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PubMed2006

Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder.

BACKGROUND: Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS. METHODS: Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed. RESULTS: Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use. CONCLUSIONS: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Adolescent↗
PubMed2001

Long-term remission of ovarian hyperandrogenism after short-term treatment with a gonadotropin-releasing hormone agonist.

OBJECTIVE: To assess the long-term effects of GnRH agonist (GnRH-a) therapy in a patient with benign ovarian hyperandrogenism. DESIGN: Case report. SETTING: University Hospital endocrine outpatient's clinic. PATIENT(S): A 55-year-old postmenopausal woman with hirsutism and virilization of ovarian origin. INTERVENTION(S): Treatment with a course of GnRH-a (triptorelin 3.75 mg IM every 28 days for 4 months). Follow-up for 3 years. MAIN OUTCOME MEASURE(S): Serum gonadotropin and androgen levels, clinical assessment using the Ferriman-Gallwey score, and assessment of ovarian morphology by ultrasonography. RESULT(S): Administration of triptorelin resulted in suppression of serum testosterone and gonadotropin values and relief of the hyperandrogenic symptoms. Upon discontinuation of treatment, the patient's serum gonadotropin levels returned to the postmenopausal range, but the testosterone levels remained normal and the patient was asymptomatic for an observation period of 3 years. CONCLUSION(S): This case is the first example of long-term remission of ovarian hyperandrogenism in a postmenopausal woman, after short-term treatment with GnRH-a. This supports the view that GnRH-a therapy could be used, even in short courses, for the long-term suppression of benign ovarian hyperandrogenism.

Adrenocorticotropic Hormone↗
PubMed2003

Frequency of the T228A polymorphism in the SORBS1 gene in children with premature pubarche and in adolescent girls with hyperandrogenism.

OBJECTIVE: Because the metabolic actions of insulin are more impaired than the mitogenic pathways in polycystic ovary syndrome (PCOS), genes coding for proteins involved in insulin-mediated glucose transport can be considered as candidate genes. The sorbin and SH3-domain-containing-1 (SORBS1) gene codes for c-Cbl-associated protein (CAP) involved in insulin-mediated glucose uptake. An association study showed that a missense variant of the SORBS1 gene is protective against obesity and diabetes. We tested the hypothesis that the frequency of the protective allele would be decreased in children with premature pubarche and adolescent girls with hyperandrogenism. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Children referred for the evaluation of premature pubarche (n = 79), adolescent girls with hyperandrogenism (n = 56), and healthy nondiabetic controls (n = 50). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency of the T228A allele in our patients and the relationship of body mass index to presence or absence of the T228A variant in our patient population. RESULT(S): Using allele-specific restriction fragment length polymorphism, allele frequencies were found to be similar among the premature pubarche, hyperandrogenism, and control groups (6.0%, 4.6%, and 8.0%, respectively). No statistically significant relationships were found between the SORBS1 genotypes and body mass index or hormone status. CONCLUSION(S): This SORBS1 polymorphism does not play a major role in premature pubarche, hyperandrogenism, and/or polycystic ovary syndrome in our patient population.

Adolescent↗
PubMed1997

Frequency of a polymorphism in the regulatory region of the 17 alpha-hydroxylase-17,20-lyase (CYP17) gene in hyperandrogenic states.

OBJECTIVE: Dysregulation of 17 alpha-hydroxylase (CYP17) has been proposed as a cause of hyperandrogenism. We have determined the prevalence of a polymorphic allele in the CYP17 gene in sporadic patients with polycystic ovaries (PCOS) compared to a reference population, and to a group of hyperandrogenic individuals, to assess its significance to androgen production. PATIENTS AND DESIGN: DNA was isolated from EDTA blood samples from 69 patients with PCOS, 63 patients with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency and 124 consecutive patients attending for a full blood examination. The thymine (T) to cytosine (C) polymorphism at -34 base pairs (bp), denoted alleles A1 and A2 respectively, was detected by amplification of DNA followed by restriction enzyme digestion. MEASUREMENTS: Testosterone and LH. The frequency of alleles A1 and A2 in each of the subject groups was determined. RESULTS: The prevalences of the A1 and A2 alleles were 75 and 25% respectively in the PCOS group which was not significantly different from that in either the hyperandrogenic or the reference group. Neither allele segregated with hyperandrogenism. CONCLUSION: The polymorphism plays no apparent role in the dysregulation of CYP17.

Adolescent↗
PubMed2000

Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche.

