Reproductive outcomes of dual trigger therapy with GnRH agonist and hCG versus hCG trigger in women with diminished ovarian reserve: a retrospective study.

BACKGROUND: Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin-releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols. METHODS: A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors. RESULTS: There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted ß = 0.538 (0.221-0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted ß = 0.277 (0.031-0.523)] and transferable embryos [1.22 vs. 0.95, adjusted ß = 0.162 (-0.005-0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR. CONCLUSIONS: Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.

The Effect of Hormonal Treatment on Ovarian Endometriomas: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effect of hormonal suppression of endometriosis on the size of endometriotic ovarian cysts. DATA SOURCES: The authors searched MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov from January 2012 to December 2022. METHODS OF STUDY SELECTION: We included studies of premenopausal women undergoing hormonal treatment of endometriosis for ≥3 months. The authors excluded studies involving surgical intervention in the follow-up period and those using hormones to prevent endometrioma recurrence after endometriosis surgery. Risk of bias was assessed with the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool. The protocol was registered in PROSPERO (CRD42022385612). TABULATION, INTEGRATION, AND RESULTS: The primary outcome was the mean change in endometrioma volume, expressed as a percentage, from baseline to at least 6 months. Secondary outcomes were the change in volume at 3 months and analyses by class of hormonal therapy. The authors included 16 studies (15 cohort studies, 1 randomized controlled trial) of 888 patients treated with dienogest (7 studies), other progestins (4), combined hormonal contraceptives (2), and other suppressive therapy (3). Globally, the decrease in endometrioma volume became statistically significant at 6 months with a mean reduction of 55% (95% confidence interval, -40 to -71; 18 treatment groups; 730 patients; p <.001; I2 = 96%). The reduction was the greatest with dienogest and norethindrone acetate plus letrozole, followed by relugolix and leuprolide acetate. The volume reduction was not statistically significant with combined hormonal contraceptives or other progestins. There was high heterogeneity, and studies were at risk of selection bias. CONCLUSION: Hormonal suppression can substantially reduce endometrioma size, but there is uncertainty in the exact reduction patients may experience.

The effect of protocatechuic acid on ovarian histopathology and reserve in rat ovarian torsion model.

OBJECTIVES: The aim of the study is to investigate the effects of Protocatechuic Acid (PCA), which is an antioxidant, anti-inflammatory and anti-apoptotic agent, on ovarian tissue and ovarian reserve against ischemia-reperfusion (IR) injury in a rat ovarian torsion model. BACKGROUND: Reactive oxygen radicals cause histopathological changes in the ovarian tissue during the reperfusion phase. PCA may have protective effects on ovarian tissue and reserve due to its antioxidant and antiapoptotic properties. METHODS: A total of 24 Wistar adult female rats were divided into 3 groups as the control (sham operation, n = 8), IR (Ischemia-Reperfusion, n = 8), and IR+PCA (Ischemia-Reperfusion + 80 mg/kg protocatechuic acid, n = 8). The IR and IR + PCA groups underwent 3 hours of ischemia followed by 3 hours of ovarian reperfusion. Protocatechuic acid (80 mg/kg) was administered to the IR+PCA group 30 minutes before reperfusion. After reperfusion, the ovaries were removed for histopathological and biochemical examination. RESULTS: Histopathological score and TUNEL+ cell count were significantly lower and AMH expression level was significantly higher in the IR+PCA group when compared to the IR group (p <0.05). However, in the comparison of the follicle counts, there was no statistically significant difference between all groups. Due to the increase in antioxidant activity, the MDA levels were found to be significantly lower in the IR+PCA group compared to the IR group (p < 0.05). CONCLUSION: Protocatechuic acid may be an effective antioxidant in protecting ovarian tissue and follicle reserve against IR injury of the ovary (Tab. 1, Fig. 4, Ref. 36).

Image-guided drainage management of tubo-ovarian abscess and the role of C-reactive protein measurements in monitoring treatment response: a single-center experience.

