BET proteins: Investigating BRDT as a potential target for male contraception

While many contraception options are available for women, birth control methods for men are limited to condoms and vasectomy. Past research into male contraceptives has focused on hormonal options but the associated side effects have thus far precluded this method from reaching the market. Non-hormonal male contraceptives and vas occlusion have also been explored, but to date no method has progressed past clinical testing. Recent interest in epigenetic research has unveiled a new potential non-hormonal male contraceptive target: the testis-specific bromodomain BRDT. Potent inhibitors for bromodomain-containing proteins are described in the literature, but a BRDT-specific compound has yet to be designed, prepared and tested. The high similarity between bromodomain proteins of the BET family makes development of selective and specific inhibitors both difficult and necessary. Selective inhibition of BRDT by a small molecule is an exciting new target in the search for a new non-hormonal male contraceptive.     

Barriers to the use of modern contraceptives and implications for woman-controlled prevention of sexually transmitted infections in Madagascar

Globally, unplanned pregnancies and sexually transmitted infections (STIs) persist as significant threats to women's reproductive health. Barriers to the use of modern contraceptives by women might inhibit uptake of novel woman-controlled methods for preventing STIs/HIV. Use of modern contraceptives and perceptions and attitudes towards contraceptive use were investigated among women in Antananarivo, Madagascar, using qualitative research. The hypothetical acceptability of the diaphragm--a woman-controlled barrier contraceptive device that also holds promise of protecting against STIs/HIV--was assessed. Women consecutively seeking care for vaginal discharge at a public health clinic were recruited for participation in a semi-structured interview (SSI) or focus group discussion (FGD). Audiotaped SSIs and FGDs were transcribed, translated and coded for predetermined and emerging themes. Of 46 participating women, 70% reported occasional use of male condoms, mostly for preventing pregnancy during their fertile days. Although women could name effective contraceptive methods, only 14% reported using hormonal contraception. Three barriers to use of modern contraceptives emerged: gaps in knowledge about the range of available contraceptive methods; misinformation and negative perceptions about some methods; and concern about social opposition to contraceptive use, mainly from male partners. These results demonstrate the need for programmes in both family planning and STI prevention to improve women's knowledge of modern contraceptives and methods to prevent STI and to dispel misinformation and negative perceptions of methods. In addition, involvement of men will probably be a critical component of increased uptake of woman-controlled pregnancy and STI/HIV prevention methods and improved health.     

Hormonal and reproductive risk factors of papillary thyroid cancer: A population-based case-control study in France

The three times higher incidence of thyroid cancer in women compared to men points to a role of female sex hormones in its etiology. However the effects of these factors are poorly understood. We analyzed the association between thyroid cancer and hormonal and reproductive factors among women enrolled in CATHY, a population-based case-control study conducted in France. The study included 430 cases of papillary thyroid cancer and 505 controls frequency-matched on age and area of residence. The odds ratios for thyroid cancer increased with age at menarche (p trend 0.05). Postmenopausal women were at increased risk, as compared to premenopausal women, particularly if menopause followed an ovariectomy, and for women with age at menopause < 55 years. In addition, use of oral contraceptives and menopausal hormone therapy reduced the association with thyroid cancer by about one third, and breastfeeding by 27%. Overall, these findings provide evidence that the risk of thyroid cancer increases with later age at menarche and after menopause, and decreases with use of oral contraceptives and menopausal hormone therapy. These findings confirm an implication of hormonal factors in papillary thyroid cancer risk, whose mechanisms need to be elucidated.     

