Venous Thromboembolism Risk Associated With Relugolix-estradiol-norethisterone Acetate Combination Therapy

The inclusion of E2 and NETA in the fixed-dose combination therapy with relugolix raises concerns about thrombotic risk due to their effects on the coagulation cascade, making VTE a key focus of safety evaluations [ 33 , 38 ]. Theoretically, the presence of E2 and NETA may induce changes in SHBG levels and coagulation proteins. The association of relugolix-CT achieves systemic E2 levels of 20 to 60 pg/mL, mimicking the early follicular phase of the menstrual cycle. This physiological range minimizes the hypoestrogenic side effects of relugolix monotherapy, such as vasomotor symptoms and BMD loss, while maintaining an effective therapeutic response. E2 plays a critical role in modulating the balance between coagulation and fibrinolysis. Even at the low levels achieved with relugolix-CT, E2 could increase hepatic synthesis of procoagulant factors such as fibrinogen and factors VII, VIII, IX, and X, while reducing fibrinolysis by elevating plasminogen activator inhibitor-1 levels. Although the E2 concentration in relugolix-CT is significantly lower than that used in traditional COCs and in some menopausal replacement therapies, these mechanisms may still result in a slight prothrombotic shift [ 31 ]. Additionally, NETA undergoes partial hepatic metabolism into EE, a potent synthetic estrogen ( Fig. 1 ), although the systemic exposure to EE from NETA metabolism is relatively low; ie, 500 µg of NETA could theoretically result in circulating levels of EE similar to an oral intake of 3 µg of EE [ 39 ]. In a phase 1 study, circulating levels of EE following the intake of relugolix-CT at the approved dose showed no measurable levels of circulating EE (ie, the levels were below the limit of quantitation of the assay, 2.5 pg/mL) [ 6 ]. Therefore, the transformation of NETA into EE in the relugolix-CT is not expected to influence the total estrogenicity of the association. In addition, the association of E2 and NETA with relugolix, which decreases endogenous E2 levels, makes the final estrogenicity of the association less important than a corresponding combination of E2 and NETA without relugolix ( Fig. 2 ). Metabolic pathway of norethisterone derivatives and their conversion to ethinylestradiol. This diagram illustrates the biosynthetic and metabolic transformations of 19-nortestosterone-derived progestins. NETA, highlighted in blue, is a widely used progestogen in hormonal therapies including in association with relugolix and estradiol. It undergoes partial hepatic conversion to EE, highlighted in red, a potent synthetic estrogen. The 500 µg NETA contained in the relugolix-CT association could theoretically correspond to an intake of 3 µg of EE [ 39 ]. Nevertheless, in a phase-1 study with relugolix-CT, circulating EE levels were below 2.5 pg/mL, which does not support a clinically significant impact on the total estrogenicity [ 6 ]. Reproduced from Shoupe et al [ 57 ]. Abbreviations: EE, ethinylestradiol; NETA, norethisterone acetate; relugolix-CT, relugolix combined therapy. Gradient of total estrogenicity of various hormonal combinations used in contraception and hormone therapy. This figure schematically integrates the procoagulant and anticoagulant pathways impacted by estrogen-containing therapies (top panel) with the corresponding gradient of total estrogenicity associated with various hormonal combinations (bottom panel). Estrogens modulate multiple hemostatic factors, including increased synthesis of procoagulant proteins (eg, fibrinogen, factors VII, VIII, IX, X), decreased anticoagulant activity (eg, protein S, TFPI), and reduced fibrinolysis, ultimately promoting thrombin generation and fibrin clot formation. The intensity of these effects correlates with the overall estrogenic potency of the regimen. The gradient at the bottom of the figure reflects the total estrogenicity of different hormonal formulations, with combinations such as relugolix-CT positioned in the intermediate range, ie, well below traditional high-dose EE-based contraceptives. The position along the gradient is derived from indirect comparisons of estrogen-induced hemostatic changes and should be interpreted cautiously in the absence of head-to-head trials. This conceptual framework underscores the importance of estrogen dose, route, and progestogen type in assessing thrombotic risk [ 31 ]. Abbreviations: EE, ethinylestradiol; relugolix-CT, relugolix