferriman-Gallwey (mF-G) score of >or=6 and were classified as hirsutism group and 58 women showed mF-G scores of

Unlabelled: A 75-year-old woman presenting with recent onset hirsutism and severely elevated serum androgen levels was evaluated to assess the source of excessive androgen production. Commonly recommended hormonal stimulation and suppression tests, and the usually employed imaging techniques were non-diagnostic. In this report, we describe a new suppression test based on the use of the GnRH receptor antagonist, cetrorelix, to determine whether androgen production was LH-dependent. Cetrorelix, administered in a daily dose of 250 microg subcutaneously, suppressed serum LH within 24 h and reduced serum androgen levels to normal within 48-72 h, indicating that androgen overproduction was of ovarian origin. This diagnosis was confirmed by laparoscopic ovariectomy., Conclusion: The cetrorelix suppression test is a simple procedure that provides valuable information regarding the source of androgen excess in postmenopausal hirsutism.

Hyperandrogenism in women can be caused by various conditions, the most prevalent of which is polycystic ovary syndrome. Common dermatologic manifestations of hyperandrogenism include hirsutism, acne, acanthosis nigricans, and androgenic alopecia. Hirsute women often have increased activity of 5 alpha-reductase, the enzyme that converts the androgen testosterone to its active metabolite, in hair follicles. Likewise, androgens affect the formation of acne by increasing sebum production from sebaceous glands in the skin. The diagnosis of polycystic ovary syndrome includes a complete history, physical examination with emphasis on evidence of androgen excess, and appropriate laboratory investigation to exclude other causes of hyperandrogenism. Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, antiandrogens, and insulin-sensitizing medications.

Context: We undertook this study to estimate the prevalence of the various androgen excess disorders using the new criteria suggested for the diagnosis of polycystic ovary syndrome (PCOS)., Setting: The study was performed at two endocrine departments at the University of Palermo (Palermo, Italy)., Patients: The records of all patients referred between 1980 and 2004 for evaluation of clinical hyperandrogenism were reevaluated. All past diagnoses were reviewed using the actual diagnostic criteria. To be included in this study, the records of the patients had to present the following available data: clinical evaluation of hyperandrogenism, body weight and height, testosterone (T), free T, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, progesterone, and pelvic sonography. A total of 1226 consecutive patients were seen during the study period, but only the scores of 950 patients satisfied all criteria and were reassessed for the diagnosis., Results: The prevalence of androgen excess disorders was: PCOS, 72.1% (classic anovulatory patients, 56.6%; mild ovulatory patients, 15.5%), idiopathic hyperandrogenism, 15.8%; idiopathic hirsutism, 7.6%; 21-hydroxylase-deficient nonclassic adrenal hyperplasia, 4.3%; and androgen-secreting tumors, 0.2%. Compared with other androgen excess disorders, patients with PCOS had increased body weight whereas nonclassic adrenal hyperplasia patients were younger and more hirsute and had higher serum levels of T, free T, and 17-hydroxyprogesterone., Conclusions: Classic PCOS is the most common androgen excess disorder. However, mild androgen excess disorders (ovulatory PCOS and idiopathic hyperandrogenism) are also common and, in an endocrine setting, include about 30% of patients with clinical hyperandrogenism.

The case of a 62-year-old woman with severe post-menopausal hirsutism is described. Her clinical history revealed regular menstrual periods until menopause at the age of 50, hysterectomy for fibromatosis at 58 years, non-insulin dependent diabetes mellitus, hypertension, obesity, severe hirsutism, which had developed in the previous 3 years, with a deeping of the voice. Examination showed android obesity, hypertension and severe hirsutism involving the face and the trunk. Endocrine evaluation pointed out regular adrenal function, serum total and free-testosterone in the adult male range, with normal androstenedione, DHEAS and 17OHP levels. Estradiol was slightly increased and LH and FSH were inappropriately low for her post-menopausal age. Computed tomography of the abdomen showed regular adrenal glands, and a radio-labeled cholesterol scan was negative. A further pelvic transvaginal ultrasonography revealed a small cystic formation near the right ovary and a slight increase in the size of the left ovary. The patient underwent bilateral ovariectomy. Histological examination showed a lipoid cell tumor within the left ovary. Immunohistochemical studies were positive for inhibin and cytokeratin. After surgery, serum testosterone fell to normal levels, gonadotropins increased to menopausal levels, confirming that the tumor was able to produce both LH, and FSH-inhibiting factors, and hirsutism greatly improved. Periodic hormonal tests remained normal and CT of the abdomen and pelvic ultrasonography did not show alterations at a 3 years follow-up.