OBJECTIVE: Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so-called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH-dependent 17-ketosteroid excess. PATIENTS AND DESIGN: Data were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7+/- 1.1 years) and in adolescence (age 15.0+/-1.9 years). MEASUREMENTS: Serum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17-hydroxyprogesterone (17-OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively). RESULTS: At diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17-OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post-ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post-ACTH 17-OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH. CONCLUSIONS: These longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.

17-alpha-Hydroxyprogesterone↗
PubMed2002

Premature pubarche in girls is associated with functional adrenal but not ovarian hyperandrogenism.

OBJECTIVE: We hypothesized that there would be evidence of functional ovarian hyperandrogenism in girls with premature pubarche (PP) at diagnosis. METHODS: White girls <8 years of age and black girls <6 years with PP (n = 15) were studied. Prepubertal girls (n = 13; 5.3-10.9 years) and early pubertal girls (n = 8) served as control subjects. The biochemical marker for functional ovarian hyperandrogenism was the 17-hydroxyprogesterone (17-OHP), androstenedione (AD), and estradiol (E2) response to subcutaneous leuprolide during adrenal suppression with dexamethasone. This was studied in girls with PP and in control subjects. RESULTS: ACTH stimulated 17-hydroxypregnenolone (17-OH Preg), dehydroepiandrosterone (DHEA), and AD levels, and 17-OH Preg:17-OHP and DHEA:AD ratios were significantly higher in girls with PP than in prepubertal control subjects (n = 18) (P < or =.003). The ovarian response to leuprolide stimulation was comparable in girls with PP and prepubertal control subjects, but the response in prepubertal study subjects was significantly lower than in pubertal control subjects (P =.016 for Delta17-OHP, P =.001 for DeltaAD, and P =.026 for DeltaE2). CONCLUSIONS: Contrary to the hypothesis, PP in girls was not associated with prepubertal evidence of ovarian hyperandrogenism but was associated with functional adrenal hyperandrogenism.

17-alpha-Hydroxyprogesterone↗
PubMed2003

Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.

Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4-19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7-31 repeats vs. 22.0, 15-32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean </=20) was associated with higher 17-hydroxy-progesterone levels post leuprolide (P = 0.009), indicative of ovarian hyperandrogenism, higher testosterone levels (P = 0.02), acne (P = 0.03) and hirsutism scores (P = 0.01), and more menstrual cycle irregularities (P = 0.04). In multiple regression, ovarian hyperandrogenism risk was related to both low birth weight (SD <-1.5: odds ratio = 17.0; 95% confidence interval: 4.2-69.2) and shorter mean CAG number (20 or less repeats: odds ratio = 7.3; 1.3-42.0). In summary, shorter androgen receptor gene CAG number, indicative of increased androgen sensitivity, increases risks for PP and subsequent ovarian hyperandrogenism. Shorter CAG repeat alleles in Barcelona compared with United Kingdom women could lead to higher prevalences of these conditions.

Adolescent↗
PubMed2003

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

Adipose Tissue↗
PubMed1996

Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism.

Previous studies have documented the association of insulin resistance and hyperandrogenism in adult women with functional ovarian hyperandrogenism (FOH) or polycystic ovary syndrome (a form of FOH). However, the possible impact of adrenal hyperandrogenism development during childhood in premature pubarche (PP) patients on postpubertal insulin secretion patterns remains unclear. The fasting insulin to glucose ratio, C peptide, early insulin response to glucose (IRG), mean blood glucose, mean serum insulin (MSI), glucose uptake rate in peripheral tissues (M), and insulin sensitivity indexes (SI) in response to a standard oral glucose tolerance test were evaluated in 13 PP girls with FOH (group A; age, 17.2 +/- 0.5 yr), 11 eumenorrheic nonhirsute PP girls (group B; age, 16.6 +/- 0.5 yr), and 21 age-matched controls (group C). Body mass indexes (BMI) were similar in the 3 groups (group A, 23.3 +/- 0.8; group B, 22.5 +/- 0.6; group C, 20.6 +/- 0.5 kg/m2). MSI values were significantly higher in FOH patients than in controls (74.7 +/- 17.6 vs. 45.7 +/- 4.1 mU/L; P < 0.01), but were not different from those in group B (63.3 +/- 11.1 mU/L). Thirty-eight percent of FOH patients (group A) and 27% of non-FOH patients (group B), all of whom had normal BMI, showed MSI levels well above the upper normal limit for controls (> 83.3 mU/L). MSI correlated with the degree of ovarian hyperandrogenism [defined by an abnormal 17-hydroxyprogesterone response to challenge with the GnRH analog leuprolide acetate; group A] and with the free androgen index [testosterone (nanomoles per L)/sex hormone-binding globulin (nanomoles per L) x 100; groups A and B)]. Although IRG, glucose uptake rate in peripheral tissues, mean blood glucose, and SI values were not significantly different in the 3 groups, 3 patients in group A and 1 patient in group B showed decreased insulin sensitivity and/or an enhanced early IRG. Among others, significant correlations between MSI and free androgen index values (r = 0.6; P < 0.002; groups A and B) and between BMI and SI (r = -0.53; P < 0.05; groups A and B) were found. Peak 17-hydroxyprogesterone responses to ACTH at PP diagnosis correlated positively with SI in both groups of patients (r = 0.53; P < 0.007). Hyperinsulinemia is a common feature in adolescent PP patients with FOH and appears to be directly related to the degree of androgen excess. Long term follow-up of PP patients into adulthood is warranted to ascertain whether hyperinsulinemia actually precedes FOH development and whether overt insulin resistance ensues.

