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Considerable researches on sex steroids and insulin action have suggested a mutual interaction between hyperandrogenemia and insulin resistance (IR). The objective of present study was to evaluate ...

This study aimed to determine whether the ovaries synthesize estradiol (E2), testosterone (T), and androstenedione (A) after menopause. The first group (30 patients) underwent surgical menopause (SM) – their ovaries were removed due to a benign condition around the time of menopause. The second group (30 patients) consisted of patients with natural menopause (NM). The E2 median level was 10.0 pg/ml (CI ± 2.18) and 9.5 pg/ml (CI ± 1.63) in the NM and SM groups (p = .69), respectively. The median level of total T was 0.12 ng/ml (CI ± 0.01) and 0.11 ng/ml (CI ± 0.03) in NM and SM, respectively (p = .96). The median level of A was 783.85 pg/ml (CI ± 154.39) and 883.48 pg/dl (CI ± 201.03) in NM and SM, respectively (p = .57). The FAI (free androgen index) was 1.06 (CI ± 0.24) and 1.35 (CI ± 0.68) for NM and SM, respectively (p = .98). We concluded that 5–10 years after menopause the ovaries are no longer relevant for sex steroid synthesis.

The aim of this study was to determine the effect of ursodeoxycholic acid (UDCA) treatment on a polycystic ovary syndrome (PCOS) rat model. Thirty-two female Wistar–Albino rats were randomly divided into four groups as follows – group 1: sham group (n: 8), group 2: letrozole-induced PCOS group (n: 8), group 3: letrozole-induced PCOS plus metformin-treated (500 mg/kg) group (n: 8) and group 4: letrozole-induced PCOS plus UDCA (150 mg/kg)-treated group (n: 8). Histopathologic examination of the ovaries, circulating estrone (E1), estradiol (E2), testosterone, androstenedione, glucose, insulin and lipid profiles were evaluated. Histopathologic examination results revealed that groups 3 and 4 had significantly lower cystic and atretic follicles compared to group 2. Besides, group 4 had significantly higher antral follicles than group 2 (8.5 ± 2.9 versus 5.4 ± 1.1; p: 0.001). Furthermore, total testosterone (4.9 ± 2.8 versus 8.8 ± 2.9; p= 0.004) and insulin levels were significantly lower in group 4 compared to group 2 (1.7 ± 0.08 versus 2.1 ± 0.5; p = 0.02). However, lipid parameters, E1, E2, glucose and HOMA-IR were comparable between the groups. Our study results demonstrated that UDCA therapy improves ovarian morphology and decreases total testosterone and insulin levels. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

The differential steroid production in the theca and granulosa cells in ovary are resulted from unique enzyme expression profiles. Among them, c-fos, a downstream target of mitogen and extracellular signal-regulated kinases (MEK/ERK) signaling, takes part in this compartment. In this study, we investigated the effect of c-fos on the steady-state levels of CYP17 and CYP19 in human ovarian granulosa-like tumor cell line (KGN) by inhibiting MEK/ERK pathway with PD98059. As a result, our finding demonstrated the distinct distribution patterns of CYP17 and CYP19 in KGN. Moreover, the MEK/ERK pathway functions to inhibit the production of CYP17, while enhance the production of CYP19 in granulosa cells, probably involving a c-fos-dependent mechanism. In conclusion, factors such as c-fos may play a crucial role in the down-regulation of CYP17 and up-regulation of CYP19 in granulosa cells, thereby suppressing androstenedione synthesis.

Combined oral contraceptives (COCs) may increase the risk for cardiovascular disease depending on the ethynyl estradiol (EE) dose and the androgenicity of the progestogens. Our objective was to evaluate the impact of a COC containing 20 mcg EE + 3 mg drospirenone on blood pressure (BP), renin-angiotensin-aldosterone system, insulin resistance, and androgenic profile of healthy young women. Eighty-one healthy young women aged 30 ± 1 years (case group, n = 49, received COC; control group, n = 32, used no COC) were assessed twice, before and after the 6-month study. Statistical analysis employed the paired t-tests and expressed the data in mean and standard deviation. Results were as follows: no changes in BP or in BMI; a significant increase in aldosterone, plasma renin activity, triglycerides, and total cholesterol levels, but a non-significant increase in HDL and no significant changes in LDL levels (these parameters remained within normal ranges); a significant increase in the HOMA-IR index and a significant decrease in dehydroepiandrosterone sulfate (SDHEA), androstenedione, total testosterone, and free testosterone levels; no significant variations in the control group parameters. An oral contraceptive combination of a low EE dose and an anti-androgenic progestogen does not negatively influence the risk factors for a cardiovascular disease.

