Endometriosis Menstrual Pain Fell to Minimal Levels Within a Median of 8 Weeks in Treatment Study
Key Takeaways
- In an exploratory analysis of the SPIRIT clinical trial program, women originally randomized to relugolix combination therapy reached minimal-to-no menstrual pain after a median of 8 weeks.
- Minimal-to-no pain meant a score of 1 or less on a 0-to-10 pain scale. This post hoc endpoint was different from the prespecified responder endpoints used in the original phase 3 trials.
- Among women originally randomized to combination therapy who entered the extension, the Kaplan-Meier cumulative probability of reaching minimal-to-no menstrual pain was estimated at 82.5% by week 24, 94.5% by week 52, and 95.3% by week 104.
- Non-menstrual pelvic pain improved more slowly. The median time to minimal-to-no pain was 32 weeks in the group originally assigned combination therapy.
- The long-term extension was open-label and did not include a continuing placebo comparison. The two-year results therefore cannot establish a two-year treatment effect versus placebo.
- Of 802 women who entered the extension, 501 completed 104 weeks of treatment. The research was industry funded, with substantial sponsor involvement and several authors reporting financial relationships with the drug’s developer.
Introduction
Endometriosis can cause significant menstrual and pelvic pain. A new analysis examined how quickly women reached minimal-to-no pain during relugolix combination therapy.
For women with endometriosis, menstrual pain can be severe enough to interfere with work, sleep, relationships, and everyday activities. A newly published analysis provides a closer look at how quickly women participating in a large clinical trial program reached very low pain levels during treatment with relugolix combination therapy.
The analysis, published September 5, 2026, in the International Journal of Women’s Health, found that among women originally randomized to relugolix combination therapy, the median time to minimal-to-no menstrual pain was 8 weeks (Lukes et al., 2026).
A median does not mean every woman experienced that result within eight weeks. In a time-to-event analysis, it represents the point by which an estimated half of the group had reached the specified endpoint.
That endpoint was also demanding. Researchers defined minimal-to-no pain as a score of 1 or less on a numerical rating scale ranging from 0, meaning no pain, to 10, representing the worst imaginable pain.
Importantly, this was not the primary pain endpoint originally used to establish the treatment’s efficacy. The 8-week result comes from an exploratory post hoc analysis of previously collected trial data.
The finding therefore provides additional information about the timing and depth of pain improvement. It should not be interpreted as a guarantee that an individual patient will experience minimal pain within eight weeks.
What the Study Examined
The analysis used data from the SPIRIT 1 and SPIRIT 2 phase 3 trials and their long-term extension.
The SPIRIT program enrolled premenopausal women aged 18 to 50 with endometriosis and moderate-to-severe dysmenorrhea, the medical term for menstrual pain, and non-menstrual pelvic pain.
Relugolix combination therapy contains three medicines in a once-daily tablet: 40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate.
Relugolix is a gonadotropin-releasing hormone receptor antagonist that suppresses ovarian hormone production. Estradiol and norethindrone acetate are included as add-back therapy intended to reduce effects associated with low estrogen, including bone loss and vasomotor symptoms.
The original SPIRIT 1 and SPIRIT 2 studies were multinational, 24-week, randomized, double-blind, placebo-controlled phase 3 trials.
A total of 1,261 women were randomly assigned in a 1:1:1 ratio to immediate relugolix combination therapy, delayed combination therapy, or placebo.
Women in the delayed-treatment group received relugolix 40 mg alone for the first 12 weeks, followed by combination therapy for the next 12 weeks.
Participants who completed the original trials and met eligibility requirements could enter an 80-week open-label extension. During the extension, all participants received relugolix combination therapy, allowing follow-up for up to 104 weeks from the beginning of the original trials.
Of the original 1,261 randomized women, 802 entered the extension. The new analysis included 799 participants. A total of 681 completed 52 weeks of treatment and 501 completed 104 weeks.
