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Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response., (Copyright © 2016. Published by Elsevier Ltd.)

Approximately 20-30% of PCOS women demonstrate excess adrenal precursor androgen (APA) production, primarily using DHEAS as a marker of APA in general and more specifically DHEA, synthesis. The role of APA excess in determining or causing PCOS is unclear, although observations in patients with inherited APA excess (e.g., patients with 21-hydroxylase deficient congenital classic or non-classic adrenal hyperplasia) demonstrate that APA excess can result in a PCOS-like phenotype. Inherited defects of the enzymes responsible for steroid biosynthesis, or defects in cortisol metabolism, account for only a very small fraction of women suffering from hyperandrogenism or APA excess. Rather, women with PCOS and APA excess appear to have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, although they do not have an overt hypothalamic-pituitary-adrenal axis dysfunction. In general, extra-adrenal factors, including obesity, insulin and glucose levels, and ovarian secretions, play a limited role in the increased APA production observed in PCOS. Substantial heritabilities of APAs, particularly DHEAS, have been found in the general population and in women with PCOS; however, the handful of SNPs discovered to date account only for a small portion of the inheritance of these traits. Paradoxically, and as in men, elevated levels of DHEAS appear to be protective against cardiovascular risk in women, although the role of DHEAS in modulating this risk in women with PCOS remains unknown. In summary, the exact cause of APA excess in PCOS remains unclear, although it may reflect a generalized and inherited exaggeration in androgen biosynthesis of an inherited nature., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context: Dehydroepiandrosterone sulfate (DHEA-S), a major circulating sex steroid prohormone, declines with age. Low levels have been associated with increased cardiovascular disease (CVD) risk and all-cause mortality, although these results have not been consistently replicated, particularly in women., Objective: Our objective was to examine the association of circulating DHEA-S levels, CVD, and mortality risk among postmenopausal women with suspected myocardial ischemia., Design: In the Women's Ischemia Syndrome Evaluation, 270 postmenopausal women underwent coronary angiography and blood hormone levels for suspected ischemia and were followed annually. The primary outcome of interest was CVD mortality; secondary analyses included all-cause mortality and nonfatal CVD events (myocardial infarction, stroke, and congestive heart failure) and angiographic obstructive coronary artery disease (CAD)., Results: Women in the lowest DHEA-S tertile had higher CVD mortality (17% 6-yr mortality rate vs. 8%; log-rank P = 0.011), and all-cause mortality (21 vs. 10%; P = 0.011) compared with women with higher DHEA-S levels. The increased CVD mortality risk [hazard ratio (HR) = 2.55; 95% confidence interval (CI) = 1.19-5.45] remained unchanged after adjustment for multiple CVD risk factors (HR = 2.43; 95% CI = 1.06-5.56) but became nonsignificant when further adjusting for the presence or severity of angiographic obstructive CAD (HR = 1.99; 95% CI = 0.87-4.59). Results were similar for all-cause mortality. Lower DHEA-S levels were only marginally but not independently associated with obstructive CAD., Conclusions: Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher CVD mortality and all-cause mortality. Our study provides valuable feasibility data useful for future investigations and possible mechanistic pathways.

Objective: To test the hypothesis that DHEAS production from DHEA occurs in hepatic cells and that this production is augmented by the presence of sex steroids or insulin., Design: In vitro prospective experiment., Setting: Academic medical center., Intervention(s): Hepatoma G2 cells cultured in media supplemented with [1] DHEA (10(-5) mol/L) only, [2] DHEA (10(-5) mol/L) + T (10(-6) mol/L), [3] DHEA (10(-5) mol/L) + E(2) (10(-6) mol/L), [4] DHEA (10(-5) mol/L) + dihydrotestosterone (10(-6) mol/L), [5] DHEA (10(-5) mol/L) + insulin (10 ng/mL), or [6] DHEA (10(-5) mol/L) + insulin (100 ng/mL)., Main Outcome Measure(s): Levels of DHEAS in the media were measured at 0, 2, 4, 6, 8, 12, 24, 48, and 72 hours after adding treatments at time-point 0., Result(s): Dehydroepiandrosterone sulfate was first detected in the hepatoma G2 cell culture media at 12 hours of incubation. The cumulative production rate of DHEAS increased linearly until 72 hours of incubation. When compared with the effect of treatment with DHEA only, treatment with DHEA plus T, dihydrotestosterone, or E(2) delayed the cumulative DHEAS production; alternatively, the addition of insulin did not alter DHEAS production., Conclusion(s): These data suggest that although hepatic cells have the ability of converting DHEA to DHEAS, neither sex steroids nor insulin results in the increased hepatic production of DHEAS.

