The injectable contraceptives depot medroxyprogesterone acetate and norethisterone enanthate substantially and differentially decrease testosterone and sex hormone binding globulin levels: a secondary study from the WHICH randomized clinical trial.
South Africa
Chanel Avenant, Mandisa Singata-Madlik, Alexis J. Bick, Donita Africander, Yusentha Balakrishna, Karl-Heinz Storbeck, Johnson Mosoko Moliki, Sigcinile Dlamini, Salndave Skosana, Jenni Smit, Mags Beksinska, Ivana Beesham, Ishen Seocharan, Joanne Batting, G Justus Hofmeyr, Janet P. Hapgood
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April 09, 2024
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April 09, 2024
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Theinjectablecontraceptivesdepotmedroxyprogesteroneacetate
Title
The injectable contraceptives depot medroxyprogesterone acetate and norethisterone enanthate substantially and differentially decrease testosterone and sex hormone binding globulin levels: a secondary study from the WHICH randomized clinical trial.
Country
| Name | Country code |
|---|---|
| South Africa | ZAR |
Abstract
HIV acquisition risk with norethisterone (NET) enanthate (NET-EN) is reportedly less than for depo-medroxyprogesterone acetate intramuscular (DMPA-IM). We investigated the effects of these progestin-only injectable contraceptives on serum testosterone and sex hormone binding globulin (SHBG) levels, since these may play a role in sexual behavior and HIV acquisition.
The open-label WHICH clinical trial, conducted at two sites in South Africa from 2018-2019, randomized HIV-negative women aged 18-40 years to 150 mg DMPA-IM 12-weekly (n = 262) or 200 mg NET-EN 8-weekly (n = 259). We measured testosterone by UHPLC-MS/MS and SHBG by immunoassay in matched pairs of serum samples collected at baseline (D0) and at peak serum progestin levels at 25 weeks post initiation (25W) (n = 214-218 pairs).
We report for DMPA-IM and NET-EN users, respectively, a substantial decrease from D0 to 25W in total testosterone (-24.3%, D0 0.560, 25W 0.423 nmol/L, p < 0.0001 and -54.1%, D0 0.551, 25W 0.253 nmol/L, p < 0.0001), SHBG (-29.8%, D0 45.0, 25W 32.7 nmol/L, p < 0.0001 and -65.1%, D0 50.2, 25W 17.6 nmol/L, p < 0.0001), and calculated free testosterone levels (-17.2%, p = 0.0371 and -40.0%, p < 0.0001). The mean percentage difference in change for total testosterone, SHBG and calculated free testosterone levels was significantly more for NET-EN than DMPA-IM (64.9%, p < 0.0001; 101.2%, p < 0.0001; and 38.0%, p = 0.0120, respectively.
The substantial and differential decrease in testosterone and SHBG levels does not explain our previous finding of no detected decrease in risky sexual behavior or sexual function for DMPA-IM or NET-EN users from D0 to 25W. Medroxyprogesterone (MPA) and NET are androgenic and are both present in molar excess over testosterone and SHBG concentrations at 25W. Any within or between contraceptive group androgenic effects on behavior in the brain are likely dominated by the androgenic activities of MPA and NET and not by the decreased endogenous testosterone levels.
The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).
The open-label WHICH clinical trial, conducted at two sites in South Africa from 2018-2019, randomized HIV-negative women aged 18-40 years to 150 mg DMPA-IM 12-weekly (n = 262) or 200 mg NET-EN 8-weekly (n = 259). We measured testosterone by UHPLC-MS/MS and SHBG by immunoassay in matched pairs of serum samples collected at baseline (D0) and at peak serum progestin levels at 25 weeks post initiation (25W) (n = 214-218 pairs).
We report for DMPA-IM and NET-EN users, respectively, a substantial decrease from D0 to 25W in total testosterone (-24.3%, D0 0.560, 25W 0.423 nmol/L, p < 0.0001 and -54.1%, D0 0.551, 25W 0.253 nmol/L, p < 0.0001), SHBG (-29.8%, D0 45.0, 25W 32.7 nmol/L, p < 0.0001 and -65.1%, D0 50.2, 25W 17.6 nmol/L, p < 0.0001), and calculated free testosterone levels (-17.2%, p = 0.0371 and -40.0%, p < 0.0001). The mean percentage difference in change for total testosterone, SHBG and calculated free testosterone levels was significantly more for NET-EN than DMPA-IM (64.9%, p < 0.0001; 101.2%, p < 0.0001; and 38.0%, p = 0.0120, respectively.
The substantial and differential decrease in testosterone and SHBG levels does not explain our previous finding of no detected decrease in risky sexual behavior or sexual function for DMPA-IM or NET-EN users from D0 to 25W. Medroxyprogesterone (MPA) and NET are androgenic and are both present in molar excess over testosterone and SHBG concentrations at 25W. Any within or between contraceptive group androgenic effects on behavior in the brain are likely dominated by the androgenic activities of MPA and NET and not by the decreased endogenous testosterone levels.
The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).
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Primary investigators
| Name | Affiliation |
|---|---|
| Chanel Avenant | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |
| Mandisa Singata-Madlik | Effective Care Research Unit, Eastern Cape Department of Health/Universities of the Witwatersrand and Fort Hare, East London, South Africa |
| Alexis J. Bick | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |
| Donita Africander | Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa |
| Yusentha Balakrishna | Biostatistics Research Unit, South African Medical Research Council, Durban, South Africa |
| Karl-Heinz Storbeck | Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa |
| Johnson Mosoko Moliki | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |
| Sigcinile Dlamini | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |
| Salndave Skosana | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |
| Jenni Smit | Wits MRU (MatCH Research Unit), Department of Obstetrics and Gynecology, Faculty of Health Sciences, University of the Witwatersrand, Durban, South Africa |
| Mags Beksinska | Wits MRU (MatCH Research Unit), Department of Obstetrics and Gynecology, Faculty of Health Sciences, University of the Witwatersrand, Durban, South Africa |
| Ivana Beesham | Wits MRU (MatCH Research Unit), Department of Obstetrics and Gynecology, Faculty of Health Sciences, University of the Witwatersrand, Durban, South Africa |
| Ishen Seocharan | Biostatistics Research Unit, South African Medical Research Council, Durban, South Africa. |
| Joanne Batting | Effective Care Research Unit, Eastern Cape Department of Health/Universities of the Witwatersrand and Fort Hare, East London, South Africa |
| G Justus Hofmeyr | Effective Care Research Unit, Eastern Cape Department of Health/Universities of the Witwatersrand and Fort Hare, East London, South Africa |
| Janet P. Hapgood | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa |