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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 ).

This study is the first attempt to examine the effects of NETA on immune cells and telocytes. The results of this study form an important knowledge base for the development of new information on the mechanism of contraceptive action of NETA in the uterus. Norethisterone acetate (NETA) is a synthetic progestogen medication commonly utilized in birth control pills, menopausal hormone therapy, and for curing abnormal uterine bleeding and endometriosis. Furthermore NETA has many beneficial uses in veterinary medicine as control and synchronization of estrous cycle. The impact of NETA on the endometrial stromal cells (ESCs), telocytes, and uterine immune cells is not well understood. Therefore, this study focuses on assessing changes in uterine immune cells, ESCs, and telocytes following exposure to NETA in albino rats. To achieve this objective, fourteen adult female albino rats were randomly divided into two groups: a control group and an NETA-treated group. Rats in the control group received daily pelleted food, water, and were oral administered of 2 ml distilled water. In contrast, rats in the NETA-treated group received daily pelleted food, water, and were orally administered 20 µg of NETA dissolved in 2 ml distilled water. The experiment spanned three weeks. The findings of this study revealed that NETA usage increases the infiltration and activity of immune cells (eosinophils, neutrophils, macrophages, lymphocytes, and mast cells). Furthermore, it enhances the vesicular activity of uterine telocytes and their communication with various immune cells. NETA also influences decidualization and the immunoexpression of progesterone receptors in uterine epithelial and immune cells. This study concludes that the primary mechanism by which NETA controls pregnancy is through decidual (pregnancy-like) effects or improper decidualization, which inhibits fertilization and implantation respectively. Our research provides evidence of the contraceptive mechanism of NETA from an immunological perspective in an animal model.

Background Greater trochanteric pain syndrome (GTPS) is pathology in the gluteus medius and minimus tendons and trochanteric bursa that causes debilitating tendon pain and dysfunction, particularly in post-menopausal women. Limited evidence in clinical studies suggests hormone changes after menopause may have a negative effect on tendon. This protocol describes a randomised controlled trial comparing the effectiveness of menopausal hormone therapy (MHT) and exercise therapy in reducing pain and dysfunction associated with GTPS in post-menopausal women. Method One hundred and sixteen post-menopausal women will be recruited and randomised to receive one of two exercise programs (sham or targeted intervention exercise) and transdermal creams (MHT cream containing oestradiol 50mcg and norethisterone acetate 140mcg or placebo cream). Interventions will be 12-weeks in duration and outcomes will be examined at baseline, 12-weeks and 52-weeks. The primary outcome measure will be the VISA-G questionnaire and secondary outcomes measures will include three hip pain and function questionnaires (Hip dysfunction and Osteoarthritis Outcome Score, Oxford Hip Score, Lateral Hip Pain questionnaire), a global change in symptom questionnaire (using a 15-point Likert scale) and a quality of life measure (AQoL-8D questionnaire). Data will be analysed using the intention to treat principle. Discussion This study is the first randomised controlled trial to compare the effectiveness of menopausal hormone therapy therapy alone, and with the combination of exercise therapy, to treat pain and dysfunction associated with GTPS. This study has been pragmatically designed to ensure that the interventions in this study can be integrated into policy and clinical practice if found to be effective in the treatment of GTPS in post-menopausal women. If successful, there is potential for this treatment regimen to be explored in future studies of other persistent tendon conditions in the post-menopausal population. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12614001157662 Registered 31 October 2014.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree ® (USA); Ryeqo ® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain. Plain Language Summary Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree ® (USA); Ryeqo ® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

Several antiepileptic drugs have clinically significant pharmacokinetic interactions with oral contraceptives (OCs) that may result in contraceptive failure. The aim of this study was to assess the effect of zonisamide on the pharmacokinetics of the individual components of a combination OC (ethinyl estradiol [EE] 0.035 mg and norethindrone [NOR] 1 mg) and on pharmacodynamic variables that may be increased in the event of reduced contraceptive efficacy (concentrations of serum luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone). This was a single-center, open-label, 1-sequence, crossover study. Healthy, premenopausal women received the combination OC for three 28-day cycles (combination OC for 21 days, followed by placebo for 7 days). Following stabilization on the OC during the first cycle, blood was collected during cycle 2 for the determination of serum EE and NOR profiles (day 14) and serum LH, FSH, and progesterone concentrations (days 13–15). Starting on day 15 of cycle 2, zonisamide was administered orally at 100 mg/d and titrated to a target dose of 400 mg/d. EE and NOR profiles and serum LH, FSH, and progesterone concentrations were obtained again in cycle 3 (in the presence of zonisamide) and compared with those from cycle 2 (in the absence of zonisamide). Thirty-seven healthy premenopausal women (mean age, 26.1 years [range, 18–51 years]; mean body weight, 65.5 kg [range, 50.4–93.1 kg]; mean height, 165.8 cm [range, 152.4–182.9 cm]) received ≥1 dose of zonisamide. Of the 33 subjects (89.2%) who completed the study, 26 (78.8%) underwent titration to a stable zonisamide dose of 400 mg/d. For EE, the mean (SD) AUC over a 24-hour dosing interval (AUC τ) was 1139 (317) pg·h/mL in cycle 2 and 1143 (312) pg·h/mL in cycle 3; the mean C max in the respective cycles was 133 (39) and 141 (46) pg/mL. For NOR, the corresponding values were 140 (48) and 159 (46) ng·h/mL for AUC τ and 21 (5.4) and 23 (6.7) ng/mL for C max. The 90% Cls for the geometric mean ratios (cycle 3:cycle 2) for AUC τ and C max fell within the accepted range for lack of interaction (0.80–1.25). There were no increases in LH, FSH, or progesterone concentrations between cycle 2 and cycle 3. In these healthy volunteers, steady-state zonisamide dosing had no clinically significant effect on the pharmacokinetics of EE or NOR. There was no pharmacodynamic evidence that zonisamide is likely to reduce the contraceptive effectiveness of OCs containing EE and NOR.

