Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

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.

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.

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) 300/1/0.5 mg as the morning dose and an elagolix 300 mg 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 (300 mg/1 mg/0.5 mg) 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.

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

STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 13 June 2019.

Effects of injectable contraception with depot medroxyprogesterone acetate or norethisterone enanthate on estradiol levels and menstrual, psychological and behavioral measures relevant to HIV risk: The WHICH randomized trial.

BACKGROUND: Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels. METHODS: This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n = 262) or NET-EN 200 mg intramuscular 8-weekly (n = 259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W). RESULTS: At 25W, median 17ß estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n = 222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n = 225), with no statistical difference between the two methods (p = 0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured. CONCLUSIONS: Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question. TRIAL REGISTRATION: PACTR 202009758229976.

Progestins as a Contributing Factor to Hepatocellular Adenoma: A Case Series and Literature Review.

STUDY OBJECTIVE: To explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA) METHODS: We describe 3 cases of adolescents and young adults who developed HA while on norethindrone (NET), as well as their management. In addition, we provide a comprehensive literature review on the association between progestins and HA. RESULTS: Since 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on NET and 5 on a prodrug of NET (4 on norethindrone acetate [NETA] and 1 on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: 4 experienced a size reduction, and 3 had complete resolution of their HA. Among our patients, 1 ceased NET and instead had a levonorgestrel intrauterine device inserted, and another swapped from NET to oral medroxyprogesterone acetate. Both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. CONCLUSION: These cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared with the levonorgestrel intrauterine device. There are no case reports relating to other forms of progestins, such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities.

Efficacy of estrogen-progestogen therapy for women with vascular retained products of conception following miscarriage or abortion.

OBJECTIVE: To assess the clinical characteristics and endocrinological background of women with vascular retained products of conception (RPOC) after miscarriage or abortion and evaluate the effect of estrogen-progestogen therapy (EPT) as an initial treatment on this population based on their endocrinological background. MATERIALS AND METHODS: Women with vascular RPOC after miscarriage or abortion at less than 20 weeks of pregnancy who were given EPT (conjugated estrogen and norethisterone) were retrospectively reviewed. Their clinical characteristics, hormonal parameters, ultrasonographic findings, and outcomes were evaluated. RESULTS: Of 35 women with vascular RPOC, 30 (86%) presented with vaginal bleeding at a visit, and 6 (17%) required inpatient management due to heavy bleeding. Among women who presented with vaginal bleeding, serum progesterone levels were significantly lower (0.25 vs. 6.5 ng/mL, p = 0.004) than those in women who did not present with vaginal bleeding. There were no differences in serum hCG levels (10.5 vs. 3.1 mIU/mL) or serum estradiol levels (65.4 vs. 162.3 pg/mL). After withdrawal bleeding following the first course of EPT, vaginal bleeding was stopped in 27 of the 30 women (90%), and 23 (66%) of all women had a thin and linear endometrium. All women could be treated by up to two courses of EPT and did not require additional interventions. The median duration to hCG normalization after the initial EPT was 24.5 (9-88) days. CONCLUSION: Women with vascular RPOC who have no bleeding had significantly higher levels of serum progesterone, indicating that administration of progestogen may have an effect on hemostasis. Endometrial bleeding can be prevented or stopped, and retained tissues can be conservatively expelled by oral administration of EPT, including norethisterone, in women with vascular RPOC.

In vitro chemo-preventive efficacy of synthetic progestin Norethindrone in human epithelial ovarian cancer.

Progestin-only based oral contraceptives are majorly used as 'minipill' to prevent unintended pregnancy and treat conditions like polycystic ovary syndrome, hirsutism, and acne. However, the dearth of literature has constrained our comprehension of the exogenous progestin in relation to ovarian cancer progression. Therefore, the aim of the present study was to evaluate the chemo-preventive potential of synthetic progestin Norethindrone (NET) in epithelial ovarian cancer in vitro. Briefly, SKOV3 cells were treated with 1, 10 and 100 µM concentrations of NET for seven days period. The assays for cell viability, wound-healing, cell cycle progression, detection of reactive oxygen species (ROS) and apoptosis were executed to illustrate the protective role of NET. To further clarify the underlying process, quantitative analysis of mRNA levels of oncogenes linked to angiogenesis, inflammation, proliferation, and metastasis (VEGF, HIF-1α, COX-2, and PGRMC1) and tumour suppressor (TP53) genes was conducted. Our study revealed that NET treatment significantly reduced SKOV3 cell growth by inducing cell cycle arrest at G2/M phase, elevating ROS levels, triggering cell death via apoptosis and necrosis, and inhibiting cell migration in a dose-dependent manner. Notably, NET also upregulated TP53 expression while concurrently downregulating VEGF, HIF-1α, COX-2, and PGRMC1 expression. Our results demonstrated that the chemo-preventive effect of Norethindrone may originate from the interaction of genes which exert a protective effect against ovarian carcinogenesis. The current findings also support further investigation, which may lead to changes in prescription practices or health-related advice for women.

