Uterine Adenomyosis Treated by Linzagolix, an Oral Gonadotropin-Releasing Hormone Receptor Antagonist: A Pilot Study with a New ’Hit Hard First and then Maintain’ Regimen of Administration

(1) Background: The aim of the present pilot study was to study the effect of a new oral gonadotropin-releasing hormone antagonist on adenomyosis. (2) Methods: Eight premenopausal women, aged between 37 and 45 years, presenting with heavy menstrual bleeding, pelvic pain, and dysmenorrhea due to diffuse and disseminated uterine adenomyosis, confirmed by magnetic resonance imaging (MRI), received 200 mg linzagolix once daily for a period of 12 weeks, after which they were switched to 100 mg linzagolix once daily for another 12 weeks. The primary efficacy endpoint was the change in volume of the adenomyotic uterus from baseline to 24 weeks, evaluated by MRI. Secondary efficacy endpoints included the change in uterine volume from baseline to 12 and 36 weeks by MRI, and also weeks 12, 24, and 36 assessed by transvaginal ultrasound (TVUS). Other endpoints were overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, amenorrhea, quality of life measures, bone mineral density (BMD), junctional zone thickness, and serum estradiol values. (3) Results: Median serum estradiol was suppressed below 20 pg/mL during the 12 weeks on linzagolix 200 mg, and maintained below 60 pg/mL during the second 12 weeks on linzagolix 100 mg. At baseline, the mean ± SD uterine volume was 333 ± 250 cm3. After 24 weeks of treatment, it was 204 ± 126 cm3, a reduction of 32% (p = 0.0057). After 12 weeks, the mean uterine volume was 159 ± 95 cm3, a reduction of 55% from baseline (p = 0.0001). A similar pattern was observed when uterine volume was assessed by TVUS. Improvements in overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia, as well as quality of life measured using the EHP-30 were also observed. Mean percentage BMD loss at 24 weeks was, respectively, −2.4%, −1.3%, and −4.1% for the spine, femoral neck, and total hip. The most common adverse events were hot flushes, which occurred in 6/8 women during the first 12 weeks, and 1/8 women between 12 and 24 weeks. (4) Conclusions: Linzagolix at a dose of 200 mg/day reduced uterine volume, and improved clinically relevant symptoms. Treatment with 100 mg thereafter retains the therapeutic benefits of the starting dose while minimizing side effects. This ‘hit hard first and then maintain’ approach may be the optimal way to treat women with symptomatic adenomyosis.

Uterine volume measurement as a determinant in route of hysterectomy

Background: Objectives of the study were to determine the role of uterine volume rather than uterine length in assessing the route of hysterectomy; to estimate the cut-off of uterine volume for route of hysterectomy; and to correlate uterine volume measured preoperatively by ultrasound with post-operative uterine weight.Methods: This was a prospective observational study including a total of 101 women who underwent hysterectomies (vaginal, laparascopic assisted vaginal hysterectomy (LAVH), total laparascopic hysterectomy (TLH), abdominal) in a period of 2 years 2 months from July 2018 to August 2020 in Mehta Multispeciality Hospital, Chetpet, Chennai. Uterine size was measured by clinical examination. Ease of the procedure with various uterine volume and routes of hysterectomy were studied.Results: 51 (50.49%) underwent vaginal route (including laparascopic hysterectomy), 50 (49.50%) underwent abdominal hysterectomy. Mean uterine volume leading to removal vaginally was 168.09±139.28 cc whereas 309.12±182.47 cc for abdominal hysterectomy (p=0.001) which was statistically significant. vaginal hysterectomy was done without difficulty up to 300 cc. Postoperative complications were less with vaginal hysterectomy compared to abdominal hysterectomy was statistically significant (p=0.0001).Uterine volume measured pre operatively by ultrasound showed positive correlation (r=0.82) with post-operative uterine weight proved that uterine volume measurements was superior to the clinical estimate of uterine size in assessing the route of hysterectomy.Conclusions: Uterine volume on ultrasonography (USG) can be a good predictor in deciding whether hysterectomy via vaginal route is possible.

