Search

Between 20 and 30% of patients with polycystic ovary syndrome (PCOS) demonstrate adrenal androgen (AA) excess, detectable primarily by elevated dehydroepiandrosterone sulfate (DHEAS) levels. Generalized adrenocortical hyperresponsivity to adrenocorticotropic hormone (ACTH) stimulation is also observed and may be the principal mechanism determining AA excess in PCOS. The causes of this abnormality are unclear, but increased peripheral metabolism of cortisol, altered factors regulating glucose-mediated glucose disposal, and perhaps ovarian sex steroids may in different ways contribute to the AA excess in PCOS. Additionally, DHEAS levels and the response of AAs to ACTH are relatively constant over time and may be a genetically determined trait.

New guidelines regarding diagnosis of polycystic ovary syndrome have been published recently. The traditional way of making the diagnosis is guided by US National Health Institute. But many experts contradicted the method of diagnosis. An agreement was found on the new guidelines at a joint meeting of ESHRE and ASRM in 2004. At the same meeting new criteria for sonographic diagnosis were suggested. The new guidelines for diagnosis of polycystic ovary syndrome have represented a reasonable compromise between different opinions and because of it they have got a great success. During 2005 a consensus conference and a special expert committee have evaluated the new guidelines and reached some conclusion. That is likely to be published in future. The diagnostic study is not complete without an evaluation of metabolic and cardiovascular risk factors. Only a better understanding of the pathogenesis of polycystic ovary syndrome can definitely establish the diagnostic criteria.

Medicine is changing and requires a more in-depth knowledge also in fields that were previously considered completely different and dedicated to other specialists. A good example of this general trend is the paper by Cerda et al. [1] that shows a high prevalence of nonalcoholic fatty liver disease (NAFLD) in women with Polycystic Ovary Syndrome (PCOS). The authors studied 41 young women with PCOS and found that 17 patients (41%) had NAFLD. In addition, 7 patients with NAFLD had increased aminotransferase levels raising the possibility of a transition to nonalcoholic steatohepatitis (NASH). Other reports have shown similar data recently [2–5]. It is time therefore that doctors caring for patients with liver diseases start to collaborate with the specialists (gynecologists, endocrinologists), who generally treat patients with PCOS and vice versa.

Composizione corporea in relazione alla sindrome dell'ovaio policistico. Increased abdominal fat has been linked to insulin resistance and increased cardiovascular risk. Because many patients with polycystic ovary syndrome (PCOS) present abdominal obesity, it may be the cause of insulin resistance in this disorder.Setting: Fat quantity and distribution were evaluated by dual x-ray absorptiometry at the Departments of Clinical Medicine at the University of Palermo and the University of Naples, Italy.Patients: A total of 110 patients with PCOS and 112 weight-matched controls were studied. Anthropometric data, blood glucose, serum insulin, and testosterone were evaluated. Total, trunk, and central abdominal fat quantity were measured by total-body dual x-ray absorptiometry.Results: Compared with weight-matched controls, patients with PCOS had similar quantity of total and trunk fat but higher quantity of central abdominal fat. This difference was not observed when comparing obese PCOS and obese controls but depended on differences between overweight and normoweight patients and controls. All obese subjects, independently of having PCOS or not, had increased central abdominal fat. The same parameter was increased in 71% of overweight PCOS, 50% of overweight controls, and 30% of normoweight PCOS patients. PCOS patients with increased central abdominal fat had significantly higher (P < 0.01) insulin levels and significantly reduced (P < 0.01) insulin sensitivity than controls with similar quantities of central abdominal fat. Overweight PCOS patients with normal abdominal fat had significantly higher (P < 0.05) insulin levels and significantly reduced (P < 0.05) insulin sensitivity than overweight controls with normal abdominal fat.Conclusions: Most obese subjects, independent of being affected by PCOS, have an abdominal form of obesity. However, abdominal fat excess may not be the only determinant of insulin resistance in PCOS.

Because adipose tissue is a complex endocrine organ that secretes many substances with profound effects on metabolism and the cardiovascular (CV) system, most obese subjects have an increased CV risk. However, 20% of obese subjects are metabolically healthy, and many studies suggest that fat distribution, in particular abdominal fat excess, is the most important factor that determines a secretion of adipose products that may increase CV risk.

Context: An altered lipid profile is common in polycystic ovary syndrome (PCOS) and is usually characterized by increased triglycerides and low high-density lipoprotein (HDL)-cholesterol levels. In the general population, these alterations are often associated with the increase of small low-density lipoproteins (LDLs) in the so-called “atherogenic lipoprotein phenotype” (ALP) that determines a further increase of cardiovascular risk. In this study, we evaluated the presence of ALP in the plasma of women with PCOS. Setting: Measurements and analysis of LDL size were performed at the Clinic of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital, Zurich. PCOS patients were recruited at the Department of Clinical Medicine, University of Palermo, and the Department of Obstetrics and Gynecology, University of Pisa. Patients: Thirty patients with PCOS (hyperandrogenism and chronic anovulation) and 24 matched controls were studied. Anthropometric data, blood glucose, serum insulin lipid profile, and LDL size and subclasses were evaluated. Results: Compared with controls, patients with PCOS had higher plasma concentrations of insulin and triglycerides and lower HDL-cholesterol concentrations but no differences in LDL-cholesterol and total cholesterol. Patients with PCOS had smaller LDL size due to a reduction in LDL subclass I, with a concomitant increase in LDL subclasses III and IV. Fourteen PCOS patients had an increase of smaller LDL particles, and it represented the second most common lipid alteration after decrease in HDL-cholesterol. However, because in this PCOS population hypertriglyceridemia was only present in two patients, complete ALP was relatively uncommon. Conclusions: Increase of type III or type IV LDL subclasses is a common finding in PCOS and represents the second most common lipid alteration after HDL-cholesterol decrease. However, in our PCOS patients, because of relatively low triglyceride levels, complete ALP is uncommon.

OBJECTIVE: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. PARTICIPANTS: Participants included expert investigators in the field. EVIDENCE: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. CONSENSUS PROCESS: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. CONCLUSIONS: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference. A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism, although a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism but recognized that more data are required before validating this supposition. Finally, the task force recognized, and fully expects, that the definition of this syndrome will evolve over time to incorporate new research findings.