A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women.

BACKGROUND AND OBJECTIVE: Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20-50 pg/mL range to minimize these undesirable effects. METHODS: This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. RESULTS: Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated. CONCLUSIONS: Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.

Dienogest versus norethisterone acetate in management of endometrial hyperplasia without atypia.

OBJECTIVES: To compare the effectiveness of dienogest (DIE) and norethisterone acetate (NETA) regimens in the treatment of endometrial hyperplasia (EH) without atypia. METHODS: Participants were premenopausal women with irregular uterine bleeding, and endometrial hyperplasia without atypia on endometrial biopsy. Enrolled patients were randomly allocated into two groups: group I got DIE 2 mg/day (orally Visanne) for 14 days (10th to the 25th day of cycle) while group II received between the 16th and 25th day of the cycle, norethisterone acetate (NETA) 15 mg/d (orally Primolut Nor) was administered for 10 days. Both groups continued the therapy for six months. RESULTS: The DIE group showed a higher resolution (32.7%) and regression (57.7%) than NETA group (31% & 37.9%, respectively) with significant regression (p = 0.039). No progression in DIE group while four (6.9%) women in NETA group were recorded a progression to complex type without a significance. Also, NETA group showed a significant persistence rate (22.5%) than DIE group (3.8%) (p = 0.005). Also number in NETA group managed by hysterectomy with significant difference (p = 0.042). CONCLUSION: If used as first-line treatment, Dienogest produces a better rate of regression and a lower incidence of hysterectomy than Norethisterone Acetate does when used in EH without atypia.

Oral Gonadotropin-Releasing Hormone Antagonists for the Treatment of Uterine Leiomyomas.

Uterine leiomyomas are common hormone-responsive neoplasms that frequently cause heavy menstrual bleeding, anemia, pelvic pressure, pain, and adverse reproductive outcomes. In this overview, the efficacy and safety of oral gonadotropin-releasing hormone (GnRH) antagonists, co-administered with menopausal replacement-level steroid hormones or used at doses to avoid complete hypothalamic suppression, are reviewed for the management of uterine leiomyomas. Oral GnRH antagonists provide rapid suppression of sex steroids and avoid the initial steroidal flare and resultant temporary worsening of symptoms typically seen with parenteral GnRH agonists. Oral GnRH antagonists are effective in reducing leiomyoma-associated heavy menstrual bleeding, with high rates of amenorrhea and improved anemia and leiomyoma-associated pain, and providing modest reduction in uterine volume when used in combination with menopausal replacement-level steroid hormones. This add-back therapy can reduce hypogonadal side effects, including hot flushes and bone mineral density loss, close to levels seen with placebo therapy. Currently, both elagolix 300 mg twice daily with once-daily estradiol (1 mg) and norethindrone (0.5 mg) and relugolix 40 mg once daily with estradiol (1 mg) and norethindrone (0.5 mg) combination therapy are approved for leiomyoma treatment by the U.S. Food and Drug Administration. Linzagolix is under investigation in the United States but approved at two does with and without steroid hormones in the European Union. The efficacy of these agents appears to be robust over a wide spectrum of clinical presentations, demonstrating that worse disease parameters at baseline do not appear to inhibit efficacy. Across clinical trials, participants largely reflected the population of individuals affected by uterine leiomyomas.

Efficacy and safety of ultra-low-dose estradiol and norethisterone in postmenopausal Brazilian women.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of oral ultra-low-dose continuous combination of 17ß-estradiol (17ß-E2) and norethisterone acetate (NETA) in postmenopausal Brazilian women. METHODS: Postmenopausal women (age 45-60 years) with amenorrhea >12 months and intact uterus, with moderate to severe vasomotor symptoms, were included. The vasomotor symptoms and endometrial bleeding were evaluated by a daily diary for 24 weeks, and the women were assessed at baseline and endpoint. RESULTS: A total of 118 women were included. The group treated with 0.5 mg 17ß-E2/0.1 mg NETA (n = 58) showed a percentage reduction of 77.1% in the frequency of vasomotor symptoms versus 49.9% in the placebo group (n = 60) (p = 0.0001). The severity score showed a reduction in the treatment group when compared to the placebo (p < 0.0001). The adverse events were comparable between the groups; however, in the 0.5 mg 17ß-E2/0.1 mg NETA group there were more complaints of vaginal bleeding; despite that, in most cycles in both treatment groups, more than 80% of women experienced amenorrhea. CONCLUSIONS: The combination of 0.5 mg 17ß-E2/0.1 mg NETA in a continuous combination regimen was shown to be effective in reducing the frequency and severity of vasomotor symptoms in Brazilian postmenopausal women.

The effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a), atherogenic and anti-atherogenic apolipoproteins levels in postmenopausal women: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: The administration of 17ß-estradiol plus norethisterone acetate seems to confer women cardioprotection, however, its impact on lipoprotein (a) and apolipoproteins' concentrations remains unclear. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a) and apolipoproteins' values in females. METHODS: We systematically searched four databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) to identify relevant publications published until March 9th, 2022. No language restrictions were applied. The random-effects model (the DerSimonian and Laird methods) was employed to calculate the weighted mean difference (WMD). RESULTS: The administration of 17ß-estradiol plus norethisterone acetate resulted in a significant decrease of lipoprotein (a) (WMD: -67.59 mg/L, 95 % CI: -106.39 to -28.80; P < 0.001) and apolipoprotein B concentrations (WMD: -3.71 mg/dL, 95 % CI: -6.68 to -0.75; P = 0.014), respectively. No effect of 17ß-estradiol plus norethisterone acetate on apolipoprotein AI (WMD: 0.23 mg/dL, 95 % CI: -3.99 to 4.46; P = 0.91) or AII (WMD: 0.21 mg/dL, 95 % CI: -2.24 to 2.68; P = 0.86) concentrations was detected. In the stratified analysis, there was a notable reduction in lipoprotein (a) levels in the RCTs with a duration of ≥6 months (WMD: -73.34 mg/L), in postmenopausal women with a BMI ≥25 kg/m2 (WMD: -69.85 mg/L) and in postmenopausal women aged ˂60 years (WMD: -61.93 mg/L). CONCLUSION: The present meta-analysis of RCTs demonstrates that 17ß-estradiol plus norethisterone acetate treatment reduces lipoprotein (a) and apolipoprotein B levels in postmenopausal women.

Fostemsavir and ethinyl estradiol drug interaction: Clinical recommendations for co-administration.

OBJECTIVES: Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies. METHODS: Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration. RESULTS: Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect. CONCLUSIONS: Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 µg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected.

Relugolix/Estradiol/Norethisterone (Norethindrone) Acetate: A Review in Symptomatic Uterine Fibroids.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate (Ryeqo®; Myfembree®) has been approved for the management of heavy menstrual bleeding associated with uterine fibroids in the USA and management of moderate to severe symptoms of uterine fibroids in the EU. Relugolix is a gonadotropin releasing hormone (GnRH) receptor antagonist that decreases serum estradiol and progesterone concentrations to postmenopausal levels. The addition of estradiol/norethisterone acetate to relugolix ameliorates relugolix-induced bone loss and hot flush. In the two phase 3 LIBERTY trials, relugolix + estradiol/norethisterone substantially decreased menstrual bleeding and improved a range of other uterine fibroid symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated, with vasomotor symptoms being the most common adverse reaction. Treatment with this combination for over up to 2 years did not induce a clinically meaningful bone loss in the majority of women. Relugolix/estradiol/norethisterone acetate, with its convenient once-daily administration, is a useful addition to current pharmacological treatment options for premenopausal women with symptomatic uterine fibroids.

Uterine fibroids are a common type of noncancerous tumours that grow in the uterus. In some women, these tumours cause debilitating symptoms, such as heavy menstrual bleeding, pelvic pain and passing of blood clots. Hysterectomy is the only definitive treatment for this condition, but is associated with some disadvantages. Less invasive procedures and medical treatments are now available to treat these symptoms. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone acetate (Ryeqo^®; Myfembree^®) has been approved to treat symptoms of uterine fibroids. This combination works by suppressing ovarian hormone levels. In clinical trials, relugolix + estradiol/norethisterone substantially reduced menstrual bleeding and improved several other symptoms in women with uterine fibroids-associated heavy menstrual bleeding. The combination was generally well tolerated and had a minimal impact on bone loss, a known adverse effect of such therapies. With its convenient once-daily administration, relugolix/estradiol/norethisterone acetate is a useful addition to current medical treatment options for premenopausal women with symptomatic uterine fibroids.

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.

Efficacy of Low-Dose Estrogen-Progestins and Progestins in Japanese Women with Dysmenorrhea: A Systematic Review and Network Meta-analysis.

