Norethindrone-Associated Transaminitis in Endometriosis Patients: A Case Series and Literature Review.

In this case series, we discuss 10 cases of norethindrone-induced transaminitis and conduct a literature review of this rare adverse event. A retrospective chart review was conducted on 10 patients (median age: 33 years) with diverse endometriosis phenotypes who received norethindrone and subsequently developed transaminitis, which is defined as elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. This condition was diagnosed in both asymptomatic and symptomatic patients, either during the work-up of acute symptoms or incidentally through routine lab tests. Our objective was to assess and characterize a case series of transaminitis associated with norethindrone use in endometriosis patients, detailing clinical presentations, management strategies, and outcomes. All cases exhibited normalization of liver function tests after discontinuation, occurring within one to 12 months with varying intervals of liver function testing. Patients receiving higher dosages (10 mg daily) demonstrated quicker resolution (average: four months). The reported adverse effects included nausea, vomiting, headache, rash, polyarthralgia, and abnormal uterine bleeding. Vigilant management, including prompt discontinuation, consistently resulted in the resolution of transaminitis. This study underscores the importance of continuous monitoring of liver function, even in asymptomatic patients on norethindrone therapy. Further investigations are imperative to identify specific groups susceptible to this adverse event.

Oral GnRH Antagonists in Combination with Estradiol and Norethindrone Acetate for Pain Relief Associated with Endometriosis: A Review of Evidence of a Novel Class of Hormonal Agents.

Current medical treatment options for endometriosis associated pains are inadequate. Evidence on effects of nonsteroidal anti-inflammatory drugs is scarce. Around one third of patients are not responsive to oral contraceptives or progestins due to progesterone resistance. Gonadotropin-releasing hormone (GnRH) agonists can only be used for a short duration because of associated side effects. Oral GnRH antagonists, including elagolix, relugolix, and linzagolix allow oral administration, induce dose dependent reduction of estradiol levels, do not cause initial flare up of endometriosis symptoms, and allow the fast return of ovarian function and menstruation after discontinuation. Elagolix at a low dose of 150 mg once daily, or the higher dose of 200 mg twice daily, significantly increased the proportion of women achieving clinically meaningful decline of dysmenorrhea, noncyclic pelvic pain, and dyspareunia. Relugolix at an oral dose of 40 mg/day results in improvement in different forms of endometriosis related pelvic pain, with an efficacy and side effect profile similar to that of GnRH agonists. Adding 1 mg of estradiol and 0.5 mg of norethindrone to 40 mg of relugolix (relugolix combination therapy) allows extension of treatment to 24 weeks with maintained efficacy and an improved side effect profile. Linzagolix, in a dose of 75 mg/day, can be used alone to treat endometriosis associated pain. For severe pelvic pain and dyspareunia, linzagolix can be used in a high dose of 200 mg/day with hormonal add-back therapy to preserve bone health.

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.

Effects of norethindrone on the growth, behavior, and thyroid endocrine system of adult female western mosquitofish (Gambusia affinis).

Progestins are mainly used in pharmacotherapy and animal husbandry and have received increasing attention as they are widely detected in various aquatic ecosystems. In this study, adult female western mosquitofish (Gambusia affinis) were exposed to different concentrations of norethindrone (NET) (solvent control, 5.0 (L), 50.0 (M), and 500.0 (H) ng/L) for 42 days. Behaviors, morphological parameters, histology of the thyroid, thyroid hormone levels (TSH, T3, and T4), and transcriptional levels of nine genes in the hypothalamic-pituitary-thyroid (HPT) axis were examined. The results showed that NET decreased sociality but increased the anxiety of G. affinis. Sociality makes fish tend to cluster, and anxiety may cause G. affinis to reduce exploration of new environments. Female fish showed hyperplasia, hypertrophy, and glial depletion in their thyroid follicular epithelial cells after NET treatment. The plasma levels of TSH and T4 were significantly reduced, but T3 concentrations were significantly increased in the fish from the H group. In addition, the transcripts of genes (tshb, tshr, tg, dio1, dio2, thrb) in the brains of fish in the M and H treatments were significantly stimulated, while those of trh and pax2a were suppressed. Our results suggest that NET may impact key social behaviors in G. affinis and interfere with the entire thyroid endocrine system, probably via affecting the transcriptional expression of upstream regulators in the HPT axis.

