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Pituitary desensitization to gonadotropin-releasing hormone increases abdominal adiposity in hyperandrogenic anovulatory women.

OBJECTIVE: To determine whether hyperandrogenism in anovulatory women affects body fat distribution. DESIGN: Prospective nonrandomized study. SETTING: An academic research environment. PATIENT(S): Ten hyperandrogenic anovulatory patients and 10 healthy women matched by body mass index. INTERVENTION(S): Regional body fat analysis was performed before and after 3 months of GnRH analogue (GnRH-a) therapy. MAIN OUTCOME MEASURE(S): Body fat distribution was measured by waist-to-hip circumference ratio, single-slice computed tomography imaging (L2-3 interspace), and total body dual-energy x-ray absorptiometry. RESULT(S): Weight, body mass index, waist-to-hip circumference ratio, total body and leg fat mass, and subcutaneous adipose area were unaffected by the presence of hyperandrogenism or the use of GnRH-a therapy. Basal abdominal fat mass, abdomen-to-leg fat mass ratio, visceral adipose area, and total visceral adipose volume were comparable in both study groups. The abdominal fat mass increased in both groups during GnRH-a therapy, whereas the abdomen-to-leg fat mass ratio rose significantly only in the hyperandrogenic patients. During GnRH-a therapy, the hyperandrogenic patients demonstrated a significant increase in visceral adipose area compared with the healthy women so that total visceral adipose volume increased significantly in the former but not the latter. CONCLUSION(S): Three months of GnRH-a administration preferentially increased abdominal fat, as measured by single-slice computed tomography imaging and total body dual-energy x-ray absorptiometry, in hyperandrogenic anovulatory women.

Abdomen↗

Human chorionic gonadotropin stimulation to assess for ovarian hyperandrogenism.

STUDY OBJECTIVE: To determine whether human chorionic gonadotropin (hCG) stimulation elicits an exaggerated 17-hydroxyprogesterone (17-OHP) response in patients with functional ovarian hyperandrogenism. METHODS: In this clinical study, healthy volunteers and hyperandrogenic patients in an outpatient General Clinical Research Center (GCRC) setting were studied. Five adolescent girls with functional ovarian hyperandrogenism were studied. Six healthy women with regular menstrual cycles volunteered for this study. Steroid hormone responses to hCG stimulation were measured before and 30, 240, and 300 minutes after hCG injection. Congenital adrenal hyperplasia was excluded through ACTH stimulation testing and molecular genetic analysis. MAIN OUTCOME MEASURE: 17-OHP responses. RESULTS: Mean basal 17-OHP concentrations were greater in the hyperandrogenic patients, 110.4+/-41.2 ng/dL versus 61.8+/-28.6 ng/dL. After hCG stimulation, 17-hydroxyprogesterone concentrations significantly increased in the patients and were unchanged in the healthy controls. CONCLUSION: hCG stimulation elicited greater 17-hydroxyprogesterone responses in adolescent girls with functional ovarian hyperandrogenism compared with healthy controls. hCG stimulation may be helpful to confirm ovarian hyperandrogenism.

17-alpha-Hydroxyprogesterone↗

Association of polymorphisms in the interleukin 6 receptor complex with obesity and hyperandrogenism.