Efficacy and Safety Analysis of Modified HSG for Infertile Patients

Objective: To test the efficacy and safety of modified hysterosalpingography (HSG) for infertile patients.Altogether 110 infertile cases from March 2018 to July 2020 were grouped into the observation group (OG, 58 cases) and the control group (CG, 52 cases) according to different therapies. The OG was treated with modified HSG, while the CG was treated with conventional HSG. The tubal patency after treatment, sex hormone levels before and after therapy [including luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2)], changes in uterine volume and endometrial thickness before and after therapy were tested and compared between the CG and the OG. The individuals were followed up for one year, and the pregnancy success rate was recorded. Finally, the adverse reactions of the CG and the OG after treatment were recorded and compared.After treatment, the sex hormone level, tubal patency, uterine volume and endometrial thickness of the CG and the OG were markedly elevated, but the improvement of the OG was more obvious than that of the CG. Follow-up analysis revealed that the pregnancy success rate of theOG was markedly higher than that of theCG, and the incidence of adverse reactions in OG was markedly lower than that in CG.The modified HSG can effectively improve the pregnancy situation of patients and has higher safety compared with the traditional HSG, so it is worth popularizing in clinic.

A Validated Model for Individualized Prediction of Live Birth in Patients With Adenomyosis Undergoing Frozen-Thawed Embryo Transfer

Background There is few predictive tools for live birth in women with adenomyosis, which provide further personalized and clinically specific information related to individualized decisions making during IVF/ICSI treatment. Methods A total of 424 patients with adenomyosis underwent frozen-thawed embryo transfer (FET) from Jan 2013 to Dec 2019 at a public university hospital were included. The patients were randomly divided into training (n = 265) and validation (n = 159) samples for the building and testing of the nomogram, respectively. Multivariate logistic regression (MLR) was developed on the basis of clinical covariates assessed for their association with live birth. Results In all, 183 (43.16%) patients became pregnant, and 114 (26.88%) had a live birth. In the multivariable analysis of the training cohort, probability of live birth was significantly correlated with the age < 37 years old (odds ratio [OR], 3.465; 95% CI, 1.215–9.885, P = 0.020), uterine volume prior ET < 102.02 cm3 (OR, 8.141; 95% CI, 2.170–10.542; P = 0.002), blastocyst transfer (OR, 3.231; 95% CI, 1.065–8.819, P = 0.023), twin pregnancy (OR, 0.328; 95% CI, 0.104–0.344, P = 0.005) and protocol in FET (P < 0.001). The statistical nomogram was built based on the five variates, age, uterine volume prior embryo transfer, twin pregnancy, stage of transferred embryo and protocol of FET, with an area under the curve (AUC) of 0.837 (95% confidence interval: 0.741–0.910) for the training cohort. The AUC for the validation cohort was 0.737 (95% confidence interval: 0.661–0.813), showing a satisfactory goodness-of-fit and discrimination ability in this nomogram. Conclusions Single blastocyst transfer, GnRH-a pretreated and smaller uterine size before embryo transfer contributed to increasing live birth rate in patients with adenomyosis. The user-friendly nomogram built on the risk factors of live birth in patients with adenomyosis, provides a useful guide for medical staff on individualized decisions making during the IVF/ICSI procedure.

Deep Learning-Based Ultrasound Imaging Diagnosis for Gonadotropin-Releasing Hormone Agonists Treatment of Central Precocious Puberty

To explore the adoption of ultrasound imaging diagnosis based on deep learning of convolutional neural networks (CNNs) in the treatment of central precocious puberty (CPP) by gonadotropin-releasing hormone agonists (GnRHa), ultrasound imaging based on CNN was utilized to treat CPP. The bone age, uterine and ovarian volume, and breast development of incomplete precocious puberty (IPP) group and CPP group were observed and recorded. The peak values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. The uterine and ovarian volume before and after GnRHa treatment of CPP were compared. The results showed that the bone age (9.03 ± 1.07), uterine volume (2.37 ± 1.52), ovarian volume (2.36 ± 0.82 mL), and breast development of the CPP group were considerably higher in contrast to the IPP group and control group ( P < 0.05 ). The LH peak (11.97 ± 5.63) and FSH peak (12.89 ± 3.15) of the CPP group were substantially higher relative to the IPP group ( P < 0.05 ). The uterine volume (1.06 ± 0.42) and ovarian volume (1.12 ± 0.49) after treatment were inferior to those before treatment ( P < 0.05 ). In short, ultrasound images based on deep learning could diagnose precocious puberty, which could also provide a certain basis for GnRHa treatment of CPP, as well as an important basis for clinical diagnosis and treatment of precocious puberty.

