Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis.

INTRODUCTION: Hormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless, combined estrogen-progestin therapy and the oral route seem to entail higher risk of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration. The present study aimed to investigate the risk of thromboembolic events in postmenopausal women using non-oral estrogen compared to women using oral estrogen and control groups (women receiving placebo or non-users of HT), as well as to assess the thrombotic impact of estrogens alone vs. combined estrogen-progestin therapy. MATERIALS AND METHODS: Systematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines. RESULTS: Twenty-two studies were included in the meta-analyses (9 case-control studies, 9 cohort studies, and 4 randomized controlled trials). As compared to control groups, VTE risk was not increased with non-oral HT, including users of estrogens and estrogens plus progestins (OR 0.97 [0.9-1.06]), non-oral estrogen therapy (ET)-only (OR 0.95 [0.81-1.10]), and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77-1.09]). Conversely, increased risk of VTE was observed as compared with control groups in users of oral HT, including users of estrogens and estrogens plus progestins HT (OR 1.72 [1.47-2.01]), oral ET-only (OR 1.43 [1.34-1.53]), and combined oral estrogen-progestin HT (OR 2.35 [1.9-2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with oral HT (OR 1.66 [1.39-1.98]). CONCLUSIONS: VTE risk was increased in postmenopausal women with no previous thromboembolic events using oral HT. Non-oral HT did not significantly affect this risk. The quality of the evidence produced in our meta-analyses is low to moderate, and further clinical trials are needed to sort out the impact of different types of progestin and different estrogen doses and administration routes on VTE risk.

Animal models of hyperandrogenism and ovarian morphology changes as features of polycystic ovary syndrome: a systematic review.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 9-18% of women in reproductive age that causes hyperandrogenism and infertility due to dysfunctional follicular maturation and anovulation. The etiology of PCOS is still poorly known, and information from experimental animal models may help improve current understanding of the mechanisms of PCOS initiation and development. Therefore, we conducted a systematic review of currently available methods for simulation of PCOS in experimental models, focusing on two main endocrine traits: ovarian morphology changes and circulating levels of sex hormones and gonadotropins.We searched the MEDLINE database for articles in English or Spanish published until October 2016. Of 933 studies identified, 39 were included in the systematic review. One study compared interventions with androgens versus estrogens, 18 used androgen-induced stimulation, 9 used estrogens or drugs with estrogen action, including endocrine disruptors, to induce PCOS-like models, and 12 used miscellaneous interventions. Broad differences were found among the studies concerning hormonal interventions, animal species, and developmental stage at the time of the experiments, and most models resulted in ovarian morphology changes, mainly increases in the number of cystic and antral follicles and decreases in the corpus luteum. Hyperandrogenism was produced by using androgens and other drugs as the stimulatory agent. However, studies using drugs with estrogenic effect did not observe changes in circulating androgens.In conclusion, medium- or long-term testosterone administration in the pre- and postnatal periods performed best for induction of a PCOS-like phenotype, in rhesus macaque and rat models respectively. In rats, postnatal exposure to androgens results in reprogramming of the hypothalamic-pituitary-ovarian-axis. Thus, comparisons between different intervention models may be useful to define the timing of reproductive PCOS phenotypes in experimental animal models.

FTO gene variants are not associated with polycystic ovary syndrome in women from Southern Brazil.

BACKGROUND AND AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, presenting polygenic traits as well as determined by environmental factors. Given the overlap between PCOS and obesity, we assessed the frequencies of SNPs rs9939609 and rs8050136 in intron 1 of the FTO gene and their haplotypes in women with PCOS and healthy controls with regular cycles from Southern Brazil and investigated their relationship with metabolic traits and endocrine parameters. SUBJECTS AND METHODS: The sample comprised 298 women (199 with PCOS and 99 non-hirsute women with regular ovulatory cycles). FTO genotyping was done by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using PHASE 2.1.1 software. RESULTS: The distribution of rs9939609 (PCOS: 32.6% TT, 45.9% TA, 21.5% AA; controls: 33.3% TT, 49.0% TA, 17.7% AA) and rs8050136 (PCOS: 21.7% AA, 43.3% AC, 35.0% CC; controls: 14.9% AA, 48.9% AC, 36.2% CC) was similar between groups. The mean age of participants was 22.7±7.1years. Women with PCOS had significantly higher BMI, waist circumference, total testosterone, and FAI vs. controls. In the PCOS group, no differences between genotypes and haplotypes were found for clinical variables. The presence of at least one risk allele for polymorphisms rs9939609 and rs8050136 was associated with higher fasting glucose levels. CONCLUSION: Our findings indicate that neither the FTO rs9939609 and rs8050136 polymorphisms nor its haplotypes are related to PCOS, but suggest an association between the presence of risk alleles of SNPs rs9939609 and rs8050136 in FTO and glucose levels in women from Southern Brazil.

Fat mass and obesity-associated gene polymorphisms do not affect metabolic response to hormone therapy in healthy postmenopausal women.

OBJECTIVE: To determine whether fat mass and obesity-associated gene polymorphisms rs9939609 T>A and rs8050136 A>C or their haplotypes influence anthropometric and metabolic variables in recently postmenopausal women receiving hormone therapy. STUDY DESIGN: In this randomized crossover study carried out in a university clinic, 86 postmenopausal women consulting for symptoms of estrogen deficiency were genotyped by real-time polymerase chain reaction for single nucleotide polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated gene. Haplotypes were constructed from the combination of polymorphisms rs9939609 and rs8050136, and their frequencies were inferred using the PHASE 2.1.1 program. Participants were clinically evaluated before and after 6 months of hormone therapy to determine body mass index (current kg/m(2)) and waist circumference, blood pressure, lipid profile (total cholesterol, HDL cholesterol and triglycerides) plasma glucose (oral glucose tolerance test), and insulin. Blood samples were also drawn for ultra sensitive C reactive protein. The lipid accumulation product index was calculated as (waist [cm] - 58) × triglyceride concentration (mmol/L). Non-normally distributed parameters were log10 transformed before statistical analysis. Measurements at baseline and at follow-up were compared with ANOVA for repeated measures. Data were considered significant at P<0.05. RESULTS: In women with the homozygous polymorphic AA genotype of the single nucleotide polymorphisms rs9939609 and the wild AA genotype of the single nucleotide polymorphisms rs8050136, lipid accumulation product index and ultra sensitive C reactive protein were higher before hormone therapy in comparison with women with other genotypes from the same single nucleotide polymorphisms group. There was no worsening of any of the anthropometric or metabolic variables, and lipid accumulation product index improved slightly after hormone therapy in SNP rs9939609 (P=0.03) and haplotype AAAA. No changes were observed after hormone therapy in SNP rs8050136. CONCLUSIONS: The presence of fat mass and obesity-associated gene risk variants in healthy early postmenopausal women does not adversely affect their response to hormone therapy.