Androgen receptors in the pubic skin and testosterone content of the blood in women with hirsutism

A study was made of "free" binding sites and the total number of sites binding androgens with the cytoplasmic receptor protein in the pubic skin biopsy specimens and testosterone in the blood serum of patients with hirsutism, degree II-III. A higher mean level of testosterone was found in the blood serum of patients with hirsutism, degree II-III, suffering from hyperandrogenism of ovarian and/or adrenal origin as compared to women with idiopathic hirsutism, degree I-III. "Free" sites of the binding of 5 alpha-dihydrotestosterone (DHT) with receptors were not revealed in most of the patients, however the total number of sites of the binding of DHT with cytoplasmic receptors were found in all the studied skin biopsy specimens. The results obtained show that there are significant differences in the testosterone level in the blood serum and the total number of DHT binding sites in the pubic skin cytosol of women with idiopathic hirsutism and patients with hirsutism, degree II-III, with hyperandrogenism of ovarian and/or adrenal origin.     

Problems of pathogenesis of ovarian and idiopathic hirsutism

The content of total testosterone (T), dehydrotestosterone (DHT), androstenedione (A), estradiol (E2), luteotropin (LH) and follicle-stimulating hormone (FSH) was studied in patients with ovarian and idiopathic hirsutism by a radioimmunoassay. The level of T-E-binding globulin (TEBG) was determined by 3H-DHT binding. Concentrations of free and TEBG-unbound T, DHT and E2 were calculated on the basis of the mass action law. The level of free and TEBG-unbound T and DHT was found to be the most reliable marker of the excessive production of androgens in hirsutism. The level of total T and DHT was raised in 50-60% of patients with hirsutism. Patients with hirsutism of ovarian genesis were characterized by considerable blood elevation of LH and FSH with still greater values in patients with menstrual disturbance, and by a rise of an A level. Difference found in hormonal indices can be used in differential diagnosis of ovarian and idiopathic hirsutism.     

Polycystic ovaries in Hirsute women with normal menses.

PURPOSE: Hirsute women with normal ovulatory menstrual function are often diagnosed as having idiopathic hirsutism. We prospectively evaluated 62 hirsute ovulatory women to determine if they had a subtle form of polycystic ovary syndrome, and if they exhibited any of the metabolic abnormalities commonly associated with classic polycystic ovary syndrome. METHODS: Baseline hormonal profiles, ovarian responses to gonadotropin-releasing hormone agonist, and ovarian morphology by ultrasound were compared in the hirsute women and two groups of ovulatory controls. RESULTS: Among 62 women, only 8 (13%) had normal androgen levels and were considered to have idiopathic hirsutism. Twenty-four (39%) had characteristic polycystic ovaries on ultrasound, an exaggerated response of 17-hydroxyprogesterone to leuprolide, or both, suggesting ovarian hyperandrogenism and the diagnosis of mild polycystic ovary syndrome. The remaining 30 women (48%) were considered to have unspecified hyperandrogenism. Age, body weight, and androgen level were similar among the hyperandrogenic subgroups. However, when compared with both normal and overweight controls and with patients with idiopathic hirsutism, the women who had mild polycystic ovary syndrome had higher fasting insulin levels [P < 0.01, mean (+/- SD) increase of 7 +/- 3 microU/mL], lower glucose-insulin ratios (P < 0.01, mean reduction of 3 +/- 1.5), higher low-density lipoprotein cholesterol levels (P < 0.05, mean increase of 26 +/- 10 mg/dL), and lower high-density lipoprotein (HDL) cholesterol levels (P < 0.01, mean reduction of 10 +/- 4 mg/dL). Compared with patients who had unspecified hyperandrogenism, these women also had higher fasting insulin levels (P < 0.05), lower glucose-insulin ratios (P < 0.05), and lower HDL cholesterol levels (P < 0.05). CONCLUSION: These data suggest that mild polycystic ovary syndrome is more common than idiopathic hirsutism, and it is also associated with subtle metabolic abnormalities.     

Hirsutism

Excess body hair, or hirsutism, is usually only a problem in women and can cause considerable psychological distress. The disorder is usually androgen mediated. Because androgens come only from the adrenal glands or gonads or by conversion in peripheral tissues of precursor steroids from these organs, the causes of hirsutism are found in these two organs. Adrenal causes include Cushing's disease, adrenal tumors, and congenital adrenal hyperplasia. Ovarian causes include tumors, polycystic ovarian syndrome, and most cases of idiopathic hirsutism. The clinical evaluation is designed to differentiate between these diagnostic possibilities. When an underlying abnormality can be identified, such as an ovarian tumor, the treatment course is clear. When the diagnosis is idiopathic hirsutism, however, the best treatment is uncertain and several available regimens are possible.     

