Progestin Treatment Research Articles

Retrospective study of the factors involved in the development of adenomyosis and the in vitro link between adenomyosis and breast cancer.

Adenomyosis is a heterogeneous disease, which differs from patient to patient. The objective of our study was to evaluate the risk factors that influence the occurrence of adenomyosis, more precisely to highlight aspects that may be used in practice. In addition, the in vitro impact of levonorgestrel (a possible predisposing factor in the occurrence of adenomyosis) on MDA-MB-231 cells was evaluated, trying to obtain a link between adenomyosis and mammary cancer. Clinical and demographic data of patients diagnosed with adenomyosis hospitalized between January and September 2023 in the Obstetrics-Gynecology Clinic were analyzed. For the in vitro assays, the MTT and LDH method was used to investigate the effect on cell viability and the potential cytotoxic effect of LG on MDA-MB-23 cells. Out of a total of 99 hysterectomies performed, the diagnosis of adenomyosis was confirmed by ultrasound in 28 cases. Among our patients, we could observe that most of cases of adenomyosis developed in women between 40 and 45 years old. Multiple pregnancies can influence the development of this uterine pathology, along with a history of uterine surgery and abortions. It was also found that treatment with sex hormones can increase the risk of adenomyosis. Our in vitro study has showed that LG stimulates the proliferation of MDA-MB-231 cells depending on the dose and time. Personal history along with progestin treatment may influence myometrial lesions, leading to diffuse or focal adenomyosis. Moreover, in vitro, LG has been shown to stimulate the proliferation of breast cancer cells.

Progestin-primed ovarian stimulation outcomes in in-vitro fertilization (IVF) – A systematic review of the literature

Background: Progestin-primed ovarian stimulation (PPOS) stimulates ovaries to block the premature surge of luteinizing hormone (LH) by using micronized progesterone or a progestin during the follicular phase instead of the conventional gonadotropin-releasing hormone (GnRH) analogues or GnRH antagonists downregulating LH to obtain multi-follicle engagement. Current work aims to assess the influence of progestogen treatment on ovarian stimulation and the ability to control LH surge, its efficacy and suitability in retrieving oocytes, without affecting the embryo quality and its benefit among infertile women long-term outcomes on children compared to standard stimulation protocols. Materials and Methods: The literature review used the randomized control trials published in the Pubmed database from January 2015 to April 2021. To generate the citation list, the following keywords were used: ‘progestin-primed ovarian stimulation’, ‘PPOS’, ‘micronized progesterone’, ‘medroxyprogesterone’, and/or ‘dydrogesterone’. The selected articles analyzed the cohort, intervention, and scheme of the progestin-primed ovarian stimulation protocol in controlled ovarian stimulation (COS) for in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) used in Assisted Reproductive Technologies (ART). Results: Overall we concluded that PPOS for IVF/ICSI in ART results in a higher number of obtained embryos, lower incidence of OHSS, equal duration of stimulation, number of retrieved oocytes, and number of MII oocytes. It is also suggested that long-term safety in children shows no significant difference between the study and control groups. Conclusions: Despite the outcomes of progestin stimulation cycles among all cohorts, we concluded that poor ovarian responders, patients with PCOS, women of advanced age and oocyte donors benefit the most from using PPOS.