PURPOSE: We aimed to compare the results of image-guided drainage in addition to antibiotic therapy (antibiotherapy) with antibiotherapy alone in the treatment of tubo-ovarian abscesses (TOAs) and evaluate C-reactive protein (CRP) levels in predicting the success of antibiotherapy. METHODS: This was a retrospective study of 194 patients hospitalized with TOA. Patients were divided into the following two groups: those who underwent image-guided drainage in addition to parenteral antibiotherapy and those who did not undergo image-guided drainage and received antibiotherapy alone. CRP levels on the day of admission (day 0), day 4 of hospitalization (day 4), and day of discharge (last day) were recorded. The percentage of decrease in CRP levels during day 4 and the last day compared with that on day 0 was calculated. RESULTS: A total of 106 patients (54.6%) underwent image-guided drainage with antibiotherapy, whereas 88 patients (45.4%) did not undergo drainage and received antibiotherapy alone. At admission, the mean CRP level was 203.4 (± 96.7) mg/L and was similar in both groups. The mean decrease in the CRP level on day 4 compared with that on day 0 was 48.5% and was statistically higher in the group that underwent image-guided drainage. Antibiotherapy failed in 18 patients, and a statistically significant difference was observed between treatment failure and the rate of decrease in the CRP level on day 4 compared with that on day 0. According to the receiver operating characteristic (ROC) analysis, if the CRP level measured on day 4 decreased by < 37.1% compared with that on day 0, the probability of treatment failure would increase (area under the curve = 0.755; 95% confidence interval, 0.668-0.841; sensitivity, 73.6%; specificity, 60%). CONCLUSIONS: Image-guided drainage combined with antibiotherapy in the treatment of TOA has high success rates, lower recurrence rates, and lower surgical requirement, and the mean decrease in the CRP level on day 4 can be monitored at treatment follow-up. In patients receiving antibiotherapy alone, if the CRP level on day 4 decreases by < 37.1%, the treatment protocol should be changed.

Artemisinin reduces acute ovarian ischemia-reperfusion injury in rats.

Artemisinin (ARS) is well known as an effective agent in the treatment of malaria through the rapid elimination of Plasmodium falciparum parasites. This study aims to investigate the effect of ARS in treating adnexal torsion, one of the most common gynecological surgical emergencies. ARS was administered intraperitoneally once 30 min before unilateral ovarian torsion in two different doses (10 mg/kg vs. 50 mg/kg). Torsion was maintained for 3 h and then held in the detorted state for 3 h. Bilateral adnexectomy was performed to measure antioxidant enzyme activities and oxidant levels on the ipsilateral ovary and to make histopathological and immunohistochemical analyses on the contralateral ovary. Ischemia-reperfusion (I/R) injury dramatically upregulated the activities of CAT, GST, and MDA levels in the ipsilateral ovary, which were all downregulated by ARS treatment. A significant increase in follicular cell degeneration, congestion, and edema in the contralateral ovary was seen in the I/R group, which was significantly reduced with ARS treatment. Furthermore, I/R injury resulted in a significant increase in apoptosis as shown by the increased levels of BAX and CASP-3, and decreased levels of BCL-2 whereas ARS significantly reduced the impact of the injury. Our data, based on a rat I/R injury model, show that both ipsilateral and contralateral ovaries are protected with ARS pretreatment, and 50 mg/kg ARS treatment demonstrates to be more effective than the 10 mg/kg ARS.

Tocilizumab is effective in preventing ovarian injury induced by ischemia- reperfusion in rats.

Ovarian torsion can be defined as the bending of the ovaries on the supporting ligament, disrupting both venous and arterial blood circulation. Insufficient blood flow causes ovarian tissue hypoxia and leads to ischemia. This study aimed to investigate whether tocilizumab has a protective effect on ischemia-reperfusion injury due to ovarian torsion in rats. Eighteen female Wistar albino rats were divided into three equal groups (Sham (SG), ischemia-reperfusion (OIR), and ischemia-reperfusion+tocilizumab (OIRT)). Degeneration, necrosis, vascular dilatation/congestion, interstitial edema, hemorrhage, and polymorphonuclear lymphocyte (PMNL) infiltration scores were significantly different between the groups (p=0.001 for all parameters). Moreover, the OIRT group had a significant improvement in these criteria compared to the OIR group (p<0.05). Additionally, there was a considerable difference between OIRT and OIR groups in the number of primordial, developing, and atretic follicles groups (p<0.05), while there was no difference in the number of corpus luteum (p=0.052). Stress markers or cytokines, such as MDA, tGSH, NF-κB, TNF-α, IL-1ß, and IL-6, were significantly different between groups (p<0.05). Furthermore, a significant improvement was found in the measured variables when the OIRT group was compared with the OIR group (p<0.05). Tocilizumab may be an alternative option for treating ischemia-reperfusion injury due to ovarian torsion.