Norethindrone suppress the germ cell development via androgen receptor resulting in male bias.

Progestins are widely used and detected in surface waters, and can affect gonad development and sexual differentiation in fish. However, the toxicological mechanisms of sexual differentiation induced by progestins are not well understood. Here, we investigated the effects of norethindrone (NET) and androgen receptor (AR) antagonist flutamide (FLU) on gonadal differentiation in zebrafish from 21 dpf (days post-fertilization) to 49 dpf. The results showed that NET caused male bias, while FLU resulted in female bias at 49 dpf. The NET and FLU mixtures significantly decreased the percentage of males compared to the NET single exposure. Molecular docking analysis showed that FLU and NET had similar docking pocket and docking posture with AR resulting in competitively forming the hydrogen bond with Thr334 of AR. These results suggested that binding to AR was the molecular initiating event of sex differentiation induced by NET. Moreover, NET strongly decreased transcription of biomarker genes (dnd1, ddx4, dazl, piwil1 and nanos1) involved in germ cell development, while FLU significantly increased transcription of these target genes. There was an increase in the number of juvenile oocytes, which was consistent with the female bias in the combined groups. The bliss independence model analysis further showed that NET and FLU had antagonistic effect on transcription and histology during gonadal differentiation. Thus, NET suppressed the germ cell development via AR, resulting in male bias. Understanding the molecular initiation of sex differentiation in progestins is essential to provide a comprehensive biological basis for ecological risk assessment.

Ultrasound-Guided Diagnosis of Multiple Uterine Fibroids in a Patient With Polycystic Ovaries and Treatment With Relugolix, Estradiol, and Norethisterone Acetate.

Uterine fibroids and ovarian cysts are common gynecological conditions that, while benign, when present simultaneously with bacterial vaginosis, can present a more complicated course of management. Symptoms of uterine fibroids include menorrhagia and dysmenorrhea, while ovarian cysts may present with pelvic pain and an adnexal mass. Each condition is typically managed separately; however, they can coexist in some patients, leading to a more complex presentation. This case report presents a 35-year-old African American female patient with the simultaneous occurrence of uterine fibroids and ovarian cysts, complicated by recurrent vaginitis, along with the treatment approach. The treatment choice, relugolix, estradiol, and norethisterone (norethindrone) acetate, is the first once-daily U.S. Food and Drug Administration (FDA) combination hormonal medication approved for menorrhagia due to fibroids. This case is unique in that although the diagnoses are common, their coexistence makes for a more complex presentation, and the course of management presents a newly approved fixed-dose combination hormonal medication. This report discusses the incidence, pathophysiology, diagnosis, and management of uterine fibroids and ovarian cysts. Factors that may contribute to the concurrence of these conditions, such as genetic, hormonal, and environmental risks, are also explored. Diagnostic modalities and ultrasound techniques are reviewed, and treatment options, such as surgery and medical management, are discussed. The importance of a patient-centered approach in the treatment of multi-symptom gynecological disorders and the need to consider conservative management are emphasized.

Norethindrone dosing for adequate menstrual suppression in adolescents.