The researchers used Kaplan-Meier time-to-event analyses to estimate how long participants took to reach minimal-to-no menstrual pain, minimal-to-no non-menstrual pelvic pain, amenorrhea, and freedom from analgesic use.
These analyses were exploratory and descriptive rather than prespecified confirmatory comparisons.
Menstrual Pain Reached Minimal Levels After a Median of 8 Weeks
Among women originally randomized to relugolix combination therapy, the median time to minimal-to-no menstrual pain was 8 weeks, or approximately two menstrual cycles.
The delayed-treatment group also had a median time of 8 weeks.
Women originally assigned placebo did not reach the median during the initial 24-week placebo-controlled period. After switching to relugolix combination therapy in the open-label extension, the placebo-origin group reached an estimated median at week 32. This post-switch estimate was not a randomized comparison with continued placebo.
Among women originally randomized to combination therapy who entered the extension, the Kaplan-Meier cumulative probability of reaching minimal-to-no menstrual pain was estimated at 82.5% by week 24, 94.5% by week 52, and 95.3% by week 104.
Those percentages need careful interpretation.
A Kaplan-Meier cumulative probability is a statistical estimate that accounts for participants having different lengths of follow-up and for censoring when participants are no longer observed.
It is not the same as simply counting the percentage of all women who started treatment and were directly observed to have minimal or no pain at each time point.
The endpoint also combined minimal and no pain. A score of 0 represented no pain, while a score of 1 also qualified.
It would therefore be misleading to translate the week 104 result into a claim that “95.3% of women were pain-free after two years.”
The 8-Week Finding Is Different From the Original Trial Endpoint
The distinction between the new endpoint and the original SPIRIT trial endpoints is particularly important.
The 2026 analysis defined minimal-to-no menstrual pain as a pain score of 1 or less.
The original SPIRIT trials used a different definition of treatment response. A woman was considered a dysmenorrhea responder if her pain decreased by at least 2.8 points from baseline without an increase in analgesic use.
For non-menstrual pelvic pain, the required reduction was at least 2.1 points without increased analgesic use.
A participant could therefore achieve a clinically meaningful response according to the original trial definition without reaching the much lower pain threshold of 1 or less.
The 8-week result describes the median time to this stricter NRS threshold. It is not the median time required to meet the original SPIRIT responder definition.
Pain Between Periods Improved More Slowly
Among women originally randomized to relugolix combination therapy, the median time to minimal-to-no non-menstrual pelvic pain was 32 weeks.
The Kaplan-Meier cumulative probability of reaching that threshold was estimated at 42.6% by week 24, 59.9% by week 52, and 70.5% by week 104.
The delayed-treatment group had a median time of 28 weeks. The placebo-origin group reached an estimated median at 40 weeks after switching to active treatment at week 24. Again, this post-switch result was not a comparison with continued placebo.
The contrast with menstrual pain may be clinically meaningful.
Suppressing menstruation can directly affect dysmenorrhea, while pelvic pain outside menstruation may involve more complicated mechanisms.
The authors discussed inflammation, fibrosis, neuropathic pain, and central sensitization as possible contributors. However, the study did not test which mechanisms were responsible for the slower improvement in non-menstrual pelvic pain.
The 70.5% Kaplan-Meier cumulative probability at week 104 also shows that reaching minimal-to-no non-menstrual pelvic pain was far from universal in the analysis.
Pain Medication Use Also Declined
Researchers also examined how long it took women to stop using analgesics for endometriosis-associated pain.
Among women originally randomized to relugolix combination therapy, the median time to analgesic-free status was 16 weeks.
The Kaplan-Meier cumulative probability of becoming analgesic-free was estimated at 68.8% by week 24, 88.6% by week 52, and 94.9% by week 104.
The investigators separately examined opioid use. In the group originally assigned combination therapy, the estimated Kaplan-Meier cumulative probability of becoming opioid-free reached 98.4% by week 104.