INTRODUCTION: Although several studies suggest beneficial effects of low-dose estrogen-progestins (LEPs) and progestins on dysmenorrhea in Japanese women, the difference in efficacy between drugs remains unknown. METHODS: We identified studies by searching the MEDLINE, Cochrane Library, and ICHUSHI databases and included randomized controlled trials (RCTs) that used total dysmenorrhea score and visual analogue scale (VAS) as outcome measures to evaluate LEPs and progestins for primary and secondary dysmenorrhea. We analyzed results by meta-analysis and network meta-analysis (NMA). RESULTS: We identified 10 articles on eight RCTs and included seven drugs (six LEPs and one progestin, i.e., dienogest) and placebo in the analysis. Meta-analysis showed improvements in total dysmenorrhea score and VAS for almost all drugs compared with placebo. In NMA, VAS in secondary dysmenorrhea improved more with dienogest than with norethisterone/ethinylestradiol (mean difference - 25.84 [95% CrI - 44.46 to - 7.15]). In the comparison of administration regimens, VAS improved more with progestin-continuous than LEP-cyclic and the surface under the cumulative ranking (SUCRA) of LEP-extended and progestin-continuous appeared to be higher than that of LEP-cyclic. CONCLUSIONS: We confirmed that LEPs and dienogest are effective for primary and secondary dysmenorrhea and suggest that continuous regimens may be more effective than cyclic regimens in improving outcomes.

Association of Progestogens and Venous Thromboembolism Among Women of Reproductive Age.

OBJECTIVE: To evaluate associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age. METHODS: This nested matched case-control study identified women aged 15-49 years from January 1, 2010, through October 8, 2018, in the IBM MarketScan databases, a nationwide sample of private insurance claims in the United States. After exclusions, 21,405 women with incident acute VTE (case group), identified by diagnosis codes, were matched 1:5 by year of birth and index date through risk set sampling to 107,025 women without prior VTE (control group). From lowest to highest systemic dose based on a modified hierarchy, progestogens studied were levonorgestrel-releasing intrauterine device (LNG-IUD), oral norethindrone, etonogestrel implant, oral progesterone, oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate (DMPA). Conditional logistic regression models adjusted for 16 VTE risk factors were used to estimate odds ratios and 99% CIs for incident acute VTE associated with current progestogen use compared with nonuse. The primary analysis treated each progestogen as a binary exposure. Dose, which varied for oral formulations, and chronicity were explored separately. Significance was set at P <.01 to allow for multiple comparisons. RESULTS: Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with nonuse (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96-4.59; DMPA: aOR 2.37, 99% CI 1.95-2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41-2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone). Sensitivity analyses that assessed misclassification bias supported the primary findings. CONCLUSION: Among reproductive-aged women using one of seven progestogens, only use of norethindrone acetate and medroxyprogesterone acetate-considered higher-dose progestogens-was significantly associated with increased odds of incident acute VTE. The roles of progestogen type, dose, and indication for use warrant further study.

Differential off-target glucocorticoid activity of progestins used in endocrine therapy.

The glucocorticoid receptor (GR) regulates transcription of genes involved in multiple processes. Medroxyprogesterone acetate (MPA), widely used in the injectable contraceptive Depo-MPA (DMPA), has off-target effects via the GR, which may result in side-effects in endocrine therapy. However, very little is known about the GR activity of other progestins used in endocrine therapy. This study compared GR activities for several progestins, using whole cell binding, dose-response, and GR phosphorylation assays, in both a cell line model and peripheral blood mononuclear cells (PBMCs). MPA, etonogestrel (ETG) and nestorone (NES) exhibit greater relative binding affinities for the GR than levonorgestrel (LNG) and norethisterone/norethindrone (NET) and are partial GR agonists for transactivation but agonists for transrepression on synthetic promoters in COS-1 cells. MPA is a potent agonist for endogenous GR-regulated GILZ and IL6 genes in PBMCs. While ETG and NES also display agonist activity on IL6, they have little effect on GILZ. In contrast, LNG and NET exhibit little to no activity in transactivation models, while both exhibit some transrepressive activity but are generally less potent and/or efficacious than MPA. Antagonist and phosphorylation assays confirmed that MPA and NES act via the GR on endogenous genes in PBMCs. Our results suggest GR-mediated dose-dependent and gene-specific transcriptional side-effects are likely to occur at physiologically relevant concentrations in vivo for MPA, may possibly occur selectively for ETG and NES, but are unlikely to occur for LNG and NET. This suggests that these progestins will exhibit differential side-effects in endocrine therapy via the GR.

Risk of breast cancer with HRT depends on therapy type and duration.

The studyVinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ 2020;371:m3873. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/risk-of-breast-cancer-with-hrt-depends-therapy-type-and-duration/.