The basis of breast cancer risk associated with hormonal therapies may lie in the regulation of cell proliferation. In a prospective, double-blind, randomized study postmenopausal women were given continuous combined hormone replacement therapy (HRT) either as estradiol valerate 2 mg/dienogest 2 mg, (E2V/DNG) or estradiol 2 mg/noretisterone acetate 1 mg (E2/NETA) for 6 months. Fine needle aspiration (FNA) biopsies were used for immunocytochemical analysis of breast cell proliferation before and during treatment. From 45 women completing the study 135 biopsies were obtained. In the total material there was a more than 4-fold increase in proliferation between baseline and 3 months (p < 0.001). The mean percentage of MIB-1 positive breast cells increased from 2.2 to 9.1%. In some individual women values were as high as 25%. No further increase was recorded at 6 months. While numerical values were somewhat lower in the E2V/DNG group, there were no significant differences between treatments. There was a positive correlation between breast cell proliferation (MIB-1%) and circulating levels of both estradiol (r(s) = 0.54, p < 0.01) and estrone (r(s) = 0.53, p < 0.01) after 3 and 6 months of treatment. No correlations with other endogenous hormones, proteins or with the two exogenous progestogens dienogest and norethisterone were observed. Increased breast cell proliferation should probably be regarded as an unwanted side-effect during HRT. Means to identify those women with the most pronounced proliferative response should be developed. The FNA biopsy technique may be a useful tool to monitor and evaluate the proliferative response to HRT in the normal breasts of postmenopausal women.

Objective To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. Methods A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17β-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. Results No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. Conclusion In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.

Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼ 24 nM for transactivation of the anti-inflammatory GILZ gene and ∼ 4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.

Background Norethisterone acetate (NETA), also known as norethindrone acetate is a progestogens medication that is widely used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders as abnormal uterine bleeding and endometriosis. There is a lack of detailed histological information regarding the effects of NETA on the uterine structure. So, the present study focuses on the uterine histological, histochemical and ultrastructure changes following the exposure to NETA in the albino rats. To do this aim, fourteen adult female albino rats were used. They were randomly divided into two equally groups: Control group and NETA treated group. Albino rats of control group were administered daily food, water and orally distilled water only, while rats of NETA treated group were administered daily orally 20 µg of NETA dissolved in 2 ml distilled water, food, and water. The experiment was continued for three weeks. Results The findings of the present work indicated that the use of NETA has negative effects on the endometrial epithelium (proliferation, autophagy and apoptosis), glands (necrotic, apoptotic or pseudosecretory glands) and stromal and myometrial reactions (granulocytes, connective tissue remodeling, apoptosis, myocytes hypertrophy). Conclusion This work revealed that NETA has desynchronized progestogenic effect on the uterine tissues of the albino rat and thereby prevent implantation and pregnancy.

Depot-medroxyprogesterone acetate (DMPA) and Norethisterone Enanthate (NET-EN) are progestin-only injectable contraceptives widely used by women in sub-Sharan Africa, where incidence of HIV-1 and HSV-2 infection remains high. Studies indicate that DMPA usage can increase the risk of HSV-2 infection, but limited data indicate no increased risk with use of NET-EN. We therefore investigated the effects of NET-EN and DMPA on susceptibility to vaginal HSV-2 infection in ovariectomized (OVX) mice and effects on immune responses, particularly in the vaginal tract (VT). OVX mice, when treated with NET-EN and infected intravaginally, had delayed genital pathology, decreased viral shedding, and extended survival compared to DMPA- or untreated OVX mice. CD4+ T cells isolated from VT showed no significant change in frequency with either contraceptive. However, DMPA significantly decreased the total number of VT CD4+ and CD8+ T cells and the number of IFN-γ producing CD4 and CD8 T cells and increased the percentage of CD4 and CD8 T cells producing TNF-α compared to untreated mice. In contrast, NET-EN significantly enhanced percentages of CD8+ T cells compared to DMPA treated mice, and frequencies of IFN-γ+ CD4 and CD8 T cells in the VT compared to untreated mice. Comparative analysis of splenic lymphocytes indicated that DMPA treatment resulted in reduction of CD4+ T cell frequency, but enhanced TNF-α+ CD4 T cells compared to untreated mice. NET-EN enhanced the frequency of CD8 T cells, as well as IFN-γ+ and TNF-α+ CD4, and IFN-γ+ CD8 T cells in the spleen compared to untreated mice. Importantly, we found DMPA treatment that significantly reduced mucin production, whereas NET-EN enhanced expression of cell-associated mucin in VT. High levels of mucin in NET-EN mice were associated with lower levels of HSV-2 virus detected in the vaginal tract. This study provides the first evidence that NET-EN treatment can delay HSV-2 infection compared to DMPA.