The risk of breast cancer and gynecologic malignancies after ovarian stimulation: Meta-analysis of cohort study.

The effects of ovarian stimulation on breast and gynecological tumor incidence remain controversial. Therefore, the aim of this meta-analysis was to study the risk of cancer in ovarian stimulation. Of the 22713 studies initially identified, 28 were eligible for inclusion. The results revealed that the impact of ovarian cancer (RR = 1.33, [1.05; 1.69]) and cervical cancer (RR = 0.67, [0.46; 0.97]) is significant among the overall effects. In subgroup analysis, in the nulliparous population (RR = 0.81 [0.68; 0.96]) was the protective factor for the breast cancer. In the Caucasians subgroup (RR = 1.45, [1.12; 1.88]), the ovarian cancer incidence was statistically significant. In the Asian subgroup (RR = 1.51, [1.00; 2.28]), the endometrial cancer incidence was statistically significant. In the subgroup of Asians (RR = 0.55 [0.44; 0.68]) and the multiparous population (RR = 0.31, [0.21; 0.46]), them can be the statistically protective factor for the cervical cancer.

Is controlled ovarian stimulation safe in patients with hormone receptor-positive breast cancer receiving neoadjuvant chemotherapy?

INTRODUCTION: Controlled ovarian stimulation (COS) for oocyte/embryo cryopreservation is the method of choice for fertility preservation (FP) in young patients diagnosed with early-stage breast cancer (eBC). Nevertheless, some challenges still question its role, particularly in the neoadjuvant setting, where concerns arise about potential delay in the onset of anticancer treatment, and in hormone receptor-positive (HR+) disease, as cancer cells may proliferate under the estrogenic peak associated with stimulation. Therefore, this review aims to examine the available evidence on the safety of COS in eBC patients eligible for neoadjuvant treatment (NAT), particularly in HR+ disease. METHODS: A comprehensive literature search was conducted to identify studies evaluating the feasibility and safety of COS in eBC and including patients referred to NAT and/or with HR+ disease. Time to NAT and survival outcomes were assessed. RESULTS: Of the three matched cohort studies assessing the impact of COS on time to start NAT, only one reported a significant small delay in the cohort undergoing COS compared with the control group, whereas the other studies found no difference. Regarding survival outcomes, overall, no increased risk of recurrence or death was found, either in patients undergoing COS in the neoadjuvant setting regardless of HR expression or in HR+ disease regardless of the timing of COS relative to surgery. However, there are no data on the safety of COS in the specific combined scenario of HR+ disease undergoing NAT. CONCLUSION: Neither the indication to NAT nor the HR positivity constitutes per se an a priori contraindication to COS. Shared decision making between clinicians and patients is essential to carefully weigh the risks and benefits in each individual case. Prospective studies designed to specifically investigate this issue are warranted.

Nonlinear relationship between gonadotropin total dose applied and live birth rates in non-PCOS patients: a retrospective cohort study.

The purpose of this article is to explore the relationship between the total dose of follicle-stimulating hormone (FSH) applied during controlled ovulation stimulation and the live birth rates (LBRs) in non-PCOS population. Many studies have found no difference between the dose of FSH application and pregnancy outcomes such as clinical pregnancy rates after fresh embryo transfer. However, a recent large retrospective analysis found a negative correlation between live birth rates and increasing dose of FSH. It is still controversial about the association between FSH dose and LBRs. In addition, no studies have yet explored the nonlinear relationship between FSH and LBRs. This cohort study included a total of 11,645 patients who had accepted IVF/intracytoplasmic sperm injection (ICSI) at the second hospital of Hebei medical university between December 2014 to December 2019. PCOS was identified by Rotterdam PCOS criteria. We researched the association between FSH total dose and live birth rates (LBRs) using multivariate regression analysis. In addition, a model for nonlinear relationships based on a two-part linear regression was applied. The analysis of threshold effects indicated that LBR increased with every 1000 IU FSH when the concentration of FSH was lower than 1410 IU (OR 1.55, 95% CI [1.05, 2.28]); however, a negative association between FSH dose and LBR (OR 0.94, 95% CI [0.89, 0.99]) was found when the FSH total dose was higher than 1410 IU. It is worth noting that the relationship between LBR and FSH dose varied among patients of different ages (OR 0.92 vs 1.06, P for interaction < 0.05).

Serum erythropoietin level is increased during stimulation for IVF but not in OHSS.

BACKGROUND: Erythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS). METHODS: 24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo. RESULTS: During IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2-13.4 IU/L and 12.5; 10.3-13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4-19.2 IU/L vs. 10.2; 8.8-12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1. CONCLUSIONS: Circulating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo's involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

Empty follicle syndrome following GnRH agonist stimulation, in a patient with PCOS treated with HCG rescue protocol, resulting in 3PN zygote formation: a case report.