MHC-correlated odour preferences in humans and the use of oral contraceptives

Previous studies in animals and humans show that genes in the major histocompatibility complex (MHC) influence individual odours and that females often prefer odour of MHC-dissimilar males, perhaps to increase offspring heterozygosity or reduce inbreeding. Women using oral hormonal contraceptives have been reported to have the opposite preference, raising the possibility that oral contraceptives alter female preference towards MHC similarity, with possible fertility costs. Here we test directly whether contraceptive pill use alters odour preferences using a longitudinal design in which women were tested before and after initiating pill use; a control group of non-users were tested with a comparable interval between test sessions. In contrast to some previous studies, there was no significant difference in ratings between odours of MHC-dissimilar and MHC-similar men among women during the follicular cycle phase. However, single women preferred odours of MHC-similar men, while women in relationships preferred odours of MHC-dissimilar men, a result consistent with studies in other species, suggesting that paired females may seek to improve offspring quality through extra-pair partnerships. Across tests, we found a significant preference shift towards MHC similarity associated with pill use, which was not evident in the control group. If odour plays a role in human mate choice, our results suggest that contraceptive pill use could disrupt disassortative mate preferences.     

Current status of fertility control methods in India

Approximately 48.2% of couples of 15 to 49 years of age practice family planning methods in India. Female sterilization accounts for 34.2%, with male sterilization declining from 3·4% in 1992–93 to 1·9% in 1998–99. Use of the condom increased to 3·1% from 2·4%. There is an urgent need for research to develop new contraceptive modalities especially for men and also for women and to make existing methods more safe, affordable and acceptable. Current efforts in India to develop a male contraceptive are mainly directed towards (i) development of antispermatogenic agents to suppress sperm production, (ii) prevention of sperm maturation, (iii) prevention of sperm transport through vas deferens or rendering these sperm infertile and (iv) prevention of sperm deposition. Research work in the field of prevention of sperm transport through vas deferens has made significant advances. Styrene maleic anhydride (SMA) disturbed the electrical charge of spermatozoa leading to acrosome rupture and consequent loss in fertilizing ability of sperm. A multicentre phase-III clinical trial using SMA is continuing and it is hoped that the SMA approach would be available in the near future as an indigenously developed injectable intra-vasal male contraceptive. The safety and efficacy of available oral contraceptives were evaluated. An indigenously developed oral contraceptive ‘Centchorman’, which is a nonsteroidal, weakly estrogenic but potently antiestrogenic, was found to be safe and effective and is now being marketed in India since 1991 as a ‘once a week’ pill. Cyclofem and Mesigyna have been recommended as injectable contraceptives with proper counselling and service delivery by Indian studies. It has been recommended that these injectable contraceptives be added to the existing range of contraceptive methods available in the National Family Planning Programme. Based on the Indian studies CuT 200 was also recommended. Studies have indicated the advantage of intrauterine devices (IUD); they are long acting, relatively easily removed and fertility returns rapidly after their removal. Recent studies have recommended CuT 200 for use up to 5 years. The combination of some plant products i.e.Embelia ribes, Borax andPiper longum has been found to be safe and effective as a female contraceptive and the results of phase-I clinical trials are encouraging. Research work is going on in the country in various areas with special reference to hormonal contraceptive — a three monthly injectable contraceptive, immuno-contraceptives, antiprogestins, etc.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

ADAMTS proteases in fertility

The reproductive organs are unique among adult organs in that they must undergo continual tissue remodelling as a key aspect of their normal function. The processes for persistent maturation and release of new gametes, as well as fertilisation, implantation, placentation, gestation and parturition involve cyclic development and regression of tissues that must continually regenerate to support fertility. The ADAMTS family of proteases has been shown to contribute to many aspects of the tissue morphogenesis required for development and function of each of the reproductive organs. Dysregulation or functional changes in ADAMTS family proteases have been associated with reproductive disorders such as polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF). Likewise, proteolytic substrates of ADAMTS enzymes have also been linked to reproductive function. New insight into the roles of ADAMTS proteases has yielded a deeper understanding of the molecular mechanisms behind fertility with clinical potential to generate therapeutic targets to resolve infertility, develop biomarkers that predict dysfunction of the reproductive organs and potentially offer targets for development of non-hormonal male and female contraceptives.     

