Prenatal Androgenization of Ewes as a Model of Hirsutism in Polycystic Ovary Syndrome.

The main clinical feature associated with hyperandrogenism in polycystic ovary syndrome (PCOS) in humans is hirsutism, where hair increases its length, pigmentation, and particularly its diameter. Currently, it is not known whether PCOS animal models also exhibit changes in the hair. Therefore, the aim of this study was to explore the wool characteristics in sheep prenatally androgenized (PA) with testosterone propionate. After 4 and 13 months of life, wool was collected from the top of the shoulder of both females and males (both androgenized and controls). The offspring sheep were followed for up to 19 months of life to evaluate testosterone and androstenedione serum levels by ultra-high-performance liquid chromatography-tandem mass spectrometry, determine insulin and glucose response to intravenous glucose tolerance test, and address estrus cyclicity during the second breeding season. PA male animals showed a reduction in wool fiber diameter at 4 months of age compared with controls (P = 0.02) but not at 13 months, whereas PA females showed increased hair diameter at 13 months (P = 0.002), with no difference at 4 months. No substantial changes in other hair parameters (length, color, and medullation) were identified. In addition, increased levels of serum testosterone were observed in PA female sheep compared with controls at 12 months (P = 0.03). Our results indicate for the first time, to our knowledge, that changes in wool fiber diameter observed in PA ewes replicate, at the translational level, the increase in hair diameter in hirsute women with PCOS.

Acne in adult women and the markers of peripheral 3 alpha-diol G activity.

BACKGROUND: Acne in adult women is a frequent hard-to-manage disease with many relapse cases. It mostly interferes with the quality of life of patients, bringing them major metabolic and social losses. As androgenic hormones play a very important role in the acne pathogenesis, the early diagnosis of hyperandrogenic states is very useful for the proper evaluation of each patient and for a better choice of therapeutic management. Defining a pattern for laboratory profile analysis is important for the control of relapses of acne breakouts in adult women, which lately has been the aim of many published studies. AIM: To establish the relation between 3 alpha-diol G levels and acne in female patients with normal androgenic status without menstrual dysfunctions. PATIENTS/METHODS: The evaluation of serum 3 alpha-androstanediol glucuronide levels through an enzymatic immunoassay method (Androstanediol Glucuronide ELISA Kit) for a direct quantitative measurement in 26 patients with grade II and III acne, ages ranging from 13 to 50. RESULTS: Among the analyzed patients, 83% had grade II acne, and among this total, 60% were aged 14 or over. According to age, 12 studied patients showed serum 3 alpha-diol G levels within normal range and 11 patients had increased levels. CONCLUSIONS: A total of 60% of adult women with acne present increased levels of androgens and among those with normal levels and without menstrual dysfunctions, 50% show an increase in 3 alpha-diol G. Therefore, a pharmacological approach with anti-androgenic drugs for acne therapy in most of these patients is advisable.

CYP21A2 genotypes do not predict the severity of hyperandrogenic manifestations in the nonclassical form of congenital adrenal hyperplasia.

There is a strong correlation between the severity of genotypes and 17OH-progesterone levels in patients with the nonclassical form of 21-hydroxylase deficiency (NC-CAH); however, there are few studies regarding the correlation with clinical signs. The aim of the study was to evaluate whether genotypes correlate with the severity of the hyperandrogenic phenotype. A cohort of 114 NC-CAH patients were diagnosed by stimulated-17OHP ≥10 ng/ml. CYP21A2 genotypes were divided into 2 groups according to the severity of enzymatic impairment; mild and severe. Clinical data and hormonal profiles were compared between the 2 groups. Age at onset of manifestations did not differ between children or adults carrying both mild and severe genotypes. Frequencies of precocious pubarche and hirsutism, with or without menstrual abnormalities, were similar between the 2 groups. There were no differences in basal testosterone levels of adult symptomatic females carrying both genotypes, but there were differences between adult females with (92.9±49.5 ng/dl) and without hirsutism (43.8±38 ng/dl) (p=0.0002). Similar frequencies of both genotypes were observed in asymptomatic females and in those with clitoromegaly. Nonclassical genotypes do not predict the severity of phenotype. Asymptomatic and virilized females carrying the same genotype suggest that there is a modulatory effect of genes involved in the androgen pathway on the phenotype.