OBJECTIVE: Interleukin-6 (IL-6), is an inflammatory cytokine that may influence the pathogenesis of obesity and hyperandrogenism. IL-6 exerts its actions through a heterodimeric receptor consisting of two membrane-bound glycoproteins: an 80-kDa IL-6 binding unit (IL6R-alpha) and a 130-kDa IL-6 signal transducer (gp130). Genetic variability at these loci might contribute to explain the development of obesity and hyperandrogenism. RESEARCH METHODS AND PROCEDURES: We have evaluated the possible association of several polymorphisms in the IL6R-alpha and gp130 genes with obesity and/or hyperandrogenism in a case-control study involving 143 hyperandrogenic patients and 45 healthy women from Spain. RESULTS: A microsatellite CA-repeat polymorphism in the IL6R-alpha locus was associated with obesity. The frequency of the common 149-bp allele was markedly increased in obese women compared with controls when considering patients and controls as a whole (0.41 vs. 0.29, chi(2) = 17.085, p < 0.050). On the other hand, the uncommon Arg148 allele of the Gly148Arg polymorphism in the gp130 gene was more frequent in controls compared with hyperandrogenic patients (0.17 vs. 0.08, chi(2) = 5.605, p = 0.026). Controls carrying Arg148 alleles had lower 11-deoxycortisol and 17-hydroxyprogesterone concentrations, a lower response of androstenedione to 1-24 adrenocorticotropin, and an almost significant decrease in free testosterone levels, suggesting that Arg148 alleles in the gp130 gene have a protective effect against androgen excess and adrenal hyperactivity. DISCUSSION: Polymorphisms in the gp130 and IL6R-alpha loci influence hyperandrogenism and obesity, respectively. Our present results further suggest that proinflammatory genotypes are involved in the pathogenesis of these common metabolic disorders.

Adult↗

Serum anti-Mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism.

BACKGROUND: Anti-Mullerian hormone (AMH) is expressed in pre- and small-antral follicles. High serum levels are found in women with polycystic ovaries (PCO), accordant with their increased content of small follicles. To evaluate the relationship between AMH, folliculogenesis and hyperandrogenism, we compared serum AMH levels between women with PCO with and without hyperandrogenism and normal controls during controlled ovarian hyperstimulation (COH). METHODS: Nineteen women with PCO and hyperandrogenism (group A), 10 women with PCO but no hyperandrogenism (group B) and 23 ovulatory women with normal ovarian morphology (group C, controls) underwent COH with the long protocol. Serum levels of AMH, estradiol, androstenedione and follicular tracking were determined before gonadotropins treatment (day 0) and every 2-4 days up to the day of HCG administration. RESULTS: AMH levels declined gradually throughout COH in the three groups, but remained higher in groups A and B compared with the controls. Significantly higher levels were found in group A compared with group B, despite comparable numbers of small follicles. Multiple regression analysis revealed that both the number of small follicles and serum androgens were correlated to AMH. CONCLUSIONS: Women with PCO have higher serum AMH levels during COH than controls. Hyperandrogenism is associated with an additional increase in AMH. It is conceivable that hyperandrogenism may reflect more severe disruption of folliculogenesis in women with PCO or may affect AMH secretion.

Adult↗

The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.

The genetic mechanisms underlying functional hyperandrogenism and the polycystic ovary syndrome (PCOS) remain largely unknown. Given the large number of genetic variants found in association with these disorders, the emerging picture is that of a complex multigenic trait in which environmental influences play an important role in the expression of the hyperandrogenic phenotype. Among others, genomic variants in genes related to the regulation of androgen biosynthesis and function, insulin resistance, and the metabolic syndrome, and proinflammatory genotypes may be involved in the genetic predisposition to functional hyperandrogenism and PCOS. The elucidation of the molecular genetic basis of these disorders has been burdened by the heterogeneity in the diagnostic criteria used to define PCOS, the limited sample size of the studies conducted to date, and the lack of precision in the identification of ethnic and environmental factors that trigger the development of hyperandrogenic disorders. Progress in this area requires adequately sized multicenter collaborative studies after standardization of the diagnostic criteria used to classify hyperandrogenic patients, in whom modifying environmental factors such as ethnicity, diet, and lifestyle are identified with precision. In addition to classic molecular genetic techniques such as linkage analysis in the form of a whole-genome scan and large case-control studies, promising genomic and proteomic approaches will be paramount to our understanding of the pathogenesis of functional hyperandrogenism and PCOS, allowing a more precise prevention, diagnosis, and treatment of these prevalent disorders.

Androgens↗

The value of the low-dose dexamethasone suppression test in the differential diagnosis of hyperandrogenism in women.

