Norethisterone Research Articles

Breast and endometrial safety of micronised progesterone versus norethisterone acetate in menopausal hormone therapy (PROBES): study protocol of a double-blind randomised controlled trial

IntroductionData suggest that micronised progesterone (mP) in menopausal hormone therapy is safer for the breast than synthetic progestins, while protection of the endometrium appears to be less effective. However, comparative...

Continuation of the levonorgestrel-releasing intrauterine device among adolescents with endometriosis

Study ObjectiveTo estimate the 1-year continuation rate of the levonorgestrel-releasing intrauterine device (LNG-IUD) in adolescents with endometriosis, and the frequency at which additional systemic hormonal treatment (HT) is utilized. MethodsA retrospective cohort study was performed of patients aged 12 – 21 years who underwent laparoscopy for endometriosis and LNG-IUD insertion at a single tertiary care institution between 2018 and 2021. ResultsWe evaluated 224 adolescents (mean age=17.0, SD=1.8 years) who underwent LNG-IUD placement during laparoscopic evaluation for endometriosis. Stage I endometriosis was most common (84.4%), followed by stage II (13.0%). Of 221 with follow-up, 208 (94.1%) had HT added or continued post-surgery. The most common additional HT was norethindrone acetate (42.5%), followed by combined hormonal contraceptives (34.8%). The 1-year LNG-IUD continuation rate was 92.0%. There were 18 IUD removals (8%) by 1 year, and the median time to removal was 118 days (IQR=159; range 8-293). Use of additional HT was associated with a lower hazard of IUD removal within the first year of use (HR = 0.19, 95% CI: 0.06-0.56, p<0.001). ConclusionThe majority of adolescents used the LNG-IUD with additional systemic HT for endometriosis management. While overall continuation was high, adolescents who were using LNG-IUD and HT were more likely to continue LNG-IUD than those who were not utilizing additional HT.

Presurgical treatment of uterine myomas with the GnRH-antagonist relugolix in combination therapy: an observational study.

To evaluate if a preoperative medical treatment with the GnRH-antagonist relugolix in combination therapy in a series of patients with abnormal uterine bleeding associated with uterine myomas may correct the anemia before scheduled surgery for myoma-associated AUB. Thirty-one patients scheduled for surgery underwent a pre-operative three-month course with a daily oral tablet of 40mg relugolix, 1mg estradiol, and 0.5mg norethindrone acetate. Hemoglobin levels, uterine volumes, largest myoma diameter, and VAS score for dysmenorrhea, pelvic pressure and bleeding discomfort, and indication to surgery were evaluated at study enrollment and at the end of therapy. Mean hemoglobin levels increased by 25%, from 9.3 ± 1.1 to 11.6 ± 1.7g/dL after three months (p < 0.001). Uterine volume decreased from 380.7 ± 273.4 mL to 281.7 ± 198.7 mL (p < 0.001), whereas the diameter of the largest myoma decreased from 6.4 ± 2.8cm to 5.5 ± 2.2cm (p < 0.001). Four patients (13%), initially planned for a laparotomy procedure, were converted to a minimally-access procedure, whereas in eight patients (26%) surgery was avoided after medical therapy. Dysmenorrhea score improved from 4.7 ± 3.2 to 0.6 ± 1.1 (p < 0.0001). Pelvic pressure score decreased from 5.9 ± 2.1 to 3.1 ± 2.3 (p < 0.0001), whereas bleeding discomfort decreased from 7.4 ± 3.0 to 0.4 ± 1.6 (p < 0.0001). Preoperative GnRH-antagonist therapy may enhance hemoglobin levels, decrease uterine and myoma size, and alleviate symptoms, potentially enabling safe surgical procedures.

Efficacy of drugs treatment in patients with endometrial hyperplasia with or without atypia: A systematic review and network meta-analysis.