Many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele containing a severe mutation of CYP21, and as such are at risk for giving birth to an infant having classic adrenal hyperplasia (CAH). Infants with NCAH typically are asymptomatic at birth, in contrast to those with CAH, but they do develop symptoms of hyperandrogenism later in childhood or as adults. This international multicenter study, conducted both retrospectively and prospectively, was an attempt to determine how often mothers with 21-OH-deficient NCAH bear infants having CAH or NCAH. The 101 women entering the study had a total of 203 pregnancies that could be evaluated. Fourteen tertiary referral centers in nine countries participated in the study. The diagnosis of 21-OH-deficient NCAH was based on a baseline or post-ACTH level of 17-hydroxyprogesterone exceeding 10 ng/mL. Where feasible, the offspring underwent genotypic analysis. Nearly half the women with NCAH presented with oligomenorrhea, and four had primary amenorrhea. More than two-thirds of pregnancies took place before the mother was diagnosed as having NCAH. Spontaneous miscarriages occurred in one-fourth of 138 pregnancies before NCAH was diagnosed but in only four of 65 pregnancies occurring after the diagnosis (6%). The incidence of CAH in 162 live births was 2.5%. Twenty-four children (15%) have been diagnosed as having NCAH. Five other female infants developed signs of hyperandrogenism but did not meet hormonal criteria for a diagnosis of NCAH. Three of the four live-bom CAH children were White Jewish or Hispanic, as were two of three NCAH mothers giving birth to a CAH child. In this international study, a woman with NCAH had a 2.5% chance of giving birth to a child having CAH and a 15% chance of having a child with NCAH. Preconception screening for 21-OH-deficient NCAH is especially important for hyperandrogenic or oligoovulatory women who wish to become pregnant. Glucocorticoid therapy before conception and/or before birth may favorably influence the outcome.

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

New diagnostic criteria for polycystic ovary syndrome (PCOS) suggested three main phenotypes: classic (hyperandrogenism and anovulation), ovulatory, and normoandrogenic. However, it is unclear whether the normoandrogenic phenotype actually represents PCOS. Overall, 6% to 8% of reproductive-aged women suffer from PCOS, making this disorder one of the most common endocrine abnormalities.

Objective: Metabolic syndrome (MBS) is a common disorder and is thought to be extremely prevalent in polycystic ovary syndrome (PCOS). In the USA the prevalence of MBS in PCOS has been reported to be as high as 43–46% using Adult Treatment Panel III (ATP-III) criteria. Because of differences in diet, lifestyle and genetic factors, we postulated that the prevalence of MBS might not be as high in Italian women. This study sought to determine the prevalence of MBS in Italian women using both the ATP-III and the World Health Organization (WHO) criteria and to determine whether the prevalence is influenced by the way in which PCOS is diagnosed. Design: Assessment of the prevalence of MBS in 282 women with PCOS, aged 18–40 years, living in western Sicily. Eighty-five age- and weight-matched normal women served as controls. Methods: Patients were divided into those with chronic anovulation and hyperandrogenism (classic PCOS; n = 225) and others with hyperandrogenism and polycystic ovaries but who were ovulatory (ovulatory PCOS; n = 57). A 75 g oral glucose tolerance test was carried out, as were lipid determinations; insulin resistance was assessed by the Quantitative Insulin-Sensitivity Check Index (QUICKI). We used ATP-III and WHO criteria to diagnose MBS. Results: Using ATP-III criteria, the prevalence of MBS was 8.2% and using WHO criteria it was 16% in Italian women with PCOS. In controls, the prevalence was 2.4% using both methods. In classic PCOS patients, MBS was higher (8.9% by ATP-III, 17.3% by WHO) than in ovulatory PCOS (5% and 10.6% respectively). Body weight significantly modified prevalence rates. Conclusion: MBS is substantially higher in women with PCOS than in the general population, and the prevalence is higher in those women diagnosed by classic criteria. However, the prevalence of MBS in PCOS appears to be much lower in Italy than in the USA.

Background Previous data on the efficacy of clomiphene citrate, the most commonly used drug for treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS), have shown a discrepancy between ovulation and pregnancy rates. In the present subanalysis (of a larger previously published randomized controlled trial), the effect of clomiphene citrate on several ultrasonographic markers of uterine receptivity in PCOS patients who ovulated under treatment was studied. Methods Thirty-three PCOS women who ovulated under 150 mg daily clomiphene citrate and 33 healthy controls were studied. Uterine, subendometrial and endometrial blood flows, endometrial thickness and pattern were assessed using serial ultrasonographic assessments. The data were analysed before and after grouping the clomiphene citrate-stimulated ovulatory cycles for reproductive outcome [unfavourable (ovulation alone or early pregnancy loss) or favourable outcome (clinical pregnancy and/or live birth)]. Results Both before and during treatment, uterine vascularity assessed at all sites was significantly lower in the PCOS group than in controls. Endometrial thickness and pattern were impaired in the PCOS group under clomiphene citrate treatment. A significant difference in all ultrasonographic parameters was observed between cycles ending in unfavourable versus those ended in favourable outcome. Conclusions Clomiphene citrate administration alters several surrogate ultrasonographic parameters of uterine receptivity, and this effect could be crucial for its efficacy.

Background Metformin has been shown to improve fertility in anovulatory patients with polycystic ovary syndrome (PCOS), inducing not only a high ovulation and pregnancy rate but also reducing the incidence of miscarriages. The aim of the present study was to evaluate the uterine effects of metformin in patients with PCOS who ovulated under metformin. Methods Thirty-seven non-obese primary infertile anovulatory patients with PCOS and another 30 age- and body mass index-matched healthy women (control group) were studied. PCOS patients were treated with metformin (850 mg twice daily) for 6 months, whereas the control group did not receive any treatment. In these PCOS patients who ovulated whilst under metformin treatment (PCOS group) and in controls, uterine, sub-endometrial and endometrial blood flow, and endometrial thickness and pattern were evaluated using serial ultrasonographic assessments. Results Before treatment, uterine, sub-endometrial and endometrial blood flows were significantly lower in patients with PCOS than in the control group. All indexes of uterine vascularization were significantly improved in the PCOS group with metformin treatment and were not different from the controls. Nor was any difference in endometrial thickness and pattern detected between PCOS and control groups. After grouping the data of PCOS patients who ovulated under metformin for cycles with favourable/unfavourable reproductive outcome, no difference in any parameter was observed. Conclusions Metformin improves all surrogate markers of endometrial receptivity in PCOS patients, without difference between patients who had favourable or unfavourable reproductive outcome.

A better understanding of the different phenotypes and of their endocrine and metabolic characteristics permits investigators to distinguish three main androgen excess disorders: classic polycystic ovary syndrome (PCOS), mild ovulatory PCOS, and idiopathic hyperandrogenism. These androgenic phenotypes differ more for the severity of the endocrine and metabolic alteration than for the etiopathogenetic mechanisms. The appearance of a particular androgenic phenotype is determined by a sum of genetic and environmental factors, but mostly by body weight.

Objective: Metabolic syndrome (MBS) is a significant health care problem in postmenopausal women and is driven largely by obesity. We wished to assess the prevalence of insulin resistance (IR), diagnosed using practical methods, and whether several adipocyte factors (adiponectin, leptin, resistin) or the gastric peptide ghrelin, associated with cardiovascular risk, might be abnormal and may relate to IR. Study design: We evaluated 37 obese postmenopausal women with MBS and 34 matched obese premenopausal controls, as well as 14 non-obese premenopausal controls. We measured fasting glucose and insulin, performed 75g 2 hr oral glucose tolerance and intravenous insulin tolerance tests to assess IR, and measured fasting lipids, adiponectin, leptin, resistin and ghrelin. Results: The kinetic decline in glucose after insulin (kITT) as a marker of IR was the most frequently abnormal test (abnormal in 81%), with QUICKI, HOMA, and a modification of the Matsuda-DeFronzo index (ISIM) abnormal in 76, 73, and 68%, respectively. The GIR was abnormal in only 35% of subjects. Leptin and resistin were elevated and adiponectin and ghrelin were decreased in the postmenopausal women, compared to both groups of premenopausal controls. BMI correlated strongly with markers of insulin resistance as well as adipocytokine values. After controlling for BMI, only leptin was predictive of ISIM. Conclusion: Being overweight after menopause results in worsening IR and elevations in adipocytokine levels. While BMI is the most important factor, abnormal adipocytokine secretion may enhance IR and increase cardiovascular risk in postmenopausal women. 2006 Mosby, Inc. All rights reserved.