Empty follicle syndrome is a rare condition characterized by failure to retrieve oocytes despite repeated careful aspiration of mature precursor follicles during controlled ovarian stimulation. This report presents a case of empty follicle syndrome in a patient with polycystic ovary syndrome using a gonadotropin-releasing hormone agonist as a trigger for final oocyte maturation. No oocytes were retrieved from the right ovary and the procedure was discontinued. The patient was administered an injection with 10,000 units of HCG and 3 oocytes were obtained after 24 hours. All oocytes were mature (MII); fertilization was performed with sperm from the patient's husband resulting in 3PN zygotes. The formation of 3PN zygotes from ICSI might be due to oocyte cytoplasmic disorders caused by long-term exposure to gonadotropins and increased duration of stimulation. Although our patient had false empty follicle syndrome and the hCG rescue protocol led to the retrieval of oocytes, the oocytes were not of good quality. As previously described, empty follicle syndrome is not a predictor of success in subsequent cycles. Our patient's next cycle was uneventful.

Assisted Reproductive Technology in the Presence of Polycystic Ovary Syndrome: Current Evidence and Knowledge Gaps.

OBJECTIVE: In this narrative review, we discuss the current evidence as well as the knowledge gaps concerning assisted reproductive technology (ART) indications, protocols, and results in the presence of polycystic ovary syndrome (PCOS). METHODS: An electronic literature search was performed for English-language publications in the last decade in databases such as PubMed, Medline, the Web of Sciences, Embase, and Scopus. RESULTS: We found evidence that ovarian steroidogenesis and folliculogenesis are deeply altered by PCOS; however, the oocyte quality and pregnancy rates after ART are not affected. Patients with PCOS are more sensitive to the action of exogenous gonadotropins and more likely to develop ovarian hyperstimulation syndrome. This risk can be mitigated by the adoption of the gonadotropin-releasing hormone antagonist protocols for pituitary blockade and ovarian stimulation, along with frozen embryo transfer, without compromising the odds of achieving a live birth. Pregnancy complications, such as miscarriage, gestational diabetes, preeclampsia, and very preterm birth, are more frequent in the presence of PCOS, requiring more intense prenatal care. It remains uncertain whether weight reduction or insulin sensitizers used before ART are beneficial for the treatment outcomes. CONCLUSION: Although PCOS is not a drawback for ART treatments, the patients need special care to avoid complications. More in-depth studies are needed to uncover the mechanisms of follicular growth, gamete maturation, and endometrial differentiation during ART procedures in the presence of PCOS.

Cocktail treatment by GnRH-antagonist, letrozole, and mifepristone for the prevention of ovarian hyperstimulation syndrome: a prospective randomized trial.

OBJECTIVE: This study is aimed to determine the efficacy of a cocktail style treatment by combining GnRH-antagonist, letrozole, and mifepristone on the prevention of ovarian hyperstimulation syndrome (OHSS) in high-risk women. METHODS: This prospective, randomized controlled clinical trial was performed between January 2018 and December 2018. A total of 170 women who identified as high risk of OHSS during the ovarian hyperstimulation and underwent cryopreservation of whole embryos. On the day of oocyte retrieval, the combination group received 0.25 mg Cetrorelix for 3 d, 5 mg letrozole for 5 d, and 50 mg mifepristone for 3 d, the mifepristone group received 50 mg mifepristone for 3 d. A total of 156 cases were included in final analysis. All the frozen embryo transfer (FET) cycles were followed up until December 2021. RESULTS: The combination group showed significantly decreased incidence of moderate and severe OHSS than mifepristone group (20.5% vs. 42.3%), with remarkably reduced serum estradiol level on hCG + 3 and + 5 d, decreased ovarian diameter, and shortened luteal phase. Oocyte retrieval number, levels of estradiol on hCG + 0 and VEGF, and ovarian diameter on hCG + 5 were associated with the severity of the symptoms. There was no significant difference in cumulative live birth rates (LBRs) between the combination and mifepristone group (74.4% vs. 76.9%). CONCLUSIONS: The combination treatment effectively reduces the incidence of moderate/severe OHSS in high-risk women.

Fertility preservation in patients with gynaecologic malignancy: Response to ovarian stimulation and long-term outcomes.