Endometrial hyperplasia (EH) is a hyperplastic endometrial lesion with irregular gland size, increased glands, and increased glandular interstitial ratio. During follow-up, some EH progressed further to endometrial cancer. It is crucial to provide timely treatment for EH and improve the overall prognosis of EH patients. We searched the PubMed, ClinicalTrials.gov., and Embase databases for studies published from their inception to March 31, 2023. The methodological quality of each study was evaluated in accordance with the Cochrane Collaboration's tool for assessing the risk of bias. The RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis statistical analysis; and the relative risk and 95% confidence interval along with the mean difference and 95% confidence interval, were used as evaluation indexes. We included 21 randomized controlled trials involving a total of 2276 women with EH, 6 studies were of high quality, and 15 were of moderate quality. The blinding of subjects and intervention providers was identified as the main source of potential bias. Six interventions were addressed in the network meta-analysis: medroxyprogesterone acetate (MPA), plus metformin, norethisterone (NET), levonorgestrel-releasing intrauterine system (LNG-IUD), megestrol acetate, and other drugs. In the direct meta-analysis, we found the probability of endometrial complete regression (CR) in the LNG-IUD group to be significantly higher than those in the NET. In the network meta-analysis, we found the probability of CR in the NET group to be significantly lower than those in the MPA and plus metformin groups, the probability of CR in the LNG-IUD group to be significantly higher than those in the NET, the probability of CR in the other drugs group to be significantly higher than those in the LNG-IUD. The NET group had the lowest incidences of endometrial complete regression, plus metformin could have a better outcome. According to the 21 randomized controlled trials included in this study, MPA is the most effective for EH endometrial outcome when applied as a single agent, while the combination of metformin can achieve a more significant effect.

Effect of ethinyl estradiol/ norethisterone acetate with and without scaling on periodontal status and high-sensitivity C-reactive protein levels in women with polycystic ovarian syndrome having gingivitis: a randomized controlled trial.

Combined oral contraceptives are used for the management of hyperandrogenism and menstrual abnormalities in polycystic ovarian syndrome (PCOS). There is a dearth of literature addressing the effect of ethinyl estradiol/norethisterone acetate (EE/NETA) on gingival and systemic inflammation in these patients. This randomized trial aims to evaluate the effect of EE/NETA with and without scaling on periodontium and high sensitivity C-reactive protein (hsCRP) levels in women with PCOS having gingivitis. Women having PCOS along with gingivitis were randomly divided into two groups: Test Group (TG, n=30) received EE/NETA + scaling with oral hygiene instructions (OHI) and Control Group 1 (CG1, n=30) received EE/NETA + OHI. Another Control Group (CG2, n=30) consisting of systemically healthy females having gingivitis and who were age and BMI matched with the test group participants received scaling along with OHI. Periodontal and anthropometric parameters were measured at baseline, 3 months and 6 months follow-up. Serum hsCRP levels were also estimated. Serum hsCRP levels and periodontal parameters were significantly decreased in all the groups after 6 months (p≤0.05). The decrease in hsCRP levels was similar among the groups (p>0.05). Significantly more reduction in gingival inflammation was observed in TG compared to CG1 (p≤0.05). EE/NETA used alone and with scaling showed no detrimental effect on gingiva and could reduce systemic and gingival inflammation in women with PCOS having gingivitis.

The effect of Norethisterone acetate on the uterus of albino rats: histological, histochemical and ultrastructure study

BackgroundNorethisterone 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.ResultsThe 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).ConclusionThis work revealed that NETA has desynchronized progestogenic effect on the uterine tissues of the albino rat and thereby prevent implantation and pregnancy.