Aromatase gene polymorphism does not influence clinical phenotype and response to oral contraceptive pills in polycystic ovary syndrome women.

AIMS: To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP). METHODS: 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables. RESULTS: Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11-20) vs. 13 (11-20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months' treatment. CONCLUSION: The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene.

Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes.

The aim of this study was to compare clinical, hormonal, and metabolic variables in women with classic polycystic ovary syndrome (PCOS), in ovulatory women presenting hirsutism, normal androgen levels, and polycystic ovaries (H+PCO), and in a group with isolated hirsutism (IH) presenting with normal ovaries and androgen levels. Waist circumference, triglycerides, and homeostasis model assessment values were significantly higher in classic PCOS even after adjustment for body mass index, and metabolic syndrome was three times more frequent in classic PCOS than in H+PCO or IH (31.3% vs. 11.9% vs. 9%), but no differences were observed regarding metabolic profile and cardiovascular risk factors between the H+PCO and IH groups, which presented with significantly more metabolic syndrome than normal controls when only overweight and obese women were considered.

Sex hormone binding globulin decrease as a potential pathogenetic factor for hirsutism in adolescent girls.

We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < or = 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < or = 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 13-14 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Sex hormone binding globulin decrease as potential pathogenetic factor for hirsutism in adolescent girls / Disminución de la globulina transportadora de hormonas sexuales como factor patogénico de hirsutismo en la adolescencia

We investigated 252 non-obese female subjects aged 13-39 years to evaluate if an exaggerated descent of sex hormone binding globulin (SHBG) levels during adolescence can play a role in the development of hirsutism. Body hair was assessed according to Ferriman and Gallwey (FG), with a stringent criterion of normality of < 4. In 13-14 years girls, SHBG and free testosterone (FT) levels were similar in "hirsute" girls (FG > 4) and controls (FG < 4, regular menstrual cycles, no acne). In 15-18 years girls, SHBG values were lower in "hirsute" girls, FT levels were similar in both groups, FG correlated inversely with SHBG. In 19-39 yr women, FT levels were higher in "hirsute" subjects, SHBG values were similar in both groups, FG correlated positively with FT. Lowest SHBG values were observed at 15-18 years, but the slope of the decrease from 1314 years values was greater in the "hirsute" group. FT values increased progressively with age, but the increase was greater in the "hirsute" group. Those results suggest an important role of SHBG decrease in adolescence vs. a more accentuated testosterone increase in adults, as factors conditioning the development of hirsutism in these two different periods of life.

Se investigaron 252 mujeres con peso normal, de 13 a 39 años de edad, para evaluar si un descenso exagerado en los niveles de la globulina transportadora de hormonas sexuales ("sex hormone binding globulin"; SHBG) puede tener un rol en el desarrollo de hirsutismo. Este signo fue evaluado con la escala de Ferriman y Gallwey (FG), empleando un criterio riguroso de normalidad < 4. En niñas de 13-14 años, tanto SHBG como la testosterona libre ("free testosterone"; FT) fueron similares en niñas "hirsutas" (FG > 4) y controles (FG < 4, ciclos menstruales regulares, sin acné). En adolescentes de 15-18 años, los valores de SHBG fueron menores en las "hirsutas", los niveles de FT fueron similares en ambos grupos y el índice de FG correlacionó inversamente con SHBG. En las mujeres de 19-39 años, los niveles de FT fueron mayores en las "hirsutas", los valores de SHBG fueron similares en ambos grupos y FG correlacionó positivamente con FT. Los valores más bajos de SHBG se observaron entre 15 y 18 años, pero la pendiente de disminución a partir de los valores de 13-14 años fue mayor en el grupo de "hirsutas". Los valores de FT se incrementaron progresivamente con la edad, pero el aumento fue mayor en el grupo de "hirsutas". Estos resultados sugieren un rol importante del descenso de SHBG en la adolescencia vs. un incremento más acentuado de los niveles de testosterona en las adultas, como factores que condicionan el desarrollo del hirsutismo en esos dos diferentes periodos de la vida.

Metformin in normal-weight hirsute women with polycystic ovary syndrome with normal insulin sensitivity.