Background: The androgen source in women with hirsutism and signs of virilism may be the ovary or adrenal gland., Cases: Three patients with androgen excess are reported. Two had hyperandrogenemia and Cushing syndrome with an adrenal mass greater than 5.5 cm; the third had a small adrenal adenoma secreting only testosterone and responsive to human chorionic gonadotropin. In all cases, the pathologic report from surgery and the long-term resolution of symptoms confirmed the benign nature of the tumors., Conclusion: Basal and dynamic hormonal tests cannot precisely differentiate ovarian from adrenal tumors. Adrenal adenomas must be considered as a cause of hyperandrogenic syndrome.

Objective: To compare the effects of cyproterone acetate and desogestrel, as part of combined oral contraceptives, on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome (PCOS)., Design: Prospective randomized clinical trial., Setting: Outpatient gynecology clinic (referral center) of a university., Patient(s): Twenty-eight adolescent girls with clinical and biological hyperandrogenism and six or less menses during the past 12 months., Intervention(s): Group A (n = 14) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily. Group B (n = 14) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily. Treatment was given for 21 days followed by a 7-day rest for a period of 12 months., Main Outcome Measure(s): Hirsutism and lipid profile were evaluated before initiation and at 3, 6, 9, and 12 months of treatment. Androgen profile was evaluated before and at 12 months of treatment., Result(s): A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups. During therapy, the levels of testosterone, free testosterone, Delta(4)-androstenedione, and 17OH-progesterone decreased significantly, whereas sex hormone-binding globulin (SHBG) increased significantly in both groups. The level of total cholesterol and low density lipoprotein (LDL) cholesterol increased significantly, whereas high density lipoprotein (HDL) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged. The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month., Conclusion(s): Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and androgen levels. Both combined oral contraceptives are associated with an increase of total cholesterol, LDL cholesterol, and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides.

A case of androgen-secreting borderline endometrioid tumor arising in endometriosis of the rectovaginal septum is presented. It occurred 10 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy for extensive endometriosis of the fallopian tubes and ovaries, adenomyosis, and leiomyomas of the uterus. We believe 7 years of unopposed continuous oral estrogen replacement therapy contributed to the malignant transformation of the endometriosis.

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.

Hormones play an important role in cutaneous physiology. The androgen hormones are of particular relevance in modulating hair growth and sebum production in the pilosebaceous unit, which is comprised of the hair follicle and sebaceous gland. Testosterone arising from the circulation is converted peripherally to its more potent, reduced form, dihydrotestosterone, by the enzyme 5 alpha-reductase. Dihydrotestosterone is primarily responsible for androgen receptor binding and exerting end-organ effects. The clinical sequelae of enhanced local androgen production include androgenetic alopecia, hirsutism, and acne. These disorders can be fraught with significant psychosocial ramifications because of their highly visible nature and impact on perceptions of masculinity and femininity.

