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.

Polish version of the Acute Cystitis Symptom Score for patients with acute uncomplicated cystitis.

Introduction: The Acute Cystitis Symptom Score (ACSS) is a self-reporting questionnaire to evaluate the symptoms and quality of life in women with uncomplicated acute cystitis (AC). The aim of the current study was the additional cognitive and clinical validation of the Polish version. Material and methods: Professional forward and backward translations from original Russian to Polish were performed by Mapi SAS. For cognitive assessment, women with different ages and educational levels were asked to comment on each item of the Polish ACSS to establish the final study version. The clinical validation was performed as a prospective, non-interventional cohort study. Women with AC (Patients) and those without (Controls) filled in the Polish ACSS during their visits to a physician's office and at a follow-up visit. Statistical analysis included ordinary descriptive values, calculation of reliability, validity, discriminative ability, responsiveness (sensitivity, specificity), and comparative analysis. Results: The cognitive assessment was performed in 60 women with a median (range) age of 44.5 (21-88) years and different educational levels: grade school (n = 8), high school (n = 25), college (n = 22), and postgraduate education (n = 5). Forty-three patients were recruited for the clinical validation study along with 34 controls. Statistical analyses resulted in excellent values of internal consistency, discriminative ability, and validity for diagnosis of AC. At a summary score of 6 and higher in the ´Typical´ domain, positive and negative predictive values were 97% and 79%, and sensitivity and specificity were 79% and 97%, respectively. Conclusions: The Polish version of the ACSS has demonstrated benefits for diagnosis and patient-reported outcome assessment. It is objective, fast, and cost-effective, and it may help to easily confirm the accurate diagnosis of AC. The Polish ASCSS can now be recommended for use in clinical and epidemiological studies, in clinical practice, or for self-diagnosis and patient-reported outcome in women with symptoms of AC.

Fertility impairment associated with uterine fibroids - a review of literature.

Uterine fibroids (also known as leiomyomas or myomas) are the most common benign tumors affecting reproductive organs in women. They are monoclonal tumors of the uterine smooth muscle, which spring from myometrium. It is estimated that they occur in 50-60% of the female population and rise to 70% by the age of 50. While mostly asymptomatic, myomas can be connected with several conditions, including abnormal bleeding with subsequent anemia, pelvic masses, pelvic pain, bulk symptoms, unfavorable impact on fertility and obstetric complications. Factors, which predispose the emergence of fibroids are: hormones, Afro-American ethnicity, age, obesity, adverse pregnancy outcome history, early menarche, genetic factors, alcohol, caffeine or eating too much red meat. On the other hand, there are factors, which can decrease this risk: pregnancy, early menopause and tobacco smoking. There are several mechanisms of fertility impairment in females with fibroids: alternations in uterus function (flawed blood supply, increased contractility), changes in the normal uterus anatomy, local hormonal changes induced by fibroids. In this review the connection between fibroids and infertility is analyzed.

Selected non-somatic risk factors for pregnancy loss in patients with abnormal early pregnancy.

INTRODUCTION AND OBJECTIVE: Spontaneous abortion constitutes one of the most frequent complication of human pregnancy. Despite intensive research efforts undertaken to date, the etiopathogenesis of early pregnancy loss has not been fully elucidated. The objective of this study was to analyze the role of selected non-somatic risk factors for early pregnancy loss in patients with various clinical manifestations of spontaneous abortion. MATERIALS AND METHODS: The study included 242 women hospitalized between 2001 and 2004 in the 3rd Chair and Department of Gynecology, Medical University of Lublin, Poland (Teaching Hospital No.4) with various clinical categories of spontaneous abortion. Each patient completed a questionnaire assessing her exposure to the examined factors. In patients with threatened abortion dismissed from the hospital with viable gestation, the course of pregnancy was followed-up using questionnaire data and medical records. RESULTS: In the studied population of women with abnormal early pregnancy course, a significant impact on the risk of miscarriage was observed in case of such factors as: exposure to stress at home and limited number of hours of nightly sleep. Factors such as occupational hazards, diet, stress, heavy housework and use of cigarettes or alcohol did not exert a significant effect on the risk of miscarriage in the studied population. CONCLUSIONS: The results of this study confirm the complexity of the early pregnancy loss etiopatogenesis. Further research need to be conducted in order to identify the non-somatic causative agents of various clinical forms of miscarriage. It may help do select women in reproductive age at high risk of early pregnancy loss and show the ways in which effective preventive measures can be introduced in such population.

The effect of ulipristal acetate treatment on symptomatic uterine fibroids within 12-months follow-up.