Regulation of androgen receptor and 5 alpha-reductase in the skin of normal and hirsute women

The hormonal activity of androgens is mediated in target cells, particularly in human skin, by two kinds of proteins: the androgen receptor and the enzyme 5 alpha-reductase. In well differentiated androgen target cells, 5 alpha-reductase achieves the transformation of testosterone (T) into dihydrotestosterone (DHT), a more active androgen than T, because of its higher affinity for the receptor. In other words, 5 alpha-reductase acts as an amplifier of the androgen signal but is not absolutely required for androgen action. Regarding the regulation of the androgen receptor, minimal information is available. However, in genital skin, the receptor seems to be predominantly localized in the cytosolic compartment before puberty in males and in the nuclear compartment after puberty. In hirsute patients, recent data on genital skin fibroblasts do not show significant differences between the binding capacity of fibroblasts from normal and hirsute women whereas there is no difference between normal men and women. 5 alpha-Reductase activity seems to be a very important step in the processes involved in androgen action. While 5 alpha-reductase activity present in the skin of external genitalia does not seem to be androgen dependent, this is not the case for the enzyme located in pubic skin. In this area, a sex difference between males and females may be observed both in skin homogenates and in cultured fibroblasts. In addition DHT added to a medium of pubic skin fibroblasts is capable of increasing 5 alpha-reductase activity. This increase is not observed when cyproterone acetate is added to the medium and in patients with testicular feminization syndrome without receptors. Pubic 5 alpha-reductase activity is an androgen receptor mediated phenomenon. In patients with hirsutism, and particularly idiopathic hirsutism, 5 alpha-reductase activity is high without an increase in circulating androgens. This may be observed both in pubic skin homogenates and in cultured fibroblasts. Thus, an excess of skin 5 alpha-reductase activity may be considered as a cause of hirsutism but both the exact level of the abnormality in the regulation of the enzyme and its genetic control remain to be elucidated.     

Normal and elevated 3 alpha-androstanediol glucuronide concentrations in women with various causes of hirsutism and its correlation with degree of hirsutism and androgen levels.

We investigated peripheral androgen metabolic activity in 54 hirsute females (HF) by evaluating the serum 3 alpha-androstanediol glucuronide (3AG) concentration, hirsutism score (HS), and etiology of hirsutism. Based on basal and ACTH-stimulated steroid profiles (1 h post-Cortrosyn, 0.25 mg, i.v. bolus), the causes of hirsutism were determined to be increased adrenal androgen production (greater than 2 SD above normal mean), increased ovarian testosterone (T) production (greater than 2 SD above normal mean basal T of ovarian source only), or idiopathic cause (normal steroid profile). Serum 3AG levels in each group of HF were significantly higher (P less than 0.01-0.001) than those in normal females [normal: 2.9 +/- 0.94 nmol/L (n = 28); HF: increased adrenal androgen production of undefined cause, 7.7 +/- 7.5 nmol/L (n = 14); 21-hydroxylase deficiency, 7.6 +/- 7.4 nmol/L (n = 5); increased ovarian T production 5.5 +/- 3.5 nmol/L (n = 18); idiopathic cause, 5.8 +/- 4.8 nmol/L (n = 17)]. However, normal 3AG levels (less than 5.2 nmol/L) were present in 50-67% of HF in each group. Collectively, 3AG levels in HF correlated significantly (P less than 0.01) with dehydroepiandrosterone (DHEA; r = 0.41) and DHEA sulfate (DS; r = 0.44), while the correlation with androstenedione (r = 0.15) or T (r = 0.19) was not significant. Serum 3AG and adrenal androgen levels decreased in all subjects after dexamethasone treatment (0.5-1 mg at hour of sleep; 2 mg/day for 3-5 days). The correlation between 3AG and HS was significant (r = 0.6-0.74; P less than 0.01-0.001) only in HF with increased adrenal androgen secretion and idiopathic cause, and was not significant (r = 0.42) in HF with increased ovarian T secretion. There was no significant correlation between androgen levels and HS. We conclude that the serum 3AG level was not consistently elevated in HF and did not differ significantly between the various causes. Significant correlations between 3AG and DHEA/DS levels, and the simultaneous decrease in 3AG and adrenal androgens after dexamethasone administration in HF suggest that adrenal androgens contribute significantly to 3AG production. The significant correlation between 3AG and HS in HF with increased adrenal androgen secretion and idiopathic cause indirectly suggests an adrenal androgen contribution to both 3AG production and hirsutism in these HF. The insignificant correlation between 3AG and HS in HF with increased ovarian T secretion may result from a confounding effect of ovarian T on hirsutism.     