12565 Expression Of Sex Hormone Receptors In Levator Ani Muscle Tissue From Patients With Pelvic Organ Prolapse

Abstract Disclosure: T. You: None. A. Halle: None. W. Xu: None. T. Potluri: None. H. Nguyen: None. S.E. Bulun: None. J. Julia Geynisman-Tan: None. H. Zhao: None. Introduction: Women with pelvic floor disorders usually have weakened pelvic floor muscles, which may cause urinary incontinence, fecal incontinence, and pelvic organ prolapse (POP). Histologically, the pelvic floor musculature in POP patients displays increased fibrosis and muscle atrophy. However, the underlying molecular mechanism for POP has not been fully investigated. We and others found that estrogen causes pelvic skeletal muscle fibrosis and inguinal hernias in male animal models. Additionally, clinical trials from the Women's Health Initiative showed women receiving estrogen-only or estrogen plus progestin treatment had statistically significant increases in the risk for urinary incontinence. However, the role of estrogen, progesterone, androgen, and their receptor expression in pelvic floor muscle is not well studied. Methods: TruCut biopsy needles were used to obtain levator ani (LA, the major pelvic floor muscle) biopsies from four groups of patients undergoing surgery: (i) 5 premenopausal women with stage II/III POP (age 38-52 years), (ii) 5 postmenopausal women with stage III POP (59-75 years), (iii) 5 age and parity matched premenopausal controls, and (iv) 5 age and parity matched postmenopausal controls. The control patients did not have any POP (stage 0) or only had sole stress urinary incontinence. H&E staining, Masson’s trichrome staining, and immunohistochemistry (IHC) staining for estrogen receptor α (ERα), progesterone receptor (PGR), and androgen receptor (AR) were performed in LA muscle tissue. Standard patient demographics (age, parity, and diagnosis) were collected. Results: We used H&E staining to morphologically assess stromal cells and myofibers obtained from LA muscle biopsies. Masson’s trichrome staining showed extracellular matrix deposition in the LA muscle from women with or without POP. In addition, we found ERα was present in the stromal cells from nearly every LA biopsy using IHC staining. ERα expression (H-Score) was similar in four groups of patients. ERα IHC staining was absent in LA myofibers. AR was highly expressed in stromal cells in all LA muscles and weakly expressed in myofibers in ∼70% of LA tissues. AR expression (H-Score) was significantly decreased in postmenopausal women with stage III pelvic organ prolapse. PGR was only expressed in a small portion of the LA sample (30%), with PGR exclusively expressed in the stroma of the LA muscle. Conclusion: Our findings indicate that sex hormone receptors (ERα, AR, and PGR) are present in LA muscle stroma, providing the foundation to further define the roles of sex steroid hormones in pelvic organ prolapse. Presentation: 6/3/2024

Integrated histological parameters define prognostically relevant groups in atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia

ObjectiveTo assess the risk of endometrial carcinoma following a diagnosis of atypical hyperplasia/endometrioid intraepithelial neoplasia by endometrial biopsy, stratified based on integrated histological parameters.MethodsAll women with atypical hyperplasia/endometrioid intraepithelial neoplasia...

Outcomes of extended progestin therapy in atypical endometrial hyperplasia patients without an initial response to progestin: a retrospective study from two tertiary centers in Korea and Taiwan.

In this study, we evaluated the role of prolonged progestin treatment on atypical endometrial hyperplasia (AEH) patients who did not achieve complete regression (CR) after at least 3 months of progestin treatment. Possible prognostic factors predicting disease regression and recurrence were also assessed. We retrospectively identified patients who had histologically confirmed persistent disease after at least 3 months of progestin treatment at two tertiary centers in Korea and Taiwan. Clinicopathologic factors and clinical outcomes were obtained from medical records. Logistic regression was used to analyze the relationship between covariates and the probability of CR and relapse. Fifty-two patients were included. Thirty-seven of 52 patients (71.2%) achieved CR after prolonged progestin treatment. Median time from starting progestin treatment to CR was 12.0 months. Daily administration of medroxyprogesterone acetate ≥200 mg or megestrol acetate ≥80 mg was associated with higher probability of regression. Nineteen of 37 patients (51.4%) experienced recurrence, with median time from CR to relapse of 15.0 months. Body mass index ≥27 was associated with higher relapse probability. Twelve of 16 patients with disease progression to endometrial carcinoma underwent surgery. The 12 cases had stage I tumors and lived without disease. Extension of progestin treatment course is feasible for AEH patients without an initial response to progestin. Higher daily progestin dosage was associated with higher probability of CR, and obesity was associated with higher risk of relapse. The patients without an initial response to progestins and whose AEH progressed to endometrial carcinoma had good prognoses.