The novel peptide PFAP1 promotes primordial follicle activation by binding to MCM5.

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.

Endometrioma increases the risk of antibiotic treatment failure and surgical intervention in patients with pelvic inflammatory disease.

OBJECTIVE: To evaluate the outcome of pelvic inflammatory disease (PID) in patients with endometriosis with and without ovarian endometrioma. DESIGN: A retrospective cohort study. SETTING: A single university-affiliated tertiary center. PATIENT(S): A total of 116 patients with endometriosis hospitalized because of PID between the years 2011-2021. Fifty-nine patients with an ovarian endometrioma component were compared with 57 patients with endometriosis without endometrioma. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was severe PID defined as the need for surgical intervention or drainage. Secondary outcomes included tubo-ovarian abscess, number of hospitalization days, a positive cervical bacterial culture or urine sexually trasmitted disease polymerase chain reaction (STD PCR) test, and readmission because of partially treated or relapsing PID. RESULT(S): PID in patients with endometrioma was found less likely to respond to antibiotic treatment with increased risk for surgical intervention or drainage compared with endometriosis patients without endometrioma (adjusted odds ratio, 3.5; confidence interval, 1.25-9.87). On admission, patients with endometrioma were older (26.5 vs. 31.0) and less likely to have an intrauterine device (19.3% vs. 5.1%) compared with patients without endometrioma. The rate of the tubo-ovarian abscess (52.5% vs. 19.3%) was significantly higher in patients with endometrioma. Readmission rate, positive bacterial culture, and hospitalization duration were higher in the endometrioma group; however, they did not reach statistical significance. Recent oocyte retrieval and patient's age were not associated with an increased risk of severe PID. CONCLUSION(S): Endometrioma patients with PID are less likely to respond to antibiotic treatment and present a higher risk for surgical intervention.

Effect of protection of enoxaparin against experimental ischemia/reperfusion injury in the rat ovary on in vitro fertilization outcomes.

OBJECTIVE: The study aimed to investigate the protection of enoxaparin (E) against experimental ischemic (I) and ischemic-reperfusion (I/R) injury in rat ovaries on in vitro fertilization outcomes. METHODS: In total, 56 adult female Sprague-Dawley albino rats were randomly assigned to 6 groups of 8 animals each: Sham, Ischemia, I/R, Sham+E, I+E, and I/R+E. Ischemia groups were subjected to bilateral adnexal torsion for 3 h. In contrast, I/R and I/R+E groups received subsequent detorsion for 3 h. Enoxaparin (0.5 mg/kg s.c.) was administered 30 min prior to ischemia (I+platelet-rich plasma) or reperfusion (I/R+I+platelet-rich plasma). Ovaries were stimulated through intraperitoneal injection of 150-300 internal units IU/kg pregnant mare serum gonadotropin. Anti-Müllerian hormone levels were measured before and after surgery in all groups. RESULTS: When the number of metaphase II oocytes was evaluated, statistically significant differences were observed between the I and I+E (p=0.001) and I/R and I/R+E (p=0.000) groups. When both I and I+E groups and I/R and I/R+E groups were compared, it was found that E application increased the number of fertilized oocytes. The number of embryos on the second day was higher in the I/R+E group than that in the I/R group. Statistically significant differences were found in the number of grade 1 embryos between the I/R and I/R+E groups (p=0.003). In comparing anti-Müllerian hormone values within the group, the highest decrease was observed in the I and I/R groups. CONCLUSION: Enoxaparin effectively minimizes ovarian damage and preserves ovarian reserve following ovarian torsion.

