Inhibin B: a potential marker of gonadal activity in patients with anorexia nervosa during weight recovery

Inhibin B is a product of the gonads and a marker for ovarian follicular development. This was a cross-sectional study designed to assess awakening of the reproductive function by studying secretion pattern of inhibin B during the weight restoration in patients with anorexia nervosa (AN). Twenty patients with AN participated at low weight [body mass index (BMI) 14.3 +/- 0.3 kg/m(2))], 22 partially weight recovered AN (BMI 17.4 +/- 0.1 kg/m(2)), 16 reached goal weight but did not restore menstrual cycles (BMI 19.5 +/- 0.1 kg/m(2)), and 13 reached goal weight and had at least six consecutive menstrual cycles (BMI 19.3 +/- 1.0 kg/m(2)). Nineteen eumenorrheic females with BMI 19.8 +/- 0.4 kg/m(2) served as controls. At low weight, patients had low basal leptin, inhibin B detectable in only 15% of samples, and LH significantly lower than in controls (P < 0.01). At weight gain, basal leptin increased, median inhibin B increased (detectable in 66.7% of samples), and LH remained low, all significantly lower than in controls (P < 0.01). Weight-recovered/amenorrheic patients further increased basal leptin, inhibin B was detectable in all samples, and LH remained low, all significantly lower than in controls (P < 0.01). In weight-recovered/cycling patients, basal leptin, median inhibin B, and LH, as expected, were not different from healthy volunteers. Inhibin B values correlated significantly with leptin (P = 0.000) and BMI (P = 0.000). In summary, gonads in patients with AN who gain weight are not entirely quiescent but have a low level of activity. Inhibin B is an early marker of gonadal activity, and with weight gain, awakening of the reproductive function is gradual, whereas factors triggering the onset of menstrual cycles still remain unknown (nutritional fat intake, psychological).     

Ovarian age-related responsiveness to human chorionic gonadotropin in women with polycystic ovary syndrome

Ovarian steroid secretion capacity starts to decline as early as around the age of 30 yr. Whether an age-related decrease in androgen secretion, as in normal women, also occurs in women with polycystic ovary syndrome (PCOS) and whether the enhanced androgen production in PCOS remains throughout the fertile period of life are not known. The aim of this study was to determine the age-related serum basal and gonadotropin-stimulated androgen levels in women with PCOS and to compare the results with those obtained from our previous study in healthy women with normal ovaries. Human chorionic gonadotropin (hCG) stimulation tests were carried out among 42 women with PCOS (age, 16-44 yr; body mass index, 31.02 +/- 1.1 kg/m(2)). An im injection of 5000 IU hCG was given 2-4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h. In women with PCOS, basal serum T and A levels were about 50% higher than in healthy women. The responses of A and T to hCG [area under the curve (AUC), 96 h)] were significantly higher in women with PCOS than in normal women [A, 1183.6 +/- 60 (+/-se) vs. 814.4 +/- 39 (P 相似文献   

Follicular arrest in polycystic ovary syndrome is associated with deficient inhibin A and B biosynthesis