A detailed investigation of hirsutism in a Turkish population: idiopathic hyperandrogenemia as a perplexing issue.

Hirsutism is a common clinical problem in women and the treatment depends on the cause of hirsutism. The study was designed to determine the various causes of hirsutism and their prevalences in a Turkish population. 168 women with hirsutism attending to Endocrinology Outpatient Clinic of Erciyes University Hospital were investigated in detail. Medical history, physical examination, and basal levels of free testosterone (fT), androstenedione, follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone-sulphate (DHEAS), 17 hydroxyprogesterone (17-OHP), 11-deoxycortisol (11-S), thyroid hormones, thyroid stimulating hormone (TSH), and prolactin were determined. ACTH stimulation test was performed for the diagnosis of non-classic congenital adrenal hyperplasia (NCAH). Pelvic/vaginal and adrenal ultrasonographies were performed for the detection of tumors and polycystic ovarian changes. Polycystic ovary syndrome (PCOS) was diagnosed in 96 (57.1 %) patients, idiopathic hirsutism in 27 (16 %), NCAH in 12 (7.1 %), adrenal carcinoma in 3 (1.8 %), and Cushing's disease in 1 (0.6 %) patient. Among patients with NCAH, 11 (91.7 %) patients had 11-beta hydroxylase (11-beta OH) deficiency, and 1 (8.3 %) had 21-hydroxylase deficiency. The etiology of hyperandrogenemia was not clear in 29 (17.4 %) patients and these patients were named as idiopathic hyperandrogenemia. The clinical presentation of 11-beta OH deficiency is indistinguishable from that of other hyperandrogenic states and ACTH stimulation test is the only way to diagnose this entity. Although PCOS is the most common cause of hirsutism, it is notable that nearly one fifth of hirsute women have no apparent cause of hyperandrogenemia.     

Functional hyperandrogenism detected by corticotropin and GnRH-analogue stimulation tests in women affected by apparently idiopathic hirsutism

The etiologic diagnosis of hirsutism is often difficult. Previous studies have reported normal basal androgen and SHBG concentrations in 33-50% of hirsute women, suggesting the presence of an "idiopathic" form of hirsutism as the most frequent cause of this problem. The recent use of GnRH-analogues together with the corticotropin stimulation test allows better understanding of whether the cause of hirsutism is androgen excess and, if so, whether the origin of the latter is ovarian, adrenal or both. The present study evaluated adrenal and ovarian function in 48 young hirsute women as well as in 78 normal women matched for body mass index and age, who acted as control group. To determine ovarian function, a single 100-microg dose of GnRH analogue triptorelin was injected s.c.; thereafter, gonadotropins, 17-hydroxyprogesterone (17-OHP), delta4-androstenedione (delta4), total testosterone (T) and estradiol were determined. To better understand the adrenal function, 250 microg of 1,24 ACTH were administrated as i.v. infusion for 5 h, and plasma cortisol (F), 17-OHP, A4, DHEAS, T, 11-desossicortisol were measured. The combined use of these two stimulation tests was able to detect mild to moderate abnormalities in the steroidogenesis of ovaries alone (23%), adrenals alone (16.6%), or both (35.4%) in most hirsute women (75%) with otherwise normal baseline androgen concentrations. In particular, patients showed significantly increased responses of 17-OHP, delta4, total T, 11-desossicortisol, and F to 1,24-ACTH administration. Moreover, they also had significantly higher 17-OHP and T responses to triptorelin. In conclusion, milder forms of functional ovarian and/or adrenal hyperandrogenism, similar to those found in clearly hyperandrogenic women, were observed and could be an underlying mechanism of idiopathic hirsutism.     