We studied 211 hyperandrogenic women with respect to clinical presentation, basal androgen levels, and the degree of cortisol and androgen suppression during a 48-h low-dose (2 mg) dexamethasone-suppression test (LDDST) to exclude ovarian and adrenal tumors. In 42 women with elevated testosterone levels, 21 of whom failed to suppress testosterone during the LDDST, the response of serum androgen levels during a 4-wk administration of 7.5 mg prednisolone in a reverse circadian regimen was also assessed. These results were compared with an additional 17 patients with histologically proven androgen-secreting tumors. Clinical presentation alone was suggestive of a virilizing tumor in 70% of patients with tumors. Serum testosterone, although occasionally only marginally elevated, was the sole androgen that was elevated in every patient with a tumor. After the LDDST, none of the patients with tumors obtained either a greater than 40% reduction or normalization of the previously elevated testosterone levels, whereas 88% of patients with nontumorous hyperandrogenism showed either normalization or suppression of more than 40%. With one exception, all of the patients with nontumorous hyperandrogenism who showed inadequate suppression of testosterone during the LDDST, and were treated with prednisolone, normalized the previously elevated androgens after 1 month of administration. In summary, in women presenting with hyperandrogenism, lack of testosterone suppression during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting tumors from patients with nontumorous hyperandrogenism in this small series. The LDDST is an easy to perform screening test that can also identify causes of hyperandrogenism due to altered glucocorticoid secretion.

Adolescent↗

The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women.

To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step (20 and 80 mU/m2.min) hyperinsulinemic euglycemic clamp combined with indirect calorimetry and tracer glucose infusion in 43 women (13 obese and 30 nonobese) with normal glucose tolerance and clinical evidence of increased androgen action (hirsutism and/or polycystic ovary syndrome) as well as 12 age- and body mass index-matched healthy controls. Hyperandrogenic women were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), or the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-mediated glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in both ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on glucose metabolism significantly increased for both the patients as a whole (F = 7.4; P < 0.01) and each treatment group separately. However, insulin action remained lower than in controls and showed no further improvement in patients reevaluated after I yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for the improvement in substrate disposal induced by antiandrogen drugs. The increase in the effectiveness of insulin was greater in the lean subjects, whereas the change was small and not statistically significant in the obese women. Response to treatment was more pronounced in women with nonovarian hyperandrogenism, particularly at the low insulin infusion rate. Endogenous glucose production in hyperandrogenic patients was similar to that in healthy women and was unaffected by therapy. In conclusion, antiandrogen treatment partially reversed the peripheral insulin resistance associated with hyperandrogenism regardless of which antiandrogen was used. These data strongly suggest that in women, androgen excess per se contributes to impairment of insulin action.

Adult↗

TNF-alpha and hyperandrogenism: a clinical, biochemical, and molecular genetic study.

To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls (mean[median] +/- SD: 7.2[7.0] +/- 3.3 pg/ml vs. 5.6[4.4] +/- 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied here (-1196C/T, -1125G/C, -1031T/C, -863C/A, -857C/T, -316G/A, -308G/A, -238G/A, and -163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-alpha levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants. In conclusion, our present results suggest that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-alpha system and androgen excess is needed before considering TNF-alpha as a significant contributing factor to the development of hyperandrogenism.

17-alpha-Hydroxyprogesterone↗

Gene analysis of steroid 5 alpha-reductase 1 in hyperandrogenic women.

AIM: To examine the gene encoding for 5alpha-reductase type 1 in hyperandrogenic women, and assess the association of its eventual mutations or polymorphisms with the development of the hyperandrogenic female pattern. METHODS: Sixteen hyperandrogenic women were included in the study. Single-stranded conformation polymorphism analysis (SSCP) and DNA sequencing were performed after polymerase chain reaction amplification of each of the 5 exons of the SRD5A1 gene in both hyperandrogenic and control group (16 participants). RESULTS: Sequence analysis identified the existence of many polymorphisms; in codon 24 of exon 1, GGC (Gly) into GAC (Asp); in codon 30 of exon 1, CGG (Arg) into CGC (Arg); in exon 3 codon 169, ACA to ACG (both encoding for threonine); in exon 5, AGA to AGG (both encoding for arginine, codon 260); and T/C polymorphism in intron 2. Polymorphisms were found in both groups. CONCLUSION: Polymorphisms of SRD5A1 gene were the same in both hyperandrogenic and healthy women, indicating no significant associations of genetic polymorphisms/variations of SRD5A1 gene with clinical manifestations of hyperandrogenic disorders in women.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

[Late onset hyperandrogenism caused by 3-beta-hydroxysteroid dehydrogenase deficiency].