Androgen excess affects between 2% and 10% of women. While the majority of these patients suffer from polycystic ovary syndrome, a few present with an androgen-secreting neoplasm. An elevated circulating total testosterone level and dehydroepiandiosterone sulfate (DHEAS) level have been proposed as screening methods for detecting ovarian and adrenal androgen-secreting neoplasms, respectively. To determine the predictive value of these tests for androgen-secreting tumors in a population of consecutive hyperandrogenic patients, we studied 478 consecutive untreated hyperandrogenic patients presenting over a ten-year period (1987-97). All had at least two of the following features: (1) oligomenorrhea (i.e. cycles > 35 days or < 8 cycles/year), (2) hyperandrogenemia (i.e. a total or free testosterone, or DHEAS > 95th percentile of controls), or (3) hirsutism (i.e. a modified Ferriman-Gallwey score > or = 6). None of these patients had a prior diagnosis of an androgen-secreting neoplasm. Basal levels of testosterone and DHEAS were determined in all patients, with transvaginal sonography and an adrenal computed tomography scan in select individuals. Of the 478 patients included, 65% had hirsutism and oligomenorrhea; 20% had hyperandrogenic oligomenorrhea; and 15% had hirsutism and hyperandrogenemia, without overt oligomenorrhea. Overall, 11 (2.3%) patients had a total testosterone > 8.7 nmol/l (250 ng/dl), of which one actually had an androgen-secreting neoplasm (i.e. true-positive). This postmenopausal patient presented with rapidly progressive virilization, and demonstrated an ovarian hilar cell tumor at surgery. The calculated sensitivity of an elevated testosterone level (> 8.67 nmol/l) for a neoplasm was 100% (1/1), the specificity was 98% (467/477), and the negative predictive value was 100% (467/467), but the positive predictive value was only 9% (1/11). Ten subjects had DHEAS levels > 16.3 mumol/l (6000 ng/ml), and none was diagnosed with an adrenocortical tumor. Although the sensitivity and positive predictive value of a high DHEAS for a neoplasm could not be calculated due to the absence of a test case, the specificity was 98% (468/478) and the negative predictive value was 100% (468/468). These data suggest that the measurement of testosterone and DHEAS is not a cost-effective method of screening for these tumors, due to the low frequency of the disorder and the fact that clinical evaluation alone is often sufficient screening.

The fundamental clinical features of PCOS include hirsutism and menstrual irregularities from the time of menarche. Obesity is present in approximately 50% of these patients, some of whom also carry a diagnosis of NIDDM. The biochemical abnormalities associated with the clinical picture include LH hypersecretion, hyperandrogenism, acyclic estrogen production, subnormal SHBG levels, and hyperinsulinemia. Hirsutism usually progresses slowly in patients with PCOS; however, the clinical presentation can resemble virilizing tumors, late-onset CAH, or Cushing syndrome. Virilization or rapidly progressive hirsutism requires immediate investigation to rule out a virilizing tumor. Goals of therapy for teenage patients include decreasing levels of bioavailable androgen, blockade of androgen action at target tissues, stabilization of the endometrium, and reduction of insulin resistance. Although the original description of PCOS by Stein and Leventhal was published in 1935, the cause of PCOS remains unknown. This reason, coupled with the fact that PCOS-related insulin resistance is an important cause of NIDDM in women, has caused this disorder to become one of interest and active investigation. Future research will likely be able to delineate mechanisms behind the defects of carbohydrate metabolism and ascertain large multigeneration kindreds for linkage analyses to identify affected genes. Future studies are also likely to confirm whether young women with PCOS are at increased risk for cardiovascular disease and other long-term health complications. As new pathophysiologic mechanisms are identified, the promise of new therapies arises, including treatments that could potentially reduce the long-term incidence of adverse health consequences.