The protective effect of erythropoietin on ischemia- reperfusion injury caused by ovarian torsion-detorsion in the experimental rat model.

Ovarian torsion is one of the most dangerous gynecological emergencies requiring surgery. A total of 50%-90% ovarian torsion cases are caused by physiological cysts, endometriosis, and other benign or malignant ovarian neoplasms. The aim of the study was to investigate the effects of erythropoietin (EPO) treatment on ischemia/reperfusion (IR) injury caused by ovarian torsion/detorsion (T/D) injury. Thirty female Wistar albino rats were divided into five groups as follows: Group I: Control; Group II: Torsion (T); Group III: Torsion/Detorsion(T/D); Group IV: Torsion/Detorsion (T/D) + EPO; Group V: EPO. Sections of the ovaries were evaluated for histopathological changes with hematoxylin and eosin stain, a immunohistochemical assay for caspase 3 expression, and the TUNEL assay for apoptosis. Ovarian sections from torsion/detorsion and torsion groups showed more hemorrhage, vascular congestion, edema, degenerative granulosa, and stromal cells. Fewer histopathological changes were found in EPO and T/D + EPO groups. Caspase 3 and TUNEL positive cells were significantly increased in the torsion/detorsion group as compared with the other groups (p < 0.05). Treatment with erythropoietin decreased the number of caspase 3 and TUNEL positive cells. The results of the study showed that erythropoietin administration is effective for recovery from degenerative changes in the ovary induced by the torsion-detorsion injury.

The effect of medical ozone therapy in addition to ovarian detorsion in ischemia reperfusion model.

This study aimed to investigate the protective effect of ozone therapy on ovarian reserve, number of ovarian follicles, ovarian morphology in a rat ischaemia reperfusion (IR) injury model. Twenty-four, Wistar Hannover rats were included. The rats were divided into three groups as control, detorsion-only, and ozone therapy + detorsion groups. There was a statistically significant difference in the follicular damage and inflammation scores between the study groups (p = .019, p = .002, respectively). The highest AMH decrease was observed in the detorsion-only group (p = .012). The total damage score was higher in the detorsion-only group than the ozone therapy + detorsion group. Preantral, small and large antral follicle numbers were less in the detorsion-only group than the ozone therapy + detorsion group. The highest postoperative day 7 TAS level was in the ozone therapy + detorsion group. TOS levels did not differ significantly between the study groups. The combination of the ozone therapy with ovarian detorsion is more effective in protecting the ovarian reserve than ovarian detorsion-only.Impact StatementWhat is already known on this subject? Adnexal torsion is a common gynecological emergency in reproductive-age women. The recommended management is the detorsion of the adnexal pedicle in patients with fertility desire.What do the results of this study add? The combination of the medical ozone therapy with conventional surgical ovarian detorsion is more effective in the protection of the ovarian reserve compared to surgical ovarian detorsion.What are the implications of these findings for clinical practice and/or further research? This study speculates that medical ozone therapy in addition to conventional surgical ovarian detorsion could preserve ovarian reserve and function if confirmed in further clinical studies.

[Ovulatory disorders under "common therapeutic principle for different diseases": essence of "Tiangui" and relationship with ovulation disorders].

The essence of the "common therapeutic principle for different diseases"(Yibing Tongzhi in Chinese for short) is the disease-syndrome combination, which is the classic mode of understanding and treating diseases in traditional Chinese medicine(TCM). This study holds the view that Yibing Tongzhi is the optimal treatment mode of ovulation disorders since ovulation disorders have the common pathogenesis, i.e., "kidney-Tiangui(reproduction-stimulating essence)-Chongren(thoroughfare and conception vessels)-uterus axis" disorder. Kidney is an important basis of the reproductive axis, where kidney essence, kidney yang, and kidney Qi are the key substances and driving forces promoting the operation of the reproductive axis. Chongren is an important transmission path. "Tiangui", the upstream substance related to the heart, brain and kidney with a connecting effect, plays a key role in the ovulation mechanism and is a representative of the reproductive axis function. There are four common Tiangui abnormalities in ovulatory disorders, including hypomenorrhea, yin and yang deficiency, abnormal exuberance of extreme yin, and abnormal phase. The dynamic changes of "Tiangui" can induce different diseases, such as polycystic ovary syndrome and hyperprolactinemia, which ultimately lead to anovulatory infertility. Therefore, with "Tiangui" as the entry point, it is the treatment trend for ovulatory disorders under Yibing Tongzhi.