恒河猴在生殖生物学中的应用进展

目的非人灵长类动物在生殖生物学研究领域是一种非常重要的实验动物。人类利用非人灵长类动物与人的生物学等方面相似的特征,开展了生殖生物学、生理学、药理学、毒理学以及生育调节等方面的研究工作,为生殖生物学基础研究以及人类健康和疾病问题的基础研究和临床前研究提供了理想的动物模型。随着生命科学的发展,对非人灵长类实验动物质量提出了更高的要求,人们认识到实验时,应用健康的优质非人灵长类动物的重要性。本文简要概括了非人灵长类动物恒河猴的生物学特性,阐述了非人灵长类动物恒河猴在生殖生物学中的应用研究。     

Impact of Pay for Performance on Prescribing of Long-Acting Reversible Contraception in Primary Care: An Interrupted Time Series Study

Background

The aim of this study was to evaluate the impact of Quality and Outcomes Framework (QOF), a major pay-for-performance programme in the United Kingdom, on prescribing of long-acting reversible contraceptives (LARC) in primary care.

Methods

Negative binomial interrupted time series analysis using practice level prescribing data from April 2007 to March 2012. The main outcome measure was the prescribing rate of long-acting reversible contraceptives (LARC), including hormonal and non hormonal intrauterine devices and systems (IUDs and IUSs), injectable contraceptives and hormonal implants.

Results

Prescribing rates of Long-Acting Reversible Contraception (LARC) were stable before the introduction of contraceptive targets to the QOF and increased afterwards by 4% annually (rate ratios  = 1.04, 95% CI = 1.03, 1.06). The increase in LARC prescribing was mainly driven by increases in injectables (increased by 6% annually), which was the most commonly prescribed LARC method. Of other types of LARC, the QOF indicator was associated with a step increase of 20% in implant prescribing (RR =  1.20, 95% CI =  1.09, 1.32). This change is equivalent to an additional 110 thousand women being prescribed with LARC had QOF points not been introduced.

Conclusions

Pay for performance incentives for contraceptive counselling in primary care with women seeking contraceptive advice has increased uptake of LARC methods.     

Hormonal contraceptive use and mate retention behavior in women and their male partners

Female hormonal contraceptive use has been associated with a variety of physical and psychological side effects. Women who use hormonal contraceptives report more intense affective responses to partner infidelity and greater overall sexual jealousy than women not using hormonal contraceptives. Recently, researchers have found that using hormonal contraceptives with higher levels of synthetic estradiol, but not progestin, is associated with significantly higher levels of self-reported jealousy in women. Here, we extend these findings by examining the relationship between mate retention behavior in heterosexual women and their male partners and women's use of hormonal contraceptives. We find that women using hormonal contraceptives report more frequent use of mate retention tactics, specifically behaviors directed toward their partners (i.e., intersexual manipulations). Men partnered with women using hormonal contraceptives also report more frequent mate retention behavior, although this relationship may be confounded by relationship satisfaction. Additionally, among women using hormonal contraceptives, the dose of synthetic estradiol, but not of synthetic progesterone, positively predicts mate retention behavior frequency. These findings demonstrate how hormonal contraceptive use may influence behavior that directly affects the quality of romantic relationships as perceived by both female and male partners.     

Reproductive and external hormonal factors and the risk of renal cell cancer in the Netherlands Cohort Study