Androgenic disorders are those conditions in women characterized by excessive androgen action. They are the most common endocrinopathy of women, affecting from 10% to 20%. Signs are: persistent acne, hirsutism and androgenic alopecia, which is the female equivalent of male pattern baldness. A subgroup, those traditionally labeled as having polycystic ovary syndrome (PCOS), additionally have anovulation, as well as menstrual abnormalities and, often, obesity. Although women with androgenic disorders usually present themselves for help with the skin or menstrual changes, there are other important implications regarding their health. Women with PCOS have varying degrees of insulin resistance, and an increased incidence of Type II diabetes mellitus, as well as unfavorable lipid patterns. The presence of these risk factors is suggested by upper segment obesity, darkening of the skin, and the other skin changes that make up acanthosis nigricans. Diagnosis involves measurement of circulating androgens (of which free testosterone is most important), together with prolactin and FSH when menstrual dysfunction is present. Many women with androgenic skin changes have normal serum androgen levels, suggesting increased end organ sensitivity to androgens. Others have hyperandrogenism (of ovarian or adrenal origin). Treatment is usually successful in controlling acne, reducing hirsutism and stabilizing, or partially reversing, androgenic alopecia. Pharmacological approaches involve suppressing androgen levels, for example, the use of an appropriate oral contraceptive, or antagonizing androgen action with several medications that have this activity. Unfortunately, most women with androgenic disorders are frustrated in their efforts to obtain medical help. Understanding androgenic disorders will enable the physician to significantly help the majority of women with these conditions.

The endrocrinologic evaluation of androgenetic phenomena is complex and difficult. The targeted use of diverse hormone determinations and functional tests, of vaginal sonography and other imaging measures as well as selective catheterization of adrenal and ovarial veins in exceptional cases, however, permit efficient and precise diagnoses.

Carcinoma of the adrenal cortex is a fairly rare entity, usually with a somber prognosis. The efficacy of treatment depends on early prognosis. We are reporting here a case of carcinoma of the adrenal cortex producing androgens, estrogens and cortisol, in which diagnosis was not achieved until two years after the onset of symptoms. Morphologic studies by CT showed local extension and metastases. After mass-reduction surgery, the patient died due to respiratory failure. This case remarks the importance of early diagnosis in this syndrome.

Objective: We describe four patients with ovarian hyperthecosis and the effects of gonadotrophin releasing hormone on clinical and metabolic variables., Design: Open out-patient study., Patients: Four women presented with post-menopausal hirsuties. They had significant hair growth across the chest, upper back and shoulders. Three had histologically proven ovarian hyperthecosis and a fourth had large ovaries visualized on ultrasound. All four women had pronounced risk factors for vascular disease; hypertension, hyperlipidaemia and glucose intolerance, and three had already developed symptomatic vascular disease., Results: Gonadotrophin releasing hormone agonist therapy resulted in significant reduction in plasma androgens and cosmetic reduction in hair growth but had no effect on hyperlipidaemia., Conclusion: The post-menopausal women described in this report were clinically considered to have hyperandrogenism due to the pathological pattern of marked body hair over the upper trunk. Treatment with GnRH was very effective at reducing the severity of the hirsuties. The post-menopausal women with hyperthecosis in this report had a high prevalence of cardiovascular disease. Since hyperandrogenism and insulin are considered risk factors for cardiovascular disease in premenopausal women with polycystic ovaries, we discuss the possible relationship between insulin and the post-menopausal ovary.

