Regulation of testicular function in men: implications for male hormonal contraceptive development

In the adult male, the testes produce both sperm and testosterone. The function of the testicles is directed by the central nervous system and pituitary gland. Precise regulation of testicular function is conferred by an elegant feedback loop in which the secretion of pituitary gonadotropins is stimulated by gonadotropin hormone-releasing hormone (GnRH) from the hypothalamus and modulated by testicular hormones. Testosterone and its metabolites estradiol and dihydrotestosterone (DHT) as well as inhibin B inhibit the secretion of the gonadotropins both directly at the pituitary and centrally at the level of the hypothalamus. In the testes, LH stimulates testosterone synthesis and FSH promotes spermatogenesis, but the exact details of gonadotropin action are incompletely understood. A primary goal of research into understanding the hormonal regulation of testicular function is the development of reversible, safe and effective male hormonal contraceptives. The administration of exogenous testosterone suppresses pituitary gonadotropins and hence spermatogenesis in most, but not all, men. The addition of a second agent such as a progestin or a GnRH antagonist yields more complete gonadotropin suppression; such combination regimens effectively suppress spermatogenesis in almost all men and may soon bring the promise of hormonal male contraception to fruition.     

Proteomic analysis of testis biopsies in men treated with transient scrotal hyperthermia reveals the potential targets for contraceptive development

Mild testicular heating safely and reversibly suppresses spermatogenesis. In this study, we attempted to clarify the underlying molecular mechanism(s) involved in heat‐induced spermatogenesis suppression in human testis. We conducted global proteomic analyses of human testicular biopsies before, and at 2 and 9 wk after heat treatment. Thirty‐one and Twenty‐six known proteins were identified with significant differential expression at 2 and 9 wk after heat treatment, respectively. These were used to characterize the cellular and molecular events in the testes when seminiferous epithelia became damaged (2 wk) and recovered (9 wk). At 2 wk post‐treatment, the changed expression of a series of proteins could promote apoptosis or suppress proliferation and cell survival. At 9 wk post‐treatment, the changed expression of proteins mainly promoted cell proliferation, differentiation and survival, but resisted cell apoptosis. Among those heat‐regulated proteins, HNRNPH1 was selected for the further functional study. We found that HNRNPH1 was an anti‐apoptosis protein that could regulate the expression of other heat‐induced proteins. In conclusion, heat‐induced reversible suppression of spermatogenesis occurred by modulating the expression of proteins related to proliferation, differentiation, apoptosis and cell survival pathways. These differentially expressed proteins were found to be key molecular targets affecting spermatogenesis after heat treatment.     

Motivational Interviewing with Computer Assistance as an intervention to empower women to make contraceptive choices while incarcerated: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Unplanned pregnancies (defined as pregnancies that are either mistimed or unwanted) and sexually transmitted infections (STIs) are important and costly public health problems in the United States resulting from unprotected sexual intercourse. Women with a history of incarceration are at increased risk for these problems given the high rates of substance abuse and commercial sex work in this population.[1] Project CARE (Contraceptive Awareness and Reproductive Education) is designed to evaluate an innovative intervention, Motivational Interviewing with Computer Assistance (MICA), aimed at enhancing contraceptive initiation and maintenance among incarcerated women who do not want a pregnancy within the next year and who are anticipated to be released back to the community. This study aims to: (1) increase the initiation of highly effective contraceptives while incarcerated; (2) increase the continuation of highly effective contraceptive use at 3, 6, 9, and 12 months after release; and (3) decrease unsafe sexual activity. METHODS: This prospective study will recruit 400 women from the Rhode Island Department of Corrections (RI DOC) women's jail at risk for an unplanned pregnancy (i.e. sexually active with men and not planning/wanting to become pregnant in the next year). They will be randomized to two interventions: a control group who receive two educational videos (on contraception, STIs and pre-conception counseling) or a treatment group who receive two sessions of personalized MICA. MICA is based on the principles of the Transtheoretical Model (TTM)[2, 3] and on Motivational Interviewing (MI),[4] an empirically supported counseling technique designed to enhance readiness to change targeted behaviors. Women will be followed at 3, 6, 9 and 12 months post release and assessed for STIs, pregnancy and reported condom use. DISCUSSION: Results from this study are expected to enhance our understanding of the efficacy of MICA to enhance contraceptive initiation and maintenance and reduce sexual risk-taking behaviors among incarcerated women who have reentered the community. Trial Registration: NCT01132950.     

Perspectives for malaria vaccination

The need for vaccines to relieve the current global resurgence of malaria is apparent. Immunity is specific for each species of human malaria and for each stage in the life cycle. Once protective immunogens have been identified for one species, the homologous molecules in other species may lead to protection. The usefulness of a particular immunogen will be determined, in part, by its antigenic diversity in the population and the potential for boosting during natural infection. Successful immunization with malarial antigens may require adjuvants to induce effective, long-lived immunity. If different vaccines become available against each stage in the life cycle, then the composition of a particular vaccine may be tailored for different objectives: protection for short periods (for example, during epidemics and for tourists), decrease in disease and death, and malaria eradication.     