combined therapy. To evaluate the VTE risk associated with E2- and NETA-containing therapies, a meta-analysis of 3 predefined cohorts based on 5 prospective, noninterventional cohort studies encompassing 235 437 premenopausal women generating 571 163 woman-years of data has been conducted and reported in the European Public Assessment Report of Ryeqo® [ 33 ] and, to some extent, in the scientific literature [ 40 , 41 ]. The cohorts were stratified to compare the atherothrombotic (ATE) and VTE risk across different estrogen and progestin combinations: Cohort A assessed E2/E2val vs EE in combination with any progestin. Cohort B focused on E2val vs EE combined with a standardized progestin, dienogest. Cohort C compared NETA vs levonorgestrel-releasing, both combined with EE. The hazard ratios (HRs) derived from the forest plots demonstrated that therapies containing E2 had a significantly lower ATE and VTE risk compared to EE-based regimens ( Figs. 3 and 4 ). Notably, when combined with standardized progestins such as dienogest (cohort B), the VTE risk reduction was more pronounced (VTE HR 0.37, 95% confidence interval 0.20-0.71; ATE HR 0.12, 95% confidence interval 0.01-0.95). In cohort C, NETA showed a comparable thrombotic risk profile to levonorgestrel when combined with EE, underscoring its relative safety as a progestin ( Figs. 3 and 4 ). These findings suggest that the combination of E2 and NETA, as formulated in the relugolix-CT association, likely presents a lower thrombotic risk than EE-containing regimens even associated with levonorgestrel, the gold standard in COC. The HR analysis from the meta-analysis reflects a favorable thrombotic risk profile for E2-containing therapies, an observation potentially even improved with the presence of relugolix, which reduces the endogenous E2 production. Indeed, as already mentioned, the E2 concentrations achieved with relugolix-CT are comparable to the early follicular phase, further reducing thrombotic risk compared to EE-based therapies. Forest plots of VTE propensity score-stratified hazard ratios including upper and lower confidence limits in different cohorts of premenopausal women. Comparisons have been made between estradiol and ethinylestradiol (at dose ≤ 30 mcg) and between EE/NETA and EE/LNG (at dose ≤ 30 mcg). Data have been extracted from the European Public Assessment Report of Ryeqo® [ 33 ] and the scientific literature [ 40 , 41 ]. Abbreviations: DVT, deep vein thrombosis; E2, estradiol; EE, ethinylestradiol; LNG, levonorgestrel-releasing; NETA, norethisterone acetate; PE, pulmonary embolism; VTE, venous thromboembolism. Forest plots of ATE propensity score-stratified hazard ratios including upper and lower confidence limits in different cohorts of premenopausal women. Comparisons have been made between estradiol and ethinylestradiol (at dose ≤ 30 mcg), between E2/DNG and EE/DNG (at dose ≤ 30 mcg) and between EE/NETA and EE/LNG (at dose ≤ 30 mcg). Data have been extracted from the European Public Assessment Report of Ryeqo® [ 33 ]. Abbreviations: AMI, acute myocardial infarction; ATE, atherothrombotic event; CVA, cerebrovascular accident; DNG, dienogest; E2, estradiol; EE, ethinylestradiol; LNG, levonorgestrel-releasing; NETA, norethisterone acetate. While concerns regarding VTE risk have historically influenced the acceptability of estrogen-containing therapies, available evidence suggests that the combination of oral E2 and NETA represents a relatively safe hormonal regimen, particularly in younger populations such as women with endometriosis or uterine myomas. The MEGA and E3N studies reported that oral E2/NETA combinations carry a moderate thrombotic risk, but it was considerably lower than that associated with EE-containing formulations [ 42 , 43 ]. Notably, the Million Women Study demonstrated that among estrogen–progestin therapies, those containing NETA were associated with a lower VTE risk compared to medroxyprogesterone acetate (relative risk 1.91 vs 2.67) [ 44 ]. Crucially, age is 1 of the most important predictors of VTE incidence, with rates rising exponentially beyond age 50 [ 45 ]. As such, the reproductive-age population typically targeted by relugolix-CT has a substantially lower baseline thrombotic risk than the postmenopausal cohorts represented in most epidemiologic studies [ 43 , 44 , 46-48 ]. Thus, when used in appropriately selected younger women, the thrombotic safety profile of E2/NETA is likely to be more favorable