Persistent vaginal bleeding during gender-affirming hormone therapy in transgender men.

PURPOSE: While it is common for menstrual cycles to cease within the initial 6 months of treatment, there are instances where some transgender men may not experience this cessation. We analyzed transgender men undergoing gender-affirming hormone therapy (GAHT) with testosterone who experienced breakthrough bleeding in order to identify the factors associated with this condition. METHODS: In this case-control study, 24 transgender men in the case group and 48 in the control group were assessed for clinical, sociodemographic, hormonal, and body composition variables using dual-energy X-ray absorptiometry. All participants had been on GATH for at least 6 months. RESULTS: A few transgender men experienced persistent breakthrough bleeding, which was associated with decreased testosterone levels and free androgen index (FAI) compared with controls (p = 0.002 and p = 0.008, respectively). Among individuals with breakthrough bleeding, 50% had testosterone levels below the lowest tertile calculated for the sample, compared with 18.8% on controls (p = 0.007). After therapy adjustment, testosterone levels increased compared with the values obtained in the initial bleeding episode (p = 0.031). Eight transgender men required the addition of an oral progestogen to achieve amenorrhea, and these individuals had higher BMI than those in whom the adjustment of the parenteral testosterone dose was adequate (p = 0.026). A univariate prevalence ratio analysis revealed a negative association of persistent bleeding with testosterone levels (p = 0.028) and FAI levels (p = 0.019). CONCLUSION: Higher BMI and lower levels of testosterone and FAI were the main factors associated with breakthrough bleeding in transgender men.

Mediterranean diet is associated with bone mineral density and muscle mass in postmenopausal women.

PURPOSE: This study aimed to investigate the association between the Mediterranean diet (MD), body composition, and bone mineral density (BMD) in postmenopausal women. METHODS: In this cross-sectional study, 105 apparently healthy postmenopausal women aged between 45 and 65 years were included. BMD, percentage body fat, and appendicular lean mass index (ALMI, appendicular lean mass/height squared) were assessed by dual-energy X-ray absorptiometry. Dietary intake was assessed by a validated food frequency questionnaire. Assessment of MD adherence was based on intake of cereals, vegetables, fruits, meats, dairy products, fish, red wine, and olive oil, and expressed as the Mediterranean diet score (MDS). RESULTS: Women with higher adherence to the MD had higher ALMI (6.6 ± 0.8 kg/m2 vs. 6.3 ± 0.7 kg/m2; p = 0.039) and lumbar spine BMD (1.076 ± 0.149 vs. 0.997 ± 0.143 g/cm2; p = 0.007) compared to those with lower MDS. Linear regression analysis adjusted for previous hormone therapy, previous smoking behavior, and habitual physical activity showed an independent positive contribution of MDS to lumbar spine BMD (mean difference 0.088 g/cm2, 95% confidence interval 0.028-0.147; p = 0.004) and ALMI (mean difference 0.296 kg/m2, 95% confidence interval 0.020-0.591; p = 0.049). CONCLUSION: Bone mineral density at the lumbar spine and ALMI were positively associated with the MDS in a sample of postmenopausal women from a non-Mediterranean region.

Dietary intake of isoflavones is associated with a lower prevalence of subclinical cardiovascular disease in postmenopausal women: cross-sectional study.

BACKGROUND: Menopause has been associated with an increased risk of cardiovascular disease. It has been shown that isoflavones protect vascular endothelial cells against induced oxidative stress injury. Therefore, the present study aimed to investigate the association between the dietary intake of isoflavones and the presence of subclinical cardiovascular disease (CVD) in postmenopausal women. METHODS: Ninety-six postmenopausal women [mean (SD) age 55.2 (4.9) years, body mass index (BMI) 27.2 (4.6) kg m-2 ] completed the study protocol. Habitual physical activity was assessed using a digital pedometer, resting metabolic rate was measured by indirect calorimetry and dietary intake was assessed via a validated food frequency questionnaire. Subclinical CVD was defined as carotid artery intima-media thickness (C-IMT) >0.9 mm and/or the presence of one or more atherosclerotic plaques in any of the studied segments. RESULTS: Mean (SD) C-IMT was 0.74 (0.2) mm, 25% of participants were found to have atherosclerotic plaques and the prevalence of subclinical CVD was 35%. Participants with subclinical CVD were more likely to consume less selenium, magnesium, folate and isoflavones, even after adjusting for total energy intake. A multivariate-adjusted regression model showed that a BMI >27 kg m-2 was associated with 90% higher risk of having ≥1 plaque and/or C-IMT >0.9 mm (P = 0.017). Higher oestradiol levels (P = 0.004) and isoflavone intake (P = 0.021) were independently associated with a lower risk of having subclinical CVD. CONCLUSIONS: In the present study, we observed that a higher isoflavone dietary intake was associated with a lower risk of subclinical CVD in postmenopausal women, independent of BMI and endogenous oestradiol levels.

