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.

Conservative Management of Uterine Adenomyosis: Medical vs. Surgical Approach

Uterine adenomyosis is a commonly encountered estrogen-dependent disease in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Although adenomyosis was previously considered a disease of multiparous women, it is becoming increasingly evident that it also affects younger nulliparous women and may compromise their fertility potential. It is clear that hysterectomy, the standard approach to definitively manage the disease, is not an option for patients wishing to preserve their fertility, so there is an urgent need to develop novel conservative strategies. We searched the current literature for available methods for conservative management of adenomyosis, including both pharmacological and surgical approaches. There is no existing drug that can cure adenomyosis at present, but some off-label treatment options may be used to tackle disease symptoms and improve fertility outcomes. Adenomyosis in patients wishing to conceive can be ‘treated’ by conservative surgery, though these procedures require highly experienced surgeons and pose a considerable risk of uterine rupture during subsequent pregnancies. While currently available options for conservative management of adenomyosis do have some capacity for alleviating symptoms and enhancing patient fertility perspectives, more effective new options are needed, with gonadotropin-releasing hormone antagonists showing encouraging results in preliminary studies.

Proceedings of the 2021 National Toxicology Program Satellite Symposium

The 2021 annual National Toxicology Program (NTP) Satellite Symposium, entitled “Pathology Potpourri,” was the 20th anniversary of the symposia and held virtually on June 25th, in advance of the Society of Toxicologic Pathology’s 40th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers’ talks along with select images that were presented to the audience for voting and discussion. Various lesions and topics covered during the symposium included differentiation of canine oligodendroglioma, astrocytoma, and undefined glioma with presentation of the National Cancer Institute’s updated diagnostic terminology for canine glioma; differentiation of polycystic kidney, dilated tubules and cystic tubules with a discussion of human polycystic kidney disease; a review of various rodent nervous system background lesions in control animals from NTP studies with a focus on incidence rates and potential rat strain differences; vehicle/excipient-related renal lesions in cynomolgus monkeys with a discussion on the various cyclodextrins and their bioavailability, toxicity, and tumorigenicity; examples of rodent endometrial tumors including intestinal differentiation in an endometrial adenocarcinoma that has not previously been reported in rats; a review of various rodent adrenal cortex lesions including those that represented diagnostic challenges with multiple processes such as vacuolation, degeneration, necrosis, hyperplasia, and hypertrophy; and finally, a discussion of diagnostic criteria for uterine adenomyosis, atypical hyperplasia, and adenocarcinoma in the rat.

Identifying Common Pathogenic Features in Deep Endometriotic Nodules and Uterine Adenomyosis

Increasing imaging data point to a link between deep endometriotic nodules (DENs) and uterine adenomyosis (AD). The study aimed to investigate this link at the histological level and detect potential features shared by the two diseases. We collected formalin-fixed paraffin-embedded tissue (endometrium and lesions) from women with DENs of the rectovaginal septum (n = 13), AD (n = 14), and control subjects (n = 14). Immunohistochemical analyses of CD41 and CD68 were conducted to explore the roles of platelets and macrophages, respectively. Picrosirius red staining was carried out to gather evidence of fibrosis. Vascular endothelial growth factor (VEGF) was assessed, and total numbers of CD31-positive vessels were calculated to investigate the mechanism governing angiogenesis. Double immunohistochemistry for CD31 and alpha smooth muscle actin (αSMA) was performed to discern stable vessels. Platelet aggregation was significantly decreased in both types of lesions compared to their corresponding eutopic endometrium and healthy controls. Macrophage numbers were higher in both lesions than in their corresponding endometrium and healthy subjects. Significantly higher rates of collagen accumulation were detected in DENs and AD lesions compared to their corresponding eutopic and healthy endometrium. VEGF expression was downregulated in the stromal compartment of AD lesions compared to the healthy endometrium. The total number of vessels per area was significantly higher in DENs and AD lesions than in the healthy endometrium. Rates of αSMA-surrounded vessels were decreased in DENs and AD lesions compared to their corresponding eutopic and healthy endometrium. We report common pathogenic mechanisms between DENs and AD, namely excessive macrophage accumulation, fibrosis, and irregular angiogenesis. Our results further support the notion of DENs and AD being linked at the histological level.

Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

P–287 Uterine adenomyosis does not affect perinatal outcomes in ART treatments

Study question Is adenomyosis associated with worse clinical and perinatal outcomes in ovum donation cycles? Summary answer Adenomyosis was associated with reduced live birth rate per embryo transfer but not with increased risk of miscarriage or worse perinatal outcomes than controls. What is known already The effect of adenomyosis on IVF/ICSI outcomes are controversial as studies addressing this issue are limited in number and heterogeneous. Conclusions withdrawn from previous works differ regarding the prospective or retrospective design of the study. Two different metanalysis conducted showed that adenomyosis reduced implantation and clinical pregnancy rate and increased miscarriage risk. However, current data regarding perinatal outcomes of assisted reproduction techniques cycles in patients diagnosed with uterine adenomyosis is scarce. Study design, size, duration A retrospective cohort study in which 3307 patients undergoing ovum donation cycles were included. Patients who underwent single embryo transfer (SET) between years 2018 and 2019 were included and divided into two groups: adenomyosis (n = 179) and controls (n = 3218). Participants/materials, setting, methods Inclusion criteria consisted of patients in an oocyte donation program who had fresh SET on day 5 blastocyst stage development. Patients diagnosed with miomas and/or severe endometriosis and those who had undergone previous uterine surgical interventions were excluded from the study. Cases consisted of patients with a history of either focal or diffuse adenomyosis diagnosed via transvaginal ultrasonography (TVUS). Main results and the role of chance Clinical pregnancy rate per embryo transfer was 82/179 (45.8%) in those women diagnosed with adenomyosis versus 1869/3218 (59.8%) in control group (OR = 0.57 95% CI. 0.41–0.78, p < 0.001). Miscarriage rate was similar in the two study groups and differences found were not statistically significant, being 15/82 (18.3%) for adenomyosis and 309/1869 (16.5%) for control group. A lower live birth rate per embryo transfer was observed in women diagnosed with adenomyosis versus control, being 68/179 (38%) and 1560/3128 (49.9%) respectively (OR = 0.615 95% CI 0.44–0.85, p = 0.002). There were no statistically significant differences between childbirth delivery methods (vaginal versus caesarean section). Furthermore, means of gestational age at the time of delivery, newborn size and weight and incidences of low birth weight, preterm birth and admission in neonate intensive care unit (NICU) did not differ between the two groups. In addition, IVF and perinatal outcomes were similar in patients with diffuse adenomyosis compared to focal adenomyosis. Limitations, reasons for caution This is an observational study and thus possible confounders cannot be completely excluded. Diagnostic of adenomyosis is complex and, despite imaging via TVUS is both sensitive and specific, different criteria may be combined in order to fully assess the diagnostic. Wider implications of the findings: Published literature has described how adenomyosis negatively impacts clinical outcomes in ART cycles; however, data regarding perinatal results is scarce. This study is of interest as it provides a first insight for clinicians showing that adenomyosis affects clinical but not perinatal outcomes in ovum donation cycle. Trial registration number Not applicable