Fifteen normal-weight (body mass index (BMI) 21.50 +/- 1.65 kg/m(2)) hirsute women with polycystic ovary syndrome and normal insulin sensitivity were treated with 850 mg metformin orally, three times daily, for 4 months. Before and at the end of the treatment, clinical data as well as serum concentrations of sex steroid hormones, gonadotropins, fasting plasma glucose and insulin, insulin resistance - homeostasis model assessment (HOMA-IR), carbohydrate tolerance and the area under the curve for insulin (AUC(insulin)) were analyzed. Three patients withdrew from the study. Seven of the remaining 12 patients presented menstrual pattern improvement, followed by ovulatory cycles at the end of the treatment period. There were no changes in BMI and hirsutism score. A significant (p < 0.05) decrease in luteinizing hormone (LH) (from 8.18 +/- 4.34 to 5.05 +/- 1.53 IU/ml), testosterone (from 104.66 +/- 27.54 to 82.00 +/- 23.05 ng/dl), fasting insulin (from 9.66 +/- 4.79 to 7.83 +/- 3.06 microIU/ml), AUC(insulin) (from 9239 +/- 3285 to 7660 +/- 2565 microUI/ml x min) and HOMA-IR (from 2.15 +/- 1.2 to 1.67 +/- 0.74), and a significant increase in follicle-stimulating hormone (FSH) (from 4.05 +/- 1.53 to 5.96 +/- 2.13 IU/ml), were observed at the end of the treatment period. A higher LH and a lower FSH predicted clinical improvement, while basal insulin and AUC(insulin) showed lower predictive value.

Nitric oxide and fibrinogen in polycystic ovary syndrome: associations with insulin resistance and obesity.

OBJECTIVE: Nitric oxide (NO) and fibrinogen levels, two markers of vascular disease, are associated with insulin resistance, a common trait in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Case-control study including 31 women with PCOS and 21 age-matched women with regular, ovulatory cycles, normal androgen levels and idiopathic hirsutism (control group). Nitrite/nitrate concentration (index of endothelium-derived NO) and fibrinogen plasma levels were assessed and analysed in association with anthropometric, metabolic and hormonal variables. RESULTS: The groups were similar in terms of age, positive family history of diabetes and Ferriman-Gallwey hirsutism score. Nitrite/nitrate and fibrinogen levels were also similar in the two groups. In contrast, in PCOS patients, insulin levels and the homeostatic model assessment were negatively correlated with NO production (r=-0.39, p=0.03 and r=-0.41, p=0.02, respectively). Age, BMI, waist circumference and waist-to-hip ratio were positively correlated with fibrinogen in both groups. CONCLUSION: The present data indicate a negative, BMI-independent association between NO levels and insulin resistance in PCOS patients. Further studies are required to clarify the role of androgens on the pathogenesis of endothelial dysfunction in PCOS and investigate androgen action and/or the gene receptor modulating NO secretion.

Isolated scrotal hair in infancy.

Nine male infants who developed scrotal hair with no other signs of virilization were evaluated. Median age for the development of scrotal hair was 4.5 months, and median age at presentation was 7.5 months. Endocrinologic investigations performed in 6 of the infants yielded normal findings. The scrotal hair receded at a mean age of 12 months, suggesting a transient benign event. The development of genital hair in boys under age 9 years is considered precocious, suggesting a possible pathological condition (eg, precocious puberty, congenital adrenal hyperplasia, adrenal or genital tumors), or may be due to premature adrenarche.

Association between ovarian volume and serum insulin levels in ovulatory patients with idiopathic hirsutism.

We assessed the influence of insulin on ovarian volume in 45 women with regular, ovulatory menstrual cycles, normal androgen levels, and isolated hirsutism (idiopathic hirsutism). Insulin levels, insulin-to-glucose ratio, and homeostasis model assessment (HOMA) were significantly higher in patients with ovarian volume >9 cm3 than in women with smaller ovaries (P<.05), and insulin levels presented a significant positive correlation with ovarian volume (r = 0.37, P=.02), which was independent of body mass index (BMI) or the luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio.

Influence of leptin, androgens and insulin sensitivity on increased GH response to clonidine in lean patients with polycystic ovary syndrome.