Background: Adipocytokines are produced by adipose tissue and have been thought to be related to insulin resistance and other health consequences. We measured leptin, adiponectin, and resistin simultaneously in women with polycystic ovary syndrome (PCOS) and age- and weight-matched controls. Our hypothesis was that these simultaneous measurements would help determine whether adipocytokine secretion is abnormal in PCOS independent of body mass and whether these levels are related to insulin resistance as well as other hormonal changes. Methods: Fifty-two women with PCOS and 45 normal ovulatory women who were age- and weight-matched were studied. Blood was obtained for adipocytokines (leptin, adiponectin, and resistin) as well as hormonal parameters and markers of insulin resistance as assessed by the quantitative insulin-sensitivity check index. Body mass index (BMI) was stratified into obese, overweight, and normal subgroups for comparisons between PCOS and controls. Results: Adiponectin was lower (P < 0.05) and resistin was higher (P < 0.05) while leptin was similar to matched controls. Breakdown of the groups into subgroups showed a strong body mass relationship for leptin with no changes in resistin although adiponectin was lower in PCOS, even controlling for BMI. In controls, leptin and adiponectin and leptin and resistin correlated (P < 0.05) but not in PCOS. In controls, all adipocytokines correlated with markers of insulin resistance but not in PCOS. Conclusions: When matched for BMI status, decreased adiponectin in PCOS represent the most marked change. This alteration may be the result of altered adipose tissue distribution and function in PCOS but no correlation with insulin resistance was found.

In hyperandrogenic women, several phenotypes may be observed. This includes women with classic polycystic ovary syndrome (C-PCOS), those with ovulatory (OV) PCOS, and women with idiopathic hyperandrogenism (IHA), which occurs in women with normal ovaries. Where other causes have been excluded, we categorized 290 hyperandrogenic women who were seen consecutively for this complaint between 1993 and 2004 into these three subgroups. The aim was to compare the prevalence of obesity, insulin resistance, and dyslipidemia as well as increases in C-reactive protein and homocysteine in these different phenotypes with age-matched ovulatory controls of normal weight (n = 85) and others matched for body mass index (BMI) with women with C-PCOS (n = 42). Although BMI affected fasting serum insulin and the Quantitative Insulin-Sensitivity Check Index, these markers of insulin resistance were greatest in C-PCOS (n = 204), followed by OV-PCOS (n = 50) and then IHA (n = 33). Androgen levels were similar in OV-PCOS and IHA but were higher in C-PCOS, whereas gonadotropins were similar in all groups. Lipid abnormalities were highest in C-PCOS and OV-PCOS and were normal in IHA. C-reactive protein was elevated in C-PCOS and OV-PCOS but not IHA. Homocysteine was elevated only in C-PCOS. Overall, the prevalence of obesity (BMI > 30) was 29% in C-PCOS, 8% in OV-PCOS, and 15% in IHA and insulin resistance (Quantitative Insulin-Sensitivity Check Index < 0.33) was 68% in C-PCOS, 36% in OV-PCOS, and 26% in IHA. The prevalence of having at least one elevated cardiovascular risk marker was 45% in C-PCOS 38% in OV-PCOS and was not increased on IHA (6%). These results suggest that among hyperandrogenic women the prevalence of abnormal metabolic and cardiovascular risk parameters is greatest in C-PCOS, followed by OV-PCOS and then women with IHA. Moreover, in that in OV-PCOS and IHA, ages and weights were similar yet the prevalence of metabolic and cardiovascular risk was greater in OV-PCOS, the finding of polycystic ovaries may be a significant modifying factor.

Objective: To investigate Müllerian-inhibiting substance (MIS) levels in women with polycystic ovary syndrome (PCOS), as well as relationships to ovarian morphology, levels of inhibin B, and other reproductive hormones. Design: Prospective clinical study. Setting: Academic endocrinology centers in Palermo, Italy and New York. Patient(s): Forty-six women with PCOS, recruited on the basis of the classic criteria of chronic anovulation and hyperandrogenism, and 25 age-matched ovulatory controls. Intervention(s): Fasting blood was obtained in all subjects in the early follicular phase (days 5–6) after spontaneous or induced menses (in PCOS), and transvaginal ultrasounds were performed. Main Outcome Measure(s): Assessment of values for luteinizing hormone (LH), testosterone (T), androstenedione (A), estradiol (E2), inhibin B, MIS, fasting insulin, and the calculated quantitative sensitivity check index (QUICKI), as well as assessments of ovarian volume and blood flow. Result(s): Women with PCOS had higher LH, T, and A; higher insulin and lower QUICKI; and higher ovarian volume and lower pulsatility index. Inhibin B concentrations were statistically significantly higher in PCOS patients (70 8.0 vs. 40 3.4 pg/mL), as was MIS (6.7 0.9 vs. 4.6 0.5 ng/mL). Inhibin B had a statistically significant direct correlation with levels of MIS (r 0.351). However, MIS, but not inhibin B, had a statistically significant positive correlation with ovarian size (r 0.350); the reproductive hormones LH, T, A, and E2; and insulin (r 0.249), independent of body mass index. Women with PCOS with the highest levels of MIS had higher ovarian volumes and values of LH, T, A, and insulin. Conclusion(s): Measurements of MIS reflect ovarian findings in PCOS better than levels of inhibin B and are more frequently elevated. However, MIS lacks sensitivity for use as a diagnostic tool in PCOS. (Fertil Steril 2005;84:1685–8. ©2005 by American Society for Reproductive Medicine.)

The polycystic ovary syndrome (PCOS) is an extremely common disorder that occurs in 4% to 7% of women of reproductive age. Although PCOS is known to be associated with reproductive morbidity and increased risk for endometrial cancer, diagnosis is especially important because PCOS is now thought to increase metabolic and cardiovascular risks. These risks are strongly linked to insulin resistance and are compounded by the common occurrence of obesity, although insulin resistance and its associated risks are also present in nonobese women with PCOS. Women with PCOS are at increased risk for impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Cardiovascular disease is believed to be more prevalent in women with PCOS, and it has been estimated that such women also have a significantly increased risk for myocardial infarction. Many lipid abnormalities (most notably low high-density lipoprotein cholesterol levels and elevated triglyceride levels) and impaired fibrinolysis are seen in women with PCOS. Early diagnosis of the syndrome and close long-term follow-up and screening for diabetes and cardiovascular disease are warranted. An opportunity exists for preventive therapy, which should improve the reproductive, metabolic, and cardiovascular risks.