These figures require the same statistical caution as the pain results. They are cumulative time-to-event estimates, not raw percentages of the original randomized population observed to be medication-free at each time point.
What the Original Randomized Trials Found
The new analysis does not establish the effectiveness of relugolix combination therapy from scratch.
The strongest comparative efficacy evidence comes from the original randomized SPIRIT 1 and SPIRIT 2 trials.
At 24 weeks, significantly more women receiving relugolix combination therapy met the prespecified dysmenorrhea responder criterion than women receiving placebo. Response rates were 75% versus 27% in SPIRIT 1 and 75% versus 30% in SPIRIT 2 (Giudice et al., 2022).
For non-menstrual pelvic pain, response rates were 59% versus 40% in SPIRIT 1 and 66% versus 43% in SPIRIT 2.
Those randomized results provide stronger comparative evidence of efficacy than findings from the later open-label period.
The 2026 analysis answers a different question. Instead of asking whether participants achieved the original prespecified degree of improvement, researchers examined how long it took them to reach a particularly low pain score.
The new findings therefore complement rather than replace the original randomized evidence.
What Earlier Two-Year Results Showed
The long-term SPIRIT extension was previously reported separately.
Among 277 women who had originally been randomized to relugolix combination therapy and continued into the extension, 84.8% met the original dysmenorrhea responder definition at week 104 or end of treatment, while 75.8% met the non-menstrual pelvic pain responder definition (Becker et al., 2024).
The extension also reported that mean bone mineral density initially declined by less than 1% and then plateaued during continued treatment.
However, the extension was open-label and noncomparative.
Everyone entering the extension received relugolix combination therapy. There was no continuing placebo group against which outcomes at week 52 or week 104 could be compared.
The long-term results therefore cannot establish a two-year treatment effect relative to placebo.
Important Limitations
Several limitations materially affect how the new results should be interpreted.
First, the minimal-to-no pain analysis was post hoc.
The pain threshold of 1 or less was not one of the original prespecified primary efficacy endpoints used in the randomized trials. The authors describe the new analyses as exploratory and descriptive.
Post hoc findings can provide useful information, but they generally offer less definitive evidence than prespecified analyses because the research question is evaluated after trial data have already been collected.
Second, the long-term extension was open-label.
Randomization and blinding applied during the initial 24 weeks. Participants entering the extension then received active relugolix combination therapy regardless of their original assignment.
The week 52 and week 104 results therefore cannot be interpreted as two-year relugolix-versus-placebo comparisons.
Third, participant attrition was substantial.
Of 802 women entering the extension, 501 completed 104 weeks of treatment.
Overall, 300 of 802 participants, or 37.4%, discontinued treatment during the extension. Participant withdrawal was the most common reason, accounting for 104 cases, while 66 participants discontinued because of adverse events.
Kaplan-Meier methods allow participants to contribute information during the period in which they were observed. Estimates at later time points, however, depend partly on assumptions about participants who were censored and no longer being followed.
The amount of dropout therefore matters when interpreting cumulative probabilities approaching 95% at two years.
Finally, group-level trial results cannot predict exactly how quickly an individual patient will respond. Endometriosis and treatment response can vary substantially between patients.
Safety and the 24-Month Treatment Limit
The 2026 analysis focused on the timing of pain improvement rather than providing a new comprehensive safety assessment.
Relugolix combination therapy is marketed in the United States as Myfembree for the management of moderate-to-severe pain associated with endometriosis in premenopausal women.
Although the SPIRIT program followed participants for up to 104 weeks, current U.S. prescribing information limits Myfembree treatment to 24 months because continued bone loss may not be reversible (U.S. Food and Drug Administration, 2025).
The prescribing information also carries a boxed warning concerning thromboembolic disorders and vascular events. Estrogen and progestin combinations, including Myfembree, increase the risk of thrombotic or thromboembolic disorders, particularly in women at increased risk for these events.