The efficacy of levonorgestrel intrauterine device, medroxyprogesterone acetate, and norethisterone acetate in the treatment of endometrial hyperplasia without atypia

Objectives: Pregestational treatments, which trigger apoptosis and suppress endometrium, are the gold standard therapy for endometrial hyperplasia without atypia. The levonorgestrel-intrauterine device is the first choice in current guidelines due to its low dose. Still, oral progestins have no clear evidence due to their lower regression rates and side effects. Here, we aimed to compare the regression rates, hysterectomy requirement, and the occurrence of side effects in the sixth month between the levonorgestrel-intrauterine device, norethisterone acetate, and medroxyprogesterone acetate treatment. Methods: A total of 60 patients were included. The study group was divided into three groups: levonorgestrel-intrauterine device group (n=20), norethisterone acetate group (n=20), and medroxyprogesterone acetate group (n=20). Demographic findings, body mass index, gravida, parity, comorbid diseases, regression, hysterectomy requirement, patient desire to continue treatment, and side effects such as amenorrhea, headache, weight gain, intermenstrual spotting, nausea, and breast tenderness were compared between three groups. Results: There was no statistically significant difference between the three groups regarding headache, weight gain, intermenstrual spotting, and breast tenderness. Regression rates were significantly higher in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.044) and norethisterone acetate group (p=0.020). Similarly, hysterectomy rates were significantly lower in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.031) and norethisterone acetate group (p=0.028). Amenorrhea was significantly more common in the levonorgestrel intrauterine device group than in other groups (p=0.020 for both), whereas nausea was rarer in the levonorgestrel intrauterine device group (p=0.047 for both). According to the patient’s satisfaction, the levonorgestrel intrauterine device was the most satisfactory treatment compared to medroxyprogesterone acetate and norethisterone acetate (p=0.028 and p=0.031). No significant difference was found between the medroxyprogesterone acetate and norethisterone acetate groups in terms of regression rates, hysterectomy requirements, amenorrhea, nausea, and patient satisfaction. Conclusion: Considering low hysterectomy requirement, high regression rates, and patient satisfaction, the levonorgestrel intrauterine device should be the first choice for endometrial hyperplasia without atypia as compared to oral progestins. Thus, patients must be informed about side effects and offered levonorgestrel intrauterine devices before oral progestins for endometrial hyperplasia without atypia.

Effect of norethisterone dose and duration in the management of abnormal uterine bleeding: a narrative review and case report.

Abnormal uterine bleeding (AUB) is an acute/chronic variation in the normal menstrual cycle that affects adolescents, women of reproductive age and perimenopausal women. AUB affects approximately 3-30% of reproductive-aged women worldwide, and reduces their quality of life and productivity whilst increasing the overall healthcare burden. Its management requires thorough medical evaluation and individualized treatment. Depending on the severity and cause of AUB, its treatment ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Although hormonal therapy is the preferred first-line measure in AUB, the available pharmacological options have various adverse effects. There exists a need for safer and more efficient treatment regimens with high patient compliance to effectively treat AUB. Norethisterone, also known as norethindrone, is a widely used synthetic analogue of progestogen. Controlled release formulations of norethisterone/ norethisterone acetate help maintain constant drug levels in the blood and exert minimal side-effects; therefore, they are promising therapeutic agents for effective AUB management. The present review summarizes the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of norethisterone/ norethisterone acetate in AUB management. We also report a case of AUB in a 40-year-old woman, who was treated with NETA tablets. The treatment resulted in favourable outcomes, and patient satisfaction.

P-308 Relugolix combination therapy vs relugolix monotherapy with transition to relugolix combination therapy for the treatment of endometriosis-associated pain: implications for cumulative benefit/risk profile