To evaluate the sex steroid profile and histomorphometry of the adrenal cortical zones of androgenized rats (wistar) with polycystic ovary syndrome treated with metformin.Thirty animals were divided into three groups: GC (regular estrous cycle), GPE (permanent estrus), and GPEM (permanent estrus + metformin 28 mg/kg for 50 days). At the end of this period, blood was collected for hormone measurement. The width of the adrenal cortical zones and the nuclear volumes were analyzed by histomorphometry. The ANOVA test was used in the statistical analysis.The adrenal glands of the androgenized animals were larger and more intensely vascularized than those of the other groups. The concentration of androstenedione in GPE was higher than that in the other groups (0.4 ± 0.1*= 0.2 ± 0.1 = 0.2 ± 01, *p 0.05). The width of the zona glomerulosa and of the zona reticularis and their nuclear volumes were greater in GPE compared to those of the other groups (GPE* GPEM = GC, *p 0.05).Metformin treatment may decrease the serum levels of androstenedione as well as the width and the nuclear volumes of the zona glomerulosa and of the zona reticularis in androgenized animals.

Basal serum 17OHP measurement remains the first screening step for nonclassic congenital adrenal hyperplasia (NCCAH) and the accuracy of the test is of high value. The aim of this study was to compare the accuracy of immunoassays to LC-MS/MS in the assessment of serum 17OHP and androgens concentration in women with hyperandrogenism and controls. 17OHP, total testosterone, androstendione and DHEA-S were measured in 39 women with clinically and/or biochemically evident hyperandrogenism and in 29 age-matched controls without clinical hyperandrogenism. 17OHP and androgens were measured by immunoassays and by LC-MS/MS. In patients group median 17OHP level measured by immunoassays was significantly higher compared to LC-MS/MS (5.49 nmol/l-ELISA NovaTec® and 3.57 nmol/l-ELISA DRG® versus 1.56 nmol/l-LC-MS/MS p 0.0001) as well as in the control group (2.58 nmol/l-ELISA DRG® versus 1.14 nmol/l-LC-MS/MS p 0.0001). Additional, unnecessary diagnostic procedures explaining elevated 17OHP level were undertaken in 85% of patients when NovaTec® test was used, in 50% when ELISA DRG® and in none when LC-MS/MS method was applied. Total testosterone, androstendione and DHEA-S concentrations in the patients and the controls assessed by the immunoassays were also significantly higher compared to LC-MS/MS. LC-MS/MS is more reliable diagnostic tool in the measurement of serum 17OHP and androgens concentrations compared to immunoassays in women with hyperandrogenism.

We report the case of a 15-year-old woman with signs of hyperandrogenism affected by a Sertoli-Leydig cell tumor (SLCT). In our patient, blood analysis showed a high testosterone (T) level (T: 8.53 nmol/L; nv 1.87 nmol/L) while the GnRH-analogue test demonstrated an exaggerated secretion of 17-hydroxyprogesterone (OHP), T, and androstenedione (A) by the ovary after stimulation. We compared the GnRH-analogue test of our patient with that obtained in a group of normal and healthy women (no. 8 subjects, 16-26 years old), men (no. 4 subjects, 18-28 years old), and in a group of PCOS patients with age and body weight compared. We found in our patient a value of OHP, 17-beta estradiol (E2) and T, from 2 to 18 times higher than healthy women. When we compared our patient with healthy men, we differently observed a comparable response of T. The response of our patient was also comparable with that observed in the PCOS group for E2. During the post-surgical follow up, the GnRH-analogue test of our patient showed a response of OHP, T, and E2 comparable with that of the PCOS group. The GnRH-analogue test is a useful tool to characterize steroidogenesis in SLCT.

Defects in cytochrome P450c17 are uncommon forms of congenital adrenal hyperplasia caused by CYP17A1 mutations. An H373L mutation in the CYP17A1 gene has been identified in Japanese and Chinese patients. This mutation impairs 17α-hydroxylase and 17,20-lyase activity.A 23-year-old Korean female (46,XX) presented with absent spontaneous puberty and hypertension. Hormonal findings were consistent with combined 17α-hydroxylase/17,20-lyase deficiency. Very high levels of progesterone and 11-deoxycorticosterone were detected, coincident with normal 17-hydroxysteroid levels. Plasma levels of dehydroepiandrosterone, androstenedione and testosterone were extremely low. Mutation analysis of the CYP17A1 gene identified a homozygous missense mutation changing His (CAC) to Leu (CTC) at codon 373. This mutation is known to completely abolish both 17α-hydroxylase and 17,20-lyase activity. The patient's nonconsanguineous parents were heterozygous for this mutation. Of note, her serum steroid levels indicated decreased, but still present, 17α-hydroxylase activity in vivo.We detected a homozygous H373L mutation in a patient with combined 17α-hydroxylase/17,20-lyase deficiency. Our findings demonstrate minimally preserved 17α-hydroxylase activity in vivo and contribute to our knowledge of the regional prevalence of this mutation in Northeast Asia.

The aim of the present study was to evaluate the impact of obesity and insulin resistance on testosterone formation from androstenedione and its contribution to biochemical hyperandrogenemia in all different phenotypic subgroups of PCOS patients. The case-control study included 1087 PCOS women and 206 regularly menstruating, ovulatory controls. The main clinical measurements included anthropometric and basal hormonal characteristics and evaluation of hyperandrogenic and insulin resistance-related features. The results were the following: In PCOS women with biochemical hyperandrogenemia, obesity significantly lowers serum A levels and increases T to A ratio. These findings were not present in PCOS women with clinical hypeandrogenemia and in normal ovulatory controls.

Ovarian Sertoli-Leydig cell tumours (SLCT), also termed arrhenoblastomas, are the most frequent virilising tumours in women of reproductive age. Very rare secretory Brenner tumours (BT) have been described, generally after the menopause. A 31-year-old woman sought medical advice for secondary amenorrhoea, progressive hirsutism and a 5-year history of virilisation syndrome with clitoromegaly. Testosterone was markedly high (285 ng/dl, N85) with moderate elevation of delta 4-androstenedione (D4AD) (311 ng/dl, N270), dehydroepiandrosterone sulfate (DHEAS) (366 μg/dl, N340) and 17-hydroxyprogesterone (17OHP) (275 ng/dl). LH was 9 IU/l, FSH 4.3 IU/l, estradiol 60 pg/ml and progesterone 314 ng/100 ml. Cortisol was decreased (1.3 μg/dl) after the dexamethasone suppression test. Pelvic MRI showed a 5-cm right ovarian tumour with a 2.5 cm nodular component and cystic areas, and two nodules measuring 11 mm and 15 mm above the right and left ovaries. After right ovariectomy by laparoscopy, pathological examination concluded on a 3-cm SLCT and a 2-cm BT; the nodules above the ovaries were dysembryoplastic cysts. Postoperatively, testosterone level was normal after 24 h (26 ng/dl), estradiol and progesterone rapidly decreased, cyclic secretion then resumed and the patient menstruated at day 27. To our knowledge, this is the first report of an ovarian tumour associating a Sertoli-Leydig cell tumour and a Brenner tumour in a patient with virilisation syndrome which resolved after ovariectomy.

Obesity and hyperandrogenaemia are key features of polycystic ovary syndrome (PCOS). The aim of this study was to investigate whether leptin and androgens are associated with obesity in PCOS subjects and identify whether there exist any genetic alterations in leptin gene in women with PCOS. The results reveal that leptin levels are elevated in women with PCOS and associate with BMI. However, irrespective of the obesity status leptin levels are higher in PCOS cases indicating that increased BMI/obesity may not be the only factor contributing to elevated levels of leptin. With regard to testosterone and androstenedione, the levels were increased in obese individuals irrespective of PCOS status. No correlation between leptin and androstenedione or testosterone was observed in controls and PCOS subjects. The single-nucleotide polymorphism G19A detected in the untranslated exon 1 of leptin gene was not associated with PCOS and does not contribute to elevated levels of leptin. The results overall suggest that androgen and leptin levels are increased in PCOS and obesity. It demonstrates that obesity is a confounding factor for hyperandrogenaemia irrespective of their PCOS status. The study rules out role of obesity status and leptin genotype in increase in leptin levels observed in PCOS cases.