OBJECTIVES: We sought to study factors predictive of achieving menstrual suppression with norethindrone vs. norethindrone acetate in adolescents, as optimal dosing is unknown. Secondary outcomes included analyzing prescriber practices and patient satisfaction. METHODS: We performed a retrospective chart review of adolescents ages <18 years presenting to an academic medical center from 2010 to 2022. Data collected included demographics, menstrual history, and norethindrone and norethindrone acetate use. Follow-up was measured at one, three, and 12 months. Main outcome measures were starting norethindrone 0.35 mg, continuing norethindrone 0.35 mg, achieving menstrual suppression, and patient satisfaction. Analysis included Chi-square and multivariate logistic regression. RESULTS: Of 262 adolescents initiating norethindrone or norethindrone acetate, 219 completed ≥1 follow-up. Providers less often started norethindrone 0.35 mg for patients with body mass index ≥25 kg/m2, prolonged bleeding, or younger age at menarche, but more often for patients who were younger, had migraines with aura, or were at risk of venous thromboembolism. Those with prolonged bleeding or older age at menarche were less likely to continue norethindrone 0.35 mg. Obesity, heavy menstrual bleeding, and younger age were negatively associated with achieving menstrual suppression. Patients with disabilities reported greater satisfaction. CONCLUSIONS: While younger patients more often received norethindrone 0.35 mg vs. norethindrone acetate, they were less likely to achieve menstrual suppression. Patients with obesity or heavy menstrual bleeding may achieve suppression with higher doses of norethindrone acetate. These results reveal opportunities to improve norethindrone and norethindrone acetate prescribing practices for adolescent menstrual suppression.

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.

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.

Potential drug-drug interaction between warfarin and norethindrone in adolescent females: A case series.

PURPOSE: In the pediatric population, warfarin remains the recommended oral anticoagulant for valvular heart disease. Warfarin carries a risk of bleeding complications that can manifest as heavy menstrual bleeding (HMB) in postmenarchal adolescent females. As a result, these patients may be started on hormonal therapies, such as norethindrone, to suppress menstruation. SUMMARY: This case series describes a potential drug interaction between warfarin and norethindrone in 3 adolescent females with a history of mechanical mitral valve replacement who developed HMB. These patients were on stable warfarin regimens before the initiation of norethindrone and subsequently experienced increases in their international normalized ratio (INR). In response, they required an up to 50% reduction in their weekly warfarin dose over 5 to 12 weeks. CONCLUSION: These observations suggest that use of norethindrone for the management of HMB may significantly potentiate the anticoagulant effect of warfarin. Close INR monitoring and aggressive dose adjustments during initiation and discontinuation of norethindrone are recommended in patients on warfarin.

Menstrual Management Choices in Transgender and Gender Diverse Adolescents.

PURPOSE: Transgender and gender diverse patients who are assigned female at birth may request menstrual management to alleviate an increased dysphoria due to menses. The objective of this study is to describe the initiation and use over time of menstrual management methods (MMMs) in transgender and gender diverse adolescents. METHODS: A retrospective chart review was conducted of patients in a multidisciplinary pediatric gender program from March 2015 to December 2020 who were assigned female at birth, identified as transgender or gender diverse, and had achieved menarche. A descriptive statistical analysis was performed. RESULTS: Of 133 patients, 119 (90%) identified as transgender male, 11 (8%) as gender nonbinary, and 3 (2%) as another gender identity. Mean age was 15 (standard deviation 1.6) years. Only 12 (9%) patients had ever been sexually active. During the study period, 48 (36%) used gender-affirming testosterone. At the initial visit, 114 (86%) patients were not using an MMM. Of 80 patients who initiated a new MMM, 3 (4%) chose continuous oral contraceptive pills, 65 (83%) used norethindrone acetate (NETA), and 9 (11%) planned levonorgestrel intrauterine device (IUD) insertion. At 1 year, 56 patients were using NETA and 20 had an IUD in place. DISCUSSION: This study provides data on MMM choice in transgender and gender diverse adolescents using these methods almost exclusively for menstrual management and not contraception. Although few patients were using an MMM at baseline, most opted to start a method when given the opportunity. The most common methods were NETA or an levonorgestrel IUD.

Bleeding Patterns of Oral Contraceptives with a Cyclic Dosing Regimen: An Overview.