Abstract Study question How does the benefit/risk profile compare in women with endometriosis-associated pain who initiated relugolix combination therapy (Relugolix-CT) vs relugolix monotherapy with transition to Relugolix-CT? Summary answer Initiation with Relugolix-CT showed a more favourable benefit/risk profile than relugolix monotherapy: similar efficacy, lower rate of vasomotor symptoms and clinically significant bone loss. What is known already Treatment of endometriosis with a gonadotropin-releasing hormone antagonist monotherapy may be associated with vasomotor symptoms (e.g. hot flushes) and bone mineral density (BMD) loss. Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg) was developed to minimise these hypoestrogenic adverse effects. In the pivotal SPIRIT 1 and 2 studies and long-term extension (LTE), once-daily Relugolix-CT demonstrated improved dysmenorrhoea early in treatment that was sustained for the duration of therapy over 104 weeks, with BMD loss &amp;lt;1%. This analysis evaluates the benefit of initiation with Relugolix-CT vs relugolix monotherapy and transition to Relugolix-CT on the 104-week benefit/risk profile. Study design, size, duration In the 24-week SPIRIT 1 and 2 studies, premenopausal women with endometriosis and moderate-to-severe pain at baseline were randomised 1:1:1 to placebo, Relugolix-CT, or delayed Relugolix-CT (relugolix 40 mg monotherapy then Relugolix-CT; 12 weeks each). Study completers were eligible to enrol in the open-label, 80-week LTE study where all women received once-daily Relugolix-CT. Efficacy and safety data over 104 weeks from the SPIRIT studies were assessed in this ad hoc analysis. Participants/materials, setting, methods Efficacy and safety were analysed as cumulative proportions, evaluating time to benefit and time to harm. Time to benefit was defined as median time to minimal-to-no dysmenorrhoea (Numerical Rating Scale score ≤1), time to harm as time to first vasomotor symptoms (hyperhidrosis, feeling hot, hot flush, night sweats and flushing), and time to lumbar spine BMD loss from baseline to &amp;gt; 3% among those meeting protocol-specified BMD criteria. Median time was not estimable for safety. Main results and the role of chance In total, 1251 women were treated in the SPIRIT 1 and 2 studies. Of 418 and 417 women in the Relugolix-CT and delayed Relugolix-CT groups, time to minimal-to-no dysmenorrhoea was 8 weeks in 56.3% and 75.7% of women, respectively, increasing to 82.5% and 86.4% at Week 24, 94.5% and 95.9% at Week 52, and 95.3% and 95.9% at Week 104. In both groups, median time to minimal/no dysmenorrhea-associated pain occurred within two menstrual cycles. Cumulative proportion of patients with first vasomotor symptoms in the Relugolix-CT and delayed Relugolix-CT groups was 4.1% and 16.8%, respectively, at Week 4, 13.5% and 35.3% at Week 24, 16.4% and 38.3% at Week 52, and 16.8% and 38.8% at Week 104. Cumulative proportion of patients with first BMD loss &amp;gt;3% in the Relugolix-CT and delayed Relugolix-CT groups was 1.1% and 5.9%, respectively, at Week 12, 10.2% and 23.5% at Week 24, 15.5% and 29.4% at Week 52, and 21.5% and 32.1% at Week 104. Given similar time to pain improvement with higher risk of vasomotor symptoms or clinically significant BMD loss with delayed Relugolix-CT treatment, these findings support the benefit of initiation of Relugolix-CT to mitigate hypoestrogenic adverse events. Limitations, reasons for caution The 80-week, open-label SPIRIT LTE did not have a control group. This evaluation was an ad hoc investigation of SPIRIT data and was not part of the prespecified statistical analysis plan. Comparisons between groups were qualitative, and no statistical inferences were generated. Wider implications of the findings Although Relugolix-CT and relugolix monotherapy showed similar efficacy benefit, monotherapy was associated with a higher risk of vasomotor symptoms and clinically significant BMD loss. The more favourable Relugolix-CT benefit/risk profile vs monotherapy helps fulfil an unmet need for long-term, effective, and well-tolerated hormonal treatment of symptoms of endometriosis. Trial registration number SPIRIT 1 (ClinicalTrials.gov: NCT03204318; EudraCT: 2017–001588–19); SPIRIT 2 (NCT03204331; 2017–001632–19); SPIRIT LTE (NCT03654274; 2017-004066-10)

Impact of relugolix combination therapy on functioning and quality of life in women with endometriosis-associated pain