CONTEXT: Previous studies suggest that inhibin subunit expression is decreased in granulosa cells of women with polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of this study was to test the hypothesis that inhibin A and inhibin B protein concentrations are also decreased in PCOS follicles. DESIGN: The design was a parallel study. SETTING: The study was performed at an in vitro fertilization suite. PARTICIPANTS: We studied women with regular cycles (n = 36) and women with PCOS (n = 8). INTERVENTIONS: Follicular fluid was aspirated from the follicles of women with PCOS (n = 14 follicles) and from women with regular cycles at various times during the follicular phase (n = 50 follicles). MAIN OUTCOME MEASURE: Inhibin A and B concentrations from PCOS follicles were compared with those in size-matched follicles, dominant follicles (> or = 10 mm), and subordinate follicles from regularly cycling women. RESULTS: Inhibin A (220 +/- 38 vs. 400 +/- 72 IU/ml; P < 0.05) and inhibin B (75.4 +/- 10.4 vs. 139 +/- 26 ng/ml; P < 0.05) concentrations were lower in the follicular fluid of PCOS follicles compared with those of size-matched follicles from regularly cycling women. Inhibin A was also lower in the follicular fluid of PCOS compared with subordinate follicles from normal women (577 +/- 166 IU/ml; P < 0.05). Inhibin A concentrations increased with increasing follicle size, resulting in significantly higher follicular fluid concentrations in dominant follicles from normal women compared with PCOS follicles (2298 +/- 228 IU/ml; P < 0.05). CONCLUSIONS: These data demonstrate that inhibin A and inhibin B concentrations are significantly reduced in the follicular fluid of women with PCOS compared with those in the follicular fluid of size-matched follicles from normal women, consistent with the decreased inhibin subunit mRNA expression in previous studies. These findings point to the potential importance of inhibins in normal follicle development and suggest that inhibin deficiency may play a role in the follicle arrest associated with PCOS.     

Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit elevated levels of serum C-reactive protein (CRP) and impaired endothelium dysfunction which are directly correlated with insulin resistance. Because rosiglitazone improves insulin sensitivity, we tested whether rosiglitazone treatment ameliorates high-sensitivity (hs)CRP levels and endothelial dysfunction in these patients. DESIGN: Thirty-one women with PCOS were recruited (mean age, 24.7+/-3.9 (s.e.) years; mean body mass index (BMI), 25.6+/-3.2 kg/m2). All women were treated with 4 mg rosiglitazone daily for 12 months. METHODS: Serum levels of testosterone, LH, FSH, sex hormone-binding globulin (SHBG), insulin and hsCRP were measured. The BMI, hirsutism scores and insulin sensitivity indices were calculated before and after treatment. Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli before and after treatment. RESULTS: After treatment with rosigitazone there were significant decreases in serum testosterone (91.2+/-37.5 vs 56.1+/-21.8 ng/dl; P < 0.01) and fasting insulin concentrations (12.5+/-7.6 vs 8.75+/-4.03 microU/ml; P = 0.015). Insulin resistance indices were significantly improved after rosiglitazone treatment (P < 0.05). There were no significant changes in BMI, waist circumference, serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, FSH and LH levels. Hirsutism score was decreased significantly after treatment (10.8+/-1.8 vs 7.6+/-1.7; P < 0.05). Twenty-four of the women reverted to regular menstrual cycles. Levels of SHBG increased significantly after treatment (28.7+/-8.7 vs 48.4+/-11.2 nmol/l; P < 0.01). Serum hsCRP levels were decreased significantly after rosiglitazone treatment (0.25+/-0.1 vs 0.09+/-0.02 mg/dl; P = 0.006). There was also significant improvement in endothelium-dependent vascular responses after rosiglitazone treatment (9.9+/-3.9 vs 16.4+/-5.1%; P < 0.01). CONCLUSIONS: We conclude that rosiglitazone treatment improves insulin sensitivity in women with PCOS. It also decreases androgen production without significant weight gain. More importantly, it has beneficial effects on endothelial dysfunction and low-grade chronic inflammation in normal weight young women with PCOS.     