The aetiology of polycystic ovary syndrome (PCOS) is unknown. It is uniquely characterized by oligomenorrhoea or amenorrhoea associated with normal or high oestrogen levels. This prospective clinical study was designed to examine the possible role of the lack of cyclical exposure to progesterone in the development of gonadotrophin and androgen abnormalities in PCOS. Gonadotrophin, androgen and oestrogen levels were measured in 15 PCOS patients and 10 normal subjects untreated and following treatment with the progestogen medroxyprogesterone acetate (MPA). When compared to control subjects, PCOS patients had significantly higher luteinizing hormone (LH) pulse height, pulse amplitude, integrated LH levels, LH response to gonadotrophin-releasing hormone (GnRH) and LH/FSH ratio; LH pulse frequency was similar in the two groups. In addition, the testosterone/sex hormone binding globulin ratio (T/SHBG), androstenedione and oestrone concentrations in the plasma were significantly higher in PCOS than in control subjects. When PCOS patients were treated with MPA for 5 days, there were significant decreases (p < 0.02-0.001) to values no longer different from normal: from 8.7 +/- 1.2 to 5.6 +/- 0.8 IU/l for integrated LH levels (untreated and MPA-treated PCOS); from 31.2 +/- 3.5 to 12.9 +/- 1.5 IU/l for LH response to GnRH; from 2.4 +/- 0.26 to 1.3 +/- 0.2 for LH/FSH ratio; and from 10.4 +/- 0.63 to 8.5 +/- 0.7 nmol/l for androstenedione. Significant decreases (p < 0.05-0.005) to values that still remained significantly higher than in normal subjects occurred for: LH pulse height, 11.05 +/- 1.3 to 6.88 +/- 0.79 IU/l (untreated and MPA-treated PCOS); LH pulse amplitude, 2.8 +/- 0.5 to 1.8 +/- 0.2 IU/l; total testosterone, 2.5 +/- 0.2 to 2.0 +/- 0.2 nmol/l; T/SHBG ratio, 14.1 +/- 1.7 to 11 +/- 1.5; and oestrone, 265 +/- 24 to 208 +/- 29 pmol/l. These results are consistent with the concept that ovulation failure and progesterone deficiency play a facilitatory role in the development of the hypothalamic-pituitary abnormality giving rise to disordered LH secretion in PCOS.

A 17 year old woman was evaluated for amenorrhoea and severe hirsutism (Ferriman-Gallway index = 31). Pelvic ultrasound demonstrated a right unilateral ovarian mass (6 x 5 cm), whereas the computed tomography for the adrenal gland was normal. Endocrinological findings revealed normal concentrations of oestradiol, progesterone, dihydroepiandrosterone sulphate, cortisol, prolactin, follicle-stimulating hormone, luteinizing hormone and adrenocorticotrophic hormone (ACTH). Total testosterone, free testosterone, androstenedione and 17-hydroxy-progesterone concentrations, already elevated at basal conditions, did not increase after an ACTH test, whereas they decreased significantly after dexamethasone administration and increased after a human chorionic gonadotrophin test. Of all the tumour markers investigated, tissue polypeptide antigen and alpha 1-fetoprotein showed an increase in concentration. Selective venous ovarian catheterization indicated the presence of an androgen-producing tumour in the right ovary. The histopathological diagnosis was consistent with a Sertoli-Leydig cell tumour ranking between an intermediate and a poor grade of differentiation, with heterologous elements characterized by mucinous epithelium of the gastro-intestinal type. An endocrine evaluation performed postoperatively showed a normalization of all serum pathological hormones and tumour markers studied. Some particular aspects were focused on and discussed.

Although hirsutism is more a cosmetic and psychosocial problem than a disease, hirsute women are often some of the most grateful patients in an endocrinologist's practice. The combination of mechanical hair removal and judicious use of medications will improve hair growth in most women. Unfortunately, no drug is approved by regulatory agencies in North America for treatment of hirsutism. Well designed comparative studies with objective end points are needed to demonstrate which drugs work best in which hirsute women. Because pharmaceutical companies are reluctant to market drugs for women of child-bearing age, there has been little industry support for such studies.

The approach to adrenal hyperandrogenism, due to genetical or non-genetical enzymatic alterations, has changed dramatically during the last 50 years. To allow a better understanding of the subject, we focused it from a historical perspective, defining four stages analyzed in detail. Now there is consent on the existence of a functional adrenal hyperandrogenism, which has an important role in acne, hirsutism and menstrual disturbances.

Hyperandrogenism must be considered in any girl with premature pubarche, unusual acne, hirsutism, or androgenetic alopecia. An association with menstrual irregularity or obesity should raise the index of suspicion. The most common causes of hyperandrogenism presenting in a teenage girl are functional ovarian hyperandrogenism, one manifestation of which is polycystic ovary syndrome, and functional adrenal hyperandrogenism, which usually seems to be due to an exaggeration of adrenarche. The plasma-free testosterone is a more sensitive indicator of hyperandrogenism than is the total testosterone concentration. The pattern of response of plasma free testosterone, DHEAS, and cortisol to dex-suppression testing can be diagnostic of the source of androgen excess. Treatment, including oral contraceptives, low-dose glucocorticoids, and antiandrogens, should be chosen according to the patient's symptoms and source of androgens and should be combined with traditional therapy for the specific dermatologic disorder.