BackgroundSeveral reproductive and hormonal factors, like age at menarche, parity, age at menopause, use of oral contraceptives and postmenopausal treatment, have been associated with the risk of renal cell cancer (RCC) in women, but results have not always been consistent. We therefore investigated the association between these factors and the risk of RCC in postmenopausal women participating in the Netherlands Cohort Study on Diet and Cancer.MethodsInformation on reproductive history, exogenous hormone use and gynecological surgery was obtained through a self-administered questionnaire at baseline in 1986. After 20.3 years of follow-up, 204 cases and 2280 subcohort members were available for case-cohort analysis. Multivariable hazard ratios (HR) were calculated using Cox Proportional Hazard analysis.ResultsWomen who reported a hysterectomy had an increased RCC risk compared to women who did not (HR, 1.42, 95%CI, 1.01–2.00). Women with a natural age at menopause between 45 and 49 years compared to 50–54 years had an increased RCC risk (HR, 1.61; 95%CI, 1.10–2.35). RCC risk was slightly and not statistically significant increased among parous women with three or more children and age at first birth before 25 years compared to nulliparous women (HR, 1.36; 95% confidence interval (CI), 0.84–2.20). No associations were observed with RCC risk for age at menarche, use of oral contraceptives and use of hormonal replacement therapy.ConclusionHysterectomy and age at natural menopause were associated with an increased RCC risk. Other hormonal and reproductive factors and RCC risk were not increased. Further studies are required to establish the mechanism(s) that explain the observed association.     

Effects of oral contraceptive use on body mass index and blood pressure among female villagers in north-east Thailand

The use of contraceptives has become prevalent among females in Thailand in the past 20 years, and oral contraceptive use has been suggested to trigger changes in fat intake, energy expenditure, fat metabolism and blood pressure. Based on field investigations of 391 married women aged 20 years or over in Yasothon Province, North-east Thailand, this study aims to elucidate the effects of oral contraceptive use on body mass index (BMI: kg/m2) and blood pressure, taking into account reproductive histories and socioeconomic conditions. The proportion of obese (BMI > or = 25) subjects was high in the age groups 30-39, 40-49 and 50-59, accounting for, respectively, 39.4%, 51.1% and 48.5% of these populations. The proportion of women with hypertension (90/140 mmHg) was 23.7%, 18.5% and 26.2% in the 40-49, 50-59 and 60-69 age groups. Current contraceptive practices in the studied population included sterilization by operation, oral contraception and injection. These methods accounted for 43.0%, 12.8% and 8.2% of the population, respectively. Sociodemographic factors such as reproductive history, years of education and household income were not significantly related to BMI or to blood pressure (ANOVA with age adjustment). In contrast, oral contraceptive users had significantly higher BMIs and diastolic blood pressures (p<0.01, ANOVA with age adjustment). Multiple regression analysis also revealed that oral contraceptive use was a weak but significant contributing factor to both high BMI and blood pressure when sociodemographic factors were taken into account and controlled for statistically. It can thus be concluded that the use of contraceptive pills, which contain oestrogen and progestin and are provided free of charge to Thai women, tend to increase BMI and to elevate blood pressure.     

Anti-infectious defense of vagina during use of low-dose monophasic contraceptives

Increase in incidence of candidal colpitis has been observed during use of contraceptive drugs. Elimination of staphylococci from genital tract after use of contraceptives was detected in 34,7% of patients. Composition of other aerobic microflora did not change. Nonspecific immune reaction was characterized by intensified phagocytosis, increase of results of NBT reduction test and level of proinflammatory cytokines. Conclusion about inappropriateness of using low-dose oral contraceptives in patients with recurrent vulvovaginal candidosis was made. Such contraceptives can be recommended to women with prolonged inflammatory diseases of reproductive system.     

Age at first coitus and choice of contraceptive method: preliminary report on a study of factors related to cervical neoplasia.

