Contemporary Anti-Retroviral Drugs (ARVDs) Disrupt Follicular Development in Female Wistar Rats

Abstract

Introduction

There are genuine concerns that long-term use of anti-retroviral drugs may be associated with reproductive complications in females. This study aimed to ascertain the effect of highly active anti-retroviral drugs on the ovarian reserve and reproductive potential of female Wistar rats and by extension to HIV-positive human females.

Methods

A total of 25 female Wistar rats, weighing between 140g and 162g, were randomly allotted into non-intervention and intervention groups, receiving the anti-retroviral drugs, Efavirenz (EFV), Tenofovir Disoproxil Fumarate (TDF), Lamivudine (3TC), and a fixed-dose combination (FDC). The dosage was administered orally at 8 am daily for 4 weeks. Serum concentrations of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinising hormone (LH), and estradiol were measured using standard biochemical techniques (ELISA). Follicular counts were made on fixed ovarian tissue from the sacrificed rats.

Results

The mean AMH level for the control group and the EFV, TDF, 3TC, and FDC groups were 11.20, 6.75, 7.30, 8.27, and 6.60 pmol/L, respectively. The EFV and FDC groups had the lowest AMH, compared to the other groups, but there was no statistically significant difference in AMH across the groups. The mean count of antral follicles was significantly lower in the group that received EFV when compared to the other groups. The corpus luteal count was significantly higher in the control group than in the intervention groups.

Conclusion

The study demonstrated a disruption in the reproductive hormones of female Wistar rats receiving anti-retroviral regimens containing EFV. Clinical studies are required to determine if these changes are seen in women receiving EFV-based treatment, as this may compromise reproductive function and predispose them to early menopause.

Keywords:

• highly active anti-retroviral therapy
• HAART
• estradiol
• anti-Mullerian hormone
• human immunodeficiency virus
• HIV
• Nigeria

Abbreviations

3TC, Lamivudine; ACOG, American College of Obstetricians and Gynecologists; AMH, anti-Mullerian hormone; EFV, Efavirenz; FDC, fixed-dose combination; FSH, follicle stimulating hormone; HAART, highly active anti-retroviral therapy; IRB, Institutional Review Board; LH, luteinising hormone; NIMR, Nigerian Institute of Medical Research; TDF, Tenofovir Disoproxil Fumarate.

Data Sharing Statement

Supporting data are available on request from the first author, Dr Aigbe Gregory Ohihoin, Clinical Sciences Department, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria; email [email protected].

Ethics Approval

Ethical approval was obtained for the conduct of this study from the Research Ethics Committee (Institutional Review Board) (IRB) of the Nigerian Institute of Medical Research (NIMR) (NIMR REC references 2018/0201 and A0724/42). As set out in the ethical approval process, the study complied with the United Kingdom revised Animals (Scientific Procedures) Act 1996 and the European Union Directive 2010/63/EU.

Acknowledgments

This paper is based on a chapter in the thesis of the first author, Aigbe G Ohihoin, to which all author authors had academic contribution or supervision. This study was funded by a grant from the Wellcome Trust ISSF Fund at Imperial College London. We acknowledge the support of the United Kingdom National Institute for Health Research Biomedical Research Centre at Imperial College London for infrastructure support. Oba Abdulrasheed and Oladele David assisted with data analysis at NIMR in Lagos, Nigeria. Álvaro Del Valle Palacios assisted with the figures. Professor Marsha Y. Morgan from University College London, London, United Kingdom, made helpful comments on the results and on the manuscript at various stages of its writing.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no competing (commercial/academic) interests in this work.

Additional information

Funding

This study was partially funded by a grant from the Wellcome Trust ISSF Fund (Grant number: 105603/Z/14/Z) at Imperial College London.