Habitual physical activity is associated with improved anthropometric and androgenic profile in PCOS: a cross-sectional study.

PURPOSE: To examine the effect of habitual physical activity (PA) on the metabolic and hormonal profiles of women with polycystic ovary syndrome. MATERIALS AND METHODS: Anthropometric, metabolic and hormonal assessment and determination of habitual PA levels with a digital pedometer were evaluated in 84 women with PCOS and 67 age- and body mass index (BMI)-matched controls. PA status was defined according to number of steps (≥7500 steps, active, or <7500 steps, sedentary). RESULTS: BMI was lower in active women from both groups. Active PCOS women presented lower waist circumference (WC) and lipid accumulation product (LAP) values versus sedentary PCOS women. In the control group, active women also had lower WC, lower values for fasting and 120-min insulin, and lower LAP than sedentary controls. In the PCOS group, androgen levels were lower in active versus sedentary women (p = 0.001). In the control group, free androgen index (FAI) was also lower in active versus sedentary women (p = 0.018). Homeostasis model assessment of insulin resistance and 2000 daily step increments were independent predictors of FAI. Each 2000 daily step increment was associated with a decrease of 1.07 in FAI. CONCLUSIONS: Habitual PA was associated with a better anthropometric and androgenic profile in PCOS.

Effects of orlistat vs. metformin on weight loss-related clinical variables in women with PCOS: systematic review and meta-analysis.

AIMS: The aim of this study was to assess the effects of orlistat on weight loss-related clinical variables in overweight/obese women with polycystic ovary syndrome (PCOS) and to compare treatment with orlistat vs. metformin in this group. METHODS: We conducted a systematic review and meta-analysis of the evidence about the use of orlistat in women with PCOS. We searched the literature published until May 2015 in MEDLINE, Cochrane Central Register of Controlled Trials and LILACS. RESULTS: Of 3951 studies identified, nine were included in the systematic review (three prospective, non-randomised studies and six randomised control trials). Eight studies used the Rotterdam criteria and 1 used NIH criteria to diagnose PCOS. Data suggest that orlistat promotes a significant reduction in BMI/weight in overweight/obese PCOS women. Eight studies evaluated orlistat impact on testosterone. Seven reported an improvement in testosterone levels. Eight studies evaluated impact on insulin resistance, and five reported improvement. Finally, five studies evaluated impact on lipid profile, and four reported improvement. Three randomised control trials were included in the fixed effects model meta-analysis for a total of 121 women with PCOS. Orlistat and metformin had similar positive effects on BMI (-0.65%, 95% CI: -2.03 to 0.73), HOMA (-3.60%, 95% CI: -16.99 to 9.78), testosterone (-2.08%, 95% CI: -13.08 to 8.93) and insulin (-5.51%, 95% CI: -22.27 to 11.26). CONCLUSION(S): The present results suggest that orlistat leads to significant reduction in BMI/body weight in PCOS. In addition, the available evidence indicates that orlistat and metformin have similar effects in reducing BMI, HOMA, testosterone and insulin in overweight/obese PCOS women. This study was registered in PROSPERO under number CRD42014012877.

Low-dose oral or non-oral hormone therapy: effects on C-reactive protein and atrial natriuretic peptide in menopause.