Adolescent↗
PubMed1997

Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism.

A deficiency of 21-hydroxylase activity is one of the most commonly inherited genetic disorders in man, with heterozygosity for CYP21 mutations affecting approximately 1 in 60 of the non-Jewish Caucasian population. We have hypothesized that heterozygosity for CYP21 mutations in women increases their risk of developing clinically evident hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and/or the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation. To test these hypotheses, we studied 38 obligate carriers for 21-hydroxylase deficiency (i.e. mothers of children with congenital adrenal hyperplasia or nonclassic congenital adreanl hyperplasia), comparing them to 27 weight-, parity-, and age-matched controls. Premenopausal carriers, not receiving hormonal treatment (n = 27), had higher mean total and free testosterone [T; 2.02 +/- 0.55 vs. 1.56 +/- 0.65 nmol/L (P < 0.007) and 0.018 +/- 0.007 vs. 0.012 +/- 0.006 nmol/L (P < 0.007), respectively] and lower mean sex hormone-binding globulin (214 +/- 62 vs. 277 +/- 129 nmol/L; P < 0.03) levels compared to controls. There was no difference in the mean basal levels of dehydroepiandrosterone sulfate, androstenedione (A4), or 17-OHP between carriers and controls. As expected, carriers exhibited higher stimulated and net increment 17-OHP levels than controls [21.1 +/- 27.1 vs. 6.2 +/- 3.1 nmol/L (P < 0.01) and 19.0 +/- 26.5 vs. 4.4 +/- 2.8 nmol/L (P < 0.009), respectively]. However, no difference was observed in the response of A4 to ACTH-(1-24) stimulation. Of the 27 carriers studied biochemically, 2 (7.4%) had a stimulated 17-OHP value between 30.3-60.6 nmol/L, and 1 (3.7%) had a 17-OHP level above 60.6 nmol/L, suggestive of nonclassic adrenal hyperplasia. Of all carriers studied genetically (n = 36), 50.0% (18 of 36) had 1, 33% (12 of 36) had 2, and 16.7% (6 of 36) had 3 or more mutations. In 27.8% (10 of 36) of carriers, the mutations were contiguous, consistent with a large gene conversion. All 38 carriers were examined for historical and physical features of hyperandrogenism. Hirsutism was defined as a Ferriman-Gallwey score of 6 or more, menstrual/ovulatory dysfunction as a history of menstrual cycles of more than 35-day, and hyperandrogenemia as total or free T, A4, and/or dehydroepiandrosterone sulfate levels above the upper 95th percentile of control values. Further, defining functional androgen excess (FAE) as the presence of at least 2 of the 3 hyperandrogenic features, 4 of 38 (10.5%) of carriers appeared to be affected (95% confidence interval, 2.9-24.8%). Assuming an expected prevalence rate of FAE in the general population of 5-20%, the frequency of FAE among our carriers was not significantly higher than expected. In conclusion, heterozygosity for CYP21 mutations does not appear to increase the risk of clinically evident hyperandrogenism, although carrying the defect was associated with higher mean and free T levels. Finally, due to the low frequency of androgen excess in our heterozygote population, we were unable to correlate the severity of the CYP21 mutation and/or the 17-OHP response to ACTH stimulation with the presence of the phenotype.

Adrenal Hyperplasia, Congenital↗
PubMed1997

The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women.

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.

Adult↗
PubMed1999

Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women.