The data reviewed in this paper suggest that a factor other than ACTH which is suppressible by treatment with glucocorticoid, plays an essential role in the regulation of adrenal androgen production. Adrenal androgen biosynthesis probably takes place exclusively in specific androgen-secreting cells. That availability of androgen substrate alone e.g. 17OH-progesterone, is not sufficient to lead to hyperandrogenaemia is clear from data which was obtained from treated patients with the 21 hydroxylase deficiency type of congenital adrenal hyperplasia. In pituitary ACTH excess, cortisol production is relatively greater than that of androgens. In contrast, in some patients with ectopic ACTH production, the excess production of androgens is relatively greater than that of cortisol. Taken together, these observations suggest that a factor closely related to ACTH, i.e. a POMC fragment other than ACTH, plays an important role in the regulation of adrenal androgen production, that in Cushing's disease the ratio of ACTH to the androgen-stimulating fragment increases, and that in some patients with ectopic ACTH syndrome the ratio of ACTH to the alternative fragment may be decreased. In addition, the data reviewed are consistent with a model for the pathogenesis of idiopathic hirsutism and polycystic ovary syndrome whereby mild adrenal androgen excess is primary to the development of these disorders. However, the identity of the putative adrenal androgen stimulating hormone has yet to be established.

Background: Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women., Methods: We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography., Results: The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P less than 0.001)., Conclusions: Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess.

Mutations in the genes for the insulin receptor, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase isomerase enzymes are associated with hyperandrogenism. These genetic causes of hyperandrogenism account for less than 10% of all cases. A major goal of future research will be to identify other genetic causes of hyperandrogenism. Evidence continues to accumulate that luteinizing hormone, insulin-like growth factor I, and insulin are major factors regulating ovarian androgen production. Optimal therapy for hyperandrogenism probably includes simultaneous suppression of androgen production and blockade of androgen action.

The free androgen index (FAI) was estimated and compared with intensiveness of hirsutism in ten anovulatory women of reproductive age referred for polycystic ovarian syndrome with LH/FSH ratio greater than 3.0. The control group consisted of five ovulatory women. The serum testosterone, SHBG, LH and FSH were measured by radioimmunoassay. The mean plasma level of hormones in the study group was following: T-5.8 +/- 1.9 nmol/l, SHBG - 51.0 +/- 18.0 nmol/l, LH - 18.5 +/- 6.0 mIU/ml, FSH - 5.0 +/- 1.2 mIU/ml, in comparison with the control group: T - 1.4 +/- 0.4 nmol/l, SHBG - 90.0 +/- 11.2 nmol/l, LH - 9.4 +/- 4.8 mIU/ml, FSH - 7.3 +/- 0.9 mIU/ml. FAI was calculated as T/SHBG ratio multiplied by 100. In contrast to the control group the seven times higher FAI did not accompany the intensiveness of hirsutism.

An association of bilateral large adrenocortical androgen-producing adenomas with polycystic ovaries in a young female is presented. She developed mild hirsutism and secondary amenorrhoea at the age of 17, and was treated for 3 years with an anti-androgen (cyproterone acetate) and ethinyloestradiol. Routine follow-up at the age of 21 showed bilateral large adrenal tumours and polycystic ovaries, together with high serum testosterone and dehydroepiandrosterone sulphate values. Bilateral adrenalectomy was performed, which resulted in lowering of the elevated androgens, and large bilateral adrenocortical adenomas were confirmed histologically. Contrary to expectations, the polycystic appearance of the ovaries persisted after adrenalectomy. This case supports the possible role of adrenal androgens in the pathogenesis of polycystic ovaries as well as the possibility of the persistence of polycystic ovaries without adrenal androgens once they have developed.