To evaluate the effect of relugolix combination therapy (relugolix CT; 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) for up to 2 years in the SPIRIT long-term extension study on functioning and health-related quality of life (QoL), using the Endometriosis Health Profile (EHP)-30 questionnaire, and assess how changes in QoL domains correlated with improvements in dysmenorrhea as well as nonmenstrual pelvic pain (NMPP). Long-term extension study of the SPIRIT phase 3 trials. Clinics and University Hospitals. Premenopausal women with moderate-to-severe endometriosis pain who previously completed the randomized SPIRIT trials were eligible to enroll in an 80-week long-term extension where all women received relugolix CT. Relugolix CT (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg). Least squares (LS) mean changes in the EHP-30 domain and total scores from baseline (pivotal) were analyzed using a mixed-effects model. Results up to 104 weeks are reported by a pivotal trial treatment group with a focus on the relugolix CT group (i.e., relugolix CT or placebo for 24 weeks, or delayed relugolix CT [relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks]). In addition, the relationships between changes in dysmenorrhea and NMPP as well as changes in EHP-30 scores were assessed. In the 277 women treated with relugolix CT, LS mean EHP-30 pain domain scores improved by 57.8% (LS mean change: -32.8; 95% CI: -35.5, -30.1), 66.4% (LS mean change: -37.7; 95% CI: -40.3, -35.0), and 72.2% (LS mean change: -41.3; 95% CI: -43.9, -38.7) at weeks 24, 52, and 104, respectively. The proportions of women with clinically meaningful improvement in the EHP-30 pain domain were 75.9%, 83.6%, and 88.6% at weeks 24, 52, and 104, respectively. Non-pain EHP-30 domain and total scores likewise improved. A positive correlation between changes in dysmenorrhea/NMPP and all EHP-30 domain scores was observed. Results were similar for the delayed relugolix CT and placebo → relugolix CT groups. Sustained reduction of endometriosis-associated pain with relugolix CT observed up to 104 weeks was accompanied by improvements in functioning and health-related QoL. These findings complement the results of the pivotal SPIRIT trials, which showed that relugolix combination therapy significantly reduced dysmenorrhea, NMPP, and dyspareunia vs. placebo in premenopausal women with endometriosis-associated pain. Registration/clinicaltrials.gov identifier: SPIRIT Extension Study (NCT03654274).

Impact of demographic and clinical factors on elagolix plus add-back therapy effects on patient-reported nonbleeding symptoms in women with heavy menstrual bleeding and uterine fibroids: a post hoc analysis of data from two clinical trials

To investigate the efficacy of elagolix plus add-back therapy (estradiol [1 mg] and norethindrone acetate [0.5 mg] once daily) on patient-reported nonbleeding symptoms and menstrual bleeding associated with uterine fibroids (UFs) across different subpopulations. Post hoc analysis of two phase 3 clinical trials-Elaris UF-1 and UF-2. A total of 76 (UF-1) and 77 (UF-2) US clinical sites. Women (N = 591) with UFs and heavy menstrual bleeding. Elagolix (300 mg) twice daily with add-back therapy (the indicated dose for UF-associated heavy menstrual bleeding) vs. placebo for 6 months. "Very much improved" or "much improved" change in nonbleeding symptoms (abdominal/pelvic pain, abdominal/pelvic pressure/cramping, back pain, and abdominal bloating) and menstrual bleeding measured using a Patient Global Impression of Change scale. Improvements were assessed in subpopulations stratified using baseline characteristics (age, race [self-reported], body mass index, and International Federation of Gynecology and Obstetrics fibroid classification). Across subpopulations, differences favored elagolix plus add-back therapy (vs. placebo) for most symptoms at month 1 and all symptoms at months 3 as well as 6. In patients with characteristics commonly associated with high disease burden (age >40 years, Black/African American), those treated with elagolix plus add-back therapy reported significantly greater improvements vs. placebo at months 1-6 (P<.05) for all nonbleeding and bleeding symptoms (P≤.05). Premenopausal women with heavy menstrual bleeding and UFs receiving elagolix plus add-back therapy experienced significant improvements in nonbleeding as well as bleeding symptoms from months 1-6, regardless of baseline characteristics. NCT02654054 and NCT02691494.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial

Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200mg twice daily with 1mg estradiol/0.5mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200mg twice daily with add-back therapy, elagolix 200mg twice daily monotherapy for 6months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of-2.43% (lumbar spine),-1.54% (total hip), and-1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of-1.58% to-1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and12. Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Treatment of uterine fibroid symptoms with relugolix combination therapy

Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormonereceptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. Methods. We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss &lt;80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed.Result. A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P&lt;0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy.Conclusions. Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids.

Medical Management of Endometriosis in Adolescent and Young Adult Women: A Review of 91 Cases of Biopsy-Confirmed Endometriosis

ObjectivesTo characterise contemporary trends in the hormonal management of endometriosis in adolescent and young adult patients with biopsy-proven endometriosis. MethodsRetrospective chart review of women aged 14–25 years who underwent laparoscopy for pelvic pain with biopsy-proven endometriosis between January 2011 and September 2020 at an academic tertiary hospital system. The final sample included 91 patients with biopsy-confirmed endometriosis. ResultsCombined oral contraceptives (COCs) were the most common initial treatment (64% of patients). Progestin-only formulations (low- and high-dose norethindrone acetate) were offered to younger patients (age 15.9 ± 2.7 years) than those offered COCs (19.9 ± 3.3 years) and levonorgestrel intrauterine devices (LNG-IUDs) (21.9 ± 1.7 years). Current treatments varied widely and included COCs (32%), LNG-IUDs (18%), oral progestins (low- and high-dose norethindrone, medroxyprogesterone) (14%), elagolix (9%), and leuprolide (8%). Oral adjuncts to LNG-IUD were common: usually low- or high-dose norethindrone (37% of patients with an LNG-IUD), but also included progesterone, COCs, and elagolix. ConclusionsOral progestins, LNG-IUDs, and COCs were the mainstay of initial treatment. Subsequent treatments varied widely and included COCs, LNG-IUDs, oral progestins, elagolix, leuprolide, and combinations of these agents. We observed that most young women switched between therapies, suggesting that a personalised approach is often used to determine treatment plans among the wide range of options currently available. This study helps define the spectrum of treatment regimens for endometriosis in adolescent females.

Preparation of a sustainable magnetic sorbent for the extraction and preconcentration of progestogens in natural water samples

A film composed of agarose and graphene (G) and magnetic nanoparticles (G-MNPs) is proposed as a sorbent for the extraction and determination of medroxyprogesterone (MED), levonorgestrel (LEV), norethisterone (NOR) and progesterone (PRO) in natural water samples. Both the preparation of the film and the extraction procedure were optimized. The optimal extraction parameters were as follows: isopropyl alcohol as activation solvent, sample pH value of 3.0, extraction time of 30 min, 1.00 mL of acetonitrile as eluent, elution time of 5 min and sample volume of 100.00 mL. HPLC with photodiode array detector was used for the separation and determination. The method presented a linear range between 2.50 and 75.0 μg L−1 for all analytes, and the LODs were between 1.40 and 1.80 μg L−1. The method was applied to natural water samples, obtaining satisfactory recovery values (75–111 %). In conclusion, for the immobilization of the G-MNPs, agarose was used, which is a non-toxic, renewable and biodegradable material. The G-MNPs-agarose film was reused up to 70 times, without losing its extraction capacity significantly and presenting excellent sorbent properties, which allow the extraction and preconcentration of the progestogens under study.

A Novel Intrauterine Device for the Spatio-Temporal Release of Norethindrone Acetate as a Counter-Estrogenic Intervention in the Genitourinary Syndrome of Menopause.