Objective: To determine how common polycystic ovarian morphology may be in women given the clinical diagnosis of polycystic ovary syndrome (PCOS) based on chronic anovulation and hyperandrogenism and whether certain hormonal factors correlate with ovarian morphology and blood flow. Design: Prospective study. Setting: Two academic endocrinology centers in Italy. Patient(s): Three hundred twenty-six women with PCOS and 50 age-matched and weight-matched ovulatory women. Intervention(s): Ultrasound assessment of ovarian morphology in patients and controls and ovarian blood flow and fasting hormone levels in a subset of 50 patients and matched controls. Main Outcome Measure(s): Ovarian morphological assessments, ovarian blood flow by pulsatility index (PI) and resistance index (RI), and measurements of gonadotropins, estrogen, sex hormone-binding globulin, androgens, inhibin B, glucose, and insulin. Result(s): Using strict ultrasound criteria, 195 woman (60%) had enlarged ovaries, 135 (35%) had normal ovarian size but characteristic morphology, and 16 (5%) had normal size and morphology. Ovarian blood flow was increased (reduced PI and RI) in PCOS. All hormonal parameters were elevated in PCOS. Ovarian size correlated only with insulin and a measure of insulin resistance. Ovarian blood flow correlated positively with insulin, T, free T, and E 2 but not with luteinizing hormone. Inhibin B showed a negative correlation with ovarian blood flow. Conclusion(s): When a clinical diagnosis of PCOS was made, virtually all women were found to have characteristic ovarian morphology. Insulin correlated with increased ovarian size as well as with increased blood flow. Blood flow also correlated positively with sex steroids but negatively with inhibin B. ©2005 by American Society for Reproductive Medicine.

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome determined in most patients by the association of two main factors: hyperandrogenism and insulin resistance. These characters are probably independent of each other and seem to be inherited by several different mechanisms. In some patients homozygous gene alteration has been found but in most patients PCOS seems to be determined by the association of gene polymorphisms that are common in the general population but alone are unable to determine phenotypic consequences. Alteration of genes that regulate the initial steps of ovarian steroidogenesis is probably the main causal factor of hyperandrogenism. Insulin resistance may be the result of many different gene alterations including insulin receptor substrate (IRS)-1 and 2, calpain-10 and peroxisome proliferator-activated receptor gamma(PPARgamma). Some polymorphisms may be protective against other gene alterations. Insulin sensitivity is also modified by socioeconomic and cultural factors that influence quantity and quality of food and energy expenditure. However, even eating behavior and weight response to food intake may be under genetic regulation. Different combinations of multiple gene polymorphisms and of environmental factors explain the heterogeneity of PCOS.

To determine the prevalence of insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) using baseline fasting blood measurements of glucose and insulin. Prospective clinical study. Academic endocrinology unit in Palermo, Italy. Two hundred and sixty-seven women with PCOS, consecutively evaluated, and 50 consecutively selected ovulating controls. Fasting blood was obtained for glucose and insulin measurements from all women. For 60 women with PCOS and 20 controls an insulin tolerance test (ITT) was also performed. Assessment of normal and abnormal values for fasting insulin, glucose/insulin ratio, and the calculated indices of the homeostasis model assessment (HOMA), quantitative sensitivity check index (QUICKI), as well as Kitt (kinetic disappearance of glucose) values after ITT. Evaluation was performed of the ability to detect IR using these methods in obese and nonobese women with PCOS. Normal insulin sensitivity was defined by insulin levels 6.4, HOMA values of 0.333. In the entire PCOS groups, IR was diagnosed in 65.4% of women using glucose/insulin ratios and in 77% and 79.2% using HOMA and QUICKI. In obese women (body mass index >28 in 48% of group), IR was present in 76.7% as measured by glucose/insulin ratios but was significantly higher (95.3%) using values of either HOMA or QUICKI (P

The purpose of this study was to determine whether parameters of ovarian blood flow distinguish between women with polycystic ovary syndrome (PCOS) who ovulate and those who are anovulatory.This was a prospectively enrolled trial, carried out as a cross-sectional comparison of 12 ovulatory patients with PCOS and 20 matched subjects with classic PCOS and 10 healthy control subjects. Hormonal parameters and ovarian blood flow by color flow Doppler imaging were obtained in the early follicular phase.Characteristic elevations in luteinizing hormone (LH) and androgens were found in both groups with PCOS compared with control groups. Women with anovulatory PCOS had high insulin levels and lower Quantitative Insulin-Sensitivity Check Index (QUICKI) values compared with women with ovulatory PCOS, although both groups had values that were different from healthy control subjects (P.01). Ovarian volume was similar in the two groups with PCOS, but pulsatility and resistance indices were lower in anovulatory PCOS (P.01) compared with ovulatory PCOS and control subjects, who had similar findings. Insulin correlated negatively with the resistance index and QUICKI correlated positively (r=0.653, P.01). There was a negative correlation between the resistance index and unbound testosterone (r=-0.5, P.05).These data suggest that differences in ovarian blood flow in anovulatory versus ovulatory women with PCOS and that hormonal factors, including insulin resistance, may influence this relationship. The alterations in blood flow in anovulatory PCOS may contribute toward or result from anovulation.

BACKGROUND The study aim was to determine differences in body mass in two populations of women (USA and Italy) with polycystic ovary syndrome (PCOS), and to assess the effect of diet on body mass and cardiovascular risk factors. METHODS Pools of women with PCOS from the USA (n = 343) and Italy (n = 301), seen between 1993 and 2001, were available for assessment. From these populations, 20 women who were seen consecutively in 2001 at each site had detailed analyses of diet and cardiovascular risk factors. RESULTS In the entire group, American women had a significantly higher body mass compared with Italian women (P < 0.01). Also, the 20 women consecutively evaluated in the USA had a significantly higher mean (+/- SD) body mass index (40.3 +/- 1.0 kg/m(2)) than in Italy (29.7 +/- 1.0 kg/m(2)). US women had worse insulin resistance, lower levels of high-density lipoprotein-cholesterol (HDL-C) (P < 0.01) and higher levels of triglycerides (P < 0.01). Dietary analysis in the two groups indicated that the total daily calorific intake was similar (USA 2277 +/- 109; Italy 2325 +/- 68 Kcal), with no appreciable differences in dietary content of protein, carbohydrate and fat. However, the dietary saturated fat content was significantly higher in US women (31.9 +/- 3 versus 18.2 +/- 2 g/day, P < 0.01). Saturated fat intake correlated negatively with HDL-C (P < 0.01). CONCLUSIONS Among women with PCOS, body mass was significantly higher in US women compared with Italian women. However, total calorie intake and dietary constituents were similar, except for a higher saturated fat in US women. It is hypothesized that diet alone does not explain differences in body mass; genetic and lifestyle factors likely contribute. An increased saturated fat intake may worsen the cardiovascular risk profile.