than suggested by data derived from older populations. This is translated by the low rate of VTE observed during the endometriosis clinical development program, since only 1 event of deep vein thrombosis and pulmonary embolism was reported for a participant treated with relugolix-CT over the 1066 patients included in the 52-week SPIRIT-1 and -2 studies [ 49 ]. Although reassuring, these data need to be confirmed in larger cohorts or by encompassing other types of data (ie, biological investigation, observational studies, and reporting in pharmacovigilance databases) to address different levels of evidence as has been done recently with body-identical estrogens used in contraception [ 14 , 50-54 ]. Most large epidemiological datasets informing thrombotic risk with oral E2/NETA regimens derive from peri- and postmenopausal cohorts, whose baseline VTE incidence exceeds that of reproductive-age women. As a result, extrapolating risk from older populations may overestimate the absolute risk in the target population for relugolix-CT. In contrast, the pivotal phase 3 programs for uterine fibroids (LIBERTY 1/2) and endometriosis (SPIRIT 1/2) enrolled only premenopausal women and reported very low absolute numbers of VTE events overall, with no race-stratified safety signal reported; treatment effects were described as consistent across subgroups, although VTE outcomes by race were not specifically presented [ 1-4 ]. This aligns with biological plausibility (lower baseline VTE risk at a younger age) and the low estrogenic exposure achieved with relugolix-CT. With respect to racial/ethnic disparities, African women bear a disproportionate burden of uterine fibroids, ie, earlier onset, greater prevalence/severity, and higher intervention rates, highlighted across contemporary reviews [ 16 , 17 ]. By contrast, the lower observed prevalence of endometriosis in African women likely reflects underdiagnosis and access disparities rather than true biological protection, suggesting that prevalence is closer across groups when ascertainment bias is minimized [ 19 , 55 ]. Importantly, neither the pivotal trials nor current regulatory documents for relugolix-CT provide race-specific VTE incidence, and the product labeling contains class contraindications without race modifiers [ 11 , 33 ]. These gaps justify targeted real-world studies to quantify VTE outcomes under add-back therapy in populations at higher baseline risk and with higher disease burden, including women from different ethnicities. Finally, we acknowledge that baseline VTE incidence varies across populations due to both biological and social determinants (eg, comorbidity profiles, adiposity, care access) [ 56 ]. In view of these factors, careful patient selection and adherence to contraindications remain paramount, while postauthorization pharmacovigilance and observational research should prioritize race-/ethnicity-stratified analyses under relugolix-CT. Nonetheless, as with all estrogen–progestin combinations, patient selection must be rigorous. According to both the European Summary of Product Characteristics and the US Prescribing Information, relugolix-CT is contraindicated in women with current or past thrombotic or thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke); in women with known inherited or acquired thrombophilia (eg, factor V Leiden, protein C or S deficiency); and in those with multiple known risk factors for thrombosis including age over 35 years and smoking, uncontrolled hypertension, severe dyslipidemia, obesity, or prolonged immobilization. Additionally, contraindications include current or history of hormone-sensitive malignancies, hepatic impairment, known osteoporosis, or undiagnosed abnormal uterine bleeding [ 10 , 11 ]. Both regulatory agencies also recommend discontinuing treatment in the event of suspected thrombotic, cardiovascular, or cerebrovascular events or signs of retinal vascular involvement (eg, sudden vision loss, diplopia). In surgical settings associated with elevated thrombotic risk, treatment interruption is advised at least 4 to 6 weeks in advance if feasible. In summary, when relugolix-CT is used in appropriately selected patients, particularly younger, premenopausal women without predisposing risk factors, the overall VTE risk remains low. This is in line with biological plausibility and observed clinical data, though strict adherence to labeled contraindications and precautions remains essential to ensure patient safety.