ANDROSTERONE GLUCURONIDE IS A MARKER OF ADRENAL HYPERANDROGENISM IN HIRSUTE WOMEN

Androsterone glucuronide (Andros-G), a dihydrotestosterone metabolite, is present in serum at concentrations at least tenfold greater than those of androstanediol glucuronide. To investigate the significance of serum androsterone glucuronide, we developed a direct radioimmunoassay for this compound and measured its levels in normal women, women with mild or severe idiopathic hirsutism (IH), hirsute women with polycystic ovarian syndrome (PCO), and non-hirsute obese women. To determine the source of Andros-G precursors, serum levels were measured before and after selective ovarian suppression with leuprolide, combined ovarian and adrenal suppression with leuprolide and dexamethasone, and adrenal stimulation with ACTH. Androsterone glucuronide levels (nmol/l; mean +/- SD) were significantly higher (P less than 0.025) in women with mild idiopathic hirsutism (IH) (185 +/- 91), severe IH (173 +/- 97), and hirsute women with polycystic ovarian syndrome (PCO) (178 +/- 102) than in normal women (110 +/- 26). Levels in non-hirsute obese women (64 +/- 19) were lower than in normal women (P less than 0.01). Baseline levels (mean +/- SEM) in hirsute women given 20 micrograms/kg/day leuprolide for 5-9 months (171 +/- 15) were not significantly changed after leuprolide alone (153 +/- 18), and were decreased after adding dexamethasone (19 +/- 6; P less than 0.001). Andros-G levels did not increase significantly in normal women 60 min after i.v. ACTH (112 +/- 14 to 126 +/- 19), but rose in IH (170 +/- 24 to 216 +/- 26; P less than 0.001) and in PCO (179 +/- 26 to 238 +/- 31; P = 0.002). We conclude that Andros-G in women arises primarily from adrenal gland precursors and is elevated in hirsute women as a group. Its levels do not correlate with the severity of hirsutism, or the presence or absence of PCO, but reflect an increased production of adrenal androgens in both IH and PCO.     

Comparison of finasteride versus flutamide in the treatment of hirsutism.

OBJECTIVE: To compare the effectiveness of finasteride and flutamide in the treatment of hirsutism in patients with polycystic ovary syndrome (PCOS) and with idiopathic hirsutism. DESIGN: Randomized study. PATIENTS: One hundred and ten hirsute patients were selected: 64 women with PCOS and 46 with idiopathic hirsutism. METHODS: Patients were assigned randomly to receive 5mg finasteride once daily or 250mg of flutamide twice daily, for 12 consecutive months. Hirsutism was evaluated at 12 months of therapy, with the Ferriman-Gallwey score and with measurement of the terminal hair diameters (microm) taken from four different body areas. Blood samples were taken for assessment of endocrine and hematochemical parameters. Side effects were monitored during the treatment. RESULTS: Both finasteride and flutamide induced a significant decrease in the hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 31.4% in the PCOS cases and by 34.2% in the idiopathic hirsutism cases, and hair diameter by 27.0-34.1% in PCOS and by 29.6-37.9% in idiopathic hirsutism. Flutamide reduced the Ferriman-Gallwey score by 56.7% in PCOS and by 50.9% in idiopathic hirsutism, and hair diameter by 50. 3-60.0% in PCOS and by 47.7-56.5% in idiopathic hirsutism. Flutamide did not induce hormone variations, while finasteride increased testosterone levels by 40% in PCOS and by 60% in idiopathic hirsutism and decreased 3alpha-androstanediol glucuronide (3alpha-diolG) by 66.7% in PCOS and by 69.5% in idiopathic hirsutism. No important side effects or changes in the hematochemical parameters were observed with finasteride, while two patients (3.6%) in the flutamide group expressed abnormal transaminase levels after 6 months of treatment. Dry skin also appeared significantly more with flutamide (67.3%) than with finasteride (23.6%). CONCLUSIONS: Both drugs are effective in the treatment of hirsutism but flutamide is more effective than finasteride.     

Lactotropic and thyrotropic functions of the hypophysis in polycystic ovary syndrome

An increase in the prolactin basal level was detected in 8 out of 50 patients with ovarian polycystosis. A test with TRH and a simultaneous determination of the levels of prolactin, TTH, T3, T4 were used in 25 patients, of them a hyperergic reaction of prolactin to TRH was detected in 5. A correlation analysis of function of the thyroid was performed. Positive correlation between the levels of prolactin and TTH in patients with hyperprolactinemia and between a maximum increment in percentage to the initial level of TTH and prolactin in patients with a hyperergic reaction of prolactin to TRH was revealed. A conclusion was made of the common nature of disorder in the mechanisms of regulation of prolactin and thyroid function in patients with ovarian polycystosis.     