GnRH agonists (GnRH-A) have been used for the treatment of hirsutism in women with ovarian hyperandrogenism. However, significant side-effects, including vasomotor symptoms and bone loss, have prevented the long term use of this therapy. In this study, we evaluated the effects of low dose (physiological) estrogen replacement on the side-effects and clinical and hormonal parameters of 22 hirsute women with ovarian hyperandrogenism when treated with a long-acting GnRH-A, Decapeptyl. Ten patients with Ferriman-Gallwey (FG) scores averaging 13.4 +/- 1.5 were randomly assigned to be treated with Decapeptyl alone (3.75 mg, im, every 28 days for 6 months), and 12 other patients with FG scores averaging 13.3 +/- 1 received Decapeptyl with estrogen (conjugated equine estrogens, 0.625 mg) for 21 days and medroxyprogesterone acetate (10 mg) for 10 days (days 12-21). After 6 months, LH was suppressed in both groups, whereas FSH was significantly reduced only in the group receiving GnRH-A with estrogen (2.5 +/- 4 vs. 4.8 +/- 0.6 IU/L; P0.01). Serum androgen levels were reduced in both groups, although the reduction of testosterone and unbound testosterone was greater in the group receiving hormonal replacement [1.73 +/- 0.3 vs. 2.57 +/- 0.4 nmol/L for testosterone (P0.05); 8.3 +/- 1 vs. 14.6 +/- 2.8 pmol/L for unbound testosterone (P0.05)]. The reduction in hirsutism scores was greater with hormonal replacement (FG scores, -4.1 +/- 0.3 vs. -2.5 +/- 0.3; P0.05), whereas the polycystic appearance of ovaries by ultrasound was decreased in both groups. Amenorrhea and vasomotor symptoms were observed only with GnRH-A alone. Serum osteocalcin rose significantly with GnRH-A alone, reflecting a change in bone turnover (0.49 +/- 0.05 to 0.64 +/- 0.09 nmol/L; P0.05), but was unchanged with hormonal replacement. Patients receiving hormonal replacement had treatment extended to 1 yr. A further improvement of hirsutism, with scores dropping into the normal range (4.9 +/- 0.7), as well as a normalization of ovarian morphology were evident at this time. In conclusion, low dose (physiological) estrogen replacement may enhance the effects of GnRH-A treatment, while preventing most of the side-effects encountered with GnRH-A alone. This may allow more prolonged treatment, which is necessary for hirsutism.

Many alternatives exist for treating hirsutism. Based on an analysis of scientific literature and on the experiences of the author, the most common anti-androgen agents are discussed in this review. Androgen receptor blockers (cyproterone acetate, flutamide and spironolactone), 5 alpha-reductase inhibitors (finasteride) and androgen-suppressing agents (gonadotrophin-releasing hormone [GnRH] agonists, oestroprogestins, corticosteroids and insulin-sensitising agents) are evaluated and compared. The importance of diagnosis in choosing the most appropriate anti-androgen treatment is also discussed.

Hirsute women with normal ovulatory menstrual function are often diagnosed as having idiopathic hirsutism. We prospectively evaluated 62 hirsute ovulatory women to determine if they had a subtle form of polycystic ovary syndrome, and if they exhibited any of the metabolic abnormalities commonly associated with classic polycystic ovary syndrome.Baseline hormonal profiles, ovarian responses to gonadotropin-releasing hormone agonist, and ovarian morphology by ultrasound were compared in the hirsute women and two groups of ovulatory controls.Among 62 women, only 8 (13%) had normal androgen levels and were considered to have idiopathic hirsutism. Twenty-four (39%) had characteristic polycystic ovaries on ultrasound, an exaggerated response of 17-hydroxyprogesterone to leuprolide, or both, suggesting ovarian hyperandrogenism and the diagnosis of mild polycystic ovary syndrome. The remaining 30 women (48%) were considered to have unspecified hyperandrogenism. Age, body weight, and androgen level were similar among the hyperandrogenic subgroups. However, when compared with both normal and overweight controls and with patients with idiopathic hirsutism, the women who had mild polycystic ovary syndrome had higher fasting insulin levels [P0.01, mean (+/- SD) increase of 7 +/- 3 microU/mL], lower glucose-insulin ratios (P0.01, mean reduction of 3 +/- 1.5), higher low-density lipoprotein cholesterol levels (P0.05, mean increase of 26 +/- 10 mg/dL), and lower high-density lipoprotein (HDL) cholesterol levels (P0.01, mean reduction of 10 +/- 4 mg/dL). Compared with patients who had unspecified hyperandrogenism, these women also had higher fasting insulin levels (P0.05), lower glucose-insulin ratios (P0.05), and lower HDL cholesterol levels (P0.05).These data suggest that mild polycystic ovary syndrome is more common than idiopathic hirsutism, and it is also associated with subtle metabolic abnormalities.

In recent years, many new therapeutic regimens for hirsutism have been introduced. This has considerably enlarged the different choices of the physician but at the same time has produced considerable confusion and uncertainty as to what is the best possible therapy for the single patient or for the different pathologies of this condition. This review presents data on the characteristics, adverse effects and effective dosage for the more commonly used drugs for hirsutism. In most patients, low doses of antiandrogens (cyproterone acetate, flutamide or spironolactone) are used with few adverse effects and good results in terms of improvement of the hirsutism. Patients with severe hyperandrogenic hirsutism may require larger doses of antiandrogens. In only a few patients, therapy with agents that primarily reduce androgen secretion (mostly a gonadotropin releasing hormone agonist) is needed. In responsive patients, dexamethasone may be used at low doses (associated with an antiandrogen) to prolong the length of the remission. Finally, agents that inhibit 5alpha-reductase activity (finasteride) may be used as alternative to low dose antiandrogen therapy but the results are often less satisfactory.

Our aim was to determine whether the clinical features of 21-hydroxylase-deficient nonclassic adrenal hyperplasia are correlated with either age at symptom onset or age at presentation, or both, and with the degree of adrenocortical abnormality.In a multicenter cohort design 220 women with nonclassic adrenal hyperplasia, with a basal or adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level30.3 nmol/L, were studied, either prospectively (n = 39) or retrospectively (n = 181). Patients were stratified by age of presentation into 5 groups: (1)10 years (n = 25), (2) 10 to 19 years (n = 64), (3) 20 to 29 years (n = 83), (4) 30 to 39 years (n = 30), and (5) 40 to 49 years (n = 16). Two patients50 years old were excluded from the analysis because of age.Ninety-two percent of patients10 years old had premature pubarche at presentation, whereas clitoromegaly and acne were each present in only 20% of these younger subjects. With only patientsor =10 years old considered, presenting clinical features included hirsutism (59%), oligomenorrhea (54%), acne (33%), infertility (13%), clitoromegaly (10%), alopecia (8%), primary amenorrhea (4%), and premature pubarche (4%). Among the patients/=10 years old, the prevalence but not the degree of hirsutism increased significantly with age. Basal levels of 17-hydroxyprogesterone in adolescents were significantly higher than the levels found either in children (10 years old) or women 40 to 49 years old (P.01 and P.03, respectively), although no difference was noted in the stimulated 17-hydroxyprogesterone levels between age groups. The adrenocorticotropic hormone-stimulated levels but not the basal levels of 17-hydroxyprogesterone were significantly higher in patients with clitoromegaly than in women without clitoromegaly. Alternatively, there were no differences in either basal or stimulated 17-hydroxyprogesterone levels between patients with and those without hirsutism, acne, or alopecia.In children10 years old the most common presenting complaint was premature pubarche, whereas hirsutism and oligomenorrhea were more common in older patients. The prevalence of hirsutism increased with age, suggesting the progressive nature of nonclassic adrenal hyperplasia. Furthermore, the adrenocorticotropic hormone-stimulated levels of 17-hydroxyprogesterone were higher in patients with clitoromegaly, which suggests that the degree of adrenocortical dysfunction in nonclassic adrenal hyperplasia determines, at least in part, the clinical presentation.

Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg sc) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (Kitt), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30–40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P < 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P < 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.

Women’s health is about the prevention, screening, diagnosis, and treatment of disorders that are unique to women. Polycystic ovary syndrome (PCOS) is extremely prevalent and probably constitutes the most frequently encountered endocrinopathy in women of reproductive age. Primary care providers do not commonly appreciate that the syndrome is associated with significant morbidity in terms of both reproductive and nonreproductive events. Having the disorder may significantly impact the quality of life of women during the reproductive years, and it contributes to morbidity and mortality by the time of menopause. A cohort of women with PCOS who were followed for many years after wedge resection (1) revealed several important findings by the time they reached the age of menopause. Their symptoms of PCOS had persisted over this time, they had a later menopause, and they had experienced a higher hysterectomy rate. Most importantly, there was a high prevalence of diabetes (16%) and hypertension (40%).

Adrenal hyperandrogenism is prevalent in many women with polycystic ovary syndrome (PCOS), although the expression of this enhanced secretion may be heterogeneous. Since no single factor acts in isolation, this study was performed to assess the influence of oestradiol (total and unbound), insulin, insulin-like growth factor (IGF)-I, IGF-II and the binding proteins IGFBP-I, and IGFBP-3, on basal and adrenocorticotrophic hormone (ACTH) stimulated adrenal androgen secretion in 25 women with PCOS and 10 matched ovulatory controls. Women with PCOS exhibited elevations of all androgens as well as unbound oestradiol, insulin and non-IGFBP-1 bound IGF-I. Positive correlations were noted between oestrogen and basal and ACTH stimulated delta 5 adrenal androgens. Serum IGF-I was only correlated with basal dehydroepiandrosterone sulphate (DHEA-S), while insulin exhibited a strong correlation with the delta 4 pathway and androstenedione formation in particular. This correlation was also confirmed by dividing the PCOS group into those women with and without hyperinsulinaemia. The activity of 17,20 lyase favouring androstenedione was increased in the hyperinsulinaemic women. By multivariate analyses, body mass index did not influence these findings. Although there are inherent difficulties in making major conclusions based on correlative analyses, it is suggested that oestrogen may have a greater influence on enhancing delta 5 adrenal androgen secretion, and insulin a greater effect on the delta 4 pathway. In turn, the relative importance of these influences may contribute to the heterogeneous nature of adrenal hyperandrogenism in PCOS.

Objective: To determine the prevalence of polycystic ovary syndrome (PCOS) among hyperandrogenic women who report normal menses. Design: Prospective observational study. Setting: Academic practice in reproductive endocrinology. Patient(s): Fifty-eight consecutively seen new patients with hyperandrogenism who reported normal menses. Intervention(s): Ovulatory status was assessed with timed serum progesterone measurements. The following tests also were carried out: vaginal ultrasound examination; measurement of the ovarian response of 17-hydroxyprogesterone (17-OHP) after the administration of leuprolide acetate, 1 mg SC; and determination of fasting serum LH, FSH, E 2 , 17-OHP, insulin, and androgen levels. Main Outcome Measure(s): Determination of ovulatory status, polycystic appearance of ovaries, and increased response of 17-OHP to leuprolide acetate. Result(s): Twelve (20.7%) of the hyperandrogenic women were anovulatory and met the usual criteria for the diagnosis of PCOS. The ovulatory patients had lower serum total and unbound testosterone levels. Thirty-one (53.4%) of the ovulatory women had polycystic ovaries on ultrasound examination and/or an increased 17-OHP response to leuprolide acetate, suggesting the diagnosis of PCOS despite the presence of ovulation. Considering both the anovulatory and ovulatory patients, 74% of the hyperandrogenic women studied could have PCOS. Conclusion(s): The data suggest that most (74%) hyperandrogenic women who report normal menses have evidence for the diagnosis of PCOS.

Objective: To evaluate the prevalence of idiopathic hirsutism in a large population of hirsute women. Design: 588 hirsute women (mean age 24 6 1, range 15‐36 years) were evaluated as outpatients at the Department of Endocrinology of the University of Palermo, Italy. The diagnosis of idiopathic hirsutism was established in hirsute patients presenting regular ovulatory menstrual cycles and normal serum androgen levels (total testosterone, unbound testosterone and dehydroepiandrosterone sulfate). Methods: Hirsutism was calculated by the Ferriman-Gallwey-Lorenzo index. Serum androgens were evaluated in the follicular phase (days 5 or 6) and normal androgen ranges were calculated as the mean 6 2 S.D. of serum levels of 30 ovulatory non-hirsute women. The presence of ovulation was determined by serum progesterone levels during the presumed luteal phase (days 21 or 22). All steroids were determined by specific RIAs. Results: 36 hirsute women (6%) had regular ovulatory cycles and normal androgen levels and were diagnosed as being affected by idiopathic hirsutism. Conclusions: Idiopathic hirsutism is a relatively uncommon cause of hirsutism, affecting approximately 6% of our population.

Objective: To determine whether the addition of dexamethasone to antiandrogen therapy prolongs the duration of remission in women with hirsutism. Design: Follow-up study of patients treated with one of four regimens: spironolactone (100 mg/d) for 1 year, dexamethasone (0.37 mg/d) for 1 year, dexamethasone (0.37 mg/d) plus spironolactone (100 mg/d) for 1 year, or dexamethasone (0.37 mg/d) plus spironolactone (100 mg/d) for 2 years. Setting: Academic medical practice in reproductive endocrinology. Patient(s): Fifty-four women with hirsutism and hyperandrogenism. Intervention(s): Ferriman-Gallwey-Lorenzo scores were obtained and serum levels of testosterone, unbound testosterone, and dehydroepiandrosterone sulfate were measured before therapy, every 6 months during therapy, and for 1 year after the withdrawal of therapy. Main Outcome Measure(s): Hirsutism scores and serum indices of hormonal changes were monitored. Result(s): Ferriman-Gallwey-Lorenzo scores and androgen levels remained low 1 year after the withdrawal of therapy in patients who were treated with dexamethasone, either alone or in combination with spironolactone. In patients who were treated with spironolactone alone, hirsutism scores had returned to baseline values after 1 year. Conclusion(s): The addition of an agent that suppresses androgen levels may be useful to prolong the duration of remission of hirsutism in women with hyperandrogenism who are treated with antiandrogens.