Clinical Predictors of Failed Medical Treatment in Patients with Tubo-ovarian Abscess: External Validation of a Recently Published Risk Score.

STUDY OBJECTIVE: To assess the external validity of a recently published clinical risk score estimating the risk of failed medical treatment in patients with tubo-ovarian abscess (TOA) based on 4 clinical variables on admission. DESIGN: The probability of failed medical treatment predicted from the reference risk score was compared with the observed rates in a retrospective cohort of patients with TOA. Results were assessed using rigorous methods for clinical prediction models. SETTING: Safety-net teaching hospital system in Houston, Texas. PATIENTS: One hundred and sixty nine consecutive patients admitted with TOA between 2011 and 2018 were included. Some were treated conservatively with intravenous antibiotic agents; others required a drainage procedure. INTERVENTION: Electronic health records were reviewed and the 4 clinical predictors of failed conservative treatment were captured (age, white blood cell count on admission, abscess size, and presence of bilateral abscess). A clinical risk score was calculated for each patient. The prediction model was created using the risk score in a multivariate logistic regression. Then the calibration, discrimination, and accuracy of the model were evaluated to perform the external validation analysis. MEASUREMENTS AND MAIN RESULTS: Among 169 eligible patients, 50.2% were successfully treated with intravenous antibiotic agents and 49.8% needed abscess drainage. Patients undergoing drainage were more likely to be older, be diabetic, to present with elevated white blood cell count and fever, and to have a larger abscess size on univariate analysis. Among the 4 known predictors of drainage, abscess size was found to be the strongest. Significant difference in clinical characteristics was noted between our cohort and the reference cohort, and the model needed recalibration to adjust for these differences. The area under the receiver operating characteristic curve was 0.77 (0.71-0.84) indicating good discrimination. The Brier score was favorable (0.19) and the observed and predicted rates were similar ranging across different risk scores. CONCLUSIONS: Our results provide external validation of a simple clinical risk score predicting failed medical treatment in patients with TOA.

Tubo-ovarian abscess: A proposed new scoring system to guide clinical management.

OBJECTIVE: To create a risk scoring system comprised of clinical and radiological characteristics that can predict the likelihood of antibiotic treatment failure of tubo-ovarian abscesses. The score should guide clinicians in identifying patients to whom early intervention should be offered instead of a prolonged trial of antibiotics. METHODS: A multicenter, retrospective cohort study carried out between January 1, 2013 and September 30, 2019, identified consecutive patients with tubo-ovarian abscess. Using a chronological split, patients were allocated to two groups for the development and subsequent validation of the postulated scoring system. Univariate and bivariate analyses were performed to identify statistically significant variables for the failure of intravenous antibiotic treatment. RESULTS: In total, 214 consecutive patients with tubo-ovarian abscesses were identified. Data from the first 150 patients were used for the development of the postulated scoring system; data from the subsequent 64 patients were used for validation. Statistically significant clinical features between those having successful and unsuccessful management were: temperature (median = 37.1℃ vs 38.2℃, P = 0.0001), C-reactive protein (151 mg/L vs 243 mg/L, P = 0.0001), and tubo-ovarian abscess diameter (6.0 cm vs 8.0 cm, P = 0.0001). These parameters were used to create a risk prediction score. A score of four or more was predictive of requiring surgical/radiological intervention of tubo-ovarian abscess (P < 0.001). The score had a sensitivity of 69% and a specificity of 88%, with area under the curve (AUC) = 0.859. CONCLUSION: Currently, there is no guidance for clinicians on when to operate on a tubo-ovarian abscess. Our prediction score is simple, using only three easily obtained clinical characteristics.

Research progress of melatonin (MT) in improving ovarian function: a review of the current status.