Mild androgen phenotypes

Mild androgen phenotypes are found in 30-40% of patients referred to an endocrine clinic because of suspected hyperandrogenic syndrome. These disorders are characterized by clinical or biological signs of hyperandrogenism in women with normal ovulatory menstrual cycles. Three main mild androgen disorders may be distinguished: ovulatory polycystic ovarian syndrome (PCOS), idiopathic hyperandrogenism, and idiopathic hirsutism. Ovulatory PCOS includes ovulatory hyperandrogenic patients presenting with polycystic ovaries. Using ESHRE/ASRM criteria for diagnosis of PCOS, this disorder is now part of PCOS spectrum. While in vivo and in vitro studies have confirmed the similarities between the two forms of PCOS, ovulatory PCOS presents clinicians with some unique problems. In fact, fertility is not a problem, but insulin resistance is present, and although milder than in classic PCOS it may be associated with an increased cardiovascular and metabolic risk. Because of this, an ovarian sonography should be performed in all ovulatory hyperandrogenic patients, and when polycystic ovaries are found cardiovascular and metabolic risk should be carefully evaluated. Ovulatory PCOS patients with altered glucose tolerance and/or with dyslipidaemia may need treatment with insulin-sensitizing agents. Idiopathic hyperandrogenism regroups ovulatory patients with increased androgen levels and normal ovaries, while idiopathic hirsutism includes ovulatory patients presenting with hirsutism but normal circulating androgens and normal ovaries. The differentiation between these two disorders may be difficult because commercial assays of androgen levels are generally unreliable. While idiopathic hyperandrogenism may be associated with insulin resistance, neither disorder is associated with an increased cardiovascular risk. The main clinical problem is hirsutism, and this may be approached by aesthetic or pharmacological therapies.     

Androstanediolglucuronide: a parameter for peripheral androgen activity before and during therapy with cyproterone acetate.

Serum 5 alpha-androstane-3 alpha,17 beta-diolglucuronide (3 alpha-AdiolG) levels were measured and the degree of hirsutism was scored in female outpatients complaining of excessive hair growth before and during treatment with cyproterone acetate. In a group of 16 patients with idiopathic hirsutism and in a group of 9 patients with either polycystic ovary syndrome and hirsutism or 21-hydroxylase deficiency and hirsutism, the serum 3 alpha-AdiolG levels were significantly increased (p less than 0.01) as compared with the serum 3 alpha-AdiolG level in a control group of 13 apparently healthy women: 3 alpha-AdiolG levels, median (range), being 5.3 (2.3-7.8) nmol/l, 8.5 (4.1-10.4) nmol/l, and 2.9 (1.5-5.2) nmol/l, respectively. In contrast to a previous report, no correlation was found between the serum 3 alpha-AdiolG levels and the Quetelet Index (N = 18, R = 0.42, p greater than 0.05), indicating an apparent ineffectiveness of the excessive androgen turnover in fat tissue. The use of the anti-androgen drug cyproterone acetate alone or in combination with ethinylestradiol in reverse sequential therapy did lower the 3 alpha-AdiolG levels significantly (p less than 0.01) together with a significant decrease (p less than 0.01) in hirsutism score. From the results of this study we therefore conclude that 3 alpha-AdiolG can be used as a parameter for peripheral androgen action before and during treatment with anti-androgens.     

The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia

Late onset congenital adrenal hyperplasia (LO CAH) can be seen in association with polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). The study aimed to find out the prevalence of LO CAH in Central Anatolia among hirsute women. Sixty-three patients with hirsutism were evaluated to determine the frequency of LO CAH by comparing them with their age and body mass index matched 28 healthy controls. Of those 63 hirsute women, 43 were diagnosed as PCOS, and 20 were diagnosed as IH. Following basal hormonal evaluation, all subjects underwent ACTH stimulation test and ACTH stimulated 17-hydroxyprogesterone (17-OH P), 11-desoxycortisol (11-DOC), cortisol (F), and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in all subjects. ACTH stimulated 17-OH P, 11-DOC, and DHEA-S levels did not differ between groups. However, stimulated F levels were found to be higher in hirsute women (p<0.001). Six out of 63 (9.52%) patients with hirsutism met the criterion for 21 hydroxylase deficiency. We found no subject presumed to have 11-beta hydroxylase deficiency, but one subject in control group (3.57%) and two patients among PCOS subjects (4.65%) had exaggerated DHEA-S response which was suggestive of mild 3-beta hydroxysteroid dehydrogenase deficiency. In conclusion, the most frequent form of LO CAH seems to be due to 21 OH deficiency among women with PCOS and IH in Central Anatolia. Mild 3-beta HSD deficiency may also be an underlying cause for hirsutism and it may be seen without any clinical presentation. Adrenal hyperactivity is likely to be the main reason of hyperandrogenemia in women with hirsutism.     

Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide

To determine the dose of the GnRH agonist leuprolide necessary to maximally suppress ovarian testosterone secretion, 10 moderately to severely hirsute women (5 with idiopathic hirsutism and 5 with polycystic ovarian syndrome) were given gradually increasing leuprolide doses, starting with either 5 or 10 micrograms/kg.day. Serum testosterone and estradiol, basal LH, and the LH response to GnRH were measured before and at the end of each treatment period, until maximal suppression of estradiol and testosterone occurred. Leuprolide was then continued for a total of 6 months to assess its clinical efficacy. Hirsutism scores and hair growth rates were determined before and after therapy. Serum estradiol and the LH response to GnRH were maximally or near-maximally suppressed in all women by the lowest doses of leuprolide used. Basal serum LH was not maximally suppressed in all women until a dose of 15 micrograms/kg.day was reached, and maximal testosterone suppression required 15 micrograms/kg.day or more in 7 of the 10 women. The addition of 0.5 mg dexamethasone daily for 4 weeks at the end of the study in 5 of the women reduced serum testosterone to undetectable levels. Symptomatic improvement in hirsutism occurred in 9 women, hirsutism scores decreased by at least 3 points in 5 women, and hair growth rates decreased in 8 women. These data indicate that low doses of leuprolide were sufficient to maximally suppress serum estradiol and the LH response to exogenous GnRH. Higher leuprolide doses were needed to maximally suppress serum testosterone and the basal LH levels. Leuprolide (20 micrograms/kg.day) effectively reduced hair growth in the majority of these women.     

Various aspects of the diagnosis of hirsutism

A study was made of total testosterone, estradiol, androstenedione, dehydroepiandrosterone-sulphate, progesterone, testosterone and estradiol binding by transport proteins (sex steroid binding by globulin and albumin) in the blood plasma, androgen cytoplasmic receptors in pubic skin biopsy in 35 patients with hirsutism of various degree of expression and disturbance of menstrual function. An increase in low active androgens (androstenedione and dehydroepiandrosterone-sulphate in most women) interpreted clinically as idiopathic form of hirsutism, was noted. Low levels of androgens in the presence of the lowest indices of estradiol, progesterone and sex steroid binding globulin and the highest results of free and albumin bound testosterone fraction as well as the index of free androgens in patients with Stage III hirsutism were found against a background of irregular menses which could promote more pronounced virilization in these women. A degree of expression of hirsutism showed correlation with the results of determination of the free androgen index reflecting androgen biological activity. The authors revealed reverse correlation of the concentration of total testosterone, its free fraction and the number of common sites of the binding of dehydrotestosterone with receptor proteins as well as the frequency of detection of androgen free receptors in the pubic skin cytosol of patients with a various degree of hirsutism.     

Body fat topography in women with androgen excess

The relationship between body fat distribution and androgen excess was determined in 168 premenopausal women of varying degrees of androgen excess. In 84 women with the polycystic ovary syndrome or idiopathic hirsutism, the waist:hips girth ratio (WHR) was 0.81 +/- 0.01 (mean +/- s.e.m.) and was significantly greater (P less than 0.001) than in an age- and weight-matched group of 84 non-hirsute women (0.77 +/- 0.01), indicating upper body fat predominance in the hirsute subjects. Plasma testosterone was directly correlated with the WHR (r = 0.55, P less than 0.001) and this relationship was independent of obesity level, supporting the hypothesis that plasma androgens are an important determinant of body fat topography in premenopausal women.     

Plasma pregnenolone and 17-OH-pregnenolone in patients with adrenal tumors, ACTH excess, or idiopathic hirsutism.

