Efficacy of very low-calorie ketogenic diet with the Pronokal® method in obese women with polycystic ovary syndrome: a 16-week randomized controlled trial

Objective: The aim of this study isto assess the efficacy of a very low-calorie ketogenic diet (VLCKD) method vs a Mediterranean low-calorie diet (LCD) in obese polycystic ovary syndrome (PCOS) women of a reproductive age.Design: Randomized controlled open-label trial was performed in this study. The treatment period was 16 weeks; VLCKD for 8 weeks then LCD for 8 weeks, according to the Pronokal (R) method (experimental group; n = 15) vs Mediterranean LCD for 16 weeks (control group; n = 15). Ovulation monitoring was carried out at baseline and after 16 weeks, while a clinical exam, bioelectrical impedance analysis (BIA), anthropometry, and biochemical analyses were performed at baseline, at week 8, and at week 16.Results: BMI decreased significantly in both groups and to a major extent in the experimental group (-13.7% vs -5.1%, P = 0.0003). Significant differences between the experimental and the control groups were also observed in the reduction of waist circumference (-11.4% vs -2.9%), BIA-measured body fat (-24.0% vs -8.1%), and free testosterone (-30.4% vs -12.6%) after 16 weeks (P = 0.0008, P = 0.0176, and P = 0.0009, respectively). Homeostatic model assessment for insulin resistance significantly decreased only in the experimental group (P = 0.0238) but without significant differences with respect to the control group (-23% vs -13.2%, P > 0.05). At baseline, 38.5% of participants in the experimental group and 14.3% of participants in the control group had ovulation, which increased to 84.6% (P = 0.031) and 35.7% (P > 0.05) at the end of the study, respectively.Conclusion: In obese PCOS patients, 16 weeks of VLCKD protocol with the Pronokal (R) method was more effective than Mediterranean LCD in reducing total and visceral fat, and in ameliorating hyperandrogenism and ovulatory dysfunction.Significance statements: To the best of our knowledge, this is the first randomized controlled trial on the use of the VLCKD method in obese PCOS. It demonstrates the superiority of VLCKD with respect to Mediterranean LCD in reducing BMI with an almost selective reduction of fat mass and a unique effect of VLCKD in reducing visceral adiposity, insulin resistance, and in increasing SHBG with a consequent reduction of free testosterone. Interestingly, this study also demonstrates the superiority of the VLCKD protocol in improving ovulation, whose occurrence increased by 46.1% in the group treated by the VLCKD method against a rise of 21.4% in the group treated by Mediterranean LCD. This study extends the therapeutic approach possibilities in obese PCOS women

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men

CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need. OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. DESIGN: Prospective multicentre study. SETTING: Ten study centers. PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems. INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high

Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men

The concept that androgen alone can provide an effective male contraceptive has been tested in a multicentre, multiphase trial by the World Health Organization. Results from this trial showed that an ester of testosterone, testosterone enanthate (TE), administered at a dose of 200 mg/week, has a very high contraceptive efficacy, and suggested that, at least in some populations, androgen alone might provide a viable option for the control of male fertility. It has been claimed that testosterone represents one of the gender-related risk factors for coronary artery disease (CAD) in men. Epidemiological and interventional studies have failed to establish a convincing relationship between testosterone and high density lipoprotein cholesterol (HDL-C). Therefore, there is concern about possible negative effects on lipoprotein asset of an androgen-alone male contraceptive. In this study we analysed the effects of long-term (12 months) administration of TE (200 mg/week) in normal healthy men. Blood samples (six men > 10 h fast = Group 1; 30 men > 4 h fast = Group 2) were drawn from 36 men, monthly before the beginning of the injections (control), every 3 months throughout the study period (treatment), and 1 month after stopping TE injections (recovery). Total cholesterol (chol), triglycerides, HDL-C and LDL-C levels were measured in these samples. Biochemical parameters were also monitored. TE administration induced a significant decrease (15-20%) in HDL-C levels that was of comparable magnitude in men from both groups (fasting and non-fasting) and occurred regardless of basal HDL-C levels. No statistically significant effect on other lipoproteins was detected. Considering all men together, HDL-C levels were decreased in 78% of the men by month 3, 83% by month 6, 94% by month 9 and 97% by month 12 of treatment. In all men the HDL-C decrease was reversible within 1 month of stopping TE administration. It is concluded that: (1) injection of 200 mg TE/week causes a 15-20% decrease in HDL-C in normal men with no effect on other lipoproteins, (2) the suppressive effect of TE is maintained throughout the 1-year-injection period, and a direct relationship between the duration of TE administration and the proportion of men showing decreased HDL-C levels, was observed. (3) The HDL-C decrease was reversible within 1 month of stopping TE administration. These data will be important in designing further studies on male contraception, and in interpreting the relationship between testosterone levels, HDL-C levels and potential cardiovascular risk

Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen

In this study we compared the effects of high-dose and low-dose testosterone enanthate (TE) administered with the same dose of cyproterone acetate (CPA). Eighteen men aged 21-45 were treated with CPA 5 mg/day and with TE 100 mg/week (n = 9; CPA-5-100) or TE 200 mg/week (n = 9; CPA-5-200) for 16 weeks. Semen analyses were performed every 2 weeks; physical examination and chemistry, hematology, gonadotropin, and testosterone measurements were performed every 4 weeks. At week 16 of treatment, sperm counts were significantly more suppressed in the CPA-5-100 group than in the CPA-5-200 group. Sperm counts returned to baseline in all subjects after hormone administration ceased. No difference in gonadotropin levels was found at any time between the 2 groups. During the treatment phase, testosterone levels were significantly higher in the CPA-5-200 group than in the CPA-5-100 group. The present study confirms that CPA/TE administration induces profound sperm suppression. An increase in the dose of androgen resulted in less profound sperm suppression despite no difference in gonadotropin suppression. These data suggest that high testosterone levels can maintain sperm production in men

Follistatin decreases activin-stimulated FSH secretion with no effect on GnRH-stimulated FSH secretion in prepubertal male monkeys

Follistatin is an activin-binding glycoprotein that decreases FSH secretion in vitro and in vivo in rats. The mechanism by which follistatin acts is unclear, but it has been suggested that it may bind endogenous activin and neutralize its effects. In this study, we wished to test the ability of follistatin to suppress FSH secretion in vivo in primates whose FSH secretion has been stimulated by activin or by GnRH. Six prepubertal male monkeys were injected intravenously with human recombinant follistatin at the dose of 90 micrograms/kg or 180 micrograms/kg plus activin (90 micrograms/kg) or GnRH (10 micrograms/kg). Frequent blood samples were drawn for 12 hours following each injection. Bio FSH and LH levels were measured in those samples. GnRH and activin each stimulated FSH bioactivity. Both doses of follistatin significantly inhibited the activin-induced increase in FSH (p < 0.05). The GnRH-induced increase in FSH was not affected by follistatin. LH levels were not affected by follistatin in any of the studies. These data suggest that follistatin can suppress the activin-induced increase in FSH in primates and is consistent with the hypothesis that follistatin can block the physiological effects of endogenous activin in primates. This effect is likely to be due to the binding of follistatin to activin either in the peripheral circulation or at the pituitary level

Annual patterns of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in normal men

Reproductive functions in most animals demonstrate seasonal fluctuations that allow young to be born at a time of the year favourable for their survival. Whether there is a seasonal change in the human reproductive system is unclear. In the present study, we measured serum concentrations of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in the same 16 normal men sampled monthly for 1 year. A statistically significant increase in all four measured hormones was found in June, with a nadir in August. Our findings suggest that a circannual rhythm of gonadotrophins and testicular hormones exists in normal men. The mechanism leading to this rhythm and the importance of the rhythm in human biology are unknown

Low dose of cyproterone acetate and testosterone enanthate for contraception in men

After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n=5) or 12.5 mg/day (CPA-12.5; n=5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1 x 10(6)/ml at week 16. Time to azoospermia was 9.0+/-1.3 and 8.7+/-0.7 weeks in groups CPA-25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti-androgenic properties holds promise as an effective, safe and reversible male contraceptive

An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic suppression in men

OBJECTIVE: To test the effectiveness, safety, and reversibility of the combined administration of cyproterone acetate and T undecanoate. DESIGN: Open clinical trial. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Eight healthy men, aged 25-42 years were selected. INTERVENTION(S): Cyproterone acetate, 12.5 mg, and T undecanoate, 80 mg, were administered orally twice daily for 16 weeks. MAIN OUTCOME MEASURE(S): Semen analyses every 2 weeks; physical examination, chemistries, hematology, prostatic-specific antigen, gonadotropins and T levels, and a questionnaire on sexual and behavioral function every 4 weeks. RESULT(S): In all subjects a profound suppression of spermatogenesis occurred; one subject became azoospermic, five subjects had sperm counts of < or = 3 x 10(6)/mL, and in two subjects sperm counts were 4 and 6 x 10(6)/mL in week 16. Sperm counts returned to baseline in all men after hormone administration was discontinued. No changes in metabolic parameters and total prostatic-specific antigen were detected. Hemoglobin and hematocrit decreased statistically significantly at week 16 of treatment and returned to baseline by week 12 of recovery. There was no change in sexual function or behavior. CONCLUSION(S): The oral administration of T undecanoate plus cyproterone acetate induces a profound suppression of spermatogenesis with no major adverse effects. These data suggest the feasibility of oral contraception in men