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Background: Progesterone only injectable contraceptives (POICs) are long acting reversible method of contraception used worldwide. Menstrual abnormalities are recognized side effects that can lead to discontinuation of these highly effective and safe contraceptives. Objectives: To determine the prevalence rate, side effects, discontinuation rate and indications for discontinuation of Norethisteroneenanthate (noristerat) and Depot Medroxyprogesterone acetate (depoprovera) at Rivers State University Teaching Hospital (RSUTH), Port Harcourt. Methods: A five year retrospective study of 874 clients attending family planning clinic at the RSUTH from 1st of January, 2015 – 31st of December, 2019. Their records were retrieved from the clinic and reviewed. Data was extracted, coded and analyzed using the statistical package for social sciences (SPSS) IBM version 25.0 (Armonk, NY). Chi square test was used as test of significance where applicable and a p-value

Norethisterone enanthate (NET-EN) and depot-medroxyprogesterone acetate (DMPA) are two forms of injectable progestin used for contraception. Whereas clinical research indicates that women using DMPA are more susceptible to HIV and other genital pathogens, causal relationships have not been determined. Providing an underlying mechanism for this connection, however, is recent work that showed DMPA weakens genital mucosal barrier function in mice and humans and respectively promotes susceptibility of wild-type and humanized mice to genital infection with HSV type 2 and HIV type 1. However, analogous effects of NET-EN treatment on antivirus immunity and host susceptibility to genital infection are much less explored. In this study, we show that compared with mice in estrus, treatment of mice with DMPA or NET-EN significantly decreased genital levels of the cell–cell adhesion molecule desmoglein-1 and increased genital mucosal permeability. These effects, however, were more pronounced in DMPA- versus NET-EN–treated mice. Likewise, we detected comparable mortality rates in DMPA- and NET-EN–treated wild-type and humanized mice after intravaginal infection with HSV type 2 or cell-associated HIV type 1, respectively, but NET-EN treatment was associated with slower onset of HSV-induced genital pathology and lower burden of systemic HIV disease. These findings reveal DMPA and NET-EN treatment of mice significantly reduces genital desmoglein-1 levels and increases genital mucosal permeability and susceptibility to genital pathogens while also implying that NET-EN generates less compromise of genital mucosal barrier function than DMPA.

X-ray powder diffraction data, unit-cell parameters, and space group for norethisterone enanthate, C27H38O3, are reported [a = 6.191(4) Å, b = 12.711(3) Å, c = 31.396(2) Å, α = 90°, β = 90°, γ = 90°, unit-cell volume V = 2471.16 Å3, Z = 4, ρcal = 1.104 g cm−3, and space group P212121]. All measured lines were indexed and are consistent with the P212121 space group. No detectable impurities were observed.

This study aimed to investigate the effects of the combined injectable contraceptive (CIC) containing estradiol valerate (EV) and norethisterone enanthate (NET-EN) on aorta function and morphology, as well as on redox status, of female Wistar rats. Female rats (9-10 weeks of age) received intramuscular injections of CIC (0.1 mg EV plus 1 mg NET-EN) or castor oil (control group, CTL) for 8 weeks, once a week. Food intake, body weight and systolic blood pressure were measured during the treatment period. Thoracic aortic segments were prepared for isometric tension recording and morphological analysis. Redox status was evaluated by total oxidant status (TOS) and lipid peroxidation (LP) on plasma and reduced glutathione (GSH) on whole blood. CIC group presented lower food intake and lower total weight gain compared to CTL group. There was no change in systolic blood pressure, vascular response of aorta to phenylephrine and acetylcholine and aorta thickness. Plasma TOS and LP values were reduced in CIC group, although GSH was not altered. It was shown that the long-term treatment with the CIC containing EV plus NET-EN does not induce endothelial dysfunction and histomorphometric changes of vascular wall, as well as improves redox status on female Wistar rats.