Bleeding irregularities are one of the major reasons for discontinuation of oral contraceptives (OCs), and therefore clinicians need to set expectations during consultations. In this review we provide an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP). We evaluated data from phase 3 trials (≥12 months) used to gain regulatory approval. Overall, each type of OC has its own specific bleeding pattern. These patterns however were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. However, this balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17ß-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen is associated with a higher rate of unscheduled and absence of scheduled bleeding than combined products.

Norethindrone alters growth, sex differentiation and gene expression in marine medaka (Oryzias melastigma).

Norethindrone (NET) is a widely used synthetic progestin, which appears in water environments and threatens aquatic organisms. In this study, marine medaka (Oryzias melastigma) larvae were exposed to 7.6 and 80.1 ng/L NET for 190 days. The effects of NET on growth, sex differentiation, gonad histology and transcriptional expression profiles of hypothalamic-pituitary-gonadal (HPG) axis-related genes were determined. The results showed that exposure to 80.1 ng/L NET caused an all-male marine medaka population and significantly decreased the growth of males. Exposure to 7.6 ng/L NET increased the ratio of males/females in the marine medaka population, decreased the growth of males and delayed the ovary maturation in females. However, the sperm maturation was accelerated by 7.6 or 80.1 ng/L NET. In females, the transcription levels of cytochrome P450 aromatase (cyp19a1a) and progesterone receptor (pgr) in ovaries, glucocorticoid receptor (gr) and vitellogenin (vtg) in livers were suppressed after exposure to 7.6 ng/L NET, which may cause delayed ovary maturation. In males, NET significantly decreased the transcription levels of follicle stimulating hormone ß (fshß) and Luteinizing hormone ß (lhß)in the brain, Estrogen receptor ß (erß)，gr and pgr in the liver, and vitellogenin receptor (vtgr) in the testes, while NET of 80.1 ng/L led to a significant up-regulation of steroidogenic acute regulatory protein (star) in the testes of males. These results showed that NET could influence growth, sex differentiation and gonadal maturation and significantly alter the transcriptional expression levels of HPG axis-related genes.

Elagolix treatment in women with heavy menstrual bleeding associated with uterine fibroid: a systematic review and meta-analysis.

BACKGROUND: Elagolix is effective and safe for treating menorrhagia in women with uterine fibroid. However, it is reported to be associated with hypoestrogenism that can be alleviated by adding estradiol/norethindrone acetate. This systematic review and meta-analysis aimed to determine the effectiveness of elagolix treatment in women with heavy menstrual bleeding associated with uterine fibroid by comparing: elagolix versus placebo and elagolix versus estradiol/norethindrone acetate. METHODOLOGY: The Cochrane Central Register of Controlled Trials (CENTRAL 2021, Issue 3 of 12), MEDLINE databases (1980 to December week 1, 2020), and trial registries for relevant randomized clinical trials were used. All randomized clinical trials were reviewed and evaluated. Random effects models were used to estimate the dichotomous outcomes and mean differences with 95% confidence intervals. Data for risk of bias, heterogeneity, sensitivity, reporting bias and quality of evidence were assessed. RESULTS: Four randomized controlled trials with 1949 premenopausal women from 323 locations were included. Elagolix improved menstrual blood loss of less than 80 ml (RR 4.81, 95% CI 2.45 to 9.45; four trials, 869 participants; moderate quality evidence) or more than 50% reduction from baseline (RR 4.87, 95% CI 2.55 to 9.31; four trials, 869 participants; moderate quality evidence) compared to placebo. There was no difference in menstrual blood loss of less than 80 ml (RR 1.08, 95% CI 1.00 to 1.16; five trials, 1365 participants; moderate quality evidence) or more than 50% reduction from baseline between the elagolix (RR 1.08, 95% CI 1.01 to 1.15; five trials, 1365 participants; high quality evidence) and elagolix with estradiol/norethindrone acetate. In both comparisons, elagolix has reduced the mean percentage change in uterine and fibroid volume, improved symptoms, and health-related quality of life. More patients had hot flush, and bone mineral density loss in the elagolix treatment compared to both placebo and elagolix with estradiol/norethindrone acetate. CONCLUSIONS: Elagolix appeared to be effective in reducing heavy menstrual bleeding caused by uterine fibroid and combination with estradiol/norethindrone acetate was able to alleviate the hypoestrogenism side effects in premenopausal women. Review registration PROSPERO CDR 42021233898.

