New research on steroid receptors suggests that the injectable contraceptive, MPA, unlike other contraceptives commonly used in South Africa, may compromise immune function and increase HIV-1 infection.
HIV-1 prevalence in young women of childbearing age is very high in sub-Saharan Africa. Pregnancy poses a significant health risk to mothers and babies due to mother-to-child HIV-1 transmission, high infant and maternal mortality, as well as enormous socio-economic challenges. The choice of contraceptive for young women is particularly important. This is complicated by controversial clinical findings that some contraceptives significantly increase susceptibility to HIV-1 infection.
Contraceptives can be administered in many different forms, including as injectable compounds, orally, as patches on the skin and in the form of long-acting intra-uterine devices. The actual hormones used, which include synthetic derivatives of the natural hormone progesterone, called progestins, also vary widely in different types of contraceptives. Each of these contraceptives has different effects. It is therefore a crucial health policy issue to find the best possible method of contraception that most effectively balances risks with health benefits.
Research by Professor Janet Hapgood and her team in the Department of Molecular and Cell Biology aims to provide insight into the safest progesterone derivative for contraceptive use by women in high risk areas for HIV-1 infection. One focus for this research is on how steroids change physiological function and the biology inside cells, via their steroid receptors. In particular, they focus on the glucocorticoid receptor (GR). This receptor is responsible for regulating all aspects of immune function in humans, including the increased or decreased expression of a number of important genes in the immune system. GR is the main receptor for cortisol, the natural stress horomone in humans; however, Hapgood's team have shown that other drugs and synthetic hormones, like some progestin contraceptives, are capable of binding to and activating the GR. This can have potentially negative effects on immune function and susceptibility to infectious diseases.
Side-effects on immune system
The team are also investigating how synthetic hormones used as contraceptives, targeted to the progesterone receptor, may "cross-talk" and target the GR instead, and how this may cause side-effects on immune function. This project received a major boost in November 2012 by the award to Professor Janet Hapgood of a US$100 000 Grand Challenges Explorations (GCE) grant, an initiative funded by the Bill & Melinda Gates Foundation, on "Determination of differential effects of progestins on HIV-1 infectivity: towards choice of progestin for contraception in high-risk developing countries."
MPA (medroxyprogesterone acetate) and NET (norethisterone enanthate) are progestins that are commonly used as injectable hormonal contraceptives in South Africa. MPA binds to the GR relatively easily, unlike NET. Recent research by Hapgood and her team shows that MPA, unlike NET and progesterone, represses the immune system in human cervical epithelial cells and human peripheral blood mononuclear cells (PBMCs). Cervical epithelial cells in the female reproductive tract represent the first line of defence in women for heterosexual HIV-1 transmission, while PBMCs are important in fighting systemic infection and contain the T-cells which are target cells for HIV-1. Importantly, these papers identify the mechanism as being via the GR.
Further research shows that MPA and NET are unlikely to exert such side affects via other steroid receptors such as the mineralocorticoid receptor (MR), but may also exert side effects via the androgen receptor (AR).
Collectively this work provides a fundamental basis for improved drug and therapeutic interventions for contraception. Importantly, the research has provided evidence for the first time that MPA, unlike NET or progesterone, may aid the HIV-1 virus by making the death of T-cells in human PBMCs more likely, acting via the GR.
Taken together, the basic research by Prof Hapgood and her postgraduate students provides strong support for re-evaluating the choice of contraceptive used by women in areas of high risk for infectious diseases, in particular HIV-1.
This research was funded by grants from the Bill and Melinda Gates Foundation, the National Research Foundation, the Poliomyelitis Research Foundation, the Medical Research Council and the University of Cape Town.
Publications from Hapgood and her team
Govender Y, Avenant C, Verhoog NJ, Ray RM, Grantham NJ, Africander D, Hapgood JP. The Injectable-Only Contraceptive Medroxyprogesterone Acetate, Unlike Norethisterone Acetate and Progesterone, Regulates Inflammatory Genes in Endocervical Cells via the Glucocorticoid Receptor. PLoS One. 2014 May 19;9(5):e96497.
Hapgood JP, Ray RM, Govender Y, Avenant C, Tomasicchio M. Differential Glucocorticoid Receptor-Mediated Effects on Immunomodulatory Gene Expression by Progestin Contraceptives: Implications for HIV-1 Pathogenesis. Am J Reprod Immunol. 2014 Jun;71(6):505-12.
Tomasicchio M, Avenant C, Du Toit A, Ray RM, Hapgood JP. The progestin-only contraceptive medroxyprogesterone acetate, but not norethisterone acetate, enhances HIV-1 Vpr-mediated apoptosis in human CD4+ T cells through the glucocorticoid receptor. PLoS One. 2013 May 3;8(5):e62895Wehmeyer, L, Du Toit, A, Lang, DM and Hapgood, JP Lipid raft- and protein-kinase C-mediated synergism between the glucocorticoid and GnRH receptor signalling pathways results in repression of proliferation via SGK-1 upregulation. J Biol Chem. 2014 Feb 19. [Epub ahead of print]
This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.
Please view the republishing articles page for more information.