Both cyproterone acetate (CPA) and the gonadotrophin-releasing hormone agonist (GnRHa) have been shown to be effective for the treatment of hirsutism. We wished to compare the effectiveness of CPA in two standard doses with GnRHa and add-back therapy and to compare the length of remission after these treatments. A total of 60 hirsute hyperandrogenic women was assigned to the following treatment groups: CPA 2 mg with 35 microg of ethinylestradiol for 21 days each month (Diane group), CPA 50 mg, days 5-15, and ethinylestradiol 50 microg, days 5-25, each month (CPA group) or Decapeptyl 3.75 mg i.m. every 28 days with the addition of conjugated oestrogen 0.625 mg, days 1-21, and medroxyprogesterone acetate 10 mg, days 12-21 (GnRHa group). Hirsutism was graded by the Ferriman-Gallwey-Lorenzo (FGL) index and anagen hair shaft diameters and serum luteinizing hormone (LH) and testosterone were assessed before and every 3 months during and after treatment. All women were treated for 1 year with 1 year follow-up. At baseline hirsutism and endocrine patterns were similar in all groups. After one year of treatment, hirsutism decreased in all groups but the changes were greater (P

Two of the newer antiandrogens, flutamide and finasteride, have proved to be as effective in treating hirsutism as cyproterone acetate (CPA). The authors compared four antiandrogen regimens in 48 hyperandrogenic women whose chief complaint was acne. The women were consecutive white women with moderate or severe acne and increased serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate. Acne was evaluated using Cook scores for diffusion of facial lesions and the severity of lesions. Nearly one third of the women also had mild hirsutism, but only 17% had menstrual irregularity. For 1 year the women received one of four regimens: 2 mg of CPA plus 35 μg of ethinyl estradiol for 3 weeks each month; 50 mg of CPA on days 5 to 15, with 25 μg of ethinyl estradiol added on days 5 to 25; 250 mg of flutamide daily; or 5 mg of finasteride daily. The women used mechanical contraception during the treatment year. All four regimens led to a significant reduction in Cook acne scores (Fig. 1). The results obtained with high-dose CPA were more marked than those achieved with low-dose CPA or flutamide, but not significantly so (Fig. 2). All three of these treatments were more effective than finasteride. No side effects were observed. Neither flutamide nor finasteride altered menstrual function, and all treated women continued to have normal blood glucose and liver enzyme values. It seems that most antiandrogenic regimens effectively treat acne in hyperandrogenic women (though finasteride is less effective) and that low doses may suffice.

Objective To assess levels of androgen metabolites thought to reflect, at least in part, peripheral androgen activity in women with androgenic alopecia and men with premature balding in an effort to determine if a common abnormality exists. Design Prospective study in various groups of women and men. Setting Reproductive Endocrine Clinic at our university medical center. Patients Ten normal ovulatory female controls and 50 hyperandrogenic women divided on the basis of hirsutism and alopecia as follows: [1] 8 hirsute women with androgenic alopecia; [2] 12 nonhirsute women with androgenic alopecia; [3] 18 hirsute women without androgenic alopecia; and [4] 12 nonhirsute women without androgenic alopecia. Ten normal men and 10 young premature balding men matched for age and weight also were compared. Intervention Blood was obtained from all subjects. Main Outcome Measure Comparison of blood hormone levels in the various groups. Results Serum T, androstenedione, and DHEAS were similarly elevated in hyperandrogenic women with and without alopecia, compared with controls. The female groups were then divided on the basis of hirsutism. Hirsute groups with and without alopecia had similarly elevated levels of unconjugated 3α-androstanediol, 3α-androstanediol glucuronide, 3α-androstanediol sulfate, androsterone glucuronide, and androsterone sulfate compared with controls. In the nonhirsute groups, androgenic alopecia patients were compared with hyperandrogenic females and cycling controls. The androgenic alopecia patients had elevated levels of 3α-androstanediol (0.75 ± 0.12 versus 0.46 ± 0.1 and 0.41 ± 0.1 nmol/L), 3α-androstanediol sulfate (200 ± 31 versus 79.6 ± 6 and 67.0 ± 4.0 nmol/L), elevated ratios of 3α-androstanediol sulfate:3α-androstanediol (267 ± 49 versus 170 ± 20 and 164 ± 49 nmol/L), elevated ratios of 3α-androstanediol sulfate:3α-androstanediol glucuronide (32.2 ± 6 versus 10.8 ± 1 and 10.0 ± 1) and lower ratios of 3α-androstanediol glucuronide:3α-androstanediol glucuronide (8.3 ± 1.8 versus 17 ± 1.7 and 15.2 ± 1.6 nmol/L). In men the premature balding group had lower levels of 3α-androstanediol glucuronide compared with the male controls (29.8 ± 4.4 versus 15.2 ± 1.6 nmol/L). Also, the ratio of 3α-androstanediol glucuronide:3α-androstanediol was significantly decreased, whereas the ratio of 3α-androstanediol sulfate:3α-androstanediol glucuronide was elevated. Conclusions These data provided evidence confirming that enhanced 5α-reductase activity occurs in androgenic alopecia but also suggests that a disorder of androgen conjugation, favoring sulfurylation over glucuronidation, may be a characteristic feature of scalp hair loss.

Objective To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women with late onset congenital adrenal hyperplasia. Design Prospective assessment of GnRH-a treatment in six women with documented late-on-set congenital adrenal hyperplasia who were not preselected. Comparisons were made to previous responses in the same patients receiving dexamethasone. Eight age- and weight-matched ovulatory women served as controls. Setting Academic medical center. Intervention Baseline blood determinations before and after IV ACTH, before and after 6months of GnRH-a treatment. Estrogen and progestin replacement was begun in all women after the 3rd month of treatment. Main Outcome Measures Serum 17-hydroxyprogesterone (17-OHP), gonadotropin, and androgen levels before and after GnRH-a treatment. Responses of 17-OHP and androgens to ACTH assessment of hirsutism using a modified Ferriman-Gallwey score. Results Gonadotropins, estrogen, androgen, and 17-OHP were suppressed with GnRH-a treatment. Levels were similar before and after estrogen and progestin replacement. Responses of 17-OHP after ACTH were blunted but still were elevated compared with responses in controls. Ferriman-Gallwey scores decreased significantly (−8±1; mean±SE). This response was greater than that observed previously with 6months of dexamethasone (−2±0.3). Conclusions Suppression of the ovary with GnRH-a treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian influence on the clinical and biochemical findings of the disorder is suggested.

Increased androgen production from the ovary, adrenal or locally in skin has been implicated in the pathogenesis of acne. Recent data have provided evidence that androsterone (Ao) metabolism is exaggerated in acne and serum metabolites of Ao differentiate between acne and hirsutism in hyperandrogenic women. Here we have extended these studies to normoandrogenic women who have moderate to severe acne. We measured serum ovarian and adrenal androgens as well as the glucuronide and sulfate metabolites of Ao and 3 alpha-androstanediol which reflect, in part, peripheral androgen action. In a group of 15 well-selected normoandrogenic patients with acne, both serum Ao glucuronide (G) and Ao were elevated (P0.01; P0.05). The ratios of Ao G to androgen precursors of both ovarian and adrenal origin were elevated as was the ratio of Ao G/Ao (P0.05). These data suggest that increased Ao metabolism is a specific abnormality found in both normoandrogenic and hyperandrogenic women with acne. Our findings also provide a rationale for antiandrogen therapy at least in some normoandrogenic women with acne.