Objective: Because of continued debate about the role of insulin in the development of hirsutism and in the induction of the polycystic ovary syndrome, we have evaluated the hormonal pattern in a group of hirsute patients., Patients: Fifty-four hirsute patients (age range 18-39 years) of whom 26 patients were obese (O) (BMI 28-53 kg/m2 and W/H greater than 0.85), 12 with ultrasonographic evidence of polycystic ovaries (O PCO) and 14 with normal ovaries. Twenty-eight patients were within normal weight range, and, of these, 14 presented ultrasonographic evidence of polycystic ovaries and 14 had normal ovaries. Two groups of age-matched subjects (obese and normal weight), normally menstruating, without hirsutism or history of endocrinopathies or ultrasonographic evidence of polycystic ovaries, served as controls., Measurements: Androstenedione and testosterone were evaluated in all patients by RIA, following ether extraction, DHEAS, LH, FSH and insulin were evaluated directly by RIA. SHBG was evaluated by the concanavalin method. Free testosterone (FT%) was calculated according to the formula FT = 4.038-1.607 log SHBG. Integrated areas under the response curve were calculated for LH and insulin respectively following i.v. administration of GnRH (100 micrograms) or oral administration of glucose (75 g)., Results: Results (mean +/- standard deviation) showed comparable values of androstenedione in all groups of obese patients and in obese controls (7.3 +/- 2.6 in patients with polycystic ovaries, 7.1 +/- 2.9 in non-polycystic ovary patients and 7.4 +/- 2.6 nmol/l in obese controls, respectively), regardless of baseline and area insulin, the presence or absence of polycystic ovaries, or hirsutism. SHBG levels showed a similar pattern (24 +/- 10, 23.8 +/- 7.9 and 36 +/- 19 nmol/l) as did the percentage of free testosterone, regardless of the presence or absence of hirsutism. Regression analysis of the insulin and LH values (baseline and area) against the androgens and SHBG plasma levels showed that only LH area correlated positively with testosterone (r = 0.36, P less than 0.03), androstenedione (r = 0.44, P less than 0.02), % free testosterone (r = 0.53, P less than 0.001), testosterone/SHBG ratio (r = 0.39, P less than 0.03) and inversely with SHBG (r = -0.57, P less than 0.001)., Conclusions: These results showed (1) no linear relationship between high levels of insulin, ovarian androgen production or free hormone availability, and (2) make it very doubtful that insulin plays a primary role in polycystic ovarian syndrome or hirsutism.