Introduction: Whether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection.Materials and Methods: Prospective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users.Results: Among 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%, p = 0.54; gonorrhea: 3.4 vs. 3.7%, p = 0.70; trichomoniasis: 5.7 vs.5.0%, p = 0.40; or syphilis: 1.5 vs. 0.7%, p = 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%, p < 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85–1.25), gonorrhea (aHR 0.88, 95% CI 0.60–1.31), trichomoniasis (aHR 1.07, 95% CI 0.74–1.54), syphilis (aHR 0.41, 95% CI 0.15–1.10), and HSV-2 (aHR 0.83, 95% CI 0.45–1.54, p = 0.56)].Discussion: Among South African participants enrolled in VOICE, DMPA-IM and NET-EN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

PROBLEM Injectable hormonal contraceptives (IHC) have been associated with altered mucosal and systemic milieu which might increase HIV risk, but most studies have focused on DMPA and not NET-EN, despite the growing popularity and lower HIV risk associated with the latter in observational studies. METHOD OF STUDY We used high-performance liquid chromatography in combination with tandem triple quadrupole mass spectrometry (HPLC-LC-MS/MS) to measure steroid hormones in plasma samples of CAPRISA004 study participants. Concentrations of 48 cytokines were measured in the cervicovaginal lavage (CVL) and plasma, and their expression was compared between participants with detectable NET-EN (n = 201) versus non-detectable IHC (n = 90). Each log10 cytokine concentration was tested as an outcome in linear-mixed models, with NET-EN detection as the main explanatory variable. Multivariable models were adjusted for potential confounders. RESULTS In bivariate analysis, detectable NET-EN was associated with reduced cervicovaginal M-CSF (P = 0.008), GM-CSF (P = 0.025) and G-CSF (P = 0.039), and elevated levels MIF (P = 0.008), IL-18 (P = 0.011), RANTES (P = 0.005) and IL-1Rα (P

Problem There is paucity of human data about the effects of depot medroxyprogesterone (DMPA) and norethisterone enanthate (Net-En) use on systemic immune function, which may have implications for reproductive tract infection susceptibility and transmissibility. We sought to evaluate the impact of injectable contraceptive use on T-cell responsiveness using T cells exposed in vivo and tested ex vivo. Methods Peripheral blood mononuclear cells were obtained from healthy, HIV-negative women after 30, 90 and 180 days of DMPA, norethisterone enanthate (Net-En) or copper intrauterine device (Cu-IUD) contraceptive use. Cells were stimulated ex vivo with phorbol myristate acetate and ionomycin, stained and analysed using flow cytometry. Mixed-effects linear models were used to evaluate change in proportions of T cells producing IFN-γ, TNF-α, IL-4 and IL-13. Results Compared with baseline, decreased proportions of IFN-γ-producing CD4+ and CD8+ T cells (p = .003, p = .006, respectively) and TNF-α-producing CD4+ and CD8+ T cells (p = .039, p = .034, respectively) were observed after 180 days of DMPA use. Decreased IL-4-producing CD4+ and CD8+ T cells (p = .045 and p = .024, respectively) were noted after 180 days of Net-En use. Decreased IL-4-producing CD4+ T cells were observed after 30 days (p = .035) and not after 180 days of DMPA use (p = .49). There were no changes in proportion of T cells producing IL-13 in DMPA users, nor any changes in IFN-γ, TNF-α and IL-13 in Net-En and Cu-IUD users. Conclusion In vivo exposure of CD4+ and CD8+ T cells to typical pharmacologic concentrations of DMPA does not cause broad suppression to stimuli; however, depletion of specific cytokine-producing T cells may occur after prolonged DMPA use.