Plasma levels of the delta5-pregnenes, pregenolone and 17-OH-pregnenolone, were measured in patients with disordered steroidogenesis. While 17-OH-pregnenolone was within the normal range in patients with hypercortisolemia due to Cushing's disease, ectopic ACTH or adrenal adenrenal adenoma, 4 of 6 patients with an adrenal carcinoma had elevated levels of this precursor. Thus, elevated plasma 17-OH-pregnenolone levels in patients with Cushing's syndrome indicate adrenal carcinoma, although a normal value does not exclude this diagnosis. Abnormal resistance of delta5-pregnenes to suppression with dexamethasone proved useful in detecting the presence of residual tumor in the post-operative evaluation of adrenal carcinoma. Basal plasma pregnenolone was within the normal range in 19 of 20 patients with Cushing's disease and was invariably normal in patients with other varieties of hypercortisolism. Since acute administration of ACTH causes marked elevation of delta5-pregnene levels while patients with chronic ACTH excess (Cushing's disease and ectopic ACTH production) have normal levels, it is suggested that ACTH has a chronic influence on the intraadrenal utilization of delta5-pregnenes in addition to stimulating their formation. In pre-menopausal women with idiopathic hirsutism, basal levels of both delta5-pregnenes were elevated (P less than 0.001). Following dexamethasone administration the absolute decrease in delta5-pregnenes levels was greater than that seen in normal subjects. This observation indicates that the metabolism of delta5-pregnenes is abnormal in patients with idiopathic hirsutism.     

Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency

We analyzed data from 20 patients with late-onset 21-hydroxylase deficiency (LOHD). Three clinical phenotypes could be distinguished among the 18 women. Seven (39%) presented with clinical features suggesting polycystic ovarian disease (PCOD). However, despite androgen levels similar to those of patients with typical PCOD, high serum LH to FSH ratios were not consistently found. Seven other women (39%) presented with isolated hirsutism, suggesting idiopathic hirsutism. The remaining 4 women (22%) had no manifestations of androgen excess and were considered to have the cryptic form of LOHD. Serum 17-hydroxyprogesterone (17-OHP) and androgen levels were similar in the 3 phenotypes, suggesting that the clinical expression of LOHD in women is modulated by individual factors, such as androgen sensitivity. The 2 men were detected by family study and were clinically normal. Since clinical diagnosis of LOHD is impossible, we concentrated on hormonal data with the aim of providing guidelines for the biological diagnosis of LOHD. Assay of basal serum 17-OHD at 0800 h in both sexes and in the early follicular phase in women was sufficient to establish the diagnosis of LOHD in most patients. If doubtful results are obtained, i.e. serum 17-OHP levels between 2 and 5 ng/ml, an ACTH test must be performed. Post-ACTH serum 17-OHP levels exceeding 10 ng/ml confirm the diagnosis of LOHD. Such results should avoid confusion with heterozygotes for 21-hydroxylase deficiency, whose frequency is high within the general population and may be even higher in patients with idiopathic hirsutism or PCOD.     

Contribution of plasma androstenedione to 5 alpha-androstanediol glucuronide in women with idiopathic hirsutism

To confirm that plasma delta 4 androstenedione (delta 4) is the main precursor for 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (Adiol G) in patients with idiopathic hirsutism (IH), delta 4 was cutaneously applied to five normal women and five women with IH. Several parameters of androgen metabolism were assayed basally and throughout the studies. Those included plasma delta 4, testosterone, and dihydrotestosterone as well as urinary Adiol G and testosterone glucuronide excretion. Under basal conditions plasma testosterone, delta 4, and dihydrotestosterone did not differ significantly between the two groups of subjects. Urinary Adiol G excretion was significantly higher (P less than 0.01) in IH patients [123 +/- 36 (SE) micrograms/24 h] than in the normal women group (45 +/- 20 micrograms/24 h). After percutaneous administration of delta 4, plasma delta 4 increased in both groups by nearly 600% and there was a 300% increase in Adiol G excretion in IH patients (336 +/- 57 micrograms/24 h), whereas only a 50% increase occurred in normal women (65 +/- 17 micrograms/24 h). We postulate that plasma delta 4 may be the main precursor accounting for the increased production of urinary Adiol G in women with IH, in whom hirsutism may be due to a high 5 alpha-reductase activity. Indeed, 5 alpha-reductase as measured in vitro in pubic skin was significantly higher in hirsute patients (224 +/- 66 fmol/mg skin X h) than in normal women (45 +/- 15 fmol/mg skin X h).