OBJECTIVES: Clinical manifestations of hyperandrogenism, including hirsutism and acne with or without dysmenorrhoea are well recognized in late onset hyperandrogenism due to deficiency in 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), yet the frequency of this deficiency in patients with post-puberty hirsutism is not well established. We therefore evaluated retrospectively this deficiency state in women who consulted our unit for manifestations suggestive of hyperandrogenism from 1990 to 1992. METHODS: We included 32 women with clinical manifestations of hyperandrogenism for whom a partial deficit in 3 beta-HSD could be searched for on the basis of hormone assays. Their mean age was 27.5 years (range 14 to 46) and the clinical manifestation was hirsutism in 21 cases, acne in 13, alopecia in 5 and dysmenorrhoea in 11. Diagnostic tests included adrenal stimulation with 0.25 mg beta 1-24 corticotrophin and immunoradioassay of plasma levels of 17-hydroxypregnenolone (17-OHPreg), 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHA) and cortisol (F). Pang's criteria for the diagnosis of partial deficiency in 3 beta-HSD were retained. We defined deficiency in 3 beta-HSD as certain when the 4 following criteria were present 60 minutes after stimulation: 17-OHPreg > 17.5 ng/ml; DHA > 20 mg/ml; 17-OHPreg/17-OHP > 9; 17-OHPreg/F.10(-3) > 53. Diagnosis was considered probable when only 3 criteria were met and was excluded in all other cases. RESULTS: Positive diagnosis of deficiency in 3 beta-hydroxysteroid dehydrogenase was made in 4 of the 32 patients and probable in 4 others. CONCLUSION: Based on our series of patients, late onset hyperandrogenism due to 3 beta-hydroxysteroid dehydrogenase deficiency would thus appear to be a relative frequent deficiency state. Since therapeutic measures can be taken, this deficiency should be carefully searched for in all young patients presenting with manifestations suggesting hyperandrogenism.

3-Hydroxysteroid Dehydrogenases↗

Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia.

This study examined the prevalence of both basal and glucose-stimulated hyperinsulinemia and acanthosis nigricans (AN) as well as the relationship between insulin and androgen levels in hyperandrogenic women. Sixty-two women who had an elevation of 1 or more plasma androgen levels were studied. The results in these women, grouped for analysis on the basis of obesity and ovulatory status, were compared to those in 36 control women of similar ages and weights. The anovulatory hyperandrogenic women had the clinical and biochemical features of the polycystic ovary syndrome (PCO). Oral glucose tolerance tests were performed with measurement of glucose, insulin, sex hormone-binding globulin (SHBG), and total and non-SHBG-bound sex steroid levels. AN was present in 29% of the hyperandrogenic women, the majority of them obese. Fifty percent of obese PCO women had AN, but they did not otherwise differ from PCO women lacking this dermatological change. Only women with PCO had significant hyperinsulinemia independent of obesity, and obese PCO women with AN had the highest serum insulin levels. Plasma glucose values during the oral glucose tolerance test were significantly increased in obese PCO women independent of the presence of AN, and 20% of these women had frank impairment of glucose tolerance. Ovulatory hyperandrogenic women had normal insulin levels and glucose tolerance. Obese and nonobese women had different relationships between sex steroid and insulin levels; obese women had significant correlations between insulin and non-SHBG testosterone levels (r = 0.30; P less than 0.05), whereas nonobese women had significant correlations between insulin and FSH (r = 0.40; P less than 0.01), dehydroepiandrosterone sulfate (r = 0.33; P less than 0.05), and SHBG (r = 0.37; P less than 0.05) levels, suggesting that the mechanisms underlying the association between sex steroid and insulin levels are complex. These findings suggest that 1) only women with PCO have hyperinsulinemia independent of obesity; hyperinsulinemia is not a feature of hyperandrogenic states in general; 2) AN is a common finding in obese hyperandrogenic women, particularly those with PCO; 3) only obese PCO women are at risk for impairment of glucose tolerance, independent of the presence of AN, suggesting that the negative impact of PCO and obesity on insulin action is additive; and 4) PCO women with AN can be considered as a subgroup of PCO and do not appear to have a distinct endocrine disorder.