Assessment of an in vivo test for 5 alpha-reductase activity using serum markers, 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide, after the cutaneous application of androstenedione (A).An A gel was applied for 6 days to the skin of normal women, male volunteers, and hirsute and nonhirsute patients with polycystic ovarian syndrome (PCOS). Blood samples were obtained at baseline and on day 6 of the A gel application. Blood samples were assayed for A, 5 alpha-androstane-3 alpha,17 beta-diol glucuronide, and androsterone glucuronide. In three hirsute women, the protocol was followed before and after receiving an oral contraceptive (OC) and spironolactone 200 mg/d for 3 months.The study was performed in the outpatient clinic of the Division of Reproductive Endocrinology and Infertility, Women's Hospital of the Los Angeles County and University of Southern California Medical Center in Los Angeles, California.A total of eight nonhirsute patients with PCOS, seven hirsute patients with PCOS, and six male volunteers were enrolled in the study. Five normal women served as a control group.Serum A increased after 6 days by a similar magnitude in all groups. Serum androsterone glucuronide showed a significant increase from baseline only in the hirsute group (P0.03), whereas the increase in 5 alpha-androstane-3 alpha,17 beta-diol glucuronide was not statistically significant.The ratio of the increases in serum androsterone glucuronide over serum A was significantly higher in the hirsute group (P0.02). In the three hirsute patients who were placed on an OC and spironolactone, serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide decreased after 3 months and did not increase with application of the gel for another 6 days.The cutaneous application of A provides a useful assessment of in vivo 5 alpha-reductase activity. However, because we found that A absorption varied considerably (30% to 62%), we suggest that this in vivo test may not provide more information than baseline determinations of 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide. It may, however, be useful as a parameter for assessing the effectiveness of various treatment regimens for hirsutism.

To determine whether the adrenal androgen 11 beta-hydroxyandrostenedione is a more sensitive and specific marker than dehydroepiandrosterone sulfate, we compared these serum androgens in 81 women with anovulatory hyperandrogenism before treatment, after corticotropin and corticotropin-releasing-factor stimulation, and after short- and long-term dexamethasone suppression. Of all subjects, 65% and 57% had elevated levels of 11 beta-hydroxyandrostenedione (greater than 2.0 ng/ml) and dehydroepiandrosterone sulfate (greater than 2.8 micrograms/ml), respectively. However, 11 beta-hydroxyandrostenedione and dehydroepiandrosterone sulfate levels did not correlate in either the women with hyperandrogenism (r = 0.12) or the 26 normal women (r = 0.29). After 0.25 mg corticotropin was administered intravenously (n = 16), 11 beta-hydroxyandrostenedione increased by 157% +/- 53% (mean +/- SEM), whereas dehydroepiandrosterone sulfate, androstenedione, dehydroepiandrosterone, and cortisol increased by 6% +/- 2%, 46% +/- 10%, 416% +/- 80%, and 2326% +/- 371%, respectively. After intravenous administration of 100 micrograms corticotropin-releasing factor to eight patients, the percent change from baseline level to peak was 148% +/- 26%, 24% +/- 5%, 61% +/- 15%, 117% +/- 15%, and 116% +/- 18% for 11 beta-hydroxyandrostenedione, dehydroepiandrosterone sulfate, androstenedione, dehydroepiandrosterone, and cortisol, respectively. After 2 mg dexamethasone for 3 days (n = 10), 11 beta-hydroxyandrostenedione, dehydroepiandrosterone sulfate, androstenedione, and testosterone were suppressed by 95% +/- 2%, 74% +/- 3%, 51% +/- 9%, and 32% +/- 9%, respectively. Suppression with 0.5 mg dexamethasone for 3 months lowered 11 beta-hydroxyandrostenedione and dehydroepiandrosterone sulfate levels equally by 50% +/- 14% and 62% +/- 12%, respectively. 11 beta-Hydroxyandrostenedione is a useful marker of adrenal androgen secretion with a calculated sensitivity and specificity greater than that of dehydroepiandrosterone sulfate. The greater sensitivity of 11 beta-hydroxyandrostenedione over dehydroepiandrosterone sulfate to adrenal stimulation and suppression suggests its unique diagnostic use.

Hirsutism in women is often explained on the basis of abnormal peripheral androgen metabolism. To determine whether serum markers of ovarian, adrenal, or peripheral androgen production may be helpful determinants in the treatment of hirsutism and to compare the efficacy of treatment with dexamethasone or spironolactone, 20 hyperandrogenic hirsute patients were treated for up to 2 years. Eleven women who were selected on the basis of sensitivity to dexamethasone were treated with a daily dose of 0.37 mg dexamethasone and had androgen levels suppressed into the normal range. Although significant (P less than .05), Ferriman-Gallwey scores decreased only by 20%: 14.2 +/- 0.5 to 11.4 +/- 0.6. Nine other women received spironolactone 100 mg/day for 1 year and did not have significant changes in serum androgens, but had a significant (P less than .01) 47% reduction in the Ferriman-Gallwey score (15.2 +/- 0.8 to 8 +/- 0.8). Thus, with either treatment, the reduction in Ferriman-Gallwey scores did not correlate with the change in androgen levels. The patients treated with dexamethasone for 1 year then received spironolactone 100 mg/day together with dexamethasone for an additional year. Serum androgen levels did not change further, but the Ferriman-Gallwey scores decreased significantly (P less than .01) from 11.4 +/- 0.6 to 3.74 +/- 0.7 (-61%). These data suggest that serum androgens are not helpful in assessing response to the treatment of hirsutism and that despite normal androgen levels, only modest clinical improvement may be expected with dexamethasone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was carried out to further characterize the pituitary-adrenal androgen responses of hyperandrogenic patients with 'classic' polycystic ovary syndrome (PCO) and others who were less distinctive and have been called 'PCO-like'. PCO-like patients differed from PCO only in that serum luteinizing hormone (LH) levels were normal and anovulation was not consistent. Ovine corticotropin-releasing factor (CRF) resulted in normal responses of adrenocorticotropic hormone and cortisol in the two groups when compared to controls, while androstenedione (delta 4A) and dehydroepiandrosterone (DHEA) responses were significantly elevated. There were no differences in the responses of PCO and PCO-like patients. Although basal DHEA levels correlated with DHEA responses of CRF, basal levels of DHEA sulfate (S) could not be used to predict CRF responses. These data further confirm that there is heightened adrenal androgen activity in PCO whether the patients are 'classic' or PCO-like. Serum DHEA-S does not appear to be a good marker for this adrenal hyperactivity and might in turn also be under the control of other factors.