The FDA labeling includes additional contraindications, warnings, and precautions involving pregnancy, osteoporosis or bone loss, hormone-sensitive malignancies, liver disease, elevated blood pressure, mood disorders, and other potential risks.
The long-term SPIRIT findings do not override the current 24-month treatment limit or eliminate the need to assess individual risks and follow appropriate monitoring.
Myfembree is not appropriate for everyone. Patients and clinicians should consult the complete prescribing information when considering treatment.
These study findings should not be used as a reason to start, stop, extend, or otherwise change treatment without discussing the potential benefits and risks with a qualified clinician.
Industry Involvement Was Substantial
The financial relationships behind the research are important context.
The study was funded by Sumitomo Pharma Switzerland GmbH, formerly Myovant Sciences GmbH, as part of the development program for relugolix combination therapy.
According to the published paper, Myovant Sciences and its clinical development organization were involved in conceptualization, study design, data collection, analysis, the decision to publish, or manuscript preparation.
Three authors were current or former employees of Sumitomo Pharma. Other authors disclosed consulting relationships, research grants, speaker fees, or personal fees involving Myovant, Sumitomo Pharma, or other pharmaceutical companies.
Medical writing and editorial assistance for the scientific paper were provided by AXON Communications and funded by Sumitomo Pharma Switzerland and Pfizer.
Industry sponsorship does not establish that the results are invalid. However, sponsor involvement and investigators’ financial relationships are relevant when evaluating an exploratory post hoc analysis of the sponsor’s drug.
Final Thoughts
The new analysis provides a useful additional perspective on the SPIRIT clinical trial data.
Among women originally randomized to relugolix combination therapy, the median time to a menstrual pain score of 1 or less was 8 weeks.
Non-menstrual pelvic pain took considerably longer to reach the same low threshold, with a median of 32 weeks.
The analysis also indicates that additional participants reached low pain levels and stopped using analgesics during longer follow-up.
But the most striking long-term numbers require restraint.
The 95.3% figure at week 104 is a Kaplan-Meier cumulative probability from an exploratory post hoc analysis. It does not mean that 95.3% of every woman starting relugolix combination therapy can expect to be pain-free after two years.
The strongest evidence that relugolix combination therapy reduces endometriosis-associated pain remains the original randomized, placebo-controlled SPIRIT trials.
The new analysis answers a narrower but useful question: among women participating in the SPIRIT program, how long did it take to reach a particularly low level of pain?
For menstrual pain, the median was 8 weeks in women originally randomized to combination therapy. Whether an individual patient will experience the same degree or timing of improvement cannot be predicted from these results.
References
Becker, C. M., Johnson, N. P., As-Sanie, S., Arjona Ferreira, J. C., Abrao, M. S., Wilk, K., Lu, M., Li, Y., Mathur, V., Warsi, Q. A., Wagman, R. B., & Giudice, L. C. (2024). Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study. Human Reproduction, 39(3), 526–537. https://doi.org/10.1093/humrep/dead263
Giudice, L. C., As-Sanie, S., Arjona Ferreira, J. C., Becker, C. M., Abrao, M. S., Lessey, B. A., Brown, E., Dynowski, K., Wilk, K., Li, Y., Mathur, V., Warsi, Q. A., Wagman, R. B., & Johnson, N. P. (2022). Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: Two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2). The Lancet, 399(10343), 2267–2279. https://doi.org/10.1016/S0140-6736(22)00622-5
Lukes, A. S., Venturella, R., Dynowski, K., Wagman, R. B., Perry, J. S., Zhong, Y., Rakov, V. G., Mechsner, S., & Johnson, N. P. (2026). Achieving minimal-to-no pain in women with endometriosis treated with relugolix combination therapy: SPIRIT Extension Trial. International Journal of Women’s Health, 18, 603470. https://doi.org/10.2147/IJWH.S603470
U.S. Food and Drug Administration. (2025). Myfembree (relugolix, estradiol, and norethindrone acetate) prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214846s012lbl.pdf