Acanthosis Nigricans↗

The relative contributions of hepatic and peripheral tissues to insulin resistance in hyperandrogenic women.

Insulin resistance is associated with hyperandrogenic states. To determine the mechanisms by which androgen excess can affect insulin action, we studied insulin sensitivity in five nonobese hyperandrogenic women and six normal women. After oral glucose administration, the hyperandrogenic women had higher serum insulin concentrations than the normal women (P = 0.05). The mean cumulative peripheral serum insulin response in the hyperandrogenic women [79.6 +/- 30.8 (+/- SD) nmol/L.300 min] was significantly greater than that in the normal women (46.6 +/- 15.1 nmol/L.300 min; P less than 0.05). In the basal state and during hyperinsulinemic (20 mU/min.m2) euglycemic clamp studies serum insulin levels were similar in the two groups. Basal and insulin-mediated suppressions of hepatic glucose production determined from [3-3H]glucose specific activity were similar in the two groups. Peripheral glucose utilization was markedly diminished in the hyperandrogenic women compared to that in the normal women (27.8 +/- 6.7 vs 48.9 +/- 12.8 mumol/min.kg fat-free mass; P less than 0.01). We conclude that the insulin resistance in nonobese hyperandrogenic women is due to peripheral, but not hepatic, resistance to the action of insulin. This marked peripheral insulin resistance may result from the effects of hyperandrogenemia on skeletal muscle fiber morphology and metabolism.

Adult↗

21-Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis.

21-Hydroxylase-deficient late-onset adrenal hyperplasia (LOAH) appears to affect 1-6% of hyperandrogenic women. Screening and diagnostic criteria for LOAH have not been well established, as these patients are clinically indistinguishable from other hyperandrogenic women. The following prospective study was undertaken to 1) determine the predictive value of screening hyperandrogenic women for LOAH with a morning follicular phase basal 17-hydroxyprogesterone (17-HP) level and 2) compare the various in vivo estimates of 21-hydroxylase activity after adrenal stimulation for the diagnosis of LOAH. Twenty-one euandrogenic control women (physically normal, without hirsutism, with regular menses, and a negative family history) were studied. The clinical population consisted of 164 consecutive unselected patients seen at the Division of Reproductive Endocrinology and Infertility of Johns Hopkins University School of Medicine between 1983 and 1987 demonstrating hirsutism and/or hyperandrogenic oligomenorrhea. Controls and patients underwent acute adrenal stimulation with 1 mg ACTH-(1-24), administered in the morning to fasting patients in the follicular phase of their menstrual cycle. Blood was sampled before and 30 min after ACTH-(1-24) administration. Steroid RIA determinations were performed for 17-HP, progesterone, testosterone, dehydroepiandrosterone sulfate, androstenedione, FSH, LH, and PRL. Three estimates of 21-hydroxylase activity were studied: the 17-HP level 30 min post-ACTH (17-HP30), the change in 17-HP (delta 17-HP0-30) and the summed rate of change in 17-HP and progesterone ([delta 17-HP0-30) + delta P0-30]/30 min). The upper 95th percentiles for these estimates of 21-hydroxylase activity in control women were 9.6 nmol/L (316 ng/dL), 8.8 nmol/L (292 ng/dL), and 0.39 nmol/L.min (13 ng/dL.min), respectively. Thirteen of 164 (7.9%) hyperandrogenic women had at least 1 abnormal 21-hydroxylase measurement. Four of these women (2.4%) had 17-HP measurements 3- to 20-fold above the upper normal 95th percentile (17-HP30 greater than 36.3 nmol/L or 1200 ng/dL) and were considered as suffering from LOAH. In our population the 3 measures of 21-hydroxylase studied clearly differentiated the LOAH women from all others, although a single 17-HP level 30 min post-ACTH was the simplest and most cost effective. Nine other hyperandrogenic women (5.5%) had at least 1 abnormal 21-hydroxylase measurement less than 3-fold the upper normal 95th percentile value and were designated as having mild 21-hydroxylase deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