Increased serum inhibin B levels after varicocele treatment

OBJECTIVE: Inhibin B is secreted by Sertoli cells in response to FSH and is the major feedback regulator of FSH secretion in man. The serum inhibin B level has emerged as a good marker of spermatogenesis and Sertoli cell function. Varicocele has been associated with infertility and disturbed spermatogenesis. We have studied the effect of varicocele treatment on serum inhibin B levels, with the aim of investigating the effect on spermatogenesis and the involvement of the Sertoli cell in varicocele pathophysiology. DESIGN AND PATIENTS: In a pre-post test design, the effect of varicocele surgery on inhibin B levels was studied in 30 infertile men. MEASUREMENTS: Endocrinology (inhibin B, FSH, LH, SHBG and testosterone) and semen analysis (sperm concentration, motility and morphology). RESULTS: In men receiving varicocele treatment, a significant increase in serum inhibin B levels was observed from 133.9 +/- 13.4 pretreatment to 167.8 +/- 16.1 ng/l after treatment (mean +/- SEM, P < 0.0001). No significant changes were observed in serum levels of FSH, LH and testosterone. The serum SHBG level decreased from 32.9 +/- 3.5 to 28.6 +/- 3.4 nmol/l (mean +/- SEM, P = 0.04) and the free androgen index was significantly increased from 66 +/- 5.9 pretreatment to 85 +/- 6.8 after treatment (P = 0.02, mean +/- SEM). Semen analysis showed a significant improvement in sperm concentration, from 6.5 +/- 1.9 pretreatment to 19.3 +/- 4.9 x 106/ml after treatment (P = 0.003, mean +/- SEM), and in sperm motility from the baseline level of 17 +/- 3 to 32 +/- 4% after treatment (P = 0.001, mean +/- SEM). CONCLUSIONS: Varicocele treatment can increase serum inhibin B levels, indicating improvement of spermatogenesis and Sertoli cell function. This finding suggests that the pathophysiology of varicocele involves impairment of Sertoli cell function or a different distribution of germ cell stages.     

Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes

Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG (cFT). Hypogonadism was defined as low FT or cFT. The mean age was 54.7 +/- 1.1 yr, mean body mass index (BMI) was 33.4 +/- 0.8 kg/m(2), and mean HbA1c was 8.4 +/- 0.2%. The mean T was 12.19 +/- 0.50 nmol/liter (351.7 +/- 14.4 ng/dl), SHBG was 27.89 +/- 1.65 nmol/liter, and FT was 0.250 +/- 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels (3.15 +/- 0.26 vs. 3.91 +/- 0.24 mIU/ml for LH and 4.25 +/- 0.45 vs. 5.53 +/- 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation of BMI with FT (r = -0.382; P < 0.01) and T (r = -0.327; P < 0.01). SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age (r = 0.538; P < 0.001) and T (r = 0.574; P < 0.001). FT correlated strongly with cFT (r = 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r = 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.     

Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

BACKGROUND Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. OBJECTIVE: To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. DESIGN: A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. SUBJECTS: Twenty-nine women with PCOS [aged 27.52 +/- 5.77 years; body mass index (BMI) 35.43 +/- 5.31 kg/m(2)] and 18 controls (aged 32.06 +/- 5.64 years; BMI 36.39 +/- 6.47 kg/m(2)). MEASUREMENTS: Serum AGE levels (U/ml), hormonal and metabolic profile. RESULTS: PCOS and controls did not differ in BMI (P = 0.58), waist-to-hip ratio (WHR) (P = 0.44), fasting insulin concentration (P = 0.45) and glucose-to-insulin ratio (GIR) (P = 0.34). PCOS women exhibited statistically higher AGE (P < 0.001) and testosterone levels (P < 0.001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9.08 +/- 1.84, post-orlistat 8.56 +/- 1.95, P = 0.001; controls: baseline 5.02 +/- 0.62, post-orlistat 4.91 +/- 0.69, P = 0.03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0.001; controls: P < 0.001), WHR (PCOS: P = 0.002; controls: P = 0.04), fasting insulin (PCOS: P < 0.001; controls: P = 0.008), and testosterone concentrations in PCOS (P < 0.001). SHBG concentration (PCOS: P = 0.004; controls: P = 0.008) and GIR (PCOS: P < 0.001; controls: P = 0.03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. CONCLUSIONS: Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes.     

Inhibin A,inhibin B,follicle-stimulating hormone,luteinizing hormone,estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.     

