Laura Patton

Obesity and infertility

Purpose of reviewTo summarize major factors affecting fertility in obesity. Recent findings Fertility can be negatively affected by obesity. In women, early onset of obesity favours the development of menses irregularities, chronic oligo-anovulation and infertility in the adult age. Obesity in women can also increase risk of miscarriages and impair the outcomes of assisted reproductive technologies and pregnancy, when the body mass index exceeds 30 kg/m2. The main factors implicated in the association may be insulin excess and insulin resistance. These adverse effects of obesity are specifically evident in polycystic ovary syndrome. In men, obesity is associated with low testosterone levels. In massively obese individuals, reduced spermatogenesis associated with severe hypotestosteronemia may favour infertility. Moreover, the frequency of erectile dysfunction increases with increasing body mass index. SummaryMuch more attention should be paid to the impact of obesity on fertility in both women and men. This appears to be particularly important for women before assisted reproductive technologies are used. Treatment of obesity may improve androgen imbalance and erectile dysfunction, the major causes of infertility in obese men.

Polycystic Ovary Syndrome Is a Risk Factor for Type 2 Diabetes: Results From a Long-Term Prospective Study

Polycystic ovary syndrome (PCOS) recently has been identified as a risk factor associated with type 2 diabetes. However, the evidence derives from cross-sectional observational studies, retrospective studies, or short-term prospective studies. This long-term prospective study of a large cohort of women with PCOS, followed from youth to middle age, aimed at estimating, for the first time, the incidence and potential predictors of type 2 diabetes in this population. A total of 255 women with PCOS were followed for at least 10 years (mean follow-up 16.9 years). Six women were patients with diabetes at baseline, and another 42 women developed type 2 diabetes during the follow-up. The incidence rate of type 2 diabetes in the study population was 1.05 per 100 person-years. The age-standardized prevalence of diabetes at the end of follow-up was 39.3%, which is significantly higher with respect to that of the general Italian female population of a similar age (5.8%). The likelihood of developing type 2 diabetes significantly increased as BMI, fasting glucose, and glucose area under the curve at baseline increased and significantly decreased as sex hormone–binding globulin (SHBG) levels at follow-up increased. This study demonstrates that the risk of type 2 diabetes is markedly elevated in middle-aged women with PCOS and suggests including BMI, glucose, and SHBG-circulating levels in the risk stratification.

Sex difference in the relationship between the hypothalamic-pituitary-adrenal axis and sex hormones in obesity.

Objective: This study was carried out to investigate the role of sex in the regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and its relationship with testosterone levels in male and female obesity.

Basal insulin-like factor 3 levels predict functional ovarian hyperandrogenism in the polycystic ovary syndrome

Aim: The aims of the study were to understand the association between insulin-like factor 3 (INSL3) and functional ovarian hyperandrogenism (FOH) in PCOS and the regulatory role played by LH. Subjects and methods: Fifteen PCOS women were classified as FOH (FOH-PCOS, no.=8) and non-FOH (NFOH-PCOS, no.=7) according to the response of 17OH-progesterone to buserelin (a GnRH analogue) with respect to 15 controls. FOH-PCOS and NFOH-PCOS were compared for basal INSL3 levels. In addition, the effect of buserelin on INSL3 concentrations and the relationship between basal and buserelin-stimulated LH and 17OH-progesterone and INSL3 were evaluated. Results: Basal INSL3 levels were higher in FOH-PCOS than NFOH-PCOS (p=0.001) and controls (p=0.001), whereas they did not differ between NFOH-PCOS and controls. In addition, FOH-PCOS had a higher response of LH to buserelin with respect to NFOH-PCOS. Within all PCOS women the levels of INSL3 positively correlated with free testosterone (p=0.022) and negatively with SHBG (r= p=0.031). Moreover, positive correlations with the absolute increase of 17OH-progesterone (p<0.001) and with the LH area under the curve (p=0.001) after buserelin administration were found. In the multiple regression analysis INSL3 persisted significantly correlated only with 17OH-progesterone response to buserelin. Finally, INSL3 was not significantly modified after buserelin administration either in FOH-PCOS or in NFOH-PCOS. Conclusions: These data suggest that INSL3 is related to FOH in PCOS women, but this association seems not to be mediated by LH, further reinforcing the concept that a pathophysiological heterogeneity for ovarian hyperandrogenism in PCOS exists.

Short-term modification of sex hormones is associated with changes in ghrelin circulating levels in healthy normal-weight men.

The aim of this study was to evaluate the effect of selective and short-term sex hormone modifications on ghrelin levels in normal-weight eugonadal men undergoing hormonal contraceptive treatments. Seven men received an oral progestin [cyproterone acetate (CPA) or dienogest (DNG)] 10 mg/day for 3 weeks (CPA-DNG group), 7 CPA orally 5 mg/day in association with testosterone enanthate (TE) im 200 mg/week for 8 weeks (CPA-TE group), and 7 placebo (PLAC) for 8 weeks (PLAC group). Anthropometry and blood levels of LH, FSH, testosterone, estradiol, glucose, insulin and total ghrelin were evaluated. At baseline, no parameters differed among the three groups. After treatment, LH and FSH decreased in both CPA-DNG and CPA-TE groups, whereas they did not change in the PLAC group. Testosterone and estradiol decreased in the CPA-DNG group to the hypogonadal range, increased in the CPA-TE group to supraphysiological concentrations and, as expected, remained unchanged in the PLAC group. Total ghrelin levels increased in the CPA-DNG, decreased in the CPA-TE and did not change in the PLAC group. Ns modifications in the other parameters were observed in any group, demonstrating that the short-term changes of circulating sex hormones are able to modify ghrelin levels. These data, therefore, suggest that sex steroids are important regulators of ghrelin in normal-weight healthy men too.

Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome

Somatostatin, an endogenous hypothalamic peptide, lowers circulating levels of luteinizing hormone (LH), growth hormone, and insulin. The presence of somatostatin receptors at both the ovarian and adrenal levels suggeststhat somatostatin analogs may be effective as a treatment for polycystic ovary syndrome (PCOS). This study evaluated one of these analogs, octreotide-LAR, a long-acting formulation, versus placebo, in 20 overweight or obese women with PCOS, 18 of whom completed the study. Octreotide has been shown to lower levels of LH, insulin, insulin-like growth factor-I (IGF-I), and androgen. It also has enhanced spontaneous and stimulated ovulation in women with PCOS. The present patients received a low-calorie diet for 1 month, after which 10 mg octreotide-LAR or placebo was injected every 28 days for 6 months. All women complied with treatment and tolerated it well. Body weight, body mass index, and waist circumference decreased, but differences from the placebo patients were not significant. Testosterone and androstenedione levels declined significantly only in actively treated patients. Both fasting and stimulated insulin levels decreased during treatment with octreotide-LAR, whereas levels of IGF-binding protein-2 (IGFBP-2) and IGFBP-3 increased. Hirsutism improved with active treatment but not in women given placebo. All women given octreotide but only one placebo recipient had ovulated by the end of the trial. Acanthosis nigricans decreased during treatment. Octreotide treatment was associated with significantly higher levels of estradiol and progesterone. One octreotide-treated woman conceived spontaneously in the second cycle after treatment stopped. Long-term benefit is observed in women with PCOS who, in addition to dieting, take octreotide-LAR over the long term. Ovulation is restored to otherwise anovulatory patients. The treatment is well-tolerated and safe.