OBJECTIVE: To assess the effects of oral low-dose and non-oral hormone therapy (HT) on ultra-sensitive C-reactive protein (CRP), atrial natriuretic peptide (ANP), and cardiovascular risk factors in postmenopause. METHODS: In this randomized, cross-over study, 44 recently postmenopausal women, with no clinical evidence of cardiovascular disease, received oral low-dose HT (estradiol 1 mg + drospirenone 2 mg/day) for 3 months. Forty-two patients received non-oral, conventional HT (1.5 mg/day percutaneous 17ß-estradiol gel or equivalent for nasal route) for 3 months followed by 200 mg/day micronized progesterone by the vaginal route (14 days during each menstrual period). After 3 months, patients were crossed over without washout. Post-HT vs. pre-HT measures were determined: lipids, glucose, body mass index, waist circumference, fibrinogen, CRP-stratified levels, and ANP levels. The study was registered at clinical trials.gov (NCT01432028). RESULTS: The mean age was 51 ± 3 years and the mean time since the menopause was 22 ± 10 months. CRP-stratified high levels decreased in a higher number of non-oral HT patients, who moved to intermediate and low levels (p = 0.02). No effect of HT was observed on ANP levels (baseline 67.4 (18.4-104.5), low-dose oral 43.5 (14.4-95.9), non-oral 39.8 (15.5-67.5) pg/ml). Markers of endothelial function did not worsen with either low-dose oral or non-oral HT: von Willebrand factor (baseline 118 ± 37%, low-dose oral 119 ± 38%, non-oral 108 ± 3%, p < 0.01), fibrinogen (baseline 356 ± 58 mg/dl; low-dose oral 343 ± 77 mg/dl; non-oral 326 ± 71 mg/dl, p < 0.01). CONCLUSIONS: Low-dose oral and non-oral HT for 6 months had neutral or beneficial effects in recently postmenopausal women with no clinical evidence of cardiovascular disease.

Adolescence and polycystic ovary syndrome: current concepts on diagnosis and treatment.

BACKGROUND: Adolescence is a time characterised by changes in reproductive hormones and menstrual patterns, which makes it difficult to diagnose polycystic ovary syndrome (PCOS) in this population. The diagnosis of PCOS has a great physical and psychosocial impact on the young person. Despite the importance of a diagnosis of PCOS at adolescence, data available are limited. AIMS: This review focuses on analysing markers of PCOS diagnosis and possible treatments in adolescence. RESULTS: Although, during adolescence, diagnosis criteria of PCOS overlap with physiological changes including clinical manifestations of hyperandrogenism (acne and hirsutism), oligo/amenorrhoea, anovulation and ovarian microcysts, there is agreement that irregular menses and hyperandrogenaemia should be used to diagnose PCOS in this population. Moreover, considering that PCOS phenotype could change through the reproductive age and that adolescents display heterogeneous ovarian morphology, it has been proposed that diagnosis of PCOS should be confirmed after the age of 18. The first-line treatment for menstrual irregularity and hirsutism are oral contraceptive pills (OCPs) and for obesity and metabolic abnormalities are lifestyle changes. Insulin-sensitizer drugs, such as metformin, may be added to the treatment in the presence of metabolic alterations. Antiandrogen drugs may also be associated for treating moderate to severe hirsutism. During adolescence, physiological changes overlap with signs and symptoms of PCOS; thus the diagnosis criteria should be carefully considered. Regarding the treatment of adolescents with PCOS, non-pharmacological interventions include lifestyle changes. Pharmacological treatments comprise OCPs, antiandrogens and metformin, used isolated or combined. CONCLUSIONS: During adolescence, physiological changes overlap with signs and symptoms of PCOS; thus the diagnosis criteria should be carefully considered. Regarding the treatment of adolescents with PCOS, non-pharmacological interventions include lifestyle changes. Pharmacological treatments comprise OCPs, antiandrogens and metformin, used isolated or combined.

Central adiposity and decreased heart rate variability in postmenopause: a cross-sectional study.