Relugolix and other GnRH antagonists exhibit mechanisms that could theoretically influence the synthesis of liver proteins and hemostasis, yet the clinical significance of these effects appears limited. Although no biological data are available for relugolix specifically, this class of therapeutic agents suppress estrogen production, leading to an opposite effect to the 1 observed with exogenous estrogenic administration, which could translate into a modest decrease in several coagulation factors (eg, factors II, VII, VIII, IX, X, and fibrinogen) and an increase of anticoagulant proteins like antithrombin and protein S [ 31 ]. However, the levels of these coagulation factors generally remain within the normal range, and there is no strong evidence to suggest a clinically significant increase in thrombotic or bleeding risk [ 31 ]. Similarly, changes in fibrinolysis, such as reductions in tissue plasminogen activator levels and an increased plasminogen activator inhibitor-1 to tissue plasminogen activator ratio, are observed but not substantial enough to result in overt hemostatic imbalance [ 31 ]. The impact of GnRH antagonists alone on SHBG is not reported in clinical trials, but the magnitude of the reduction should not be clinically relevant and is opposite to the effect mediated by the add-back therapy. Nevertheless, such data are not available for GnRH antagonists alone or in association with E2/NETA but could be of interest as no direct comparisons with other therapies are currently available. Clinical trials and observational studies investigating the risk of VTE with GnRH antagonists have not identified a particular risk with this therapeutic class but even a better profile compared to GnRH agonists [ 32 ]. Notably, the lower E2 levels induced by these treatmentsa are even inferior to those observed in the early follicular phase of the menstrual cycle [ 33 , 34 ]. Relugolix 40 mg alone led to infra-physiological estrogen levels (levels are below 10 pg/mL, ie, below the level of untreated women with a normal menstrual cycle), impairing any impact on hemostasis [ 35 ] and, importantly, clinical trials and postmarketing surveillance have not reported an increased incidence of VTE in patients treated with GnRH antagonists alone [ 36 , 37 ]. Considering these findings, the hemostatic effects of relugolix alone and other GnRH antagonists are considered neutral and not linked to any thrombotic risk.

Current evidence supports the VTE and ATE safety profile of the relugolix-CT combination, particularly when used in its approved indications for endometriosis and HMB associated with uterine myomas. Data from biological investigations, as well as meta-analyses comparing E2 to EE and NETA to levonorgestrel, consistently demonstrate a lower thrombotic risk associated with E2/NETA combinations than with EE-based COCs, which remain the standard first-line therapy in endometriosis. In addition, the relugolix–E2/NETA formulation is characterized by low systemic E2 exposure and extremely low levels of circulating EE resulting from NETA metabolism, further supporting its favorable safety profile. While extrapolations from postmenopausal cohorts suggest a moderate thrombotic risk with oral E2 and NETA combinations, the actual risk in reproductive-age women, ie, the primary candidates for relugolix-CT, appears substantially lower, as confirmed by pivotal trials. Nonetheless, African women represent a particularly important subgroup, given their higher prevalence of uterine fibroids and VTE. Unfortunately, specific data on VTE incidence in this population under relugolix-CT remain scarce. Future real-world studies and postmarketing surveillance should therefore pay particular attention to this subgroup to ensure equitable and evidence-based guidance. Based on the data presented, the current body of evidence does not indicate a VTE risk higher than that observed with EE-levonorgestrel-releasing COCs or even potentially lower due to E2. Nonetheless, as with all estrogen-containing therapies, careful patient selection remains essential, particularly in individuals with known thrombotic risk factors, in accordance with the contraindications outlined in the Summary of Product Characteristics.

Uterine myomas and endometriosis are prevalent gynecological conditions affecting millions of women worldwide, often resulting in significant morbidity and diminished quality of life [ 15 ]. Uterine myomas, benign tumors of the smooth muscle cells in the uterus, are estimated to affect up to 70% to 80% of women by age 50, with African American women being disproportionately impacted [ 16 , 17 ]. Endometriosis, characterized by ectopic growth of endometrial-like tissue outside the uterus, affects 2% to 10% of reproductive-aged women and up to 50% of women experiencing infertility or chronic pelvic pain [ 18 ]. Both conditions are hormonally influenced, presenting a complex interplay of genetic, epigenetic, and environmental factors. Their management requires a multifaceted approach tailored to individual patient profiles [ 19 ]. Uterine myomas require a tailored approach based on symptom severity, fibroid characteristics, and patient goals. According to recent reviews, first-line treatment for HMB includes antifibrinolytics such as tranexamic acid and the