17-alpha-Hydroxyprogesterone↗

Abnormalities of 21-hydroxylase gene ratio and adrenal steroidogenesis in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to acute adrenal stimulation.

One to 2% of hyperandrogenic women demonstrate a 17-hydroxyprogesterone (17-HP) level greater than 36.3 nmol/L (1200 ng/dL) after acute ACTH-(1-24) adrenal stimulation, consistent with 21-hydroxylase (21-OH) deficient late-onset adrenal hyperplasia (LOAH). The following study was undertaken to endocrinologically and genetically define hyperandrogenic patients with an exaggerated 17-HP response to ACTH stimulation, and which do not represent LOAH. Of 265 consecutive patients suffering from hirsutism and/or hyperandrogenic oligomenorrhea, 23 (8.7%) demonstrated a 17-HP level 30 min post stimulation greater than 9.6 nmol/L or 316 ng/dL (the upper 95th percentile in 41 eumenorrheic nonhirsute healthy control women). Seven patients or five separate families (1.8% of total) demonstrated poststimulation 17-HP levels consistent with LOAH. Of the remaining 16 patients, the net increment in 17-HP (delta 17-HP0-30) was within normal limits in seven (2.6%) and these women were assumed to have a normal 17-HP adrenocortical response superimposed on an elevated basal level of nonadrenal (e.g. ovarian) origin. In the remaining nine hyperandrogenic patients (3.4%) various abnormalities of adrenal response were noted in all but one patient, consistent with adrenal hyper-responsiveness. One patient demonstrated an 11-deoxycortisol poststimulation level greater than 3-fold the upper 95th percentile of normal, consistent with 11-hydroxylase LOAH and was excluded from further study. Six of these women were available for further genetic characterization, all Caucasian and unrelated. Three were heterozygotes for HLA-B14, three for B40, and one for B35 antigen, HLA-types associated with the inheritance of 21-OH deficiencies. Although, normally there are two 21-OH genes (a pseudogene and a functional gene) present in a 1:1 ratio, we have previously reported a high frequency of 21-OH gene ratio abnormalities in LOAH. All but one of our patients demonstrated an abnormal 21-OH gene ratio. In conclusion, 3.4% of our hyperandrogenic population demonstrated an exaggerated 17-HP increment after ACTH stimulation, not consistent with LOAH or increased extraadrenal 17-HP production. The increased prevalence of HLA alleles known to be linked to inherited defects of 21-OH function and the increased frequency in 21-OH gene ratio abnormalities suggest that a majority of these individuals may be carriers for these genetic disorders. However, the adrenocortical abnormalities noted were more consistent with a generalized hyperreactivity of the adrenal to ACTH stimulation, than a specific enzyme deficiency, implying that carrier status for 21-OH deficiency may be incidental to the hyperandrogenism.

17-alpha-Hydroxyprogesterone↗

Utilization of commercial laboratory results in management of hyperandrogenism in women.