ObjectivesYoung women in sub-Saharan Africa are at high risk of STIs and unintended pregnancies, yet hormonal contraceptive (HC) use may affect STI risk. We compared the influence of three HCs on the incidence and prevalence of STIs and bacterial vaginosis (BV) in South African adolescents.MethodsOne hundred and thirty adolescents between 15 and 19 years were randomised to the injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) (Triphasil or Nordette) or a combined contraceptive vaginal ring (CCVR; NuvaRing) for 16 weeks (clinicaltrials.gov/NCT02404038). Vaginal samples were collected at baseline and 16 weeks post contraceptive initiation for STI and BV testing.ResultsIn an intention-to-treat analysis, no significant differences in BV prevalence were found between study arms. The overall incidence of any STI at follow-up was high: 16.2% in the COC arm; 25.7% in the Net-En arm; and 37.1% in the CCVR arm. The incidence rate (IR) of any STI was similar between Net-En (IR 0.74 (95% CI 0.34 to 1.41)) and the oestrogen-containing contraceptives (IR 0.78 (95% CI 0.47 to 1.22)). A lower IR of Chlamydia trachomatis (incidence rate ratio (IRR) 0.68 (95% CI 0.19 to 1.99)) and Neisseria gonorrhoeae (IRR 0.25 (95% CI 0.01 to 1.35)) but a higher IR of Mycoplasma genitalium (IRR 16.0 (95% CI 2.96 to 400)), was observed in the Net-En arm compared with the oestrogen-containing contraceptives, although the overall incidence of M. genitalium was low (4.7%). In an exploratory analysis, the risk of any STI and N. gonorrhoeae was lower in the COC arm compared with CCVR. A per-protocol analysis yielded similar results.ConclusionOur results suggest that use of Net-En may be associated with increased risk of M. genitalium compared with oestrogen-containing contraceptives but not with overall STI risk. COC use may decrease STI risk relative to CCVR.

PROBLEM: Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En). METHOD OF STUDY: Peripheral blood mononuclear cells collected from women aged 18–34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4). RESULTS: Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline. CONCLUSION: Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.

Access to effective affordable contraception is critical for individual and public health. A wide range of hormonal contraceptives (HCs), which differ in composition, concentration of the progestin component, frequency of dosage, and method of administration, is currently available globally. However, the options are rather limited in settings with restricted economic resources that frequently overlap with areas of high HIV-1 prevalence. The predominant contraceptive used in sub-Saharan Africa is the progestin-only three-monthly injectable depot medroxyprogesterone acetate. Determination of whether HCs affect HIV-1 acquisition has been hampered by behavioral differences potentially confounding clinical observational data. Meta-analysis of these studies shows a significant association between depot medroxyprogesterone acetate use and increased risk of HIV-1 acquisition, raising important concerns. No association was found for combined oral contraceptives containing levonorgestrel, nor for the two-monthly injectable contraceptive norethisterone enanthate, although data for norethisterone enanthate are limited. Susceptibility to HIV-1 and other sexually transmitted infections may, however, be dependent on the type of progestin present in the formulation. Several underlying biological mechanisms that may mediate the effect of HCs on HIV-1 and other sexually transmitted infection acquisition have been identified in clinical, animal, and ex vivo studies. A substantial gap exists in the translation of basic research into clinical practice and public health policy. To bridge this gap, we review the current knowledge of underlying mechanisms and biological effects of commonly used progestins. The review sheds light on issues critical for an informed choice of progestins for the identification of safe, effective, acceptable, and affordable contraceptive methods., Review of clinical, animal, and ex vivo data on mechanisms whereby hormonal contraception may increase HIV-1 acquisition reveals evidence for several plausible biological mechanisms for medroxyprogesterone acetate.

BackgroundEvidence from observational studies suggests an increased risk of HIV acquisition among women using depot medroxyprogesterone acetate (DMPA) contraception.MethodsWithin the context of a South African programme to increase women's access to the intrauterine contraceptive device (IUD), we conducted a pragmatic, open-label, parallel-arm, randomised controlled trial (RCT) of the IUD versus injectable progestogen contraception (IPC) at two South African hospitals. The primary outcome was pregnancy; secondary outcomes included HIV acquisition. Consenting women attending termination of pregnancy services were randomised after pregnancy termination between July 2009 and November 2012. Condoms were promoted for the prevention of sexually transmitted infections. Voluntary HIV testing was offered at baseline and at 12 or more months later. Findings on HIV acquisition are reported in this article.ResultsHIV acquisition data were available for 1290 initially HIV-negative women who underwent a final study interview at a median of 20 months after randomisation to IPC or an IUD. Baseline group characteristics were comparable. In the IPC group, 545/656 (83%) of participants received DMPA, 96 (15%) received injectable norethisterone enanthate, 14 (2%) received the IUD and one received oral contraception. In the IUD group 609 (96%) received the IUD, 20 (3%) received IPC and 5 (1%) had missing data. According to intention-to-treat analysis, HIV acquisition occurred in 20/656 (3.0%) women in the IPC arm and 22/634 (3.5%) women in the IUD arm (IPC vs IUD, risk ratio 0.88; 95% confidence interval 0.48–1.59;p=0.7).ConclusionsThis sub-study was underpowered to rule out moderate differences in HIV risk, but confirms the feasibility of randomised trial methodology to address this question. Larger RCTs are needed to determine the relative risks of various contraceptive methods on HIV acquisition with greater precision.Trial registration numberPan African Clinical Trials Registry number PACTR201409000880157 (04-09-2014).

Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15–19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation., Hormonal contraception may alter women’s susceptibility to HIV. Here, the authors report the results of a randomized clinical trial substudy assessing the effects of injectable Net-En, oral contraceptives (COC) and Nuvaring on vaginal microbiota and cytokines, associating COC with lower microbial diversity and Nuvaring with increased inflammation.

Background Young women in sub-Saharan Africa are at high risk for sexually transmitted infections (STIs) and often rely on hormonal contraception (HC) to prevent unwanted pregnancies. Some observational data suggest that HC might affect STI risk. We examined the impact of three HC methods on the adolescent STI incidence and BV prevalence in a randomized trial. Methods 130 adolescent females aged 15 to 19 from Cape Town were enrolled and randomized into three study arms: 1. injectable norethisterone enanthate (NET-EN), 2. combined oral contraceptives (COCs) or 3. combined contraceptive vaginal ring (CCVR) for 16 weeks. Participants then switched to a second HC for a final four months. Vaginal samples were collected at baseline, crossover and exit for STI (chlamydia, gonorrhoea, mycoplasma and trichomoniasis) and bacterial vaginosis (BV) testing by Nugent scoring. Results At baseline, the BV and STI prevalence was 44% and 42%, respectively. There were no significant differences in STI incidence between study arms at crossover, however in an according to protocol analyses, participants using COCs were significantly less likely to present with any STI than participants using either NET-EN (OR 0.22, 95% CI 0.06–0.71, p=0.017) or CCVR (OR 0.21, 95% CI 0.05–0.69, p=0.015). Specifically, participants on CCVR were more likely to be infected with N. gonorrhoea (OR 11.7, 95% CI 2.0–224, p=0.025). These associations stayed significant after adjusting for sexual risk behaviour, including condom use. There was a decreased prevalence of BV in the COC arm and an increased BV prevalence in the NET-EN and CCVR arms at crossover, but these differences were not statistically significant. Conclusion Use of COCs was associated with lower BV prevalence and STI incidence compared to NET-EN and CCVR use. Disclosure No significant relationships.

Objective Long-acting reversible contraceptive (LARC) method uptake has been low within the context of HIV prevention trials. Within a multinational study (MTN-020/ASPIRE), the Contraceptive Action Team improved LARC accessibility and uptake. In this secondary analysis, we determined the rate of contraceptive method continuation among the women enrolled. Study design ASPIRE was a randomized, double-blinded, placebo-controlled phase III safety and effectiveness study of the Dapivirine Vaginal Ring for HIV-1 prevention. Between 2012 and 2014, sexually active women aged 18–45 from Malawi, South Africa, Uganda and Zimbabwe were enrolled. All participants were required to use contraception for enrollment to the study and could choose between all highly effective contraceptive methods available in their respective countries. Women were seen monthly and could change methods at any time. Continuation rates from study enrollment to 6 and 12 months were determined. Results The overall contraceptive method continuation rate was 77% (1972/2551) at 6 months and 66% (1694/2551) at 12 months. The 6- and 12-month continuation rates were highest for implantable contraceptives (89%, 82%) followed by copper intrauterine device (83%, 77%). Rates of continuation for injectable contraceptives depot medroxyprogesterone acetate (80%, 69%) and norethisterone enanthate (71%, 54%) were higher than for oral contraceptives, which were continued at 47% at 6 months and 35% at 12 months. The continuation rates of all methods did not differ by users with and without previous contraceptive experience. Conclusions LARC methods have the highest rates of continuation at 12 months and should be routinely offered in the context of HIV prevention trials in sub-Saharan Africa. Implications Intrauterine devices and contraceptive implant continuation was high at 12 months among women participating in an HIV prevention trial in sub-Saharan Africa and LARCs and should be routinely offered.