It was recently suggested that precocious pubarche associated with subsequent functional ovarian hyperandrogenism and hyperinsulinemia could have a common origin in reduced fetal growth. We previously reported that young women born with intrauterine growth retardation (IUGR: birth weight less than the third percentile) were hyperinsulinemic and less insulin sensitive than women born with normal birth weight. The aim of the present study was to investigate whether these IUGR-born women demonstrated hyperandrogenism compared with controls. Our study population was composed of 130 IUGR-born women and 150 controls, of similar age (20.6 +/- 3.2 vs. 20.4 +/- 2.0 yr). Hormonal contraception in terms of frequency and medication, including antiandrogenic therapy, was identical in the 2 groups. After adjustment for hormonal contraception, being born with IUGR had no independent effect on serum androgen concentrations. In women who were not receiving hormonal contraception, no statistical differences were found between IUGR-born women (n = 67) and controls (n = 64) for delta4-androstenedione (2.26 +/- 0.68 vs. 2.24 +/- 0.55 ng/mL; P = 0.76), dehydroepiandrosterone sulfate (2294 +/- 1117 vs. 2489 +/- 1235 ng/mL; P = 0.24), testosterone (0.82 +/- 0.85 vs. 0.70 +/- 0.26 ng/mL; P = 0.80), or serum sex hormone-binding protein concentrations (45.5 +/- 28.2 vs. 53.1 +/- 30.3 nmol/L; P = 0.27). In both IUGR and control groups, sex hormone-binding protein correlated negatively with fasting insulin (r = -0.23; P = 0.03 and r = -0.26; P = 0.05), but serum androgen levels did not correlate with insulin. In summary, hyperinsulinemia observed in young women born with IUGR is not associated with hyperandrogenism. Consequently, our results do not support the hypothesis of a common in utero programming of hyperandrogenism and hyperinsulinemia.

Adolescent↗
PubMed1999

The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS). As insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of PCOS, we hypothesize that they may also have a role in the hyperandrogenism of premature adrenarche. Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underwent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S(I)) was assessed using the frequently sampled i.v. glucose tolerance test with tolbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, sex hormone-binding globulin, and free testosterone (T) were also obtained. The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean S(I) for the entire group was 6.78 +/- 5.21 x 10(-4) min/microU x mL (normal prepubertal S(I), 6.5 +/- 0.54 x 10(-4) min(-1) x microU(-1) x mL(-1)). However, 15 of the 35 girls had an S(I) that was more than 2 SD below the mean reported for normal prepubertal children. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II-III pubertal girls. The girls were divided into two groups based on their S(I) (group I, S(I) >2 SD below the mean for age; group II, normal S(I)). The group I girls with a reduced S(I) had significantly higher ACTH-stimulated levels of 17OHPreg (group I, 760 +/- 87.84 ng/dL; group II, 428.9 +/- 46.28 ng/dL; P = 0.002), 17OHPreg/17OHP ratio (group I, 3.95 +/- 0.36; group II, 2.96 +/- 0.35; P = 0.05), 17OHPreg/DHEA (group I, 2.06 +/- 0.21; group II, 1.4 +/- 0.13; P = 0.01), and free T (group I, 1 +/- 0.23 ng/dL; group II, 0.49 +/- 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the S(I) correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with S(I) (r = -0.94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also correlated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05). To summarize, the ACTH-stimulated delta5-steroid levels were higher in prepubertal girls with premature adrenarche and reduced S(I). There was a significant inverse correlation among ACTH-stimulated hormone levels, S(I), and IGFBP-1, whereas IGF-I correlated directly with ACTH-stimulated androgens. These findings support the hypothesis that insulin and IGFs may have a role in the hyperandrogenism of premature adrenarche just as they do in PCOS. Hence, in certain girls with premature adrenarche, hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.

Adrenocorticotropic Hormone↗
PubMed2002

The -597 G-->A and -174 G-->C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism.