OBJECTIVE: To investigate the impact of waist circumference (WC) on heart rate variability in 87 apparently healthy, postmenopausal women. METHODS: In this cross-sectional study, time- and frequency-domain heart rate variability indices were determined at rest and during sympathetic stimulation with mental stress. Patients were stratified according to WC ≥ or < 88 cm. The mean (± standard deviation) age was 55 ± 5 years. The median time since menopause was 6 (range 1-22) years. Age and time since menopause were similar. RESULTS: The mean body mass index was 27.12 ± 4.49 kg/m². Metabolic syndrome was diagnosed in 26 (29.5%) participants. Thirty-eight participants (43.6%) had hypertension. Women with WC ≥ 88 cm had higher body mass index, glucose and insulin (both fasting and after a 75-g oral glucose tolerance test), HOMA, triglycerides, and free androgen index (p < 0.05). The metabolic syndrome was more frequent in women with WC ≥ 88 cm (24.13% vs. 5.74%; p < 0.01). At rest, women with WC ≥ 88 cm presented lower vagal modulation, expressed by a reduction in the mean of all normal RR intervals (mean RR) (p < 0.01) and root mean square of successive differences of adjacent RR intervals (rMSSD) (p < 0.05) than women with WC < 88 cm. Mental stress significantly increased sympathetic modulation in both groups, expressed by reduction in high frequency (HF), increase in low frequency (LF) and LF/F ratio, and reduction in mean RR and rMSSD. CONCLUSIONS: Less favorable metabolic profile and lower cardiac vagal modulation with preserved sympathetic responsiveness were found in participants with WC ≥ 88 cm, suggesting that central adiposity may be associated with decreased heart rate variability in apparently healthy, postmenopausal women.

Haplotype TGTG from SNP 45T/G and 276G/T of the adiponectin gene contributes to risk of polycystic ovary syndrome.

BACKGROUND: Haplotypes of adiponectin gene single nucleotide polymorphisms (SNP) might be related to metabolic disorders. AIM: To assess whether the prevalence of SNP 45T/G and 276G/T of the adiponectin gene and their haplotypes differ between polycystic ovary syndrome (PCOS) and non-hirsute cycling controls and to investigate the relationship between these haplotypes and risk factors for cardiovascular disease. SUBJECTS AND METHODS: In this case-control study, 80 women with PCOS and 1500 non-hirsute controls with regular cycles underwent clinical and laboratory measurements. Genotype distribution was analyzed by conventional PCR-restriction fragment length polymorphism. RESULTS: Compared to controls, PCOS women had greater body mass index (BMI) (31.0±7.9 kg/m² vs 23.4±4.6 kg/m²; p<0.001), waist circumference (92.2±18.8 cm vs 74.5±10.2 cm; p<0.001), and systolic and diastolic blood pressure (124.6±19.9 vs 111.5±13.0 mmHg and 79.2±12.5 vs 71.8±10.6 mmHg; p<0.025), as well as a worse lipid profile (p<0.007), even after adjustment for age and BMI. Genotype distribution was similar in PCOS and controls (45T/G: p=0.399; 276G/T: p=0.135). Six haplotypes were inferred and their frequencies differed significantly between the groups (p=0.001). The TGTG haplotype was more frequent in PCOS than controls (41.3 vs 18.9%). In PCOS, the GG genotype for SNP 276 (p=0.031) and the TGTG haplotype (p=0.023) were associated with higher systolic blood pressure vs other genotypes and haplotypes. Body composition, glucose, insulin, and lipid profile were similar across genotypes and haplotypes in both groups. CONCLUSIONS: Haplotype TGTG from adiponectin gene variants 45T/G and 276G/T is related to susceptibility to PCOS, and might be associated with increased blood pressure in PCOS.

Association between adipose tissue expression and serum levels of leptin and adiponectin in women with polycystic ovary syndrome.

We reviewed emerging evidence linking serum levels and adipose tissue expression of leptin and adiponectin in women with polycystic ovary syndrome (PCOS). Previous data obtained by our group from a sample of overweight/obese PCOS women and a control sample of normal weight controls, both stratified by BMI, were reanalyzed. Circulating levels of leptin and adiponectin were determined by commercially available enzyme-linked immunosorbent assays. Adipose tissue total RNA was reserve-transcripted into complementary DNA samples, which were used as templates for quantitative real-time PCR amplification. Positive correlations were found between serum and mRNA levels for both leptin (r = 0.321; P = 0.005) and adiponectin (r = 0.266; P = 0.024). Determination of leptin and adiponectin serum levels could serve as an indirect method to assess adipocyte production, since leptin and adiponectin are predominantly produced by subcutaneous adipocytes in women.

Models and mechanisms of metabolic regulation: genes, stress, and the HPA and HPG axes.