Our aim was to investigate whether insulin sensitivity, leptin, androgen or estradiol levels are associated with disturbed GH response to clonidine in lean patients with polycystic ovary syndrome. Fourteen lean polycystic ovary syndrome patients, 11 ovulatory patients presenting idiopathic hirsutism and 10 non-hirsute, normal women with regular cycles paired for age and BMI were included in a cross-sectional study. Baseline hormonal and metabolic variables were assessed and analyzed in association with GH response to oral administration of 0.3 mg of clonidine. Delta GH was significantly higher in the PCOS group than in the IH and control groups (p = 0.014). The groups were similar in terms of body mass index, insulin, glucose, total and HDL cholesterol, triglycerides and estradiol levels. Free androgen index (r = 0. 454, p = 0.015) and leptin (r = 0.419, p = 0.023) were positively correlated with the homeostasis model assessment. The homeostasis model assessment was the only variable that significantly correlated with GH response to clonidine (r = 0.375, p = 0.029) (vs. estradiol, free androgen index, leptin and LH). Nonetheless, when the analysis was adjusted for leptin levels and free androgen index, the statistical significance of this correlation was lost. The increased GH secretion observed in our lean PCOS patients may be associated with slight changes in insulin sensitivity, even in the absence of clinical evidence of insulin resistance. This association seems to be modulated by leptin and androgen levels.

Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping.

Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3betaHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3betaHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3betaHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (Delta5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3betaHSD2 deficiency. Basal and ACTH-stimulated Delta5-17P levels (nanomoles per liter) ranged from 4-41 (-0.2 to 14 sd) and 36-97 (3.5-15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69-153 (25-57 sd) and 201-351 (36-65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Delta5-17P to F ratios ranged from 11-159 (0.5-25 sd) and 42-122 (2.4-11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29-282 sd) and 487-1523 (52-167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3betaHSD2 deficiency in children with premature pubarche: ACTH-stimulated Delta5-17P and Delta5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Delta5-17P and Delta5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Delta5-17P levels and Delta5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3betaHSD2 deficiency.

[Effectiveness of flutamide alone or combined with oral contraceptives in the treatment of hirsutism in women]. / Eficacia de la flutamida en el tratamiento del hirsutismo. Contribución del uso combinado con anticonceptivos orales en mujeres normoandrogénicas.

BACKGROUND: Flutamide is an antiandrogen devoid of other hormonal effects, except for a decrease in the secretion of adrenal androgens such as dehydroepidandrosterone sulphate (DHEA-s) and androstenedione. AIM: To assess the effectiveness of flutamide in the treatment of hirsutism, used as monotherapy or combined with oral contraceptives (OC). PATIENTS AND METHODS: Women with peripheral hirsutism (defined as the presence of normal serum androgen levels and normal ovulatory menstrual cycles) were assigned to receive flutamide alone (500 mg/day) or flutamide plus an OC (ethynylestradiol 0.03 mg and desogestrel 150 microg). Hirsute with hyperandrogenism (polycystic ovary syndrome) were assigned to receive flutamide plus an OC. The degree of hirsutism was assessed using a clinical score (Moncada) at three, six and twelve months of therapy. RESULTS: Twenty five women with peripheral hirsutism received flutamide alone and 18 receive flutamide plus the contraceptive. Eighteen women with polycystic ovary syndrome were studied. At three months, the reduction in hirsutism was 11.2, 15.9 and 24.7% in women with peripheral hirsutism receiving flutamide alone or flutamide plus OC and in hyperandrogenic women receiving flutamide plus OC, respectively. At twelve months, the figures were 57.2, 57.3 and 52.5% respectively. In hyperandrogenic women, at baseline and three months, serum testosterone levels were 0.96 and 0.42 ng/nl and serum DHEA-s levels were 2,980 and 1,490 ng/ml respectively. No collateral effects of treatment or elevations in serum transaminase levels were observed. CONCLUSIONS: Flutamide is effective in the treatment of hirsutism in women with normal or elevated androgen levels. Adding OC did not improve the efficacy of the drug.

Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: influence on LH and relationship with hormonal, metabolic, and anthropometric measurements.