To evaluate whether genetic variability at the IL-6 gene (IL-6) is associated with hyperandrogenism, we studied four common polymorphisms in the IL-6 promoter (-597G-->A, -572G--> C, -373A(n)T(n), -174G-->C) in 85 hyperandrogenic patients and 25 healthy women. We found 5 different haplotypes when considering the 3 biallelic polymorphisms at positions -597, -572, and -174 of IL-6 (relative frequencies in parentheses): GGG (0.505), AGC (0.377), GGC (0.059), GCG (0.055), and GCC (0.005). The frequencies of the GGG haplotype were 0.559 in patients and 0.320 in controls, whereas those of the AGC haplotype were 0.318 in patients and 0.580 in controls (chi(2) = 12.145; P < 0.02). The -597G-->A and -174G-->C polymorphisms were in linkage disequilibrium (chi(2) = 152.220; P < 0.00001), and were associated with patient or control status. -597G and -174G alleles were more frequent in patients in homozygosity or considering subjects homozygous and heterozygous for G alleles as a whole (P < 0.05 for all analyses). In healthy women G alleles at -597 and -174 were associated with statistically significant higher circulating levels of IL-6 and basal cortisol, 11-deoxycortisol, and 17-hydroxyprogesterone and a tendency (P < 0.10) for higher total T concentrations compared with -597A and -174C alleles. On the contrary, neither the -572G-->C nor the -373A(n)T(n) polymorphism was related to hyperandrogenism or influenced any clinical or biochemical variable. In conclusion, our present results suggest that the -597G-->A and -174G-->C polymorphisms in IL-6 are involved in the pathogenesis of hyperandrogenic disorders.

Adult↗
PubMed2002

Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation.

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

Adult↗
PubMed1999

Syndromes of hyperandrogenism in women.

BACKGROUND: Although the actual incidence is not known, hyperandrogenism seems common among Australian women. Most women with syndromes of hyperandrogenism present with symptoms such as acne, hirsutism and androgenic alopecia, or menstrual irregularity. OBJECTIVES: The aim of this overview is: to put in perspective the various causes of hyperandrogenism in women, provide a guide to evaluation of affected women; and briefly review current management strategies. DISCUSSION: Hyperandrogenism in women is also associated with significant health problems including infertility, insulin resistance, gestational diabetes, type 2 diabetes mellitus and dyslipidaemia which may or may not be linked with obesity.

Acne Vulgaris↗
PubMed2002

[Acne in adult women: data from a national study on the relationship between type of acne and markers of clinical hyperandrogenism].

INTRODUCTION: The role of hyperandrogenism in acne occurring or persisting in adult women is controversial. Studies reported have often been carried out in hospital settings. The aim of this nationwide prospective and descriptive study was to evaluate the frequency of clinical hyperandrogenism in a large number of adult acneic women visiting dermatologists in a non-hospital setting. PATIENTS AND METHODS: Three hundred and fifteen dermatologists completed clinical questionnaires concerning the next five female patients with acne at their private practices. These patients had to be between 25 and 45 years of age. The questionnaire covered patients' demographic characteristics, medical history, gynaecological status and acne history. Patients' acne, seborrhea and cycle disorders were described, as well as other signs suggesting hyperandrogenism, such as hirsutism and alopecia. RESULTS: A total of 1 135 questionnaires were analyzed. Nearly 50 p. 100 of the patients had major scalp or facial seborrhea, 18.4 p. 100 hirsutism, 7 p. 100 alopecia and 32.2 p. 100 menstrual cycle abnormalities. When these signs were present, acne was more often retentional, with more scarring and more widespread. CONCLUSION: This prospective study in a large number of patients in a non-hospital setting shows that acne in adult women is frequently associated with clinical hyperandrogenism.

Acne Vulgaris↗
PubMed1994

[Strategies in screening of nonclassical forms of congenital adrenal hyperplasia caused by P450c21 deficiency in hyperandrogenic women].

BACKGROUND: The value of the measurement of the serum level of 17-hydroxyprogresterone (170HP) and the stimulation test with adrenocorticotropin (ACTH) with and without previous slowing with dexamethasone was determined to detect congenital adrenal hyperplasia (CSH) due to a deficiency of P450c21 in hyperandrogenic women. METHODS: Three hundred seventy women consecutively attended for hyperandrogenism were studied. Stimulation tests of 170HP were performed with 250 micrograms i.v. of synthetic ACTH with previous administration of 1 mg of dexamethasone in 191 of the patients. The test was performed without previous dexamethasone in the remaining 179 patients. RESULTS: Nineteen patients with unclassical forms of CSH by deficiency of P450c21 were detected. Another 19 were considered as probable heterozygotes. The basal levels of 170HP with and without previous dexamethasone showed negative predictive value of nearly 100%, indicating the validity of their use in selecting patients for the stimulation test. No significant differences were seen in the increases of post ACTH 170HP observed between the tests carried out with and without dexamethasone. CONCLUSIONS: The frequency of congenital adrenal hyperplasia by deficiency of P450c21 in the hyperandrogenic women studied was found to be 5.1%. The low frequency together with the predictive value of the basal concentrations of 170HP indicate that the systematic routine use of the ACTH test as a means of scrutiny of CSH in hyperandrogenic women is unjustified.

17-alpha-Hydroxyprogesterone↗