A variety of models have been developed to better understand the mechanisms underlying individual variation in susceptibility to obesity. This review discusses several of these models and explores their role in understanding individual vulnerability to metabolic disease and the environmental factors around which metabolic perturbations occur. Recently, the focus of models has shifted towards heterogeneous populations, in which individuals characterized by a high vulnerability and individuals that are seemingly resistant can be identified. The use of these heterogeneous studies has lead to the identification of several novel biomarkers predicting obesity. This review therefore focuses on nontraditional factors, which are not directly implicated in metabolic regulation. First, the evidence from rodent knockout models for genetic factors involved in obesity is discussed. Second, the role of a stressful environment, particularly the early life environment is investigated along with a discussion of circadian disruption and metabolic disorders. Finally, the impact of sex-steroids, as exemplified by polycystic ovarian syndrome, is discussed. Overall, the data presented in our review demonstrate that in most cases interplay between genetic and environmental factors best predicts disease development. Our review shows that susceptibility to obesity may be explained by complex interactions between traditional homeostatic mechanisms, such as the hypothalamic peptide, and less studied mechanisms, like steroids and neurotrophic factors.

Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil: a pilot study.

BACKGROUND: Evidence suggests that precocious pubarche (PP) girls may have higher risk of developing polycystic ovary syndrome (PCOS) at later ages. Vitamin D receptor (VDR) gene polymorphisms have been implicated in the risk of diabetes and PCOS, but little is known about the role of VDR in PP. AIM: To assess the frequencies of VDR gene ApaI, TaqI, BsmI, and FokI polymorphisms and to determine whether these variants are associated with sex hormone concentrations in patients with PP and controls from southern Brazil. SUBJECTS AND METHODS: Blood was collected from 36 girls with PP and 197 controls for genotyping of BsmI and FokI polymorphisms using real-time PCR and of ApaI e TaqI polymorphisms using restriction fragment length polymorphism. Hormone levels were also determined. RESULTS: Genotype GG of the ApaI single nucleotide polymorphism (SNP) was more frequent in PP (30.6%) than in controls (16.2%) [odds ratio (OR): 2.269; confidence interval 95% (95%CI): 1.015-5.076; p=0.042]. This genotype was also associated with lower estradiol [35.30 (14.80-50.48) pg/ml vs 12.22 (6.49-23.69) pg/ml; p=0.025] and total testosterone levels (0.52 (0.39-0.84) ng/ml vs 0.20 (0.11-0.47) ng/ml; p=0.005) as compared with the TT + TG genotypes in girls with PP. The distribution of TaqI, BsmI, and Fokl SNP was similar in PP and controls, and no association was found between these polymorphisms and sex steroid levels. CONCLUSIONS: The ApaI SNP of the VDR gene was associated with PP in the studied population and may modulate ovarian steroid secretion in these girls.

Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil: A pilot study.

BACKGROUND: Evidence suggests that precocious pubarche (PP) girls may have higher risk of developing polycystic ovary syndrome (PCOS) at later ages. Vitamin D receptor (VDR) gene polymorphisms have been implicated in the risk of diabetes and PCOS, but little is known about the role of VDR in PP. AIM: To assess the frequencies of VDR gene ApaI, TaqI, BsmI, and FokI polymorphisms and to determine whether these variants are associated with sex hormone concentrations in patients with PP and controls from southern Brazil. SUBJECTS AND METHODS: Blood was collected from 36 girls with PP and 197 controls for genotyping of BsmI and FokI polymorphisms using real-time PCR and of ApaI e TaqI polymorphisms using restriction fragment length polymorphism. Hormone levels were also determined. RESULTS: Genotype GG of the ApaI single nucleotide polymorphism (SNP) was more frequent in PP (30.6%) than in controls (16.2%) [odds ratio (OR): 2.269; confidence interval 95% (95%CI): 1.015-5.076; p=0.042]. This genotype was also associated with lower estradiol [35.30 (14.80-50.48) pg/ml vs 12.22 (6.49-23.69) pg/ml; p=0.025] and total testosterone levels (0.52 (0.39-0.84) ng/ml vs 0.20 (0.11-0.47) ng/ml; p=0.005) as compared with the TT + TG genotypes in girls with PP. The distribution of TaqI, BsmI, and Fokl SNP was similar in PP and controls, and no association was found between these polymorphisms and sex steroid levels. CONCLUSIONS: The ApaI SNP of the VDR gene was associated with PP in the studied population and may modulate ovarian steroid secretion in these girls.