BACKGROUND: The known association between leptin, obesity and insulin action suggests that leptin may have a role in polycystic ovarian syndrome (PCOS) but this has only been addressed peripherally. METHODS: We assessed the influence of leptin on LH and investigated the relationship between leptin and body mass index (BMI), waist:hip ratio (WHR), androgen concentrations, fasting insulin and insulin:glucose ratio (IGR) in 27 women with PCOS and in 20 age- and weight-matched women with regular, ovulatory menstrual cycles and idiopathic hirsutism (IH). RESULTS: Leptin concentrations were significantly higher in obese PCOS women than in normal weight women with either PCOS or IH (P = 0.0028), but did not differ between obese women with PCOS and IH. WHR, insulin concentrations and IGR were significantly higher in obese PCOS patients in comparison with the three other groups. In IH patients, the association between leptin concentrations and WHR was lost after adjustment for BMI. In PCOS patients, a significant correlation was observed between leptin and fasting insulin concentrations, IGR, WHR and LH. After adjustment for BMI, only the correlation with LH remained significant. A stepwise regression model was set up with LH as the dependent variable to test the hypothesis that the concentrations of leptin might be modulating the concentrations of LH in PCOS patients. The relationship of LH concentrations with IGR was found to be BMI dependent. In contrast, leptin concentrations contributed negatively and significantly to LH concentrations, independently of either BMI or IGR. CONCLUSIONS: We speculate that the known attenuation in basal or stimulated response of LH in obese PCOS patients might be related to leptin resistance, which could influence LH hypersecretion. In IH ovulatory patients, normal LH concentrations suggest the presence of preserved regulatory mechanisms of GnRH pulsatility. Further studies are needed to specifically investigate the proposed correlation between leptin and GnRH modulation in PCOS.

[Treatment of hirsutism with spironolactone and with spironolactone plus dexamethasone]. / Tratamiento del hirsutismo con espironolactona y con espironolactona más dexametasona.

BACKGROUND: Spironolactone has an anti androgenic effect, inhibiting the binding of androgens to their receptor. This antagonistic effect is the basis for the use of spironolactone in the treatment of hirsutism. AIM: To study the effectiveness and safety of spironolactone in the treatment of hirsute women and of the association of spironolactone plus dexamethasone in the treatment of hirsutism with glucocorticoid sensitive hyperandrogenism. PATIENTS AND METHOD: Sixteen women (group 1) with peripheral hirsutism (defined as those with normal androgens levels, normal menstrual cycles and ovulation) and 24 women (group 2) with glucocorticoid sensitive hyperandrogenic hirsutism were studied. Group 1 was treated with spironolactone 50 mg hid and group 2 with same spironolactone dose plus dexamethasone 0.5 mg at 23 h during one month and 0.25 mg thereafter. Patients were followed during one year. RESULTS: After one year of treatment, a 54% reduction in Moncada hirsutism escore was observed in group 1 and 52% reduction in group 2. Observed secondary effects of spironolactone were increases in diuresis, fatigability, acne aggravation and seborrhea in two patients. Two additional patients had spotting. No secondary effect attributable to glucocorticoid use were observed. CONCLUSIONS: Spironolactone is effective and safe in the treatment of hirsutism. Androgenic supression did no increases its effectiveness, underscoring the peripheral anti androgenic activity os spironolactone.

Spironolactone as a single agent for long-term therapy of hirsute patients.

OBJECTIVE: To assess the androgen-suppressing effect of spironolactone, and the use of this drug as a single agent in the long-term therapy of hirsute patients with either polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). Standard cyproterone acetate (CPA) treatment was used to evaluate the results obtained with spironolactone. DESIGN: Prospective randomized study. PATIENTS: Forty-six hirsute women were separated randomly into two groups, stratified for polycystic ovary syndrome. For 12 months, Group 1 (21 patients, 10 PCOS) received spironolactone only (200 mg/day). Group 2 (23 patients, nine PCOS) received CPA (50 mg/day) with ethinyl oestradiol (35 microgram/day). MEASUREMENTS: Ferriman-Gallwey clinical score for hirsutism and serum testosterone, androstenedione, and LH levels. RESULTS: In IH patients, hirsutism regressed equally with spironolactone (21 +/- 2-14.5 +/- 2) and CPA (23 +/- 2-13 +/- 2). In PCOS patients, the mean score for hirsutism after 12 months was significantly lower with CPA (12 +/- 1) than with spironolactone (16 +/- 1). Testosterone levels did not change with spironolactone; with CPA there was a decrease from baseline in PCOS (47% and 51%, 6 and 12 months) and IH patients (31% and 30%). Androstenedione levels also declined from baseline in CPA-treated PCOS patients (38% and 39%, 6 and 12 months). Androgen levels were significantly different between the groups after 6 and 12 months. LH levels decreased with CPA (72%) but not with spironolactone. CONCLUSION: Our results suggest that spironolactone used as a single agent is as effective as cyproterone acetate combined with oestradiol for long-term treatment of patients with idiopathic hirsutism. In PCOS patients, spironolactone is still effective for reducing hirsutism; however, for treatment of the hormonal or metabolic manifestations associated with PCOS, it may be necessary to combine spironolactone with either an antigonadotrophic agent or a drug that improves peripheral insulin sensitivity.

