A Plain Language Summary to learn about relugolix combination therapy for the treatment of pain associated with endometriosis.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called SPIRIT 1 and SPIRIT 2. The SPIRIT 1 and SPIRIT 2 studies compared how well a medicine called relugolix combination therapy worked in relieving pain in women with moderate to severe endometriosis compared to a placebo, a pill with no active medication. Endometriosis occurs when tissue similar to what normally lines the uterus grows in other places, such as the ovaries, fallopian tubes, and bowels. WHAT WERE THE RESULTS?: Researchers looked at 1261 adult women with moderate to severe endometriosis. Randomly, 420 (33%) of these women were assigned to relugolix combination therapy, 420 (33%) were assigned to delayed relugolix combination therapy (relugolix alone first and then relugolix combination therapy for the remainder of the study), and 421 (33%) were assigned to placebo. The SPIRIT 1 and SPIRIT 2 studies showed that more women taking relugolix combination therapy (75% from SPIRIT 1 and 75% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain during menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (27% from SPIRIT 1 and 30% from SPIRIT 2). The SPIRIT 1 and SPIRIT 2 studies also showed that more women taking relugolix combination therapy (59% from SPIRIT 1 and 66% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain between menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (40% from SPIRIT 1 and 43% from SPIRIT 2). Women taking relugolix combination therapy had less pelvic or groin pain during and between menstrual periods within 4 weeks of starting the medicine. The most common side effects were headaches, the common cold, and hot flushes or feeling hot among women taking relugolix combination therapy, delayed relugolix combination therapy, and placebo. Relugolix combination therapy was considered safe for those with no major medical problems. Women taking relugolix combination therapy had little to no loss of bone mineral density (a way of knowing how strong bones are) after 24 weeks of treatment. WHAT DO THE RESULTS OF THESE STUDIES TELL US?: Women with moderate to severe endometriosis taking relugolix combination therapy had much less pain from endometriosis than women taking placebo. Clinical Trial Registration: NCT03204318 (SPIRIT-1); NCT03204331 (SPIRIT-2) (ClinicalTrials.gov).

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).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

[Usefulness of saliva estradiol determinations for monitoring of hormonal fluctuancy]. / Przydatnosc oznaczania estradiolu w slinie w monitorowaniu stanu hormonalnego.

Synthesis and catabolism of estradiol, the main estrogen from the period of maturation to menopause, is regulated for very complicated manner. Also many factors are involved in the process of absorption of orally given hormone. From this reason the body concentration of estradiol needs of permanently control. We studied of possibility to replace blood serum by saliva compared the concentrations of this hormone in the both body fluids. In this purpose estradiol was determined by the method of microparticle enzyme immunoassay (MEIA) in the blood and in the saliva obtained by the method of absorption with three different kits called "Salivette" in 25 women with pregnancy and in childbed. High correlation between concentrations of estradiol in saliva and blood serum was stated; the highest for polyester like absorption material.