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy

Background Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists. Case presentation A 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired. Conclusions To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Accuracy of Doppler Assessment of the Uterine Arteries in Healthy Girls for the Diagnosis of Pubertal Onset

Purpose: To evaluate the accuracy of the uterine artery pulsatility index (PI) for the diagnosis of pubertal onset in girls. Methods: Cross-sectional study of girls with normal pubertal development. Puberty was diagnosed by the presence of Tanner breast development score ≥2. All girls underwent pelvic ultrasound and Doppler imaging of the uterine arteries. We evaluated the uterine artery PI and uterine, endometrial, and ovarian measurements. We used ROC curves with cutoffs determined by Youden index for data analysis. Results: We included 169 girls aged 5-16 years who underwent 202 pelvic ultrasound examinations. Prepubertal girls had a significantly higher mean PI (mean, 6.70; SD, 2.15) than girls in initial puberty (mean, 4.14; SD, 1.55) and in late puberty (mean, 2.81; SD, 1.05) (P<0.001 for all comparisons), which reflects a progressive increase in blood flow to the uterus with the progression of puberty. ROC curve analysis showed that the PI was able to identify the onset of puberty with a mean area under the curve of 0.838 (SD, 0.04) (P<0.001), and the PI cutoff point of 5.05 had a sensitivity of 77%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 79%. The combination of PI <5.05 plus uterine volume >3.75 cm³ had a sensitivity of 73%, specificity of 95%, PPV of 97%, and accuracy of 79% to detect initial puberty. Conclusions: The significant reduction in the PI during pubertal development combined with increasing uterine volume can be a valuable, highly specific, noninvasive tool to confirm the onset of puberty.

Uterine Development During Induced Puberty in Girls with Turner Syndrome

ObjectiveMost girls and women with Turner syndrome (TS) require estrogen replacement therapy (ERT) to initiate or maintain pubertal development. Most likely, the most fundamental effect of ERT in hypogonadism is the promotion of uterine growth. The optimal ERT model is still being discussed. The present study aimed to assess uterine size in girls with TS in the prepubertal state during and after the induction of puberty and compare it to a healthy population.MethodsThe analysis encompassed 40 TS girls. The prepubertal and postpubertal control groups contained 20 healthy girls each. All patients with TS were treated with 17-ß estradiol. Uterine imaging was performed with two-dimensional (2D) transabdominal ultrasound. The uterine volume (UV) and fundocervical antero-posterior ratio (FCR) were calculated in patients with TS before the pubertal induction, after 6-12 months of estrogen replacement therapy (ERT), after ≥ 36 months of ERT or ≥ 12 months after menarche.ResultsThe average age of TS patients at estrogen introduction and at the last control visit, when the uterus was considered mature, was 12.9 years and 16.1 years, respectively. The UV in patients with TS at the beginning of ERT was 1.55 ± 1.22 cm3 and was not significantly different from the UV in the prepubertal controls. The mature UV in patients with TS was 31.04 ± 11.78 cm3 and was significantly smaller than the UV of the postpubertal controls (45.68 ± 12.51 cm3, p&lt;0.001). The FCR in girls with TS did not differ significantly from that in the prepubertal and postpubertal control groups, respectively. No prognostic factors could be established for the final UV. By the last control visit, thelarche had advanced in most patients to Tanner 4 and 5 (37.5% and 40%, respectively).ConclusionsBefore the onset of ERT, patients with TS have a uterus similar in size to that in prepubertal healthy girls. Pubertal induction in patients with TS causes a significant increase in the UV that is detectable after 6-12 months of ERT. The mature uterus is smaller in patients with TS than in the age-matched healthy population.

