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Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan Africa. Insufficient robust data on their relative side-effects and serum concentrations limit understanding of reported outcomes in contraception trials. The WHICH clinical trial randomized HIV-negative women to DMPA-IM (n = 262) or norethisterone enanthate (NET-EN) (n = 259) at two South African sites between 2018–2019. We measured serum concentrations of study and non-study progestins at initiation (D0) and peak serum levels, one week after the 24-week injection [25 weeks (25W)], (n = 435) and investigated associations between study progestin levels, and BMI and weight of participants. Peak median serum concentrations were 6.59 (IQR 4.80; 8.70) nM for medroxyprogesterone (MPA) (n = 161) and 13.6 (IQR 9.01; 19.0) nM for norethisterone (NET) (n = 155). MPA was the most commonly quantifiable non-study progestin at D0 in both arms (54%) and at 25W in the NET-EN arm (27%), followed by NET at D0 in both arms (29%) and at 25W in the DMPA-IM arm (19%). Levonorgestrel was quantifiable in both arms [D0 (6.9%); 25W (3.4%)], while other progestins were quantifiable in ≤ 14 participants. Significant negative time-varying associations were detected between MPA and NET concentrations and weight and BMI in both contraceptive arms and a significant increase was detected for peak serum progestin concentrations for normal weight versus obese women. Contraceptive-related reported outcomes are likely confounded by MPA, more so than NET, with reported DMPA-IM effects likely underestimated, at sites where DMPA-IM is widely used, due to misreporting of contraceptive use before and during trials, and ‘tail’ effects of DMPA-IM use more than six months before trial enrolment. Peak serum levels of MPA and NET are negatively associated with BMI and weight, suggesting another source of variability between trial outcomes and a potential increase in side-effects for normal weight versus overweight and obese women. Trail registration: The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976 ).

Background The progestin norethisterone (NET), which is structurally related to testosterone, and its enanthate form (NET-EN), are used in contraception in women. Oral NET has been shown to interfere with testosterone measurements by some chemiluminescence microparticle immunoassays (CMIA). However, whether serum NET in NET-EN users interferes with these assays is unknown. Methods Serum samples were obtained from women randomized to the injectable contraceptives NET-EN or depo medroxyprogesterone acetate intramuscular (DMPA-IM) in a clinical trial conducted in South Africa. Testosterone concentrations were compared after measurement by Abbott Architect CMIA and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), from matched samples collected at baseline (D0) and 25 weeks (25W) after initiation. Results At 25W, testosterone concentrations in the NET-EN arm were significantly higher (271%) using the CMIA compared to the UHPLC-MS/MS method. Contrary to the UHPLC-MS/MS results showing a significant decrease in testosterone concentrations in the NET-EN arm from D0 to 25W, a significant increase was determined by CMIA. Conversely, in the DMPA-IM arm at 25W, no significant difference in testosterone concentrations between the two methods was detected, and both methods showed a significant decrease in testosterone from D0 to 25W. Conclusions We show for the first time that physiological concentrations of NET in premenopausal NET-EN users interfere with testosterone quantification using a CMIA method. The degree of interference is much higher and occurs at lower concentrations of NET than has previously been reported for oral NET and confounds the biological outcome of NET-EN use on testosterone concentrations, individually and relative to DMPA-IM. Trial registration The WHICH trial was retrospectively registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).