In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study

OBJECTIVE: An age-related decline in serum total and free testosterone concentration may contribute to ill health in men, but limited data are available for men > 70 years of age. We sought to determine the distribution and associations of reduced testosterone concentrations in older men. DESIGN: The Health in Men Study is a community-representative prospective cohort investigation of 4263 men aged > or = 70 years. Cross-sectional hormone data from 3645 men were analysed. METHODS: Early morning sera were assayed for total testosterone, sex hormone binding globulin (SHBG) and LH. Free testosterone was calculated using the Vermeulen method. RESULTS: Mean (+/- s.d.) serum total testosterone was 15.4 +/- 5.6 nmol/l (444 +/- 162 ng/dl), SHBG 42.4 +/- 16.7 nmol/l and free testosterone 278 +/- 96 pmol/l (8.01 +/- 2.78 ng/dl). Total testosterone correlated with SHBG (Spearman's r = 0.6, P < 0.0001). LH and SHBG increased with age (r = 0.2, P < 0.0001 for both). Instead of declining, total testosterone increased marginally (r = 0.04, P = 0.007) whilst free testosterone declined with age (r = -0.1, P < 0.0001). Free testosterone was inversely correlated with LH (r = -0.1, P < 0.0001). In multivariate analyses, increasing age, body mass index (BMI) and LH were associated with lower free testosterone. CONCLUSIONS: In men aged 70-89 years, modulation of androgen action may occur via an age-related increase in SHBG and reduction in free testosterone without a decline in total testosterone concentration. Increasing age, BMI and LH are independently associated with lower free testosterone. Further investigation would be required to assess the clinical consequences of low serum free testosterone, particularly in older men in whom total testosterone may be preserved.     

Serum inhibin levels in polycystic ovary syndrome: basal levels and response to luteinizing hormone-releasing hormone agonist and exogenous gonadotropin administration

Serum inhibin levels were measured by RIA twice weekly for 4 weeks in 5 women with the polycystic ovary syndrome (PCOS). These were compared to those in 10 women with normal menstrual cycles. Serum inhibin levels were similar in the 5 PCOS women (mean, 199; range, 126-266 U/L) and were not significantly different from those in the normal women during the early follicular phase (227; 100-485 U/L) or midfollicular phase (243; 143-412 U/L) of their cycles. Inhibin levels were higher (P less than 0.001) in the late follicular phase (408; 227-732 U/L), at midcycle (623; 367-1058 U/L), and during the midluteal phase (1245; 898-1727 U/L) in the normal women compared to those in the PCOS group. Serum inhibin levels were also measured in PCOS (n = 8) and infertile (n = 14) women after the rise and subsequent diminished gonadotropin secretion that occurred during LHRH agonist administration. In both groups, serum LH and FSH increased after initiation of LHRH agonist administration; this increase was accompanied by parallel rises in serum estradiol and inhibin before suppression (PCOS women: r = 0.71; P less than 0.001; n = 108; infertile women: r = 0.42; P less than 0.05; n = 163). All hormone levels, including inhibin, decreased during continued LHRH administration. Five PCOS women underwent ovulation induction using combined LHRH agonist and human menopausal gonadotropin administration. Serum estradiol and inhibin rose in parallel in response to exogenous gonadotropins (r = 0.92; P less than 0.001; n = 77). In conclusion, we found no evidence of a primary defect in ovarian inhibin physiology in women with PCOS in terms of either basal or gonadotropin-stimulated (exogenous or endogenous) secretion.     

Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years.