Background. The main goal of the present study was to assess the influence of the androgen receptor gene CAG repeat polymorphism on hyperandrogenism and its phenotypical features in patients with polycystic ovary syndrome (PCOS).Methods. CAG repeat lengths were analyzed in 97 oligo-anovulatory women with ultrasound features of PCOS. All individuals were assessed for endocrine parameters and their phenotypical features were recorded. These parameters were correlated with the CAG repeat lengths.Results. PCOS patients with a bi-allelic mean lower than 21 repeats had lower dihydrotestosterone levels (p = 0.007), lower androstenedione levels (p = 0.023), lower luteinizing hormone levels (p = 0.023), a lower luteinizing hormone/follicle-stimulating hormone ratio (p = 0.021) and the highest percentage of patients with acne and/or hirsutism (p = 0.021).Conclusions. Our findings support the hypothesis that the PCOS phenotype may result from either elevated androgen levels or an enhanced sensitivity to androgens ca...

The length of the androgen receptor gene CAG repeat [AR (CAG)(n)] modulates the activity of the androgen receptor (AR), and this polymorphism has been shown to modulate body fat mass and serum concentrations of insulin in men. We hypothesized that shorter AR (CAG)(n) is associated with metabolic syndrome (MBS) or its components in women.In a cross-sectional controlled study we studied 52 Finnish women aged 34-55 years with MBS and 69 age-matched controls. All participants were recruited from a sample of women drawn from the Finnish population register. We compared the mean AR (CAG)(n) in the two groups. Furthermore, we correlated the AR (CAG)(n) with serum testosterone, androstenedione, dehydroepiandrosterone sulfate and several parameters of glucose and lipid metabolism in each group and in all 121 women.There was no difference in the biallelic mean AR (CAG)(n) between the MBS and the control group (21.6+/-0.2 vs. 21.8+/-0.2, not significant). The AR (CAG)(n) did not correlate significantly with any of the clinical or biochemical parameters of glucose or fat metabolism. However, it correlated negatively with serum testosterone (-0.195, p = 0.04) and androstenedione concentrations (-0.205, p = 0.03) in all studied women.The AR (CAG)(n) is not a major determinant of MBS in women but it contributes to ovarian androgen production.

Soluble intercellular adhesion molecule-1 (sICAM-1) is ranked as one of the endothelial dysfunction markers and factors predicting diseases of the cardiovascular system. The main objective of this study was to assess the serum concentration of sICAM-1 in women with polycystic ovary syndrome (PCOS) and to verify correlations between serum sICAM-1 levels and selected anthropometric, metabolic and hormonal indices. The study assessed 57 women with PCOS (mean age 28.2 +/- 6.4 years). That group was further divided into two subgroups: the first with body mass index (BMI)or =25 kg/m2 (21 women of mean age 27.4 +/- 7.0 years) and the second with BMI25 kg/m2 (36 women of mean age 28.6 +/- 6.0 years). In the control group there were 22 healthy women (mean age of 31.6 +/- 8.5 years). That group again was divided accordingly to BMI into two subgroups: the first with BMI25 kg/m2 (ten women, mean age 30.2 +/- 8.4 years) and the second with BMI25 kg/m2 (12 women, mean age 31.7 +/- 8.7 years). The results demonstrated statistically significantly higher mean concentrations of sICAM-1 in women with PCOS as compared to healthy individuals from the whole control group and also from the control subgroup of women with BMI25 kg/m2. There was no statistically significant difference in sICAM-1 concentration between the PCOS group and the control subgroup with BMIor =25 kg/m2 In conclusion, higher concentrations of sICAM-1 in women with PCOS may confirm the presence of a higher risk for cardiovascular diseases in this group. Further studies are therefore necessary to identify both the factors that are responsible for the increase in sICAM-1 concentration and the clinical usefulness of routine sICAM-1 measurement in females with PCOS.

Our objective was to investigate the effects of age, weight, body mass index (BMI), sex steroid receptor status and serum parameters such as estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and leptin on the size of a malignant breast tumor. A total of 62 premenopausal (median age 44.0 years) and 151 postmenopausal (median age 59.1 years) Caucasian women undergoing lumpectomy or mastectomy for invasive breast cancer were examined. Patient parameters (age, body weight, BMI), tumor parameters (tumor size, estrogen and progesterone receptor status) and serum parameters (estradiol, testosterone, androstenedione, DHEAS and leptin) were measured. An increase of BMI and DHEAS levels was associated with larger tumors by partial correlation (rp) analysis (rp = 0.418, p = 0.008; and rp = 0.329, p = 0.041, respectively), whereas higher androstenedione levels corresponded with smaller tumors. Furthermore, BMI, androstenedione and DHEAS levels were correlated: an increase in DHEAS was associated with higher androstenedione serum concentrations (rp = 0.603, p0.001), but was also associated with a lower BMI (rp = -0.378, p0.001). BMI and androstenedione serum concentrations were also associated (rp = 0.242, p = 0.009), thus closing a circle of mutual interactions. We conclude that, although breast cancer progression is characterized by autonomous growth that has become independent of growth regulatory mechanisms, tumor size at the time of detection is influenced by a complex system of counter-regulatory feedback mechanisms that might represent the body's physiological attempt to control the size of a malignant tumor.

To compare the serum androgens level during the third trimester of pregnancy between normotensive and pre-eclamptic women.A case-control study was performed on 64 pregnant women with the gestational age of 28-34 weeks. 32 women were pre-eclamptic (case group), and 32 women were normotensive till term gestation (control group). The serum level of androgens including sex hormone binding globulin (SHBG), total and free testosterone, androstenedione (ADD), and dehydroepiandrosterone sulfate (DHEA-S), were compared between the two groups.The women of the two groups had no statistically significant difference according to age, gestational age, BMI (body mass index), parity and fetal sex. Serum level of SHBG (90.86 ± 9.30 vs. 55.86 ± 8.02 nmol/l, p = 0.02), total testosterone (3.70 ± 0.57 vs. 2.06 ± 0.24 ng/ml, p = 0.01), free testosterone (1.28 ± 0. 17 vs. 0. 74 ± 0.07 pg/ml, p = 0.01), and ADD (2.47 ± 0.10 vs. 2.17 ± 0.10 ng/ml, p = 0.04), was higher in the pre-eclamptic women. However, there was no difference between the two groups for DHEA-S (0.75 ± 0.18 vs. 0.51 ± 0.08 μg/ml, p = 0.19).Serum androgen levels during third trimester of pregnancy are higher in pre-eclamptic women and this may propose an effect of androgens in the pathogenesis of pre-eclampsia.

The aim of this study was to investigate whether the absence or presence of acne or hirsutism in 248 women with polycystic ovary syndrome was associated with different clinical, endocrine, metabolic and ultrasonographic factors. Patients were divided into three groups: 96 (38.7%) without any androgenic symptoms; 94 (37.9%) with only hirsutism; and 58 (23.4%) with only acne. The cycle alterations (oligomenorrhea or amenorrhea) and the echographic ovarian morphology (polycystic or multifollicular ovaries) showed no significant differences between the three groups. Hirsutism was associated with a greater incidence of obesity and insulin resistance, with an increase of 17-hydroxyprogesterone, ovarian and adrenal androgens, 3alpha-androstanediol glucuronide, insulin, insulin-like growth factor-I and low luteinizing hormone, sex hormone binding globulins and insulin-like growth factor binding protein-1 levels. Acne was associated only with the lowest 3alpha-androstanediol glucuronide levels. Therefore, two different pathogenetic mechanisms may play a role in the onset of acne and hirsutism.

In order to study androgen secretion during controlled ovarian hyperstimulation for in-vitro fertilization-embryo transfer, an open randomized study comparing the response to recombinant or urinary follicle-stimulating hormone (FSH) in down-regulated cycles was performed. During FSH administration significant increases in testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) levels were observed. During the same period a slight decrease in luteinizing hormone (LH) levels was seen. At all times during the stimulation period a significant correlation between estradiol and testosterone or androstenedione levels was observed. We conclude that FSH, through granulosa derived paracrine factors, initiates thecal androgen synthesis and secretion.

We studied the in vitro response to insulin of granulosa-lutein cells derived from patients with polycystic ovary syndrome (PCOS) and clinically defined insulin resistance. Insulin sensitivity was assessed by continuous infusion of glucose with model assessment test (CIGMA). Insulin resistant (PCOS-IR; n = 8), noninsulin resistant (PCOS-NIR; n = 9) patients with PCOS, and women with tubal factor infertility (TF; n = 8) underwent controlled ovarian stimulation with long-term gonadotropin-releasing hormone (GnRH) agonist, recombinant follicle stimulating hormone (FSH), and in vitro fertilization. Primary cultures of granulosa-lutein cells were incubated with insulin (10, 100, 500 ng/ml) and/or luteinizing hormone (LH) (10, 100 ng/ml) in the presence of low density lipoprotein (100 micrograms/ml). The progesterone and lactate accumulation were measured in the culture medium. LH potently stimulated the progesterone secretion in all groups. Insulin alone had no effect on progesterone release in any of the groups, but stimulated lactate formation in the PCOS-NIR and TF groups. Insulin augmented the effect of LH on progesterone secretion selectively in the PCOS-NIR group. The expression of the insulin receptor was determined by Western blotting in separate cultures of granulosa-lutein cells, and showed receptor down-regulation in the PCOS-IR patients. We infer that the in vitro effect of insulin on progesterone and lactate release by granulosa-lutein cells is impaired in insulin resistant PCOS patients.