levonorgestrel-releasing intrauterine device [ 20 , 21 ]. Tranexamic acid is effective for HMB management, while the levonorgestrel-releasing intrauterine device should not be recommended to treat uterine fibroid symptoms other than abnormal uterine bleeding [ 21 ]. Selective progesterone receptor modulators like ulipristal acetate have been used to reduce fibroid size and bleeding, although their usage has been restricted due to concerns about rare but serious liver injuries [ 22 ]. GnRH antagonists, including relugolix, have thus revolutionized fibroid management. These oral agents rapidly reduce HMB and fibroid-related symptoms while maintaining bone health through add-back therapy, here, with E2 and NETA [ 1 , 2 ]. Clinical trials have demonstrated significant improvements in menstrual blood loss, with 87.7% of patients achieving a reduction below 80 mL per month within 12 months of treatment [ 2 ]. GnRH antagonists are particularly useful for women seeking a nonsurgical approach or those preparing for surgical interventions such as myomectomy or hysterectomy. The inclusion of add-back therapy ensures that patients can achieve the benefits of hormonal suppression without experiencing the adverse effects of hypoestrogenism, thereby improving adherence and long-term outcomes [ 5 ]. While no studies directly compare oral combination pills to transdermal E2 with 2 oral agents, evidence from other chronic diseases strongly supports single-pill strategies for optimizing adherence [ 23 , 24 ]. Regarding endometriosis, the European Society of Human Reproduction and Embryology (ESHRE) guidelines emphasize a structured and evidence-based approach [ 19 ]. Pharmacological therapy is the cornerstone of treatment, particularly for symptom management [ 19 ]. For endometriosis-associated pain, the ESHRE recommends hormonal therapies, including combined oral contraceptives (COCs), a levonorgestrel-releasing intrauterine system, or an etonogestrel-releasing subdermal implant, as first-line treatments. GnRH antagonists, such as relugolix, have emerged as a promising option due to their rapid suppression of gonadotropin release and avoidance of the flare effect seen with GnRH agonists. These are currently recommended as second-line treatment by the ESHRE, but the add-back therapy is strongly advised to avoid side effects related to the generated hypoestrogenic environment [ 19 ]. Indeed, on multiple-dose administration of relugolix, initial decreases in pituitary and ovarian hormone concentrations are consistently maintained during once-daily administration through the 24-hour dosing interval, reflecting a sustained suppression of the hypothalamus-pituitary-gonadal axis. Specifically, mean concentrations of E2 on day 14 measured at various postdose time points were consistently low (range: 3.9-4.7 pg/mL), demonstrating that after administration of a 40-mg dose of relugolix, E2 concentrations are maintained as low and stable over the entire 24-hour dosing interval [ 25 ]. This was translated into clinical observations and in the relugolix 40-mg dose groups of the phase II studies, hot flushes were reported more frequently compared with placebo (38.9% vs 3.5% and 52.4% vs 8.2%, respectively) and a greater mean (±SD) percent change from baseline in BMD (measured by a dual-energy X-ray absorptiometry scan) was observed at week 12 (−2.27 ± 2.21% vs −0.2 ± 2.22% and −2.1 ± 2.20% vs −0.1 ± 1.7%, respectively) [ 26 , 27 ]. The rationale for add-back therapy thus lies in its ability to mitigate the hypoestrogenic side effects associated with GnRH analogs, such as BMD loss, vasomotor symptoms, and mood disturbances [ 28 , 29 ]. In 1992, Barbieri hypothesized that achieving systemic E2 concentrations between 30 and 45 pg/mL would lead to the improvement of symptoms associated with endometriosis while minimizing the undesirable consequences of hypoestrogenism [ 9 ]. Studies have confirmed the efficacy of this approach in preventing bone loss and reducing vasomotor symptoms while ensuring continued symptom control [ 30 ]. For example, the addition of low-dose E2 and NETA to GnRH analogs has been shown to maintain bone health and improve quality of life, making long-term treatment more tolerable and effective [ 30 ]. Relugolix was thus proposed in combination with E2 and NETA as add-back therapy, as supported by phase 1 study of Lukes et al [ 6 ]. This combination has demonstrated, in the later phase 3 development programs, efficacy in reducing endometriosis-associated pain and reducing uterine fibroids-related menstrual blood loss while mitigating adverse events [ 1 , 3 ]. The integration of add-back therapy into GnRH analog treatment thus represents a significant advancement, ensuring efficacy while minimizing side effects and improving adherence to multiple agents. Nevertheless, while side effects are better controlled with add-back therapy, regulatory authorities consider that these combinations should not be administered to women with a potential risk of venous thrombosis due to the known prothrombotic profile of estroprogestin combinations [ 10 , 11 ]. The next sections of this article provide a comprehensive overview of the current level of evidence regarding the impact on hemostasis and the potential associated risk of VTE with GnRH antagonists and add-back therapy.