OBJECTIVE: To assess the effect of age on clinical, endocrine and sonographic features associated with polycystic ovary syndrome (PCOS) in normogonadotrophic anovulatory infertile women of reproductive years. DESIGN: Cross-sectional study. METHODS: Four hundred and seventy-two oligo-amenorrhoeic infertile patients, presenting with normal FSH and oestradiol concentrations, aged 17-42 years underwent a standardised initial evaluation including: cycle history, body mass index, waist-to-hip ratio and transvaginal ultrasound scanning of ovaries. Fasting blood samples were obtained for extensive endocrine evaluation. Cycle duration, serum levels of gonadotrophins, androgens, oestradiol, insulin, glucose, inhibin B as well as mean number of follicles, ovarian volume and ovarian stroma echogenicity were assessed. RESULTS: Older women had significantly lower LH and androgen and inhibin B serum levels. Similarly, older women presented with a reduced number of ovarian follicles. Age was inversely correlated with cycle duration (r=-0.112, P=0.02), LH (r=-0.154, P=0.001), testosterone (r=-0.194, P=0.001), androstenedione (r=-0.170, P=0.001), dehydroepiandrosterone (r=-0.157, P=0.001), insulin (r=-0.126, P=0.02), inhibin B (r=-0.118, P=0.03) serum levels and mean follicle number (r=-0.100, P=0.03). A positive correlation was observed between age and glucose to insulin ratio (r=0.138, P=0.009). CONCLUSIONS: Advanced age in normogonadotrophic anovulatory infertile women is associated with lower LH and androgen levels and with a decreased number of ovarian follicles. Although during reproductive years observed differences are relatively small, these age-related changes may affect the observed incidence of PCOS.     

Inhibin A and inhibin B responses to gonadotropin withdrawal depends on stage of follicle development.

Previous studies demonstrate that inhibin A and B are differentially secreted across the menstrual cycle. To test the hypothesis that the responses of inhibin A and inhibin B to partial gonadotropin withdrawal are influenced by the stage of follicular development, a maximally suppressive dose of the Nal-Glu GnRH antagonist (150 microg/kg) was administered to normal cycling women during the midfollicular (MFP; n = 8), late follicular (LFP; n = 6), and midluteal phase (MLP; n = 5) to assess ovarian responsiveness over a broad range of developmental stages. Administration of the GnRH antagonist resulted in a significant decrease in LH (75 +/- 5%, 63 +/- 3%, and 84 +/- 7%; P < 0.05) and FSH (23 +/- 9%, 32 +/- 5%, and 39 +/- 6%; P < 0.04) during the MFP, LFP, and MLP, respectively. During the MFP, partial withdrawal of gonadotropins resulted in disappearance of the dominant follicle on ultrasound accompanied by a decrease in estradiol (E2; 64.9 +/- 11.4 to 23.9 +/- 3.3 pg/mL; P < 0.02) and inhibin B levels (121.6 +/- 14.8 to 28.4 +/- 4.8 pg/mL; P < 0.002) from baseline to near the limit of detection. Inhibin A was near the limit of detection in this cycle stage (0.8 +/- 0.1 IU/mL). When gonadotropins were withdrawn during the LFP, the size of the dominant follicle remained stationary in four of five subjects, and inhibin B (84.1 +/- 14.1 to 22.2 +/- 3.4 pg/mL; 71 +/- 5%; P < 0.02), inhibin A (4.4 +/- 1.1 to 1.3 +/- 0.5 IU/mL; 71 +/- 7%; P < 0.02), and E2 (236.8 +/- 48.2 to 95.6 +/- 39.0 pg/mL; 61 +/- 12%; P < 0.02) decreased similarly. Time to ovulation was shorter in association with higher inhibin A (r = -0.67; P < 0.02) and E2 (r = -0.79; P < 0.003), but there was no relation to inhibin B. During the MLP, decreased gonadotropin levels resulted in the disappearance of corpus luteum function with a significant decrease in inhibin A (9.0 +/- 0.4 to 0.7 +/- 0.1 IU/mL; 92 +/- 1%; P < 0.0001) in combination with decreased E2 (150.4 +/- 22.9 to 23.8 +/- 4.2 pg/mL; 83 +/- 3%; P < 0.005) and progesterone (12.6 +/- 2.6 to 0.9 +/- 0.2 ng/mL; 92 +/- 2%; P < 0.01). Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after GnRH antagonist administration during the LFP. However, before antagonist administration, the positive correlation between estradiol and inhibin A and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B secretion is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration during the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.     