The plasma levels of beta-endorphin were studied in 64 women with polycystic ovarian disease (PCOD), from whom was selected a group of 23 women with normal weight and amenorrhea of < 36 days. On day 21, beta-endorphin levels were: mean 64.92 pg/ml; SD 37.32 pg/ml; 95% CI 48.38-81.47 pg/ml. It was also observed that their levels of opioid peptide were reduced, compared with women who had normal ovulatory cycles, both in the follicular phase (mean 70.93 pg/ml; SD 24.59 pg/ml; 95% CI 76.84-99.77 pg/ml) and luteal phase (mean 88.30 pg/ml; SD 31.80 pg/ml; 95% CI 76.84-99.77 pg/ml). The results were statistically significant (p < 0.05) for levels in PCOD patients compared with those of the luteal phase in women with normal ovulatory cycles. The decreased levels of beta-endorphin were negatively related to luteinizing hormone (LH) levels, which might explain the rise of LH levels in women with PCOD who control their weight and at the time of amenorrhea, although it is not clear if central opioid activity is reflected in the peripheral blood.

We have evaluated serum leptin concentrations in two forms of genetic obesity. The subjects examined were eight women with Down syndrome and eight women with Prader-Willi syndrome. All patients were in the reproductive age range and were obese (body mass indexor = 27 kg/m2). Plasma leptin values, analyzed as a function of body mass index showed a statistically significant correlation in both Prader-Willi (r = 0.985; p0.001) and Down syndrome patients (r = 0.943; p0.001). Obese Down syndrome women exhibited significantly lower leptin values (10.8 +/- 1.1) as compared to patients with Prader-Willi syndrome (31 +/- 2.6; p0.01). The linear correlation between leptin and insulin in the two groups of patients was not statistically significant. The data suggested that obesity in Prader-Willi subjects could be caused by failure of leptin to reach its target in the brain, as a consequence of defects in the receptor or in postreceptor processing, whereas data on obese patients with Down syndrome could be due to a different pathogenetic origin.

We describe the case of a 35-year-old woman with an ovarian steroid-cell tumor secreting markedly elevated levels of testosterone (28.3 nmol/l), dehydroepiandrosterone sulfate (19.7 mumol/l), androstenedione (34.7 nmol/l) and 17-hydroxyprogesterone (100.5 nmol/l) into plasma. We could find no report within the literature of androgens at the levels described in this patient. Herein we review the literature and discuss the possible endocrine etiology of the excess androgens observed in this case. We also discuss the differential diagnosis, investigation and interpretation of androgens of adrenal and ovarian origin.

In recent years numerous studies have suggested insulin to be an important regulator of ovarian function and hyperinsulinemia to be associated with hyperandrogenism. An oral glucose-tolerance test was carried out in 240 women with polycystic ovary syndrome and, based on its result, 142 of the women (59.2%) were insulin resistant or hyperinsulinemic and 98 (40.8%) were normoinsulinemic. Compared with the normoinsulinemic group, the hyperinsulinemic group had a greater incidence of obesity (52.8 vs. 21.4%), secondary amenorrhea (24.6 vs. 9.2%), androgenic symptoms (85.9 vs. 67.4%) and, in particular, hirsutism with or without acne (71.8 vs. 48.0%). Moreover, the hyperinsulinemic group had significantly higher plasma levels of androstenedione, testosterone, free testosterone and insulin, and lower levels of luteinizing hormone, estradiol and sex hormone-binding globulin.

In an in vitro fertilization (IVF) and embryo transfer program with human menopausal gonadotropin/human chorionic gonadotropin treatment no oocytes were recovered in 18 out of 788 cycles. Estradiol (E2), progesterone (P) and androstenedione contents of 27 follicles obtained from five of the 18 patients were radioimmunologically measured and P:E2 ratio calculated. Control values of 20 follicles were obtained from four of these five patients in subsequent IVF cycles. A total of 17 oocytes were harvested. Estradiol, progesterone and androstenedione mean +/- SEM values (nmol/l) were, respectively, 4246 +/- 1484, 3751 +/- 1768 and 1920 +/- 641 in the failed cycles and 2504 +/- 908, 13,678 +/- 4749 and 509 +/- 87 in the successful ones. P:E2 ratios were 0.88 +/- 1.03 and 5.67 +/- 1.70, respectively. The differences in these levels of progesterone, androstenedione and the ratios of P:E2 were significant (p0.01). It is concluded that the probable cause of 'empty follicles' is inappropriate luteinization and they are not characteristic for a given patient or for stimulation with human menopausal gonadotropin/human chorionic gonadotropin.

