Randomized trial comparing luteinizing hormone supplementation timing strategies in older women undergoing ovarian stimulation

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Differential Regulation of PIWI-LIKE 2 Expression in Primordial Germ Cell Tumor Cell Lines by Promoter Methylation

PIWI-LIKE 2, a member of the ARGONAUTE protein family, is exclusively expressed in pre-pachytene and pachytene stages of spermatogenesis. PIWI-LIKE 2 acts in the germ cell development and the silencing of retrotransponsons to maintain the genomic integrity and stem cell character. In the present study we investigated DNA methylation as potential mechanism for the regulation of human PIWI-LIKE 2 expression in cell lines related to spermatozoa precursor cells. We detected a high methylation of the PIWI-LIKE 2 promoter in TCam-2 cells, while in NT2/D1 cells the promoter was hypomethylated. Concordantly, PIWI-LIKE 2 expression is higher in NT2/D1 cells than in TCam-2 cells. By demethylation of the promoter with 5′-Aza-2′-deoxycytidine, PIWI-LIKE 2 expression in TCam-2 was increased, while in NT2/D1 no alterations in PIWI-LIKE 2 expression could be detected. In conclusion, we analyzed the DNA methylation driving PIWI-LIKE 2 expression in undifferentiated germ cell tumors and demonstrated an epigenetic basis for PIWI-LIKE 2 expression in this cell type

The aging male: investigation, treatment and monitoring of late-onset hypogonadism in males

Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. The demographics clearly demonstrate the increasing percentage of the population that is in the older age groups. The data also support the concept that testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adults (age 20-30 years) men. The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment on multiple target organs of hypogonadal men and recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. Long-term data on the effects of testosterone treatment in the older population are limited and specific risk data on the prostate and cardiovascular systems are needed. Answers to key questions of functional benefits that may retard frailty of the elderly are not yet available. The recommendations described below were prepared for the International Society of Andrology (ISA) and the International Society for the Study of the Aging Male (ISSAM) following a panel discussion with active participation from the audience sponsored by the ISA on the topic at the 4th ISSAM Congress in Prague in February 2004.peer-reviewe

An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism

Subject disposition. (EPS 1138 kb

APHRODITE criteria:addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function

Research question: Can a novel classification system of the infertile male - 'APHRODITE' (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) - stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception?Design: A collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing.Results: Five patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility.Conclusion: The APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility.</p

APHRODITE criteria:addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function

Research question: Can a novel classification system of the infertile male - 'APHRODITE' (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) - stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception?Design: A collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing.Results: Five patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility.Conclusion: The APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility.</p

Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME).

SummaryAims The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG). Methods The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2–3 years. Independent adjudication was performed on all mortalities and CV outcomes. Results Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events. Conclusions Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry

Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: A pharmacogenetic study

Study question: Does the spermDNAfragmentation index (DFI) improve depending on the FSH receptor (FSHR) genotype as assessed by the nonsynonymous polymorphisms rs6166 (p.N680S) after 3 months of recombinant FSH treatment in men with idiopathic infertility? summary answer: FSH treatment significantly improves sperm DFI only in idiopathic infertile men with the p.N680S homozygous N FSHR. what is known already: FSH, fundamental for spermatogenesis, is empirically used to treat male idiopathic infertility and several studies suggest that DFI could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is known that the FSHR single nucleotide polymorphism (SNP) rs6166 (p.N680S) influences ovarian response in women and testicular volume in men. study design, size and duration: Amulticenter, longitudinal, prospective, open-label, two-arm clinical trial was performed. Subjects enrolled were idiopathic infertile men who received 150 IU recombinant human FSH s.c. every other day for 12 weeks and were followed-up for a further 12 weeks after FSH withdrawal. Patients were evaluated at baseline, at the end of treatment and at the end of follow-up. participants/materials, setting, methods: Eighty-nine men with idiopathic infertility carrier of the FSHR p.N680S homozygousNor S genotype, FSH 64 8 IU/l and DFI &gt;15%,were enrolled. A total of 66 patients had DFI analysis completed on at least two visits. DFI was evaluated in one laboratory by TUNEL/PI (propidium iodide) assay coupled to flow cytometry, resolving two different fractions of sperm, namely the 'brighter' and 'dimmer' sperm DFI fractions. main results and the roleof chance: Thirty-eightmen(57.6%)were carriers of the p.N680S homozygousNand 28 (42.4%) of the homozygous S FSHR. Sperm concentration/number was highly heterogeneous and both groups included men ranging from severe oligozoospermia to normozoospermia. Total DFI was significantly lower at the end of the study in homozygous carriers of the p.N680SNversus p.N680S S allele (P = 0.008). Total DFI decreased significantly from baseline to the end of the study (P = 0.021) only in carriers of the p.N680S homozygous N polymorphism, and this decrease involved the sperm population containing vital sperm (i.e. brighter sperm) (P = 0.008). The dimmer sperm DFI fraction, including only nonvital sperm, was significantly larger in p.N680S S homozygous patients than in homozygous N men (P = 0.018). Total DFIwas inversely related to total sperm number (P = 0.020) and progressive sperm motility (P = 0.014).Whenpatients were further stratified according to sperm concentration (normoozospermic versus oligozoospermic) or -211G&gt;T polymorphism in the FSHB gene (rs10835638) (homozygous Gversus others), the significant improvement of sperm DFI in FSHR p.N680S homozygousNmen was independent of sperm concentration and associated with the homozygous FSHB -211G&gt;T homozygous G genotype. limitations, reasons for caution: The statistical power of the study is 86.9% with alpha error 0.05. This is the first pharmacogenetic study suggesting that FSH treatment induces a significant improvement of total DFI in men carriers of the p.N680S homozygousNFSHR; however, the results need to be confirmed in larger studies using a personalized FSH dosage and treatment duration. wider implications of the findings: The evaluation of sperm DFI as a surrogate marker of sperm quality, and of the FSHR SNP rs6166 (p.N680S), might be useful to predict the response to FSH treatment in men with idiopathic infertility. study funding/competing interest(s): The study was supported by an unrestricted grant to M.S. and H.M.B. from Merck Serono that provided the drug used in the study. MS received additional grants from Merck Serono and IBSA as well as honoraria from Merck Serono. The remaining authors declare that no conflicts of interest are present. trial registration number: EudraCT number 2010-020240-35

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