Adrenal androgen excess in hyperandrogenism: relation to age and body mass.

OBJECTIVE: To determine whether DHEAS levels in hyperandrogenic (HA) women retain the normal age-related decrease. DESIGN: Prospective study. SETTING: Academic tertiary care medical center. PATIENT(S): One hundred forty-five HA patients with hirsutism and/or oligo-ovulation and 53 healthy women. INTERVENTION(S): Blood samples were obtained on days 3-8 of the menstrual cycle or after an IM progesterone-induced withdrawal bleed. MAIN OUTCOME MEASURE(S): Serum samples were assayed for progesterone, total testosterone, sex hormone-binding globulin, free testosterone, and DHEAS. RESULT(S): Controls and HA patients were similar in body mass index and age. A negative correlation between DHEAS levels and age, but not body mass index, was found among controls. In HA patients. DHEAS levels decreased with age. Dehydroepiandrosterone sulfate levels correlated with the hirsutism score in HA patients. When HA patients were subdivided into those with low, middle, and high DHEAS levels, those with low DHEAS levels were older and weighed more than those with high DHEAS levels. CONCLUSION(S): The negative association between DHEAS levels and age is preserved in HA women. Hyperandrogenic patients with high DHEAS levels are younger, thinner, and more hirsute than those with lower DHEAS levels. These findings suggest that the diagnosis of adrenal androgen excess in HA patients may require the use of age-adjusted normative values.

The effects of spironolactone on testosterone fractions and sex-hormone binding globulin binding capacity in hirsute women.

This study explored the effect of the anti-androgen spironolactone on sex-hormone binding globulin (SHBG) and the distribution of circulating testosterone (T) into various free and bound fractions in seven women with hirsutism assessed before and then monthly for three months on a regimen of spironolactone, 100 mg bid as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgen parameters and serum T fractions studies. None of the women were judged obese based upon body mass index values. After three months of spironolactone therapy, there was little change in the hirsutism index, and measurement of serum T, androstenedione, DHEA-S and 17 beta-estradiol showed no significant changes, the same occurring with SHBG-binding capacity. However, there was a shift in the distribution of circulating T, with a decrease in SHBG-bound T and an increase in albumin-bound and free T (non-SHBG-bound fractions). As previous reports suggest that non-SHBG-bound fractions represent bioavailable fractions, the current data suggests that T fraction studies may not be clinically useful parameters of hyperandrogenism in women receiving antiandrogen therapy.

Serum levels of androstanediol glucuronide, total testosterone, and free testosterone in hirsute women.

OBJECTIVE: To determine the serum levels of androstanediol glucuronide (3 alpha-diol G), total T, and free T in hirsute and nonhirsute women. DESIGN: Controlled clinical study. PATIENTS: Hirsute women with oligomenorrhea, hirsute women with regular ovulatory cycles, and nonhirsute women with regular cycles were selected. MAIN OUTCOME MEASURE: Serum levels of 3 alpha-diol G, total T, and free T were measured in 8 hirsute with oligomenorrhea and 11 hirsute women with regular ovulatory cycles and compared with 20 nonhirsute women with regular cycles (control group). Serum 3 alpha-diol G was also measured during the follicular, periovulatory, and luteal phases in hirsute women with regular cycles. RESULTS: Serum levels of 3 alpha-diol G did not change during the menstrual cycle, in addition we observed that there was no difference between the levels of 3 alpha-diol G, total T, and free T in hirsute women with regular cycles when compared with normal women. These three serum androgens were elevated only in the hirsute women with oligomenorrhea. Besides, there was better correlation between total T and free T (r = 0.81) than total T and 3 alpha-diol G (r = 0.49) or free T and 3 alpha-diol G (r = 0.66). CONCLUSION: The findings suggest that serum 3 alpha-diol G does not provide additional benefit as a marker of hirsutism than serum total or free T.