Melatonin (MT) is an endogenous hormone mainly synthesized by pineal cells, which has strong endogenous effects of eliminating free radicals and resisting oxidative damages. Melatonin (MT) can not only regulate the body's seasonal and circadian rhythms; but also delay ovarian senescence, regulate ovarian biological rhythm, promote follicles formation, and improve oocyte quality and fertilization rate. This review aimd to provide evidence concerning the synthesis and distribution, ovarian function, and role of MT in development of follicles and oocytes. Moreover, the role of MT as antioxidative, participating in biological rhythm regulation, was also reviewed. Furthermore, the effects of MT on various ovarian related diseases were analyzed, particularly for the ovarian aging and polycystic ovary syndrome (PCOS).

The Role of Androgen Supplementation in Women With Diminished Ovarian Reserve: Time to Randomize, Not Meta-Analyze.

The management of patients with diminished ovarian reserve (DOR) remains one of the most challenging tasks in IVF clinical practice. Despite the promising results obtained from animal studies regarding the importance of androgens on folliculogenesis, the evidence obtained from clinical studies remains inconclusive. This is mainly due to the lack of an evidence-based methodology applied in the available trials and to the heterogeneity in the inclusion criteria and IVF treatment protocols. In this review, we analyze the available evidence obtained from animal studies and highlight the pitfalls from the clinical studies that prevent us from closing the chapter of this line of research.

Melatonin ameliorates ovarian dysfunction by regulating autophagy in PCOS via the PI3K-Akt pathway.

Emerging evidence has demonstrated that melatonin (MT) plays a crucial role in regulating mammalian reproductive functions. It has been reported that MT has a protective effect on polycystic ovary syndrome (PCOS). However, the protective mechanisms of MT remain poorly understood. This study aims to explore the effect of MT on ovarian function in PCOS and to elucidate the relevant molecular mechanisms in vivo and in vitro. We first analysed MT expression levels in the follicular fluid of PCOS patients. A significant reduction in MT expression levels was noted in PCOS patients. Intriguingly, reduced MT levels correlated with serum testosterone and inflammatory cytokine levels in follicular fluid. Moreover, we confirmed the protective function of MT through regulating autophagy in a DHEA-induced PCOS rat model. Autophagy was activated in the ovarian tissue of the PCOS rat model, whereas additional MT inhibited autophagy by increasing PI3K--Akt pathway expression. In addition, serum-free testosterone, inflammatory and apoptosis indexes were reduced after MT supplementation. Furthermore, we also found that MT suppressed autophagy and apoptosis by activating the PI3K-Akt pathway in the DHEA-exposed human granulosa cell line KGN. Our study showed that MT ameliorated ovarian dysfunction by regulating autophagy in DHEA-induced PCOS via the PI3K-Akt pathway, revealing a potential therapeutic drug target for PCOS.

Long-Term Medical Therapy after Laparoscopic Excision of Ovarian Endometriomas: Can We Reduce and Predict the Risk of Recurrence?

OBJECTIVES: Up to 32% of women experience anatomic recurrence after conservative surgery for endometriomas, while pain recurs in 10-40% of cases. Long-term postoperative hormonal therapy is recommended to prevent disease recurrence. We evaluated the efficacy of long-term therapy with estroprogestins (EPs) or progestins (Ps) in preventing endometrioma recurrence, as identifiable cysts and subjective symptoms, after laparoscopic excision. DESIGN: This retrospective cohort study included 375 women submitted to laparoscopic endometrioma excision. Women were followed up at 6 and 12 months and then yearly after surgery. Based on postoperative medical therapy, women were divided into 4 groups: nonusers, cyclic EP users, continuous EP users, and progestogen users. Materials, Setting, Methods: Anamnestic and anthropometric characteristics were collected as well as clinical and surgical data. Gynecological examination, and transvaginal and transabdominal ultrasound scans were performed. Pain (numerical rating score >5) and endometrioma recurrence at ultrasound (ovarian cyst with typical sonographic features ≥10 mm in mean diameter) were recorded at each examination. The reoperation rate in women with recurrence was investigated. RESULTS: The median follow-up was 3.7 years with a maximum of 16.7 years. Most patients used EPs (119 cyclic and 61 continuous users), 95 used P, and 100 were nonusers. In 135 women (36%), endometriotic cyst recurrence was diagnosed, with a mean diameter of 18.7 ± 10.8 mm (range 10-55 mm). The median recurrent cyst-free time was 7.9 years (95% CI 5.8-10.8). Dysmenorrhea was the first symptom to reappear, affecting 162 patients (43.2%). Upon multivariable regression analysis, continuous users had a lower risk of relapse (OR 0.56, 95% CI 0.32-0.99), in terms of both cysts and symptom recurrence, than patients who received no medications. The reoperation rate was 16.2%. LIMITATIONS: The main limitation of this study is its retrospective design. Also, women switching therapies throughout the follow-up period were sorted into one of the study groups based on the longest treatment taken, without considering the discontinuation rates. CONCLUSIONS: Long-term EPs, administered in a continuous regimen and starting immediately after conservative surgery for endometriomas, seem to reduce the disease recurrence risk.