Plasma homocysteine in polycystic ovary syndrome: does it correlate with insulin resistance and ethnicity?

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and premature coronary artery disease (CAD). Hyperhomocysteinaemia is a recognized risk factor for atherosclerosis, particularly among migrant South Asians, and has recently been shown to be correlated positively with the degree of insulin resistance/hyperinsulinaemia. OBJECTIVES: To compare total plasma homocysteine (Hcy) in PCOS with controls from ethnic groups at high and low risk of insulin resistance. METHODS: Case control study of three ethnic groups, Sri Lankans (SL), British Asians (BA) and white Europeans (C), with and without PCOS at specialist centres in Sri Lanka and Yorkshire, UK. Fasting total plasma Hcy concentration was analysed by fluorescence polarization immunoassay and examined for any correlation with age, body mass index (BMI), central obesity, fasting insulin and insulin sensitivity [calculated by the Quantitative Insulin Sensitivity Check Index (QUICKI) method], lipids and testosterone in each ethnic group. RESULTS: Eighty SL with PCOS and 45 controls, 47 BA with PCOS and 11 controls, and 40 C with PCOS and 22 controls were studied. Both Asian groups with PCOS were younger than affected Europeans (P = 0.008). Sri Lankans with PCOS had significantly lower BMI values than other affected groups: mean +/- SEM (SL) 26.3 +/- 0.95; (BA) 30.59 +/- 7.54; (C) 32.1 +/- 5.95 kg/m2 (P = 0.006). However, waist : hip ratios (WHR) of Sri Lankans with PCOS were similar to others: mean +/- SEM (SL) 0.97 +/- 0.01 (BA) 1.04 +/- 0.02 (C) 0.92 +/- 0.01, P = 0.33. Mean plasma Hcy was significantly higher in all PCOS groups than in their ethnically matched controls (Student's t-test): (SL) 10.2 +/- 1.9 vs 9.0 +/- 3.8, P = 0.01; (BA) 7.9 +/- 1.9 vs 6.8 +/- 2.5, P < 0.0001; (C) 8.3 +/- 2.3 vs 6.8 +/- 1.5, P = 0.0007 micromol/l. Sri Lankans with PCOS had significantly greater Hcy concentrations than British Asians and Europeans with PCOS [P = 0.001; single-factor analysis of variance (anova)] and also significantly greater fasting insulin concentrations [(SL) 242.9 +/- 38.9; (BA) 89.4 +/- 8.9; (C) 48.6 +/- 4.8 pmol/l (P = 0.0003)] and significantly lower QUICKI [(SL) 0.308 +/- 0.004; (BA) 0.335 +/- 0.005; (C) 0.375 +/- 0.002 (P = 0.0007)]. Fasting plasma Hcy correlated best with fasting insulin (r = 0.56, P = 0.0001) and QUICKI (r =-0.53, P < 0.0001) in Sri Lankans with PCOS. Hcy in PCOS subjects from all three ethnic groups correlated significantly with fasting insulin following adjustment for age, BMI and WHR (r = 0.45, P = 0.0001), but this was not evident in the controls (r =-0.32, P = 0.1). CONCLUSIONS: Elevation of fasting plasma homocysteine in PCOS varies with ethnicity and correlates significantly with fasting insulin. High homocysteine in young Sri Lankans with PCOS has major implications for their long-term risk for atherosclerosis.     

Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P<0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B, <15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.     

Correlation of plasma insulin and insulin-like growth factor-I with indices of androgen transport and metabolism in women with polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS. DESIGN: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women. PATIENTS: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2. MEASUREMENTS: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured. RESULTS: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens. CONCLUSIONS: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.     

Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors and are considered to be at increased risk for atherosclerosis. Elevated concentrations of advanced glycation end-products (AGE), which exert their effects through interaction with specific receptors (RAGE), have been implicated in the cellular and tissue damage during atherosclerotic processes. DESIGN/PATIENTS: We investigated serum AGE levels in 29 young women with PCOS as well as the expression of their receptor, RAGE, in circulating monocytes and compared them levels with 22 healthy control women. MEASUREMENTS/RESULTS: Women with PCOS had higher levels of serum AGE proteins compared to healthy individuals (9.81 +/- 0.16 vs. 5.11 +/- 0.16, P < 0.0001), and increased RAGE expression was observed in monocytes of PCOS women compared to controls (30.91 +/- 10.11 vs. 7.97 +/- 2.61, P < 0.02). A positive correlation was observed between AGE proteins and testosterone (T) levels (r = 0.73, P < 0.0001). The correlation between AGE proteins and T levels remained high (partial correlation coefficient = 0.61, P = 0.0001) after controlling for body mass index (BMI), insulin levels and the area under the curve for glucose (AUCGLU) during an oral glucose tolerance test (OGTT). A positive correlation was also observed between AGE proteins and the free androgen index (FAI) (r = 0.58, P < 0.0001), waist-to-hip ratio (WHR) (r = 0.31, P < 0.02), insulin (r = 0.46, P < 0.001), homeostasis model assessment (HOMA) (r = 0.47, P < 0.0001), AUCGLU (r = 0.52, P < 0.002) and RAGE (r = 0.59, P < 0.01). A negative correlation was observed between AGE proteins and glucose/insulin ratio (GLU/INS) (r = -0.35, P < 0.01), and the quantitative insulin sensitivity check index (QUICKI) (r =-0.50, P < 0.01). In multiple regression analysis T was the only independent predictor of AGE levels (P < 0.0001, b = 0.044) between BMI, insulin, SHBG and AUCGLU (adjusted R2 = 0.59, F = 44.41, P < 0.0001). CONCLUSION: These data clearly demonstrate, for the first time, that PCOS women without overt hyperglycaemia have increased AGE levels and elevated RAGE expression when compared with controls.     

Differential regulation of inhibin A and inhibin B by luteinizing hormone, follicle-stimulating hormone, and stage of follicle development

Inhibin B and inhibin A exhibit unique patterns of secretion across the follicular phase of the menstrual cycle. To test the hypothesis that the distinct patterns of inhibin B and inhibin A secretion result from differential regulation by LH and FSH, a series of controlled experiments was designed to dissect the specific effects of LH and FSH at distinct stages of follicle development. After GnRH agonist desensitization, women with small antral follicles were treated with recombinant human LH (rhLH), rhFSH, or rhFSH and estradiol (E(2)). rhLH or rhFSH was also administered when follicles reached the preovulatory stage in gonadotropin-stimulated or spontaneous cycles. At the small antral stage of development, rhFSH, but not rhLH, administration increased inhibin B (17.4 +/- 4.6 to 321.0 +/- 97.0 pg/mL; P < 0.05), inhibin A (0.6 +/- 0.1 to 2.6 +/- 0.6 IU/mL; P < 0.05), and E(2) [15.8 +/- 3.6 to 95.3 +/- 26.9 pg/mL (58.0 +/- 13.2 to 349.8 +/- 98.7 pmol/L); P < 0.05]. The inhibin B increase preceded inhibin A by 48 h. Addition of E(2) to FSH resulted in a greater increase in inhibin B (23.2 +/- 6.4 to 865.2 +/- 294.5 pg/mL; P < 0.05) than FSH alone (P < 0.05). At the preovulatory stage, rhLH administration increased inhibin A (15.9 +/- 10.3 to 21.5 +/- 13.7 IU/mL; P < 0.05) and E(2) [669.4 +/- 285.5 to 943.6 +/- 388.1 pg/mL (2457.4 +/- 1048.1 to 3464.0 +/- 1424.7 pmol/L); P < 0.05], but not inhibin B, as did rhFSH administration in spontaneous cycles [E(2): 226.4 +/- 102.7 to 264.7 +/- 121.0 pg/mL (831.1 +/- 377.0 to 971.7 +/- 444.2 pmol/L); P < 0.05; inhibin A: 2.6 +/- 1.3 to 3.7 +/- 1.9 IU/mL; P < 0.05; and inhibin B: 76.3 +/- 32.2 to 77.6 +/- 32.8 pg/mL; P = NS]. These findings suggest that increases in both FSH and E(2) in the early follicular phase result in increased inhibin B secretion at early stages of follicle development, whereas the selective LH rise in the late follicular phase favors inhibin A secretion from more mature follicles. Thus, both differential secretion of LH and FSH and the stage of follicle development determine the patterns of inhibin A and inhibin B secretion in the normal menstrual cycle.     

Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents

Approximately half of all women with polycystic ovary syndrome (PCOS) are overweight or obese, and studies have reported endocrine and metabolic differences between lean and obese women with PCOS. PCOS has not been as extensively investigated in the adolescent population. The objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course. We studied an ethnically heterogeneous group of 48 adolescents: 11 nonobese with PCOS [age, 16.1 +/- 1.9 yr; body mass index (BMI), 22.5 +/- 1.5 kg/m(2)], 22 obese with PCOS (age, 15.5 +/- 1.4 yr; BMI, 35.9 +/- 6.2 kg/m(2)), and 15 obese controls (age, 14.4 +/- 1.5 yr; BMI, 35.8 +/- 7.1 kg/m(2)). Fasting levels of glucose, insulin, proinsulin, hemoglobin A1c, testosterone, SHBG, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone sulfate (DHEAS), LH, FSH, IGF-I, IGF binding protein-1, free IGF-I, and lipids were measured. Six of the 11 nonobese PCOS subjects, 11 of the 22 obese PCOS subjects, and six of the 15 controls underwent standard oral glucose tolerance testing. The insulin response to the oral glucose tolerance test was measured by the insulin area under the curve (I(AUC120)). Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. The nonobese adolescents with PCOS demonstrated higher levels of LH, SHBG, Delta4-A, DHEAS, dihydrotestosterone, free IGF-I, and high-density lipoprotein, and lower low-density lipoprotein, compared with the obese PCOS group. Fasting levels of insulin and proinsulin, I(AUC120), and log I(AUC120) were higher, and the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index were lower in the obese compared with the nonobese PCOS subjects. Greater levels of LH and androgens, including total and free testosterone, Delta4-A, and DHEAS, and lower SHBG levels were found in the obese PCOS group compared with the obese controls. Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS and a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS.     

Nocturnal secretory dynamics of inhibin B and testosterone in pre- and peripubertal boys

To investigate the secretory dynamics of testosterone and inhibin B, we collected samples every 20 min from 2000 h to 0800 h in 20 boys. Boys in group 1 (n = 5) were aged less than 8 yr, group 2 (n = 5) were aged more than 8 yr but 1.5 yr or more before pubertal onset, group 3 (n = 5) were studied 1.0 yr or less before pubertal onset, and group 4 (n = 5) were in early puberty. Testosterone increased after midnight in peripubertal boys, coinciding with the onset of LH pulsatility, and showed a pulsatile pattern in 6 of 10 of these boys. Cross-correlation analysis indicated significant temporal coupling between LH and testosterone. Inhibin B was higher in groups 3 and 4, compared with groups 1 and 2 (P < 0.01) and showed a downward trend overnight with no evidence of pulsatility and no evidence of short-term interactions with LH, FSH, or testosterone. Inhibin B and LH nocturnal means were both inversely correlated with time before pubertal onset (r(s) > or = -0.85, P < 0.01). Only LH nocturnal mean and amplitude, respectively, contributed independently to prediction of testosterone and inhibin B nocturnal means, explaining 71 and 65% of their variability. We conclude that both testosterone and inhibin B are related to nocturnal LH release in peripubertal boys but over different time scales.