The incidence of cancer of the uterine cervix appears to be species-specific, thus confounding extrapolation of results from studies with experimental animals. In humans, the incidence varies more by social groups than does any other primary cancer. In a recent study, Puerto Ricans were found to have a 25 times higher risk of cervical cancer than Jews. Blacks had 4 times the risk of non-Jewish Caucasians. Age at 1st coitus (AFC) and number of coital partners have been related to increased risks. Upper socioeconomic level women have had contraceptive pills prescribed more often than others. Initial interviews and recordings of gynecologic results have been completed by the Institute for Survey Research for 25,000 American women attending large clinics and group health centers in 9 continental cities and 3 cities in Puerto Rico. Data concerning contraceptive, sexual, and reproductive history have been completed for almost 12,000. Years of education and current age have had a significant effect (p less than .001) on AFC. Gravida was also significantly related to AFC (p less than .001). The AFC of North American blacks was lower than others. Women who chose to use the pill were found to have a higher prevalence of cytologic dysplasia at the time of choice than other women. Data provide no evidence to suggest that the widespread use of oral contraceptives since the mid-1960s has been followed by increasing rates of carcinoma in situ. Other epidemiological research has failed to reveal retrospective associations between oral contraceptive use and abnormal cervical cytology. Present results are consistent with this pattern.     

Changes in contraceptive use and fertility: Panama, 1976 to 1984

Abstract

From 1976 to 1984 important demographic changes occurred in Panama. The total fertility rate declined from 4.5 to 3.7, and contraceptive use amongmarried women 20–44 years of age increased from 55 per cent to 63 per cent. However, using data from three national level reproductive health surveys which were conducted in Panama in 1976, 1979, and 1984, we found that most of the changes took place between 1976 and 1979. Since 1979, overall contraceptive use and fertility have remained virtually unchanged, although there has been an important method‐mix shift toward an increase in the use of contraceptive sterilization and IUD's, with an accompanying decline in the use of oral contraceptives. Although the singulate mean age at marriage remained relatively constant, the average duration of breastfeeding rose 23 per cent during the period. Further gains in contraceptive prevalence and reduction in unplanned fertility in Panama will largely depend on enhanced program efforts first begun in the early 1970's by the Panama Ministry of Health. Future program efforts especially should be directed toward encouraging young couples to space their children more effectively by using temporary methods of contraception.     

Reproductive performance of repeat breeders in dairy herds

The objectives were to characterize repeat breeding in dairy cows, including reproductive performance and risk factors. Data from 613 Holstein Friesian cows in nine dairy herds across Japan were enrolled. A repeat breeder was defined as a cow that did not become pregnant after three inseminations, despite no clinically detectable reproductive disorders. In contrast, cows that became pregnant within three inseminations were considered to have normal fertility. Of the 613 cows, 87.3% eventually became pregnant after repeated AI (maximum calving to conception interval was 435 d). Mean (±SEM) first AI conception rate, days in milk at first AI, calving to conception interval and service per conception were 38.3%, 82 ± 2 d, 125 ± 3 d, and 2.0 ± 0.1 times, respectively. Normal fertility cows (n = 479) required only 114 ± 3 d to conceive and 1.7 ± 0.1 inseminations per pregnancy, whereas repeat breeders (n = 86) required significantly more days to conceive (211 ± 10) and more inseminations per pregnancy (4.7 ± 0.2). Based on survival analysis, it took 94 d after calving for 50% of normal fertility cows to become pregnant, compared to 155 d for repeat breeders. For repeat breeders, 31.4, 50.0, and 58.1% became pregnant within 210, 300, and 435 d after calving, respectively. The risk factors for repeat breeding were parity (relative risk [RR] = 0.809; P = 0.058), resumption of postpartum ovarian cycles (RR = 1.928; P = 0.009), and days in milk at first AI (RR = 0.991; P = 0.039). In conclusion, repeat breeder dairy cows had very poor reproductive performance. Lower parity, abnormal resumption of postpartum ovarian cycles, and shorter days in milk at first AI were risk factors for repeat breeding.     