The intramuscular progestin-only injectable contraceptive, depo-medroxyprogesterone acetate (DMPA-IM), is more widely used in Sub-Saharan Africa than another injectable contraceptive, norethisterone enanthate (NET-EN). Epidemiological data show a significant 1.4-fold increased risk of HIV-1 acquisition for DMPA-IM usage, while no such association is shown from limited data for NET-EN. We show that MPA, unlike NET, significantly increases R5-tropic but not X4-tropic HIV-1 replication ex vivo in human endocervical and ectocervical explant tissue from pre-menopausal donors, at physiologically relevant doses. Results support a mechanism whereby MPA, unlike NET, acts via the glucocorticoid receptor (GR) to increase HIV-1 replication in cervical tissue by increasing the relative frequency of CD4+ T cells and activated monocytes. We show that MPA, unlike NET, increases mRNA expression of the CD4 HIV-1 receptor and CCR5 but not CXCR4 chemokine receptors, via the GR. However, increased density of CD4 on CD3+ cells was not observed with MPA by flow cytometry of digested tissue. Results suggest that DMPA-IM may increase HIV-1 acquisition in vivo at least in part via direct effects on cervical tissue to increase founder R5-tropic HIV-1 replication. Our findings support differential biological mechanisms and disaggregation of DMPA-IM and NET-EN regarding HIV-1 acquisition risk category for use in high risk areas.

Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24–11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44–2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal fluid of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility., Author summary Alterations to the mucosal environment of the female genital tract have been associated with increased HIV acquisition in women. As both the vaginal microbiome and hormonal contraceptives affect mucosal immunity, we investigated their interaction with HIV susceptibility. We characterized the vaginal microbiomes in 685 women from the CAPRISA-004 trial, who utilized three major types of hormonal contraceptives including injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In the 40% of women with Lactobacillus-depleted microbiomes, HIV acquisition was not different between contraceptive groups. However, in the 60% of women with Lactobacillus as the dominant bacterial taxa, HIV acquisition risk was 3-fold higher (in women using DMPA relative to women using NET-EN and COC). Higher serum medroxyprogesterone acetate levels in Lactobacillus dominant women associated with increased cervicovaginal inflammation pathways in the mucosal proteome, biomarkers of which associated with HIV susceptibility. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility.

Objective and design: Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data. Methods: We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception. Results: We identified 10 new reports of which five were considered ‘unlikely to inform the primary question’. We focus on the other five reports, along with nine from the previous review, which were considered ‘informative but with important limitations’. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher quality studies of hazard ratio 1.4. Conclusion: Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring.

Context: The development of a safe and effective reversible method of male contraception is still an unmet need. Objective: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. Design: Prospective multicentre study. Setting: Ten study centers. Participants: Healthy men, aged 18–45 years, and their 18- to 38-year-old female partners, both without known fertility problems. Intervention: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. Main Outcomes Measures: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. Results: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8–97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59–4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5–97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. Conclusions: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.

Progestogen-only injectable contraceptive is a highly effective, long lasting and reversible agent of fertility control. The objective is to determine the profile of the acceptors, side effects and indication for discontinuation of progestogen-only injectable contraceptives at UCTH, Calabar. This was a retrospective study of the clients who used progestogen-only injectable contraceptives at the family planning unit between 1st January 2008 and 31st December 2014. A total of 1392 clients used the injectable progestogen-only contraceptive out of 5986 total contraceptive users giving the prevalence rate of 23.3% over the period. Of these, 60.4% of the clients accepted the depot medroxyprogesterone acetate, while 39.6% accepted the norethisterone enanthate. It was mostly utilized by multiparous women, clients with tertiary education and those in their third decade of life. Secondary amenorrhea was the commonest side effect in 47.7% of the clients. Over the study period, 243 (19.8%) discontinued the method and 48.1% discontinued due to secondary amenorrhea while 31.4% was due to desire to get pregnant. Progestogen-only injectable contraceptive was associated with multiple side-effects, with secondary amenorrhea being the most common, and menstrual irregularity was the main reason for discontinuation. Providing adequate information to clients about this method of contraception and its probable side effects, supportive counseling during initiation of contraception and re-enforcement during follow-up visit can go a long way in enhancing patient satisfaction and hence continuation of progestogen-only injectable contraceptive despite minor side effects.