The genitourinary syndrome of menopause (GSM) is a widely occurring condition affecting millions of women worldwide. The current treatment of GSM involves the use of orally or vaginally administered estrogens, often with the risk of endometrial hyperplasia. The utilization of progestogens offers a means to counteract the effects of estrogen on the endometrial tissue, decreasing unwanted side effects and improving therapeutic outcomes. In this study, a norethindrone acetate (NETA)-loaded, hollow, cylindrical, and sustained release platform has been designed, fabricated, and optimized for implantation in the uterine cavity as a counter-estrogenic intervention in the treatment of GSM. The developed system, which comprises ethyl cellulose (EC) and polycaprolactone (PCL), has been statistically optimized using a two-factor, two-level factorial design, with the mechanical properties, degradation, swelling, and in vitro drug release of NETA from the device evaluated. The morphological characteristics of the platform were further investigated through scanning electron microscopy in addition to cytocompatibility studies using NIH/3T3 cells. Results from the statistical design highlighted the platform with the highest NETA load and the EC-to-PCL ratio that exhibited favorable release and weight loss profiles. The drug release data for the optimal formulation were best fitted with the Peppas-Sahlin model, implicating both diffusion and polymer relaxation in the release mechanism, with cell viability results noting that the prepared platform demonstrated favorable cytocompatibility. The significant findings of this study firmly establish the developed platform as a promising candidate for the sustained release of NETA within the uterine cavity. This functionality serves as a counter-estrogenic intervention in the treatment of GSM, with the platform holding potential for further advanced biomedical applications.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial

ObjectiveTo evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. Study DesignWe used standard chemoluminescent assays to evaluate endogenous hormones [estradiol (E2), progesterone (P4), FSH, LH] and liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) to simultaneously analyze concentrations of ethinylestradiol (EE), dienogest (DNG), norelgestromin (NGMN), norethindrone (NET), gestodene (GSD), levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate (NES), medroxyprogesterone acetate (MPA), and drospirenone (DRSP), in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥ 80kg reporting no recent use of hormonal contraception. ResultsWe enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of a progestin [MPA (n=58, 11.2%), LNG (50, 9.6%), ENG (11, 2.1%), NET (5, 0.96%), NGMN (3, 0.06%), or DRSP (1, 0.02%)]. LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in 8 other women: ENG/MPA (1); ENG/LNG (2); MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive [MPA ≥ 0.1ng/mL, n = 19; NGMN/LNG ≥ 0.2ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4]. We detected concentrations of serum P4 ≥ 3ng/mL, indicative of luteal phase (post-ovulation) status, in an additional 194 (37.3%) samples. ConclusionsMore than one third of enrolled in our clinical trial of oral emergency contraception had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception recent use of hormonal contraception. This results would have decreased the expected risk of pregnancy in the study. ImplicationsMany participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using non-inferiority designs or historical controls.Keywords

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III.

Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to identify metabolic markers in the cerebrospinal fluid (CSF) of children with SMA types II and III. CSF samples were collected from 40 patients with SMA (27 with type II and 13 with type III) and analyzed for metabolites. We identified 135 metabolites associated with SMA types II and III. These were associated with lysine degradation and arginine, proline, and tyrosine metabolism. We identified seven metabolites associated with the Hammersmith Functional Motor Scale: 4-chlorophenylacetic acid, adb-chminaca,(+/-)-, dodecyl benzenesulfonic acid, norethindrone acetate, 4-(undecan-5-yl) benzene-1-sulfonic acid, dihydromaleimide beta-d-glucoside, and cinobufagin. Potential typing biomarkers, N-cyclohexylformamide, cinobufagin, cotinine glucuronide, N-myristoyl arginine, 4-chlorophenylacetic acid, geranic acid, 4-(undecan-5-yl) benzene, and 7,8-diamino pelargonate, showed good predictive performance. Among these, N-myristoyl arginine was unaffected by the gene phenotype. This study identified metabolic markers are promising candidate prognostic factors for SMA. We also identified the metabolic pathways associated with the severity of SMA. These assessments can help predict the outcomes of screening SMA classification biomarkers.