Reproductive effort and growth in the prosobranch snail,Viviparus ater

Summary We compared two populations of Viviparus ater from Lake Zürich and Lake Maggiore with respect to the reproductive investment of individual females throughout their lives. Based on field observations of the bumber and size of offspring and from measurements of the differences between growth rings on the shells we constructed a probabilistic model for the life history of the females. A simulation showed that the overall productivity of females was higher in Lake Zürich than in Lake Maggiore. The higher productivity of females in Lake Zürich was due to faster growth before maturity and higher fecundity after maturity. The reproductive effort, as measured by the percentage of assimulated energy used for reproduction, remained constant throughout the life of the females in Lake Zürich, whereas it declined with age in Lake Maggiore. We interpret this as the outcome of a reproductive strategy that avoids risks due to reckless reproduction, rather than as two different strategies which have been selected in response to different habitat types.     

Molecular approaches to contraceptive development

The next generation of contraceptives will be based on the identification of novel molecules essential for reproductive processes and will rely on the refinement of older as well as newer technologies. Functional analysis of naturally occurring reproductive genetic disorders and creation of mice null for specific genes would greatly assist in the choice of genetic targets for contraceptive development. Structure-based design of drugs as exemplified by the preparation of an orally active non-peptide gonadotropin releasing hormone (GnRH) would revolutionize drug formulation and delivery for a peptide analogue. This review examines some of the molecular targets that may change contraceptive choices in the future.     

Effects of phytogenic feed additives on the reproductive performance of animals

The reproductive performance of ruminants is economically significant, and its improvement is a primary goal of the livestock industry to ensure its sustainability. Several approaches have been developed to use phytogenics as feed additives for several proposes, such as reducing methane emissions, and as an alternative to antibiotics. Phytogenics have potent antioxidant, anti-inflammatory, immunomodulatory, and metabolism-regulatory properties, and they are present at high levels in animal feeds. This current review considers the potential use of medicinal herbs on the reproductive performance of animals. The influence of diet on the fertility complications commonly noted in ruminants is of global interest. Although the effects of phytogenics on ruminant digestion and absorption are well-explored, their impact on reproductive performance remains poorly investigated. This review focuses on the influence of phytogenics on semen quality, hormonal profiles, and hematobiochemical indices in male ruminants. Based on available data, phytogenics are perceived to improve oocyte quality, reproductive performance, and pregnancy. However, further more comprehensive research on the benefits and potential hazards of the use of phytogenics is required to improve reproductive performance in ruminants.     

Reduced reproductive function in wild baboons (Papio hamadryas anubis) related to natural consumption of the African black plum (Vitex doniana)

Several authors have suggested that the consumption of plant compounds may have direct effects on wild primate reproductive biology, but no studies have presented physiological evidence of such effects. Here, for two troops of olive baboons (Papio hamadryas anubis) at Gashaka-Gumti National Park, Nigeria, we show major seasonal increases in levels of fecal progesterone metabolites in females, and provide evidence that this is linked to the consumption of natural plant compounds. Increases in fecal progestogen excretion occurred seasonally in all females, in all reproductive states, including lactation. Detailed feeding data on the study animals showed that only one food species is consumed by both troops at the time of observed progestogen peaks, and at no other times of the year: the African black plum, Vitex doniana. Laboratory tests demonstrated the presence of high concentrations of progestogen-like compounds in V. doniana. Together with published findings linking the consumption of a related Vitex species (Vitex agnus castus) to increased progestogen levels in humans, our data suggest that natural consumption of V. doniana was a likely cause of the observed increases in progestogens. Levels of progestogen excretion in the study baboons during periods of V. doniana consumption are higher than those found during pregnancy, and prevent the expression of the sexual swelling, which is associated with ovulatory activity. As consortship and copulatory activity in baboons occur almost exclusively in the presence of a sexual swelling, V. doniana appears to act on cycling females as both a physiological contraceptive (simulating pregnancy in a similar way to some forms of the human contraceptive pill) and a social contraceptive (preventing sexual swelling, thus reducing association and copulation with males). The negative effects of V. doniana on reproduction may be counter-balanced by the wide-range of medicinal properties attributed to plants in this genus. This is the first time that physiological evidence has been presented of direct effects of plant consumption on the reproductive biology of wild primates.