Clinicopathological characteristics and fertility preserving treatment of atypical polypoid adenomyoma.

Atypical polypoid adenomyoma (APA) is a rare benign tumor frequently diagnosed in young women that may coexist with or progress to atypical endometrial hyperplasia (EAH) or endometrioid endometrial carcinoma (EEC). This study aimed to investigate which subset of patients with APA are prone to concurrent or subsequent EAH or EEC, evaluate the necessity of progestin treatment in patients with APA only after achieving a complete response (CR) through hysteroscopic lesion resection, and assess the impact of concurrent APA on the fertility-preserving treatment of EAH or EEC. This retrospective single-center study analyzed 86 patients with APA treated at the Obstetrics and Gynecology Hospital of Fudan University between January 2010 and October 2021. Patients with EAH or EEC only who underwent fertility-preserving treatment during the same period were matched in a 2:1 ratio with patients with concurrent APA and EAH or EEC. The clinicopathological characteristics, treatments, and prognosis were analyzed. The median patient age was 31 years (range 21-47 years). Among the 86 included patients, nine underwent total hysterectomy, 62 received conservative treatment, and the remaining 15 were lost to follow-up. A comparison of the 16 patients with APA only versus the 58 patients with APA and concurrent or subsequent EAH or EEC revealed that a homeostasis model assessment of insulin resistance (HOMA-IR) of > 2.2 (P = 0.047) and high-density lipoprotein (HDL) concentration of < 1.2 mmol/L (P = 0.028) were independent risk factors for EAH or EEC in patients with APA. Among the 17 patients with APA only who received conservative treatment and achieved a CR after hysteroscopic lesion resection, 13 received hormone treatment for a median duration of 6.3 months. The median follow-up time for these 17 patients was 49.0 months, during which no recurrence of APA was observed, but six patients developed endometrial hyperplastic diseases. Regarding the impact of concurrent APA on fertility-preserving treatment for EAH or EEC, the median time to achieve a CR was 24.0 weeks (95% confidence interval [CI]: 23.0-40.4) in the APA group and 26.0 weeks (95% CI: 24.3-32.3) in the non-APA group (P = 0.424). There were no significant differences between the two groups in the outcomes of fertility-preserving treatment. Patients with APA only may still develop endometrial hyperplastic diseases after complete resection of the lesion under hysteroscopy to achieve a CR, particularly those with a HOMA-IR of > 2.2 or HDL concentration of < 1.2 mmol/L. Concurrent APA did not affect the efficacy of fertility-preserving treatment in patients with EAH or EEC.

Factors influencing pregnancy rate and loss after laparoscopic artificial insemination with frozen-thawed semen in Lohi sheep under sub-tropical conditions.

This study evaluates factors influencing pregnancy rates per artificial insemination (P/AI) and pregnancy loss in Lohi ewes undergoing laparoscopic AI with frozen-thawed semen under sub-tropical conditions. Data from three experiments comprising ewes (n = 358) of mixed parity (nulliparous; NP and parous; P), various body condition score (BCS) and assigned to long-term (LTP, 11 days) and short-term (STP, 5 days) oestrus synchronization regimen across high breeding season (HBS) and low breeding season (LBS) were analysed. Laparoscopic insemination was conducted 54 h post-sponge removal. Pregnancy diagnosis and loss were evaluated on days 35 and 90 post-insemination via ultrasonography. Results showed parity significantly influenced P/AI, with nulliparous ewes achieving higher pregnancy ratios than parous ewes (p = .001). BCS significantly influenced P/AI (p < .05), with a quadratic relationship observed between BCS and season (BCS*BCS*Season; p = .07). Progestin treatment did not significantly influence the ratio of pregnant ewes (p = .07). Pregnancy losses were significantly higher during LBS than HBS (p < .05), irrespective of progestin treatment. In conclusion, parity and BCS significantly influenced P/AI, with BCS demonstrating a quadratic association with season. Ewes bred during LBS experienced higher pregnancy losses than HBS, irrespective of progestin treatment.

