The blood-testis barrier (BTB) is a selectively permeable membrane barrier formed by adjacent Sertoli cells (SCs) in the seminiferous tubules of the testes that develops intercellular junctional complexes to protect developing germ cells from external pressures. However, due to this inherent defense mechanism, the seminiferous tubule lumen can act as a pharmacological sanctuary site for latent viruses (e.g., Ebola, Zika) and cancers (e.g., leukemia). Therefore, it is critical to identify and evaluate BTB carrier-mediated drug delivery pathways to successfully treat these viruses and cancers. Many drugs are unable to effectively cross cell membranes without assistance from carrier proteins like transporters because they are large, polar, and often carry a charge at physiologic pH. SCs express transporters that selectively permit endogenous compounds, such as carnitine or nucleosides, across the BTB to support normal physiologic activity, although reproductive toxicants can also use these pathways, thereby circumventing the BTB. Certain xenobiotics, including select cancer therapeutics, antivirals, contraceptives, and environmental toxicants, are known to accumulate within the male genital tract and cause testicular toxicity; however, the transport pathways by which these compounds circumvent the BTB are largely unknown. Consequently, there is a need to identify the clinically relevant BTB transport pathways in in vitro and in vivo BTB models that recapitulate human pharmacokinetics and pharmacodynamics for these xenobiotics. This review summarizes the various in vitro and in vivo models of the BTB reported in the literature and highlights the strengths and weaknesses of certain models for drug disposition studies. SIGNIFICANCE STATEMENT: Drug disposition to the testes is influenced by the physical, physiological, and immunological components of the blood-testis barrier (BTB). But many compounds are known to cross the BTB by transporters, resulting in pharmacological and/or toxicological effects in the testes. Therefore, models that assess drug transport across the human BTB must adequately account for these confounding factors. This review identifies and discusses the benefits and limitations of various in vitro and in vivo BTB models for preclinical drug disposition studies.

While hormonal contraceptives are efficacious and available in several forms for women, perception of safety and concern over side effects are a deterrent for many. Existing non-hormonal contraceptives include permanent sterilization, copper intrauterine devices (IUDs), chemical/physical barriers such as spermicides and condoms, as well as traditional family planning methods including withdrawal and the rhythm method. Individuals who wish to retain their fertility in the future can achieve highest adherence and efficacy with long-acting, reversible contraceptives (LARCs), though there is only one, the copper IUD, that is non-hormonal. As rates of unintended pregnancies remain high with existing contraceptive options, it is becoming increasingly attractive to develop novel pregnancy prevention methods for both women and men. Non-hormonal contraceptives can target a variety of critical reproductive processes discussed here. This review focuses on identified non-hormonal contraceptive targets and subsequent drug candidates in development.

Despite increased access to contraception over the last 60 years, unplanned pregnancies continue to contribute to economic disparities and overpopulation. Additionally, the burden of family planning falls primarily on women, as a reliable pharmaceutical male contraceptive has yet to be developed. The objective of this literature-based systematic review was to identify compounds for future study from natural sources with potential nonhormonal male contraceptive activity. After the exclusion of extracts and compounds with known hormonal mechanisms, 26 unique compounds were identified from natural species. The plant source, compound class, structure, target, mechanism of action, safety/toxicity profile, and in vitro, in vivo, and human studies for each compound were evaluated and discussed. β-Caryophyllene, embelin, oleanolic acid, triptonide, and N-butyldeoxynojirimycin (NB-DNJ) were selected as the five most promising compounds for future study using prespecified criteria such as number of studies, efficacy and safety profile, reversibility, and previous use in humans for any indication. In order to move forward with development of a male contraceptive from a natural source, additional studies are needed to determine the predicted safety and efficacy for in vivo and human clinical trials.

Oleanolic acid (OA) and its derivatives are widely found in diverse plants and are naturally effective pentacyclic triterpenoid compounds with broad prophylactic and therapeutic roles in various diseases such as ulcerative colitis, multiple sclerosis, metabolic disorders, diabetes, hepatitis and different cancers. This review assembles and presents the latest in vivo reports on the impacts of OA and OA derivatives from various plant sources and the biological mechanisms of OA activities. Thus, this review presents sufficient data proposing that OA and its derivatives are potential alternative and complementary therapies for the treatment and management of several diseases.