Estradiol/nomegestrol acetate as a first-line and rescue therapy for the treatment of ovarian and deep infiltrating endometriosis.

PURPOSE: Estradiol valerate/nomegestrol acetate (E2V/NOMAC) is a new combined oral contraceptive with a good tolerability profile and low drop-out rates, which was shown to improve menstrual-related symptoms. This study aims to evaluate its effectiveness in the control of symptoms and progression of disease in women with ovarian endomestriomas and deep infiltrating endometriosis (DIE). METHODS: This was a retrospective cohort study on 39 women with pelvic endometriosis treated with E2V/NOMAC. We assessed for each patient, at the beginning of treatment and after 6 months, the painful symptoms, through a global VAS (Visual Analogue Scale) index and the size of the greatest ovarian and/or deep infiltrating endometriotic lesions. RESULTS: After 6 months of treatment, a significant reduction was observed for the global VAS score for pain symptoms and for the mean size of ovarian endometriomas, whereas DIE lesions did not present significant changes in mean size. CONCLUSIONS: E2/NOMAC was effective in reducing pain symptoms associated with pelvic endometriosis and the size of ovarian endometriomas, whereas DIE lesions remained stable. This therapy could provide good results in the control of symptoms and disease progression in women with pelvic endometriosis.

Target identification and drug discovery by data-driven hypothesis and experimental validation in ovarian endometriosis.

OBJECTIVE: To identify targets and discover drugs for ovarian endometriosis (OE) DESIGN: A basic study based on a data-driven hypothesis and experimental validation SETTING: Center for Reproductive Medicine PATIENT(S)/ANIMAL(S): Fourteen patients with OE and 7 healthy donors were recruited, and 15 female C57/BL6 mice were involved. INTERVENTION(S): Samples of OE lesions and normal endometrium were obtained. The ITPR1-knockdowned ectopic human endometrial stromal cells (HESCs) were subjected to ribonucleic acid (RNA) sequencing, cell-counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, and flow cytometry. Camptothecin was administered to HESCs and in an OE mouse model. MAIN OUTCOME MEASURE(S): ITPR1 expression in OE lesions and normal endometrium, cell proliferation and apoptosis of HESCs with ITPR1 knockdown or camptothecin treatment, and autograft volume in the OE mouse model RESULT(S): Two significant OE-relevant gene modules were identified and involved the PI3K/Akt and aging-relevant pathways. Fifteen hub genes were identified and confirmed, among which the most significant gene, ITPR1, was robustly elevated in OE lesions. RNA sequencing revealed that ITPR1 was highly relevant to cell proliferation and apoptosis, which was further confirmed by CCK-8 assay, EdU staining, and flow cytometry analysis. ITPR1 knockdown inhibited cell proliferation and induced HESC apoptosis. The candidate drugs targeting these modules were screened, among which camptothecin and irinotecan were identified as promising drugs. Both compounds suppressed HESC proliferation and induced apoptosis; ITPR1 expression was suppressed by camptothecin. The therapeutic effect of camptothecin was also validated in the OE mouse model. CONCLUSION(S): This study identified the therapeutic targets and promising drugs for OE and shed light on the use of camptothecin in OE treatment.