Background Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely to result in ectopic pregnancies than some other methods such as combined hormonal and barrier contraceptives. Objective To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies. Data sources We searched electronic databases for articles in any language published through May 2015 describing studies of progestin-only injectables and implants. We also searched bibliographies and review articles for additional studies. Study selection and extraction Studies that reported any pregnancies were included in the review. Independent data extraction was performed by two authors based on predefined data fields, and where possible, we calculated the proportion of pregnancies that were ectopic and the ectopic pregnancy incidence rate per 1000 woman-years. Results Fifty-three studies of implants and 28 studies of injectables were identified; 79% reported pregnancy location. The proportion of ectopic pregnancy ranged from 0 to 100% with an incidence of 0-2.9 per 1000 woman-years in studies of marketed levonorgestrel implants. Studies of etonogestrel implants and the injectables, depot-medroxyprogesterone acetate and norethisterone enanthate, reported few ectopic pregnancies. Conclusion Progestin-only contraceptive implants and injectables protect against ectopic pregnancy by being highly effective in preventing pregnancy overall; however, the absolute risk of ectopic pregnancy varies by type of progestin. Risk of ectopic pregnancy should not be a deterrent for use or provision of these methods.

Background: Progestogen‑only injectable contraceptives (POICs) remain the most popular contraceptive method in Nigeria. Considering how widely used POICs are worldwide, there is little published evidence of their safety and effectiveness. There is also a paucity of research to determine associations between the influence of age and parity and the preferred choice of POICs in women.Aim: This study was to determine the use prevalence and the influence of age and parity on the preferred choice of POIC, and also the reasons for discontinuation among users of POICs at the family planning clinics of OAUTHC, Ile‑Ife.Materials and Methods: A retrospective record of 324 women who chose POICs out of a total of 1,029 clients seen at the family planning units of the hospital was collected for the period between January and December 2015. Information relevant to this study objectives was extracted using a purpose‑designed proforma. Data were analyzed with SPSS version 16, and results were presented as frequencies and percentages. Pearson Chi‑square test was used as test of significance where applicable and a P value < 0.05 was considered statistically significant.Results: The prevalence of POIC during the study period was 31.49%. Depo‑Provera (depot medroxyprogesterone acetate [DMPA]) was the most popular injectable preferred by the women. Age and parity had significant effects on the preferred injectable contraception with P values of 0.032 (CI 0.088‑0.099) and 0.002 (CI 0.009‑0.013), respectively, as younger clients with lower parity preferred Noristerat while preference for DMPA increased with age and parity. Majority (67%) did not experience any side effect; secondary amenorrhea was the most common side effect experienced by 27% of the clients. Only 34% continued with the method for the duration of study while 66% discontinued for different reasons.Conclusion: POICs are very effective and safe long‑acting reversible method of contraception. While DMPA may be the more popular overall choice, norethisterone enanthate (NET‑EN) is preferable in younger women of low parity.Keywords: Depoprovera; Ile-Ife; Noristerat