Effect of the Monthly Injectable Combined Contraceptives versus Oral Contraceptive Pills on Mood.

BACKGROUND: Contraceptive agents are widely used by women of reproductive age, and resulting depression is the most common side effect of this usage. This study aimed to study the effect of monthly injectable combined contraceptives versus that of combined oral contraceptive pills (COC) on patients' mood. METHODS: A prospective cohort study was conducted on 124 females aged 18-45 years attending the Kom-Ashfeen Family Medicine Unit, El-Kalyubia, Egypt. Participants were divided into three groups according to their choice: group A included 44 participants who received monthly combined injectable contraceptives (CIC); group B included 40 participants who took COC; and group C included 40 participants who used the copper intrauterine device (IUD). The Patient Health Questionnaire-9 (PHQ-9) score was assessed at the beginning of the study and after 6 months of follow-up. RESULTS: After 6 months of follow-up, there were mild but statistically significant increases in the PHQ-9 score in groups A and B, with group A (CIC users) showing the highest increase. Approximately 34.1%, 27.5%, and 15% of CIC, COC, and IUD users, respectively, moved from the non-depression stage to mild depression after 6 months; this change was statistically significant in groups A and B only. CONCLUSION: Monthly injectable combined contraceptives and oral contraceptive pills were associated with an increased risk of developing mild depression; this risk was higher in users of CICs, although the difference was not statistically significant. Thus, it is crucial to counsel patients about this possible risk and to follow them up. However, further studies are required to confirm our results.

Nonhormonal therapy for endometriosis: a randomized, placebo-controlled, pilot study of cabergoline versus norethindrone acetate.

OBJECTIVE: To estimate the efficacy and safety of a novel nonhormonal therapeutic agent, cabergoline, compared with that of the standard clinical therapy, norethindrone acetate (NETA), for the treatment of endometriosis-associated pain in young women with endometriosis. DESIGN: Randomized, double-blind, placebo-controlled pilot study. SETTING: Tertiary care center. PATIENTS: Women (n = 9) with surgically confirmed endometriosis. INTERVENTIONS: A random, double-blind assignment to either NETA (5 mg/day) + placebo twice weekly or cabergoline (0.5 mg) twice weekly + placebo daily for 6 months. MAIN OUTCOME MEASURES: We collected the measures of pelvic pain and laboratory parameters every 3 months. RESULTS: We observed a decrease in pain scores and increase in pain relief in women randomized to receive cabergoline, who appeared to show similar or more improvements than women treated with NETA. The serum measures of vascular endothelial growth factor receptor 1 declined over 6 months in those who received cabergoline. Cabergoline was well tolerated, and no serious adverse events occurred. CONCLUSIONS: Safe, effective adjunct treatments are lacking for patients with endometriosis who do not respond to standard care. Because the growth of endometriosis requires angiogenesis, blood vessel growth is an attractive therapeutic target. This pilot study suggests that cabergoline, a vascular endothelial growth factor pathway inhibitor, is an effective therapeutic option for women with chronic pain due to endometriosis. Building upon this investigation, we will conduct larger, randomized trials of cabergoline, advancing research on the best treatments for endometriosis-particularly disease resistant to hormonal therapies. CLINICAL TRIAL REGISTRATION NUMBER: clinicaltrials.gov; registration number NCT02542410.