Treatment outcomes according to various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia – Multicenter retrospective study (KGOG2033)

ObjectiveTo investigate pathologic complete response (pCR) and recurrence outcomes using various progestin treatment strategies in patients with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN). MethodsMedical records of patients diagnosed with AH/EIN and undergoing follow-up endometrial biopsy after progestin treatment between 2011 and 2020 were retrospectively reviewed. Clinical factors and treatment outcomes were analyzed according to initial progestin treatment (oral progestin [OP], levonorgestrel-releasing intrauterine device [LNG-IUD], and combination), OP dose, and maintenance treatment using Pearson's χ2, Fisher's exact test, and Kaplan-Meier analysis. ResultsOf 124 patients included, 74, 37, and 13 were in the OP, LNG-IUD, and combination groups, respectively. The pCR rate was 79.8% and recurrence rate was 21.2%. The pCR rates within 3 and 6 months were significantly higher in the OP group than in the LNG-IUD group, but were not significantly different within 12 and 24 months. Recurrence rate was significantly higher in the OP group than in the LNG-IUD group. The pCR rate and recurrence rate had no significant differences between the combination group and the other groups. Excluding the LNG-IUD group, 53 and 34 patients received low- and high-dose OP, respectively. The pCR and recurrence rates were comparable between the low- and high-dose OP groups. Maintenance therapy was significantly associated with lower recurrence rate. ConclusionsAlthough OP alone achieved more short-term pCR than the other groups, more recurrences occurred after pCR than LNG-IUD alone. High-dose OP as well as combination of OP and LNG-IUD did not increase pCR or reduce recurrence. Maintenance therapy may reduce the recurrence rate after pCR.

Abstract B030: DNA methylation profiling identifies subset of low-grade endometrial neoplasms with poor response to progestin therapy

Abstract Purpose: We aimed to investigate the DNA methylation profile of low-grade endometrial neoplasms before and after progestin therapy. Methods: This is a retrospective cohort of patients with endometrial intraepithelial neoplasia/atypical hyperplasia (EIN/AH) and grade 1 endometrial endometrioid carcinoma (EEC) treated with progestin therapy. DNA was extracted from 24 formalin-fixed paraffin-embedded (FFPE) tumors before and 19 tumors after progestin therapy (median interval between specimens: 12.1 months). Methylation profiling was performed using the Illumina Infinium Methylation EPIC array. Laser-capture microdissection was used to enrich samples with low tumor content. Results: Twenty-four patients with a median age of 38 years were included. Majority of patients were nulligravid (58%), and self-identified as non-Hispanic (83%) and white (42%). Ten patients had a diagnosis of EIN/AH, while 14 were grade 1 EEC. Ten cases showed complete response, 7 partial responses, 8 showed no response between the pre- and post-treatment samples. Ten patients had regression of disease on follow-up, while 9 showed persistent tumor. In 5 patients, clinical outcome could not be assessed due to short time of exposure (&amp;lt;6 months). Unsupervised clustering based on top 3,000 differentially methylated sites (DMS) in 24 pre-treated tumors identified 2 different groups. Cluster 1 (n= 11) was composed of significantly older patients (p=0.047; median age: 39 vs 37 years) and more likely to have EEC on histologic examination (p=0.016; 100% vs 54%). Tumors in Cluster 1 were more likely to show absence of pathologic response following progestin therapy (p= 0.038; 55% vs 8%). Although no statistical significance was reached regarding clinical outcome (p=0.2), patients in Cluster 1 showed regression of disease in only 29% of cases (2/7), while in Cluster 2, 67% of patients showed regression of tumor (8/12). There was no difference regarding gravidity, race/ethnicity, body mass index, type of progestin, and follow-up time. KEGG pathways analysis revealed that the most significantly different pathways between the 2 clusters were: maturity onset diabetes of young, neuroactive ligand-receptor interaction, and signaling pathways regulating pluripotency of stem cells. Pairwise differential DNA methylation analysis between 15 pairs of pre- and post-treatment samples that passed quality control showed a hypermethylation effect of progestin therapy in the majority of DMS, including sites in open sea, northern and southern shores and shelves. Although there were sites in CpG islands with a hypermethylation pattern after treatment, progestin therapy had a predominantly hypomethylation effect on CpG islands. The gene set enrichment based on DMS showed significant change in genes mostly related to cell-cell adhesion following progestin therapy. Conclusion: DNA methylation profiling identifies a subset of EIN/AH and grade 1 EEC with poor response to progestin therapy. The methylation landscape of these low-grade neoplasms undergoes changes after progestin treatment. Citation Format: Lawrence H. Lin, Kyriaki Founta, Nyasha Chambwe, Deborah F. DeLair. DNA methylation profiling identifies subset of low-grade endometrial neoplasms with poor response to progestin therapy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B030.

Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.

To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed. HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.

Nationwide status of progestogen treatment to prevent spontaneous preterm birth: A questionnaire survey for childbirth healthcare facilities in Japan.

This study aimed to investigate the current status of progestogen treatment for pregnant women at a high risk for preterm birth (PTB) in childbirth healthcare facilities in Japan. A web-based nationwide questionnaire survey regarding progestogen use for prevention of PTB was conducted among childbirth healthcare facilities from 2019 to 2021. Valid responses were obtained from 528 facilities (25.2% of those surveyed), including 155 tertiary perinatal facilities (making up 92.3% of all tertiary perinatal care facilities). In the survey period, progestogen treatment was implemented in 207 facilities (39.2%) for PTB prevention. Regarding types of progestogens, 17α-hydroxyprogesterone caproate was used in 170 facilities (82.1%), with a low dose (125 mg/week) administered in 62.9% of the facilities to comply with the regulations of the national health insurance system, although 250 mg/week is considered the best dose. Vaginal progesterone was used in 36 facilities (17.4%), although the cost of vaginal progesterone was not covered by health insurance. Of the facilities not administering progestogen treatment, approximately 40% expressed that vaginal progesterone would be their first choice for PTB prevention in daily practice if it would be covered by health insurance in the future. Due to the current regulations of the Japanese health insurance system, 17α-hydroxyprogesterone caproate, rather than vaginal progesterone, was mainly used for PTB prevention. Despite global evidence supporting vaginal progesterone as the approach with the highest efficacy, only a limited number of facilities have utilized it due to the current drug use regulations in Japan.

Progesterone-induced progesterone receptor membrane component 1 rise-to-decline changes are essential for decidualization.

Decidualization of endometrial cells is the prerequisite for embryo implantation and subsequent placenta formation and is induced by rising progesterone levels following ovulation. One of the hormone receptors contributing to endometrial homeostasis is Progesterone Receptor Membrane Component 1 (PGRMC1), a non-classical membrane-bound progesterone receptor with yet unclear function. In this study, we aimed to investigate how PGRMC1 contributes to human decidualization. We first analyzed PGRMC1 expression profile during a regular menstrual cycle in RNA-sequencing datasets. To further explore the function of PGRMC1 in human decidualization, we implemented an inducible decidualization system, which is achieved by culturing two human endometrial stromal cell lines in decidualization-inducing medium containing medroxyprogesterone acetate and 8-Br-cAMP. In our system, we measured PGRMC1 expression during hormone induction as well as decidualization status upon PGRMC1 knockdown at different time points. We further conferred proximity ligation assay to identify PGRMC1 interaction partners. In a regular menstrual cycle, PGRMC1 mRNA expression is gradually decreased from the proliferative phase to the secretory phase. In in vitro experiments, we observed that PGRMC1 expression follows a rise-to-decline pattern, in which its expression level initially increased during the first 6days after induction (PGRMC1 increasing phase) and decreased in the following days (PGRMC1 decreasing phase). Knockdown of PGRMC1 expression before the induction led to a failed decidualization, while its knockdown after induction did not inhibit decidualization, suggesting that the progestin-induced 'PGRMC1 increasing phase' is essential for normal decidualization. Furthermore, we found that the interactions of prohibitin 1 and prohibitin 2 with PGRMC1 were induced upon progestin treatment. Knocking down each of the prohibitins slowed down the decidualization process compared to the control, suggesting that PGRMC1 cooperates with prohibitins to regulate decidualization. According to our findings, PGRMC1 expression followed a progestin-induced rise-to-decline expression pattern during human endometrial decidualization process; and the correct execution of this expression program was crucial for successful decidualization. Thereby, the results of our in vitro model explained how PGRMC1 dysregulation during decidualization may present a new perspective on infertility-related diseases.