P–299 Efficacy and safety of linzagolix for the treatment of severe adenomyosis: Initial results from a pilot study

Study question Is a once daily regimen of the GnRH antagonist, linzagolix, high-dose (200mg) for 12 weeks then low-dose (100mg) for 12 weeks, effective in severe adenomyosis? Summary answer After 12 weeks, there was marked shrinkage of uterine volume, regression of adenomyotic lesions and symptom improvement (pain, anemia), 24 weeks data is pending. What is known already Suppression of estradiol using GnRH antagonists has been shown to be an effective treatment for endometriosis and uterine fibroids. Linzagolix is an investigational, oral GnRH receptor antagonist, which dose-dependently reduces E2 levels, providing full suppression (serum E2 &lt; 20 pg/mL) and partial suppression with once daily oral dosing of 200 mg and 100 mg, respectively. We hypothesized that a regimen of full suppression for 12 weeks followed by partial suppression maintenance therapy for 12 weeks could be effective for the treatment of severe adenomyosis. Study design, size, duration This was a single-center, open-label exploratory study in women with symptomatic adenomyosis confirmed by Magnetic Resonance Imaging (MRI) (EudraCT number: 2017–004–042–14). Patients were recruited from a single private clinic and infertility research unit between March 2019 to June 2020. Participants/materials, setting, methods Eligible patients were premenopausal women 18 to 48 years old with symptomatic uterine adenomyosis confirmed by MRI, moderate-to-severe pain and abnormal uterine bleeding. The primary measure of efficacy was the reduction in uterine volume assessed by MRI. Other endpoints included adenomyosis lesion volume, pelvic pain, haemoglobin, uterine bleeding and quality of life (EHP–30 domains: pain, control and powerlessness, emotional well-being, social support and self-image). Main results and the role of chance Eight (3 black and 5 white) enrolled subjects had mean±SD age 42±3 years and weight 75±19 kg. At baseline (day 2 of the cycle) all patients presented with pelvic pain, severe dysmenorrhea and heavy menstrual bleeding. In all cases, MRI showed an enlarged uterus (mean±SD volume 343±253 cm3) with severe adenomyosis characterized by heterogenous myometrium with multiple myometrial cysts. The mean±SD junctional zone was 29.0±14.2 mm. Median serum estradiol was suppressed to 12 pg/mL by 4 weeks and this was maintained up to 12 weeks. After 12 weeks, mean±SD uterine volume was 162±117 cm3, a 57±16% reduction from baseline, with marked regression of adenomyotic lesions and the junctional zone was 21.0±13.4 mm. Mean±SD overall pelvic pain score (0–10 NRS) was reduced from 8.4±1.1 at baseline to 2.4±3.4 (p = 0.0035) and there were also improvements in dysmenorrhea, dyspareunia, non-menstrual pelvic pain and dyschezia scores. No subjects reported uterine bleeding between Weeks 4 to 12. Mean±SD haemoglobin was 12.1±2.0 at baseline and 12.8±1.1 at 12 weeks. Anemia at baseline (≤10g/dL) was resolved by 12 weeks. Substantial improvements were observed on each of the EHP–30 domains. The most common side effect was the expected hypoestrogenic side effects of hot flushes, which were reported by 6/8 subjects. Limitations, reasons for caution This was a single-centre, open-label pilot study in 8 patients with symptomatic adenomyosis. We report the results after the first 12 weeks treatment of a high full suppression dose of linzagolix. Results after 24 weeks will further inform on the potential for a low partial suppression dose to maintain efficacy. Wider implications of the findings: The initial results of this open-label pilot study in women with severe adenomyosis indicate that a high full suppression dose of linzagolix 200 mg is effective in reducing uterine and adenomyosis lesion size, reducing abnormal uterine bleeding and pelvic pain and improving quality of life. Trial registration number EudraCT number: 2017–004–042–14