Perspectives for TNF-alpha-targeting therapies

Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now better defined. Therapy with slow-acting, disease-modifying antirheumatic drugs (DMARDs), such as low-dose methotrexate, which is generally accepted as a standard, leads to a significant amelioration of symptoms but does not stop joint destruction. Due to these disappointing treatment options and the identification of certain inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies, cytokine-receptor/human-immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. Clinical trials testing anti-TNF-alpha agents, alone or in combination with methotrexate, have convincingly shown the feasibility and efficacy of these novel approaches to the therapy of RA. A clinical trial testing combination therapy with chimeric (mouse/human) anti-TNF-alpha monoclonal antibody infliximab and methotrexate showed, for the first time in any RA trial, that there was no median radiological progression in the groups given infliximab plus methotrexate over a 12-month observation period. Similar encouraging results might arise from trials employing other TNF-alpha-directed agents, such as the fully human monoclonal antibody D2E7, the p75 TNF-alpha-receptor/Ig construct, etanercept, or others, as discussed in this review. Combination partners other than methotrexate will be established as suitable cotreatment along with anti-TNF-alpha biologicals. Forthcoming new indications for TNF-alpha-targeted therapies are discussed.     

Male contraceptive technology for nonhuman male mammals

Contraceptive techniques applied to males have potential to mitigate diverse instances of overpopulation in human and animal populations. Different situations involving different species dictate that there is no ideal male contraceptive, and emphasizes the value of varying approaches to reducing male fertility. A majority of work in this field has focused on non-surgically destroying the testes or obstructing the epididymis, and suppressing gonadotropin secretion or inducing immune responses to reproductive hormones or sperm-specific antigens. Injection of tissue-destructive agents into the testes or epididymides can be very effective, but often is associated with unacceptable inflammatory responses and sometimes pain. Hormonal vaccines are often not efficacious and provide only short-term contraception, although GnRH vaccines may be an exception to this generality. Finally, there are no clearly effective contraceptive vaccines based on sperm antigens. Although several techniques have been developed to the point of commercialization, none has yet been widely deployed other than surgical castration.     

African communal basis for autonomy and life choices

I argue that the metaphysical capacity of autonomy is not intrinsically valuable; it is valuable only when used in relation to a community's values and instrumentally for making the proper choices that will promote one's own and the community's well‐being. I use the example of the choice to take one's life by suicide to illuminate this view. I articulate a plausible African conception of personhood as a basis for the idea of relational autonomy. I argue that this conception is better understood as a social‐moral thesis, and not a metaphysical thesis. A metaphysical thesis gives an account of the abstract nature of an atomic individual, his agency, and rational choice. The social‐moral thesis indicates that personhood and autonomy are positive and relational to the life plans, well‐being, material conditions, and the best means for achieving them that are made available and possible by harmonious living in a community. This idea of autonomy is not just having the capacity of freewill; it also involves how such freewill is used, in terms of how an individual's choices are guided by internalized communal values.     

Career choices,work patterns and perceptions of undergraduate education of McMaster medical graduates: comparison between men and women.

A survey of the first six classes to graduate from McMaster University''s medical school was carried out 5 years after graduation for the classes of 1972 to 1974 and 2 years after graduation for the classes of 1975 to 1977. Although the men and women entered similar fields of medicine the women were more likely to have taken time away from work and to be working fewer hours, and more women than men were influenced by their spouses in their career choices. More women than men expressed some dissatisfaction with the 3-year undergraduate program, and more women identified the "anxiety level created" as a weakness of the program. The women compared their preparation for the first year of postgraduate training with that of other trainees somewhat less favourably than did the men.     

Perspectives for Chemical Modifications of Enzymes

Abstract

The contents of this review include current information on advances regarding the chemistry and chemical modifications (surface and internal) of enzymes that affect their kinetic behavior. As an illustrative example of identifying catalytically essential amino acid residues at the active site(s), the case of liver alcohol dehydrogenase is shown.     

Sulphation of contraceptive steroids

The sulphation of a number of contraceptive steroids by rabbit tissue in vitro was investigated. With liver tissue the three synthetic gestagens (norethisterone, norgesterel and lynestrenol) were sulphated at different rates and none was sulphated as rapidly as dehydroepiandrosterone; sulphation occurred at the tertiary 17 beta-hydroxyl group. The synthetic oestrogen ethynyloestradiol was sulphated more rapidly than dehydroepiandrosterone, both mono and disulphates being formed. Of the other tissues studied, sulphation occurred with stomach and lung but not with heart, spleen, muscle, kidney or adipose tissue. These in vitro studies provide confirmation of in vivo findings regarding sulphate conjugates of the synthetic steroids.