Background A high endogenous progesterone luteal state in the menstrual cycle has been independently associated with Human Immunodeficiency Virus (HIV) incidence in epidemiological studies. Hormonal contraception particularly high dose Depot Medroxyprogesterone Acetate (DMPA) is also thought to increase the risk of HIV acquisition. Inconsistent reports of this association have led us to hypothesize that unsuppressed endogenous progesterone level in women who reported hormonal contraception (HC) use may be an explanation for increased vulnerability to HIV. Methods This pilot study was a secondary cross-sectional analysis of data and laboratory testing of stored specimens collected from women who participated in the SAMRC HIV prevention MDP 301 trial during 2005–2009 in South Africa. Serum progesterone levels were measured in 39 women at the point of first positive HIV diagnosis during study follow-up and 36 women who remained HIV uninfected at the 52-week study exit visit. Results Overall, the median (IQR) progesterone level in 49 women using hormonal contraception was 0.39 ng/ml (IQR 0.13–0.45) and 48 (97.9%) women had a progesterone level 3.0 ng/ml, the median progesterone level in women using DMPA remained marginally higher at 0.42 ng/ml (IQR 0.27–0.45) than women using Norethisterone Enanthate (NET-EN) (0.31 ng/ml; IQR 0.13–0.41, p = 0.061). For women using hormonal contraception, the median progesterone level did not differ between women with recent HIV infection or women who remained HIV negative (0.39 vs 0.38 ng/ml, p = 0.959). Similarly, the median progesterone level in women using DMPA or NET-EN did not differ by HIV status (0.43 vs 0.41 ng/ml, p = 0.905; 0.24 vs 0.31 ng/ml, p = 0.889). Conclusion Among women using hormonal contraception, DMPA or NET-EN we did not observe a significant difference in progesterone levels between women with recently acquired HIV infection and women who remained HIV negative. Our findings suggest that endogenous progesterone levels remain suppressed in the presence of hormonal contraception and are not likely to be associated with HIV acquisition.

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.

Background In South Africa, hormonal contraception is widely used in women over the age of 40 years. One of these methods and the most commonly used is depot-medroxyprogesterone acetate (DMPA) which has been found to have a negative effect on bone mass. Limited information is available on the effect of norethisterone enanthate (NET-EN) on bone mass, and combined oral contraceptives (COCs) have not been found to be associated with loss of bone mass. The aim of this study was to investigate bone mineral density (BMD) in pre and perimenopausal women (40–49 years) in relation to use of DMPA, NET-EN and COCs for at least 12 months preceding recruitment into the study and review associations with body mass index (BMI) and menopausal status. Methods One hundred and twenty seven users of DMPA, 102 NET-EN users and 106 COC users were compared to 161 nonuser controls. Menopausal status was assessed, BMI and forearm BMD was measured at the distal radius using dual X-ray absorptiometry. Comparison analysis was conducted at baseline and 2.5 years. Results There was no significant difference in BMD between the four contraceptive user groups (p = 0.26) with and without adjustment for age at baseline or at 2.5 years (p = 0.52). The BMD was found to be significantly associated with BMI (p =

Los autores han estudiado el efecto anticonceptivo de 17-alfa hidroxi-19-Norprogesterona capronato (SN - 582) en 21 mujeres normales; el efecto está presente durante 6-8 semanas después de la Inyección de 200 mg. Durante este tiempo se observaron irregularidades menstruales como la localización y la amenorrea, pero su incidencia fue menor que las producidas por el enantato de noretisterona (SN - 393).

Norethisterone enanthate (NET-EN) is a fatty acid ester of norethisterone. The single crystallographic data of NET-EN [a = 6.09236(14) A, b = 12.7347(3) A, c = 30.1234(8) A, α = β = γ = 90°, unit-cell volume V = 2337.11 A3, Z = 4, and space group P212121] were obtained by using acetone as a solvent. The interaction of NET-EN with human serum albumin (HSA) was investigated using different optical techniques and molecular modeling. The fluorescence quenching between NET-EN and HSA was a static quenching process. The fluorescence lifetime measurement provided us with an insight into the occurrence of static quenching. Three commercially available steroid hormone drugs, namely, norethindrone, norethindrone acetate, and ethisterone, were weaker than NET-EN in terms of binding capability with HSA. Displacement experiments demonstrated that similar to progesterone, the binding site of NET-EN was mainly located in site 1 of HSA. A circular dichroism (CD) study showed that NET-EN had a minimal effect on the local conformation of the HSA molecule. This study provided useful information for the better understanding and use of NET-EN.