Androgenicity and venous endothelial function in post-menopausal women.

BACKGROUND: Endothelial dysfunction is one of the early signs of cardiovascular damage. High androgen levels have been related to inflammatory endothelial markers in pre- and post-menopausal women. AIM: This cross-sectional study aimed at investigating whether free androgen index (FAI) [estimated by dividing total testosterone (nmol/l) by SHBG (nmol/l) x 100] is related to endothelial function during post-menopause. SUBJECTS AND METHODS: Twenty-six post-menopausal women were assessed with the dorsal hand vein compliance technique. Acetylcholine (Ach) and sodium nitroprusside (SNP) dose-response curves were constructed to test endothelium-dependent and independent relaxation, respectively. RESULTS: Mean age was 54 yr (+/-4) and median time since menopause was 6 yr (interquartile range: 3-9). Patients were stratified according to FAI levels into two groups: FAI greater than or less than the group median of 2.5. Waist-to-hip ratio (WHR) was significantly higher in the group with FAI>2.5, as well as median dose of Ach for maximal vasodilation [720 (360-3600) ng/min with FAI>2.5 vs 36 (0.36-360) ng/min with FAI

Lipid accumulation product index: a reliable marker of cardiovascular risk in polycystic ovary syndrome.

BACKGROUND: Metabolic disturbances are common features of polycystic ovary syndrome (PCOS), which possibly enhance the risk of cardiovascular disease. The aim of this study was to assess the accuracy of lipid accumulation product (LAP) index as a marker of cardiovascular risk in PCOS patients. METHODS: Case-control study including 51 PCOS patients aged between 14 and 35 years and 44 body mass index (BMI) and age-matched controls. Measures included the LAP index, homeostasis model assessment (HOMA) index, glucose tolerance and plasma hormones, cholesterols and triglycerides. RESULTS: LAP index was positively correlated with HOMA index in all subjects (r = 0.70; P < 0.001). Waist circumference (WC) (P = 0.002), HOMA index (P < 0.001) and LAP index (P = 0.035) were higher in PCOS patients than controls. On receiver operating characteristic curve analysis, an LAP index of 34.5 (sensitivity: 84%; specificity 79%) showed a better performance than non-high-density lipoprotein cholesterol, WC or BMI to identify insulin resistance (IR) in all subjects. In PCOS patients, the positive and negative predictive values for LAP > or = 34.5 were 91 and 74%, respectively, compared with 73 and 61%, respectively, for WC > or =80 cm, and 43 and 20%, respectively, for WC > or =88 cm. CONCLUSIONS We have confirmed that IR is more common in PCOS than BMI-matched control women. Furthermore, the LAP index, an easily obtainable measure, is associated with HOMA index and an LAP > or = 34.5 is an additional risk factor for cardiovascular disease in PCOS patients.

Androgen receptor and 5alpha-reductase are expressed in pelvic endometriosis.

The aim of this study was to evaluate whether androgen receptor (AR) and the enzymes that convert testosterone into the more potent androgen dihydrotestosterone, 5alpha-reductases (5alpha-R1 and 5alpha-R2) are expressed in pelvic endometriosis. The study involved 21 infertile women who underwent laparoscopy and were divided into two groups: control (n= 13) and endometriosis (n= 8) according to the histological and laparoscopic findings. Endometrial and endometriotic implant biopsies were performed. By reverse transcription polymerase chain reaction and immunohistochemistry, AR, 5alpha-R1 and 5alpha-R2 messenger RNA and protein were detected in biopsies of pelvic endometriosis, as well as in the eutopic endometrium of both groups. These findings suggest that active androgens may be formed within the endometriotic tissue and that both local and systemic androgens have the potential to act on endometriotic cells.

Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations with phenotype.

We investigated the presence of mutations/polymorphisms in the FSH receptor (FSHR) gene and their association with phenotype in women with premature ovarian failure (POF) in southern Brazil. Clinical and hormonal variables were determined in 36 46,XX women with primary or secondary amenorrhea before the age of 40 yr, FSH >40 IU/l and ovarian failure. DNA was isolated from peripheral leukocytes. Exons 6, 7, 9, and 10 of the FSHR gene were analyzed by PCR, restriction enzyme analysis, denaturing gradient gel electrophoresis, and direct sequencing. No inactivating mutations were found. Exon 10 had two polymorphisms, Ala307Thr and Ser680Asn (allelic frequency: 52.9 and 35.7%, respectively), which were not related to FSH, LH or estradiol serum levels. Ovarian size and small ovarian follicles on transvaginal sonography were not associated with FSHR genetic variants. In contrast, the last menstruation occurred significantly earlier in patients with the Ala307Thr polymorphism (A: age=33.3+/-7.1 yr vs T: 28.6+/-11.4 yr, p=0.04). In conclusion, we did not identify inactivating mutations in exons 6, 7, 9, and 10 of the FSHR gene. A high frequency of two polymorphisms that are in linkage disequilibrium was found in exon 10 of the FSHR gene. The presence of the Ala307Thr polymorphism may be associated with a more precocious onset of clinical disease.

Nitric oxide and fibrinogen in polycystic ovary syndrome: associations with insulin resistance and obesity.

OBJECTIVE: Nitric oxide (NO) and fibrinogen levels, two markers of vascular disease, are associated with insulin resistance, a common trait in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Case-control study including 31 women with PCOS and 21 age-matched women with regular, ovulatory cycles, normal androgen levels and idiopathic hirsutism (control group). Nitrite/nitrate concentration (index of endothelium-derived NO) and fibrinogen plasma levels were assessed and analysed in association with anthropometric, metabolic and hormonal variables. RESULTS: The groups were similar in terms of age, positive family history of diabetes and Ferriman-Gallwey hirsutism score. Nitrite/nitrate and fibrinogen levels were also similar in the two groups. In contrast, in PCOS patients, insulin levels and the homeostatic model assessment were negatively correlated with NO production (r=-0.39, p=0.03 and r=-0.41, p=0.02, respectively). Age, BMI, waist circumference and waist-to-hip ratio were positively correlated with fibrinogen in both groups. CONCLUSION: The present data indicate a negative, BMI-independent association between NO levels and insulin resistance in PCOS patients. Further studies are required to clarify the role of androgens on the pathogenesis of endothelial dysfunction in PCOS and investigate androgen action and/or the gene receptor modulating NO secretion.

Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review.

Testosterone is the main hormonal agent used for cross-sex hormone therapy in female-to-male transgender persons. Our aim was to systematically review the literature concerning the effects of testosterone on body mass index (BMI), blood pressure, hematocrit, hemoglobin, lipid profile, and liver enzymes in transgender men. PUBMED and EMBASE were searched for studies published until March 2017. Studies were included if they reported interventions with any dose of testosterone and comparison of variables before and during treatment. Of 455 potentially eligible articles, 13 were reviewed. Study duration ranged from 6 to 60 months, sample size ranged from 12 to 97 patients, and the most common treatment was parenteral testosterone undecanoate 1000 mg/12 weeks. Slight but significant increases in BMI were reported (from 1.3 to 11.4%). Three out of seven studies assessing the impact of different testosterone formulations on blood pressure detected modest increases or clinically irrelevant changes in this variable. In another study, however, two patients developed hypertension, which was resolved after cessation of testosterone therapy. Decreases in HDL-cholesterol and increases in LDL-cholesterol were consistently observed. Eight studies observed a relationship between testosterone and increased hemoglobin (range: 4.9-12.5%) and hematocrit (range: 4.4-17.6%), but discontinuation of androgen therapy was not necessary. In one study, two patients developed erythrocytosis (hematocrit >52%) after 9 and 12 months of treatment. One study analyzing testosterone formulations observed smaller increases in hemoglobin and hematocrit with testosterone gel. Six studies assessing liver function showed slight or no changes. Overall, the quality of evidence was low, given the lack of randomized clinical/controlled trials and the small sample sizes. In conclusion, exogenous testosterone administration to transgender men was associated with modest increases in BMI, hemoglobin/hematocrit, and LDL-cholesterol, and with decreases in HDL-cholesterol. Long-term studies are needed to assess the long-term risks of testosterone therapy, particularly as they relate to cardiometabolic risks such as diabetes, dyslipidemia and the metabolic syndrome.