Responses to laparoscopic ovarian laser vaporization were studied in 17 anovulatory patients with clomiphene citrate-resistant polycystic ovarian disease (PCOD). Ovulatory cycles were obtained in 14 patients (82%). A total of 11 patients (65%) conceived within 1-8 months. Measurements of basal serum hormone levels before and after the procedure in 12 patients revealed a significant decline in testosterone, dihydrotestosterone and androstenedione. In addition, luteinizing hormone (LH) levels decreased, but not significantly. On the other hand estradiol levels slightly increased and a surge in luteal progesterone levels was noted. Serum levels of sex hormone binding globulin, prolactin, dehydroepiandrosterone (DHEA) sulfate, 17-OH-progesterone and follicle stimulating hormone (FSH) remained unchanged. These results suggest that ovarian laser vaporization is very useful when clomiphene citrate fails in PCOD, and has no risk of ovarian hyperstimulation syndrome or multiple gestation, which is frequently observed in ovulation induction with drugs. Most of the endocrine abnormalities associated with PCOD are corrected by the laser procedure.

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the 24-h blood profiles of cortisol in obese and non-obese women with polycystic ovary syndrome (PCOS), for comparison with the levels in healthy women (controls). The levels of other hormones, such as androgens, which are known to be disturbed in PCOS, were also compared. Luteinizing hormone (LH) and androgen (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)) concentrations were significantly (p < 0.005) raised in patients with PCOS, compared to those in control women. Sex hormone binding globulin (SHBG) concentration was significantly lower in women with PCOS, particularly in those who were overweight. There was a significant negative correlation between body mass index (BMI) and SHBG concentrations (r = -0.59; p = 0.006). Mean 24-h cortisol concentrations were similar in women with PCOS and controls, as well as in the obese and non-obese PCOS patients. However, the 24-h blood cortisol profile pattern was significantly different in women with PCOS as compared to the controls (p = 0.0039). Significantly lower cortisol levels were observed during the night (levels were determined between 20.00 and 04.00 and are expressed as the area under the curve) in subjects with PCOS, compared to the control women (p = 0.02). These changes were most marked in the non-obese women with PCOS who had lower blood cortisol levels during the night than either the controls or the obese PCOS subjects. Our finding of significantly lower cortisol concentrations during the night could reflect a subtle abnormality of adrenal steroid secretion in women with PCOS.

3 alpha, 17 beta-androstanediol-glucuronide (Adiol-G) has been described as a marker of local androgen excess due to the increased activity of 5 alpha-reductase in the cells of the hair follicles. In order to test the diagnostic value of Adiol-G, the serum level was compared to that of testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione and to the body mass index in 44 women with androgenic symptoms (Group I), 27 women with menstrual disturbances but no androgenic symptoms (Group II), and 48 healthy women (Group III) who served as controls. Adiol-G was significantly higher (7.8 +/- 5.1 nmol/l) in women with androgenic symptoms than in the other groups, but there was a considerable overlap. Serum testosterone was also found to be higher in Group I than in Groups II and III, respectively. There was a significant correlation between Adiol-G and testosterone, and Adiol-G and DHEA-S. No significant correlation could be shown to exist between androstenedione and Adiol-G. When Adiol-G and testosterone were simply classified as 'normal' or 'increased' (Adiol-G 9.4 nmol/l; testosterone greater than 2.4 nmol/l), higher than normal values of the former were found in the presence of normal testosterone in only 4% of the cases. It is concluded that the level of Adiol-G generally parallels that of testosterone. Consequently, it does not seem to be an effective marker of peripheral androgen excess.