AIM OF THE STUDY: The purpose of the study was to monitor the effect of ulipristal acetate treatment on symptomatic uterine fibroids within 12-months follow-up. MATERIAL AND METHODS: Fifty six patients with symptomatic uterine fibroids qualified for surgical treatment were included in the prospective observational study. All patients received preoperative oral UPA treatment for 3 months (1 × 5 mg). Patients that refused surgical treatment after UPA therapy were followed-up for the next 9 months. The volume of the intramural fibroid was estimated by TV-US using and integrated VOCAL 3D imaging program at baseline, after 3 months of UPA treatment and further at 3-months intervals. RESULTS: Before UPA mean dominant fibroid volume was estimated to be 216.0 cm(3) (38.4-768.2 cm(3)) and decreased to 117.6 cm(3) (12.6-668.0 cm(3)) after 3 months of UPA therapy. Mean percentage volume reduction was 45.6%. Mean hemoglobin level increased from an initial 10.1 g/dL (6.8-12.9 g/dL) to 12.6 g/dL (10.1-14.8) after 3 months of UPA therapy. At 12 months after initiating UPA treatment mean dominant fibroid volume decreased by 43.9%. In one third of followed-up patients the effect of 3 month UPA therapy persisted for the next 9 months. CONCLUSIONS: Three month UPA therapy decreases fibroid volume and improves hemoglobin level before planned surgical treatment. In one third of followed-up patients the effect of 3 month UPA therapy persisted for the next 9 months.

Predicting the results of uterine artery embolization: correlation between initial intramural fibroid volume and percentage volume decrease.

INTRODUCTION AND OBJECTIVE: Uterine artery embolization (UAE) is a minimally invasive treatment option for symptomatic fibroids. Long-term follow-up studies have shown that at five-year follow-up after UAE, up to 30% of patients required a hysterectomy. Therefore, it seems of utmost importance to identify patients, who are unlikely to benefit from UAE. It has been postulated that the percentage volume reduction of fibroids may predict long-term UAE outcome. The results of available studies are equivocal, therefore it seemed of interest to investigate the correlation between the preinterventional intramural fibroid volume and imaging outcome of UAE in premenopausal patients. MATERIAL AND METHODS: Uterine artery embolization was performed in 65 premenopausal patients with symptomatic, intramural fibroids. Dominant fibroid volume was assessed using an integrated VOCAL (Virtual Organ Computer-aided AnaLysis) imaging program at baseline and 3 months after UAE. The percentage reduction of fibroid volume was calculated. The association between preinterventional fibroid volumes and percentage volume reductions was determined with the Spearman rank correlation test. RESULTS: Before UAE, the median dominant fibroid volume was 101 cm(3) (range 23.6-610). At three-month follow-up the median dominant leiomyoma volume decreased to 50.4 cm(3) (range 6.9-193.9). Median percentage reduction of fibroid volume three months after UAE was calculated at 50.1% (range 2.7-93.5). The Spearman correlation test between the preinterventional dominant fibroid volume and percentage volume reduction showed a statistically significant, positive correlation (R = 0.33; p = 0.006). CONCLUSIONS: The percentage volume reduction of intramural leiomyomas after UAE seems to be more pronounced in the case of larger tumors.

Placenta percreta leading to uterine rupture at 18 weeks of pregnancy with consecutive hysterectomy: a case report.

A 26-year-old woman in the fourth pregnancy with a history of two Cesarean sections and one dilation and curettage was admitted to the hospital at 18 weeks of gestation with acute abdominal pain. Life-saving laparotomy revealed uterine rupture and placental invasion into the uterine wall. Supracervical hysterectomy was performed. This case shows that pathological placentation due to previous cesarean sections may be the cause of uterine rupture.

[Uterine artery embolization--clinical problems]. / Embolizacja tetnic macicznych--zagadnienia kliniczne.

The aim of the study was to present clinical issues concerning uterine artery embolization (UAE) in women with uterine fibromas. In order to ensure high clinical efficiency of UAE and prevent subsequent complications, it is necessary to carefully select patients eligible for the procedure. Patients with intramural fibromas, who do not plan to conceive, are the best candidates for the procedure. Fibroma necrosis, with following infection, and premature ovarian failure remain to be the most common complications after UAE. UAE may cause amenorrhea and increase FSH levels, what is typical for menopause. Thus, it may be responsible for problems with conception as well as optimal development of a pregnancy. It may also cause premature, iatrogenic menopause. This complication significantly more frequently occurs in women over the age of 45 as compared to younger patients. UAE is considered as an alternative therapeutic procedure, available to women who do not desire the surgery or wish to preserve the uterus. Patients subject to this procedure should be informed about the possible side effects.