OBJECTIVE: To compare results from testosterone radioimmunoassay kits commonly used by commercial laboratories as well as their reference ranges and to analyze the scientific literature for ranges of serum testosterone levels in normal women and those with hyperandrogenism. METHODS: We reviewed quality assurance reports of various testosterone ligand challenges from four groups of laboratories and summarized testosterone data from 17 published reports about normal women and 14 studies of hyperandrogenic women. RESULTS: A significant variability was demonstrated between the radioimmunoassay kits at all concentrations (for example, a sample with a mean testosterone level of 96.1 ng/dL was reported by some laboratories as containing 71.8 ng/dL and by others as 123.4 ng/dL). All laboratories provide essentially the same "reference range" (approximately 10 to 90 ng/dL) but do not report how the range was established. The scientific literature clearly shows a significant separation in serum testosterone levels between normal (that is, not hyperandrogenic) and hyperandrogenic women. Most hyperandrogenic women had testosterone levels >50 ng/dL, whereas most normal control subjects had levels <40 ng/dL. Thus, most of these women with hyperandrogenism would have been considered to have normal testosterone levels if the reference ranges of commercial laboratories were used. CONCLUSION: These data illustrate the difficulty that physicians face when they are required to use different commercial laboratories to measure serum testosterone levels. We propose that (1) reference ranges be established on a clinically defined population for each hormone and method used, (2) laboratory reports include information about method and reference range population, and (3) physicians be allowed to choose which laboratories are used for their patients' hormone determinations, for consistency of results.

Journal Article↗

Hyperinsulinemia and ovarian hyperandrogenism. Cause and effect.

The evidence that supports the hypothesis that hyperinsulinemia causes ovarian hyperandrogenism was reviewed. The most dramatic clinical expression of the association between hyperinsulinemia and hyperandrogenism is the HAIR-AN syndrome. In the HAIR-AN syndrome, severe insulin resistance results in a compensatory hyperinsulinemia that stimulates ovarian androgen production. Acanthosis nigricans, a dermatologic manifestation of severe insulin resistance, is an epiphenomenon of the disease. Hyperandrogenic (HA) women can be divided into two major groups: insulin-resistant (HA-IR) and non-insulin-resistant (HA-nIR). HA-nIR women have markedly elevated LH, often have minimally elevated serum prolactin, and have polycystic ovaries. HA-IR women have minimally elevated LH, markedly elevated plasma insulin, and stromal hyperthecosis. Women with HA-nIR probably have a primary hypothalamic-pituitary abnormality as the cause of their hyperandrogenism. Women with HA-IR probably have a primary metabolic abnormality as the cause of their hyperandrogenism. The relationship between hyperinsulinemia and hyperandrogenism is one example of the complex interrelationships that exist between central metabolism and reproduction.

Acanthosis Nigricans↗

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

Adolescent↗

Prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess.

OBJECTIVE: We sought to determine the prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia among adult hyperandrogenic women with dehydroepiandrosterone sulfate excess. STUDY DESIGN: Thirty consecutive hyperandrogenic women with hirsutism, oligomenorrhea, or both and dehydroepiandrosterone sulfate levels of >8.5 micromol/L and 24 control subjects were studied. Basal sex hormone binding globulin, total and free testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and basal and 60-minute corticotropin-stimulated 17-hydroxypregnenolone and dehydroepiandrosterone were measured, and the increment (change from basal to 60-minute value) was calculated. RESULTS: Twenty-six (87%) and 25 (83%) of the 30 hyperandrogenic patients studied had 60-minute dehydroepiandrosterone and change in 0- to 60-minute dehydroepiandrosterone levels greater than the mean + 2 SD of control subjects, respectively. Six (20%) and 6 (20%) of the 30 hyperandrogenic patients had 60-minute 17-hydroxypregnenolone and 0- to 60-minute change in 17-hydroxypregnenolone levels greater than the mean + 2 SD of control subjects, respectively. However, none of the subjects had either 60-minute 17-hydroxypregnenolone levels or 60-minute dehydroepiandrosterone levels or both associated with the diagnosis of genetically proved 3beta-hydroxysteroid dehydrogenase deficiency (>5-fold of the control mean value). CONCLUSION: 3beta-Hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia is rare even among adult hyperandrogenic patients with adrenal androgen excess.

17-alpha-Hydroxyprogesterone↗