Non-classical adrenal hyperplasia due to 21-hydroxylase enzyme deficiency (NC21OHD) causes hirsutism, acne and menstrual irregularities in women. Clinically, patients with NC21OHD may be indistinguishable from other hyperandrogenic women, as they all present with similar symptoms. An elevated response of cortisol precursors like 17 alpha-hydroxyprogesterone (17-OHP) to ACTH stimulation is a valuable diagnostic criteria. In this study, 32 hirsute adolescent girls, aged 13-19 years, underwent i.v. adrenocorticotrophic hormone (ACTH) (Synacthen 0.25 mg) stimulation test. The results were compared with those of the controls. The plasma levels of 17 alpha-hydroxyprogesterone, cortisol, dehydroepiandrosterone sulphate (DHEA-S), androstenedione, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and prolactin were established before, and 60 min after the infusion of ACTH to both patients and controls. Six patients demonstrated an increase in both the 17 alpha-hydroxyprogesterone levels and the 17 alpha-hydroxyprogesterone/cortisol ratio on ACTH stimulation, almost twice that of the mean +/- 2SD in the control group and ten times that in one patient. Six patients with abnormal elevation of 17 alpha-hydroxyprogesterone were considered heterozygotes for 21-hydroxylase enzyme deficiency, and one patient was presumed to have NC21OHD. Human leukocyte antigen (HLA) analysis supported these diagnoses. In this study, the incidence of NC21OHD in hirsute adolescent girls in our population was investigated, and NC21OHD was found in only one of 32 patients.

Fifty-four hyperandrogenized women were studied to evaluate the importance of the adrenal or ovarian contribution to androgen secretion. Forty-six had the polycystic ovarian (PCOD) syndrome. Eight normal women represented a control group. The endocrine study was performed during the follicular phase. The plasma samples were collected at 7.00 am (A1) and at 11.00 pm (A3). Dexamethasone 2 mg was administered orally at 11.30 pm and blood samples were collected the day after, at 7.00 am (B). The adrenocorticotropic hormone (ACTH) was injected, 250 micrograms i.v. and samples were collected after 60 min. Cortisol dehydroepiandrosterone-sulfate (DHEAS), androstenedione, testosterone and 17-hydroxyprogesterone (17OHP) were measured. The hyperandrogenized patients had A1 androgen levels higher than the controls (p less than 0.01). 17OHP and androstenedione A3 values showed a cortisol-related decrease. After dexamethasone, androgen levels, since DHEAS, were normalized in all patients. We found that baseline androgen levels and circadian and dexamethasone-inhibited amounts were strongly correlated (p less than 0.01). The ACTH test revealed five cases of enzymatic adrenal deficiencies. Moreover, the amplitude of the response of 17OHP and androstenedione to ACTH is predictable in relation to both circadian and dexamethasone-inhibited amounts (p less than 0.01). In conclusion, our study confirms and makes quantifiable the importance of the adrenal contribution to androgen secretion in hyperandrogenized patients. The ACTH test is important for detecting the presence of mild enzymatic adrenal defects.

We have studied 131 women affected by benign or malignant breast disease, in order to explore their endocrine status. We evaluated basal concentrations of the following hormones: FSH, LH, PRL, estrone (E1), estradiol (E2), testosterone (T), androstenedione (A), DHEAS and SHBG. Basal hormone levels in these patients were not significantly different from those in normal age-matched subjects. However, in premenopausal women, 31% of patients with benign disease and 34.4% with malignant lumps exhibited an elevated FSH/LH ratio (greater than 1) and lower T levels, compared to those having a normal FSH/LH ratio. The difference in T levels was not coupled with the expected specular variations in SHBG levels. Moreover, in none of the group considered, T concentrations or E2/T were significantly correlated with SHBG levels. These data seem to suggest an altered regulation of SHBG in these patients, in whom the modulation of SHBG by circulating sexual steroids appears to be different when compared with normal subjects.

The endogenous concentrations of testosterone (Testo), androstenedione (Adion), 5-androstene-3 beta, 17 beta-diol (Adiol), dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) have been measured in endometrium, myometrium and vagina from 23 premenopausal women at different stages of the cycle. The tissue to plasma gradient was positive for all androgens except DHEAS; a significant correlation existed between plasma and tissue levels of Adiol and DHEAS. In all tissues significant correlations were calculated between Adiol and DHEA, Adion and Testo, and Adiol and DHEAS. Except for Testo, androgen concentrations were different in the tissues with a significant correlation between the tissues, each tissue seeming to be able to create its own specific intratissue androgen pattern. During the cycle Testo was highest in myometrium and vagina and Adion in myometrium and endometrium during the secretory phase. Except for DHEA, androgens were preferentially localized in the cytosol fraction of the cells. From this localization and the known inhibitory effects of androgens on the activity of estrogen metabolizing enzymes, it is postulated that androgens play a role in enzymatic rather than receptor-mediated processes in uterine cells.