In 46 patients showing mild or moderate hirsutism, and 49 age-matched regularly menstruating women without symptoms the following hormone and protein serum levels were measured: Total testosterone (T), free testosterone (fT), dehydroepiandrosterone sulfate (DHEAS), androstendione (ASN), sex hormone binding globulin (SHBG), free androgen index (FAI) as expressed by the T/SHBG ratio, cortisol, Prolactin (PRL), LH/FSH ratio, 3 alpha-androstanediol glucuronide (ALG), basal and poststimulated 17-hydroxyprogesteron (17OH-P) and (in some cases) basal and poststimulated 11-deoxycortisol (S). The study was designed for exploring the diagnostic significance of these parameters and evaluating the extent to which they contribute in establishing the source of hyperandrogenism. The mean values of all but one (PRL) of the hormone and protein levels varied significantly from the controls, T, DHEAS, FAI and ALG showing the greatest differences. Most frequently elevations of T, DHEAS, and FAI values were established, the levels of which exhibited a highly significant correlation. In 96% of the hirsute women the elevation of 1 to 3 of these parameters was demonstrated. FAI was shown to be associated with a higher diagnostic accuracy than did SHBG or fT. In 9/43 patients increased values of ALG were found, which as an important metabolite of dihydrotestosterone reflects peripheral androgen activity, particularly of the skin. In every case these abnormal values were combined with elevated levels of other androgens (T, DHEAS, ASN). It is concluded from these limited data that an isolated elevation of ALG due to primary accentuation in 5 alpha-reductase is a rare or even non-existing occurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To re-evaluate the concept of polycystic ovarian syndrome (PCOS) in view of androgenic function., Design: Patients were studied endocrinologically and ultrasonographically., Setting: This study was performed as a clinical investigation., Patients, Participants: Sixty-nine euprolactinemic anovulatory patients with luteinizing hormone (LH) hypersecretion and 18 normal volunteers were selected., Interventions: One hundred micrograms of LH-releasing hormone were administered., Main Outcome Measure(s): It was possible to divide PCOS patients into three types., Results: Patients with neither hirsutism nor elevation of serum androstenedione (delta 4) and/or testosterone (T) were designated as type I PCOS (n = 20). Patients without hirsutism but with elevated delta 4 and/or T were referred to as type II PCOS (n = 33). Patients with both hirsutism and elevation of delta 4 and/or T were defined as type III PCOS (n = 16). Concentrations of delta 4 appeared gradedly increasing in types I, II, and III in that order, whereas T concentrations were significantly higher in types II and III than in control. Ultrasonographically, cystic ovaries were found in 88%, 84%, and 100% of types I, II, and III patients, respectively., Conclusions: It is postulated that each type may represent a subset of whole spectrum of PCOS from Stein-Leventhal syndrome to simple anovulation with LH hypersecretion.

The pedigrees of 192 girls aged 14.19 with different forms of hyperandrogenism (HA) have been studied. The hirsutism has been taken as a main symptom in analysis of pedigrees. The verification of different models of HA inheritance allows considering HA to be a multifactorial disease which is inherited as a quasi-alternative model. The coefficient of heritability is equal to 0.65-1.0.

Many different disease processes can result in a phenotype of hirsutism, anovulation, and oligomenorrhea or amenorrhea. An important goal of reproductive endocrinologists is to identify specific genetic diseases that can produce the hyperandrogenic phenotype. Two genetic disorders that can result in the hyperandrogenic phenotype are 1) mutations in the 21-hydroxylase gene (adrenal hyperplasia), and 2) mutations in the insulin receptor gene (the syndrome of hyperandrogenism-insulin resistance and acanthosis nigricans). The identification of these two genetic causes of hyperandrogenism provides the opportunity to investigate new approaches to prenatal diagnosis and therapy, genetic analysis of pedigrees, and innovative forms of therapy.

Selective percutaneous venous catheterization (SPVC) was performed to ascertain the source of androgen excess (AE) in 3 virilized women (12, 50 and 58y) in whom hormonal and radiologic investigation (ultrasonography and computerized tomography) was inconclusive. In all cases, elevated testosterone levels remained unsuppressed with dexamethasone, but were adequately suppressed by normal basal DHEA-S and cortisol. SPVC for T and F determinations (and the T/F ratio) were performed before surgery in all cases and during surgery in case 3. A T/F ratio of 152.4 and 71.8 (with an ovary-peripheral vein gradient [OPG] of 637 and 1173 ng/dl) identified the right and left ovary as the source of androgen excess respectively in cases 1 and 2, whereas the T/F ratio (87.4 and 97.2) and OPG (749 and 1162 ng/dl) were increased in both ovaries in patient 3. Thus, lateralization was evident in cases 1 (R ovary Leydig cell tumor) and 2 (L ovary hemangioma and stromal luteinization) whereas bilateral production in case 3 was confirmed by biopsy (PCO). Pre-operative identification of the origin of AE by SPVC is essential in defining proper treatment for patients suspected of harboring a neoplasia. Because it is not widely available nor devoid of complications, SPVC should only be indicated in hirsute/virilized women whose basal plasma testosterone and DHEA-S levels are in the tumoral range, i.e. higher than 150 ng/dl and 700 micrograms/dl, respectively.