A 23-year-old East Indian woman with no significant medical history, except a depot-norethisterone enanthate injection taken 3 weeks prior to admission, presented with a gradually worsening headache for the past 5 days. She had no fever, vomiting, neck stiffness, focal weakness or rash, and examination was unremarkable with no focal neurological deficits. Vasculitic, thrombophilia and sepsis screens were normal. A brain CT scan showed a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and Magnetic Resonance Venogram (MRV) confirming a signal void. She was diagnosed to have multiple cerebral venous sinus thrombosis due to norethisterone enanthate. She made a complete recovery following treatment with mannitol, dexamethasone and anticoagulants. A follow-up brain MRI done at 6 months was normal.

Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we identified 22 studies published by January 15, 2014 which met inclusion criteria; we classified thirteen studies as having severe methodological limitations, and nine studies as "informative but with important limitations". Overall, data do not support an association between use of oral contraceptives and increased risk of HIV acquisition. Uncertainty persists regarding whether an association exists between depot-medroxyprogesterone acetate (DMPA) use and risk of HIV acquisition. Most studies suggested no significantly increased HIV risk with norethisterone enanthate (NET-EN) use, but when assessed in the same study, point estimates for NET-EN tended to be larger than for DMPA, though 95% confidence intervals overlapped substantially. No data have suggested significantly increased risk of HIV acquisition with use of implants, though data were limited. No data are available on the relationship between use of contraceptive patches, rings, or hormonal intrauterine devices and risk of HIV acquisition. Women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition, and like all women at risk of HIV, should be empowered to access and use condoms and other HIV preventative measures. Programs, practitioners, and women urgently need guidance on how to maximize health with respect to avoiding both unintended pregnancy and HIV given inconclusive or limited data for certain HC methods.

Introduction In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV‐1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long‐acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV‐1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods. Methods MTN‐020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV‐1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin‐based injectables or implants during follow‐up. Screening for the above STIs occurred semi‐annually. Results Over 3440 person‐years of follow‐up, 408 cases of C. trachomatis (incidence 11.86/100 person‐years), 196 of N. gonorrhoeae (5.70/100 person‐years) and 213 cases of T. vaginalis (6.19/100 person‐years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users. Conclusion Among African women at high HIV‐1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin‐based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.

Summary Whether or not the use of hormonal contraception affects risk of HIV acquisition is an important question for public health. We did a systematic review, searching PubMed and Embase, aiming to explore the possibility of an association between various forms of hormonal contraception and risk of HIV acquisition. We identified 20 relevant prospective studies, eight of which met our minimum quality criteria. Of these eight, all reported findings for progestin-only injectables, and seven also reported findings for oral contraceptive pills. Most of the studies that assessed the use of oral contraceptive pills showed no significant association with HIV acquisition. None of the three studies that assessed the use of injectable norethisterone enanthate showed a significant association with HIV acquisition. Studies that assessed the use of depot-medroxyprogesterone acetate (DMPA) or non-specified injectable contraceptives had heterogeneous methods and mixed results, with some investigators noting a 1·5–2·2 times increased risk of HIV acquisition, and others reporting no association. Thus, some, but not all, observational data raise concern about a potential association between use of DMPA and risk of HIV acquisition. More definitive evidence for the existence and size of any potential effect could inform appropriate counselling and policy responses in countries with varied profiles of HIV risk, maternal mortality, and access to contraceptive services.

Summary Background Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. Methods In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Findings Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6–24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06–3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8–24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12–3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Interpretation Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. Funding US National Institutes of Health and the Bill & Melinda Gates Foundation.

Objectives: To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. Design/methods: We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular. Results: Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users. Conclusions: In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies. (C) 2012 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkins

The long-acting progestogen injectable contraceptives depot medroxyprogesterone acetate and norethisterone enanthate have been found to adversely affect bone mineral density in adult premenopausal women and adolescents. The effect of combined oral contraceptives on bone mineral density is variable, with no effect reported in premenopausal women; however, growing evidence suggests that low-dose combined oral contraceptives may be detrimental to bone mineral density in adolescents and young women. Much less information is available on other hormonal methods. Concerns regarding bone loss in depot medroxyprogesterone acetate users resulted in a US FDA black-box warning for this method. No restriction has been placed on the use of other progestogen-only or combined oral contraceptive methods. There are now concerns that these recommendations should be reviewed as new information emerges regarding low-dose combined oral contraceptives and evidence grows that supports recovery of bone mineral density postdiscont...