Predicting Progestin Therapy Response With PTEN, PAX2, and β-Catenin in Patients With Endometrioid Precancer.

This study investigates the predictive value of biomarkers PTEN, PAX2, and β-catenin for therapeutic outcomes in patients with atypical endometrial hyperplasia or endometrioid intraepithelial neoplasia undergoing progestin therapy. In a retrospective study of 128 patients, we analyzed a total of 351 endometrial biopsy samples and categorized outcomes into responders (absence of residual disease) and nonresponders (presence of residual disease). We found aberrant biomarker expression in pretreatment cases: 48% for PTEN, 65% for PAX2, and 36% for β-catenin. Approximately 77.3% of patients responded to progestin treatment, with nonresponders showing significantly higher initial PTEN loss (75.86% vs 39.79%, P < 0.001). Nonresponders also demonstrated significant PTEN loss (53.33% vs 20.55%, P < 0.001), PAX2 loss (57.33% vs 41.22%, P < 0.05), and β-catenin nuclear staining (53.45% vs 27.91%, P < 0.01) in follow-up samples. In addition, nonresponders exhibited lower recovery of intact PTEN and PAX2, along with higher β-catenin aberrancy in cases initially showing normal β-catenin levels. We conclude that persistent aberrant PTEN and PAX2 expression, coupled with emerging aberrant β-catenin in follow-ups, indicates a greater likelihood of treatment failure. Conversely, the absence of these aberrations suggests successful progestin therapy. Our findings highlight the utility of this 3-marker panel in assessing residual disease status and predicting progestin treatment outcomes, thus offering critical insights for patient management.

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice.

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1-, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2α. Treatment with 17-α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy.IMPORTANCEPregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. When outbred dams, with semi-allogenic fetuses, were infected with 2009 H1N1, in addition to pulmonary virus replication, lung damage, and inflammation, the placenta showed evidence of transient cell death and inflammation that was mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone were associated with detrimental effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment that is safe to use in pregnancy, prevented placental damage and inflammation and adverse fetal outcomes. This novel therapeutic option for the treatment of influenza during pregnancy should be explored clinically.

Weight-Loss and Metformin-Use Improve the Reversal Rate in Patients with Endometrial Hyperplasia.

To evaluate the therapeutic outcomes of weight loss and metformin use in patients with endometrial hyperplasia (EH), and to identify the factors influencing treatment efficacy. This study included data from patients diagnosed with either EH or endometrial atypical hyperplasia (EAH). Patients selected a progestin treatment regimen based on their diagnosis. Those with concurrent obesity or insulin resistance received additional weight management support and metformin therapy. Follow-up assessments were conducted every 3-6 months. A total of 202 patients were included. The metformin group exhibited significantly greater improvement in abnormal uterine bleeding (91.5% vs 57.1%, p < 0.001) and in ultrasound findings (91.5% vs 66.7%, p < 0.001) than the non-metformin group. Patients who achieved >3% weight loss and those using metformin showed a significantly higher rate of disease reversal than those with ≤3% weight loss (91.2% vs 77.6%, p = 0.034) and the non-metformin group (93.2% vs 52.4%, p < 0.001). At follow-up durations exceeding 12 months, metformin use was associated with a significantly higher disease reversal rate (82.1% vs 42.9%, p = 0.048) and a lower recurrence rate (12.8% vs 28.6%, p = 0.048). Weight loss of >3% (odds ratio: 0.041, 95% confidence interval: 0.004-0.437, p = 0.008) and metformin use (odds ratio: 0.059, 95% confidence interval: 0.011-0.311, p = 0.001) were both independently associated with improved reversal rates in patients with EH/EAH. Combining progestin therapy with weight loss and metformin is more effective in reversing EH than progestin alone. Regular metformin use, alongside weight loss, serves as a protective factor in EH management, with the protective effect of metformin increasing with longer use.

Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.

Impact of abnormal uterine bleeding care in premenopausal patients prior to endometrial malignancy diagnosis

BackgroundLiterature evaluating the management of abnormal uterine bleeding in premenopausal patients prior to endometrial malignancy diagnosis is lacking. ObjectiveTo evaluate predictors and consequences of inadequate evaluation and management of abnormal uterine bleeding and time to endometrial sampling in premenopausal patients prior to endometrial malignancy diagnosis.Study Design.This was a retrospective cohort study of premenopausal individuals with endometrioid endometrial cancer or atypical hyperplasia at a single institution from 2015 to 2020.. Complete noninvasive management encompassed pelvic exam, ultrasound, and progestin treatment before or in conjunction with the endometrial sampling of diagnosis. Multivariable logistic and ordinal odds models were used to evaluate predictors and outcomes. Results152 subjects were included, 80.3 % with cancer and 19.7 % with atypical hyperplasia. The majority of patients had anovulatory bleeding, obesityand recent health care. Only 20.4 % had complete nonvinvasive management, and only 12.5 % had complete noninvasive management or endometrial sampling within 2 months of presentation with abnormal bleeding. Class III obesity reduced the likelihood of complete assessment and increased time to sampling, while age 45 and up and parity reduced time to sampling. Most patients had partial workup but no progestin treatment and long intervals before endometrial sampling after presentation to a provider with abnormal bleeding. Incomplete workup correlated to worse cancer grade and stage. ConclusionDespite high clinical risk and health care contact, most patients had insufficient gynecologic management preceding a diagnosis of endometrial malignancy. Inadequate care correlated to worse oncologic outcomes and demonstrates missed opportunities for early detection and prevention of endometrial cancer.

Age as a Predictor of Time to Response for Patients Undergoing Medical Management of Endometrial Cancer

Objective: To explore the pathologic response rate to primary progesterone treatment in patients with Endometrial Intraepithelial Neoplasia (EIN) and early-stage endometrioid-type Endometrial Adenocarcinoma (EAC). Methods: Retrospective chart data were collected for patients with either EIN or EAC receiving primary progesterone treatment between 2015 and 2022. The presence of complete or partial response, time to response, and other demographic and treatment factors were recorded to determine independent predictors of response to progestin treatment. Results: In total, 112 women who were diagnosed with EIN or EAC were treated with upfront progestin therapy, of whom 79 had sufficient follow-up to assess response. Fifty patients (63%) responded, of whom 10 (20%) ultimately relapsed. Response was more robust among patients with EIN (79%, n = 33) compared with patients who had cancer (46%, n = 17). The median time to respond was 5.8 months overall. Diagnosis of EIN, younger age at diagnosis, and any pathologic evidence of progesterone effect were all predictors of treatment response. Younger patients had a significantly shorter time to partial or complete response with a median time to response of 5.9 months in patients ≤ 45 and 13.8 months in patients &gt; 45. Conclusion: Our study demonstrated a lower overall response rate (63%) than reported in previous studies, especially for patients with cancer (46%). Younger patients had a significantly shorter time to respond than older patients. Pathologic progesterone effect observed at any time during treatment was a significant predictor of treatment response regardless of diagnosis and could serve as an early predictor of response to therapy.

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.