Effects of injectable contraception with depot medroxyprogesterone acetate or norethisterone enanthate on estradiol levels and menstrual, psychological and behavioral measures relevant to HIV risk: the WHICH randomized trial
South Africa
Mandisa Singata-Madliki, Jenni Smit, Mags Beksinska, Yusentha Balakrishna, Chanel Avenant, Ivana Beesham, Ishen Seocharan, Joanne Batting, Janet P. Hapgood, G Justus Hofmeyr
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December 05, 2023
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December 05, 2023
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EffectsOfInjectableContraceptive
Title
Effects of injectable contraception with depot medroxyprogesterone acetate or norethisterone enanthate on estradiol levels and menstrual, psychological and behavioral measures relevant to HIV risk: the WHICH randomized trial
Country
| Name | Country code |
|---|---|
| South Africa | ZAR |
Abstract
Background
Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels.
Methods
This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n=262) or NET-EN 200 mg intramuscular 8-weekly (n=259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W).
Results
At 25W, median 17ß estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n=222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n=225), with no statistical difference between the two methods (p=0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured.
Conclusions
Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question.
Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels.
Methods
This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n=262) or NET-EN 200 mg intramuscular 8-weekly (n=259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W).
Results
At 25W, median 17ß estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n=222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n=225), with no statistical difference between the two methods (p=0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured.
Conclusions
Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question.
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Primary investigators
| Name | Affiliation |
|---|---|
| Mandisa Singata-Madliki | Effective Care Research Unit, Eastern Cape Department of Health/Universities of the Witwatersrand and Fort Hare, East London, 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 |
| Yusentha Balakrishna | Biostatistics Research Unit, South African Medical Research Council, Durban, South Africa |
| Chanel Avenant | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, 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 |
| Janet P. Hapgood | Department of Molecular and Cell Biology, University of Cape Town, Cape Town, 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 |