Objective: To test the hypothesis that increasing DHEAS levels is associated with improved insulin resistance in patients with polycystic ovary syndrome (PCOS)., Design: Cross-sectional cohort analysis., Setting: Academic medical center., Patient(s): Three hundred fifty-two women with PCOS., Intervention(s): Patients presenting for evaluation of symptoms related to androgen excess were evaluated physically and biochemically through laboratory analysis., Main Outcome Measure(s): Circulating DHEAS, total T, free T, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) levels, and calculated homeostasis model assessment of insulin resistance (HOMA-IR)., Result(s): Bivariate analysis indicated that all parameters were associated with HOMA-IR, except 17-OHP and age, and confirmed a negative correlation between DHEAS and HOMA-IR. Multivariate analysis indicated that increases in DHEAS, SHBG, 17-OHP, and age were associated with decreasing HOMA-IR, whereas increases in free T, body mass index (BMI), and waist-to-hip ratio (WHR) were associated with increasing HOMA-IR. In decreasing order of importance, the following variables predicted insulin resistance: BMI > WHR > age > DHEAS > free T > SHBG > 17-OHP., Conclusion(s): DHEAS is negatively correlated to insulin resistance in patients with PCOS, and in our model ranked just behind other well-established predictors including BMI, WHR, and age. Whether this is due to a direct beneficial effect on insulin action by adrenal androgens such as DHEA, or whether DHEAS simply reflects the circulating levels of hyperinsulinemia, remains to be determined.

Context: Adrenal androgen excess is common in polycystic ovary syndrome (PCOS) and appears to be heritable. CYP3A7 metabolizes dehydroepiandrosterone and its sulfate (DHEAS). A promoter variant, CYP3A7*1C, which results in persistent expression in adults, was associated with reduced DHEAS levels in a previous study, which led us to consider CYP3A7*1C as a modulator of adrenal androgen excess in patients with PCOS., Objective: The objective was to replicate the association between CYP3A7*1C and reduced DHEAS levels in PCOS patients and assess its possible role in modulating testosterone levels., Design: Women with and without PCOS were genotyped for CYP3A7*1C, and this variant was tested for association with DHEAS and total and free testosterone., Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center (Los Angeles, CA)., Participants: A total of 287 white women with PCOS and 187 controls were studied., Main Measurements: CYP3A7*1C genotype, PCOS risk, and androgen levels were measured., Results: PCOS subjects who carried the CYP3A7*1C variant had lower levels of serum DHEAS and total testosterone (P = 0.0006 and 0.046, respectively). The variant was not associated with PCOS risk., Conclusion: This study replicated prior work of the association of CYP3A7*1C and decreased DHEAS in a different population of young PCOS women, providing further genetic evidence that CYP3A7 plays a potential role in modulation of DHEAS levels. Adult expression of CYP3A7 may modify the PCOS phenotype by ameliorating adrenal androgen excess.

Context: The adrenal androgen (AA) metabolite dehydroepiandrosterone sulfate (DHEAS) is often elevated in women with polycystic ovary syndrome (PCOS); AA excess in PCOS appears to be, in part, a heritable trait. Dehydroepiandrosterone (DHEA) sulfonation is controlled by the enzymes DHEA sulfotransferase (SULT2A1) and steroid sulfatase (STS). Polymorphisms in these genes have not been evaluated as modulators of DHEAS level in PCOS., Objective: The aim was to test the hypothesis that variants in the SULT2A1 and STS genes are associated with DHEAS levels in women with PCOS., Design: Women with and without PCOS were genotyped for seven single nucleotide polymorphisms (SNPs) in SULT2A1 and seven SNPs in STS. SNPs and haplotypes were determined and tested for association with DHEAS., Setting: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles., Participants: A total of 287 white women with PCOS and 187 controls participated in the study., Main Measurements: SULT2A1 and STS genotype and DHEAS levels were measured., Results: In women with PCOS, SNP rs182420 in SULT2A1 was associated with DHEAS (P = 0.0035). Two haplotypes carrying the minor allele of rs182420 were also associated with DHEAS (P = 0.04 each). Variants within STS were not associated with DHEAS level. No associations were observed in control women., Conclusion: This study presents genetic evidence suggesting a potential role of SULT2A1, but not STS, in the inherited AA excess of PCOS.

We studied 259 consecutive unselected white patients with the polycystic ovary syndrome (PCOS) and 161 matched controls for a common polymorphism of CYP17, the gene encoding for P450c17alpha, and did not observe an important modulatory effect of this variant on circulating DHEAS. It does not appear that this common variant of CYP17, a T to C substitution in the 5' promoter region, plays a significant role in the adrenal androgen excess of PCOS.

Objective: To determine whether amelioration of insulin resistance in polycystic ovary syndrome (PCOS) with the insulin sensitizer troglitazone (TGZ) decreases circulating adrenal androgens (AAs), as reflected by DHEAS levels., Design: Prospective, randomized, double-blind clinical trial., Setting: Multicenter study., Subject(s): Three-hundred five women with PCOS., Intervention(s): Subjects were randomly assigned to receive either placebo (PBO; n = 73) or TGZ in doses of 150 mg/day (TGZ-150; n = 78), 300 mg/day (TGZ-300; n = 77), or 600 mg/day (TGZ-600; n = 77) for 20 weeks. Blood was sampled before (week 0) and at week 20 of treatment., Main Outcome Measure(s): DHEAS, insulin, and glucose levels were determined in the blood samples., Result(s): There were no differences in age, body mass, or racial composition among the groups. Our results indicate that basal insulin declined in a dose-related fashion. Likewise, TGZ administration caused a dose-related decrease in DHEAS levels. To detect extreme effects, we subsequently subdivided patients receiving PBO or TGZ-600 into tertiles according to initial DHEAS levels. Patients receiving PBO in the lowest (n = 27) and highest (n = 22) DHEAS tertiles experienced a 16.8% +/- 62.0% and a -11.1% +/- 17.4% change in DHEAS levels during the study, respectively. Alternatively, patients with PCOS receiving TGZ-600 in both the lowest (n = 29) and the highest (n = 23) DHEAS tertiles experienced a drop in DHEAS levels (-18.7% +/- 27.2% and -26.4% +/- 17.2%, respectively), a significant difference from PBO., Conclusion(s): In conclusion, improving the insulin resistance-related hyperinsulinemia of PCOS with TGZ results in a decrease in DHEAS levels, regardless of initial DHEAS level. Whether the observed suppression is the direct result of decreased insulin levels or whether it reflects other direct and indirect effects of TGZ remains to be determined.

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

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.

Adrenal androgen (AA) excess, primarily in the form of dehydroepiandrosterone sulfate (DHEAS), affects over 50% of women with the polycystic ovary syndrome (PCOS). Nonetheless, it is unclear what role AA excess plays in the PCOS-associated oligo-ovulation. We have hypothesized that AAs are important in the maintenance of the ovulatory dysfunction of women with PCOS and AA excess, which can be improved by glucocorticoid suppression. To test our hypothesis we prospectively studied 36 unselected women, ages 18-40 yr, with PCOS; i.e. oligomenorrhea (cycles > 35 days in length), and clinical/ biochemical evidence of hyperandrogenism (i.e. hirsutism and/or hyperandrogenemia), after the exclusion of related disorders. After informed consent, all patients underwent an acute ACTH-(1-24) stimulation test, measuring androstenedione, dehydroepiandrosterone (DHEA) and cortisol (F), and were then treated with dexamethasone 0.5 mg/day for four cycles. Ovulatory function was assessed before and during treatment using a basal body temperature calendar and day 22-24 progesterone (P4) levels. If patients were anovulatory (P4 < 4 ng/mL), a withdrawal bleed was induced by the administration of 100 mg P4 in oil i.m. Before and during treatment the levels of total and free testosterone (T), sex hormone-binding globulin, androstenedione, DHEA, DHEAS, cortisol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were monitored. With therapy, all patients demonstrated a significant decrease in all androgens (-40-60%), a 24% increase in sex hormone-binding globulin, and no change in LH/FSH. Mean body weight increased by over 4 kg (4.4%) during treatment. Of the 138 cycles monitored, 78% remained anovulatory. Twenty-five percent, 17%, 14%, and 20% of the first, second, third, and fourth treatment cycles, were ovulatory, respectively (P = 0.381). Of the 36 patients studied, 18 (50%) did not demonstrate a single ovulatory cycle (i.e. a day 22-24 P4 level > 4 ng/mL); and of the remaining, 10 (28%) had only one, five (14%) had two, and three (8%) had three ovulatory cycles. There were no significant differences either in physical features, basal hormones, adrenal response to ACTH stimulation, or hormonal levels at the end of treatment, between those women ovulating and those not. Finally, there were no differences in ovulatory response to dexamethasone therapy between women with (n = 14) and without (n = 22) DHEAS excess (i.e. DHEAS > 2750 ng/mL). In conclusion, the data from this prospective study do not suggest that continuous dexamethasone suppression results in consistent ovulation in any PCOS patient, regardless of basal DHEAS levels. Furthermore, this treatment is associated with significant side-effects, notably weight gain. Finally, these data suggest that, while AA may be an important risk factor for PCOS, once the syndrome is established, they play a limited role in the associated ovulatory dysfunction.