OBJECTIVE: To the best of our knowledge, the available evidence on the effect and efficacy of controlled ovarian stimulation (COS) in this group of patients remains poorly reported. Concerns related to the impact of stimulation to cancer progression and recurrence, as well as the risk of disease dissemination during egg collection, might explain the aforementioned trend. METHODS: Overall, our FP Service received 192 gynaecological referrals, between 2005 and 2021, regarding gynaecologic conditions mainly cancer related. A total of 68 (35.4%) patients underwent COS. These patients were diagnosed with the following gynaecologic pathologies: 33 cases (48,5%) of cervical cancer were noted (stage 1b1-2b), 25 ovarian pathology (36.7%), 9 cases (13.2%) of endometrial cancer, and a single case of vaginal cancer (1.5%). RESULTS: The mean age of patients attending the fertility preservation service was 31.5 (std 5.8). The patients presenting to their initial appointment with a mean BMI 24.5 (IQR 6.9) and a median AFC of 12 (IQR 13). The mean duration of COS was 11 days (IQR 3), and the median dose of gonadotrophins was calculated at 300 IU (IQR 75 IU). In 95.4% of the cases, GnRH agonist was used as a trigger for final maturation. The median number of follicles measuring more than 14 mm at the time of trigger was 11 (IQR 8), whereas the median number of oocytes collected was 11 (IQR 9). The complication rate was reported at less than 2%. So far, one in four women of this FP group (17/68, 25% of the overall group) returned to our service to claim their cryopreserved eggs/embryos and successful livebirths were reported in 58.8% of this sample (10/17 cases). The mean time to return to use their oocytes/embryos was 36 months (min value 16 months - max value 85 months). There was no significant difference in mortality rate between patients who received FP vs those who did not (hazard ratio of mortality was estimated at 0.91 (p-value 0.88)). CONCLUSION: Based on our findings, ovarian stimulation for patients presenting with gynaecologic malignancy is a safe and efficient method of fertility preservation. Undoubtedly, the sample size is limited, however our results are reassuring and highlight the efficacy of COS for the purpose of FP based on data coming from the largest Assisted Conception Unit of the South-East of the UK.

Race, ovarian responsiveness, and live birth after in vitro fertilization.

OBJECTIVE: To determine if ovarian responsiveness to gonadotropin stimulation differs by race/ethnicity and whether this predicts live birth rates (LBRs) in non-White patients undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Academic infertility center. PATIENT(S): White, Asian, Black, and Hispanic patients undergoing ovarian stimulation for IVF. INTERVENTION(S): Self-reported race and ethnicity. MAIN OUTCOME MEASURE(S): The primary outcome was ovarian sensitivity index (OSI), defined as (the number of oocytes retrieved ÷ total gonadotropin dose) × 1,000 as a measure of ovarian responsiveness, adjusting for age, body mass index, infertility diagnosis, and cycle number. Secondary outcomes included live birth and clinical pregnancy after first retrievals, adjusting for age, infertility diagnosis, and history of fibroids, as well as miscarriage rate per clinical pregnancy, adjusting for age, body mass index, infertility diagnosis, duration of infertility, history of fibroids, and use of preimplantation genetic testing for aneuploidy. RESULT(S): The primary analysis of OSI included 3,360 (70.2%) retrievals from White patients, 704 (14.7%) retrievals from Asian patients, 553 (11.6%) retrievals from Black patients, and 168 (3.5%) retrievals from Hispanic patients. Black and Hispanic patients had higher OSIs than White patients after accounting for those with multiple retrievals and adjusting for confounders (6.08 in Black and 6.27 in Hispanic, compared with 5.25 in White). There was no difference in OSI between Asian and White patients. The pregnancy outcomes analyses included 2,299 retrievals. Despite greater ovarian responsiveness, Black and Hispanic patients had lower LBRs compared with White patients, although these differences were not statistically significant after adjusting for confounders (adjusted odds ratio, 0.83; 95% confidence interval [CI], 0.63-1.09, for Black; adjusted odds ratio, 0.93; 95% CI, 0.61-1.43, for Hispanic). Ovarian sensitivity index was modestly predictive of live birth in White and Asian patients but not in Black (area under the curve, 0.51; 95% CI, 0.38-0.64) and Hispanic (area under the curve, 0.50; 95% CI, 0.37-0.63) patients. CONCLUSION(S): Black and Hispanic patients have higher ovarian responsiveness to stimulation during IVF but do not experience a consequent increase in LBR. Factors beyond differences in responsiveness to ovarian stimulation need to be explored to address the racial/ethnic disparity established in prior literature.

Early pregnancy complications including recurrent pregnancy loss and obesity.

This review on early pregnancy complications and obesity will focus on the known pregnancy complications such as miscarriage (whether spontaneous or after fertility treatment), polycystic ovaries and risk of miscarriage, recurrent pregnancy loss, ectopic pregnancy, hyperemesis gravidarum and birth defects. Evidence will be assessed and mechanistic pathways for the outcomes will be described. We know that obesity is now a pandemic and has an impact on early pregnancy complications. The evidence has been summarised to provide the reader with a comprehensive overview and advice for pregnant women with obesity in early pregnancy.

Elevated antimüllerian hormone levels are not associated with preterm delivery after in vitro fertilization or ovulation induction.

OBJECTIVE: To investigate the association between antimüllerian hormone (AMH) and preterm birth risk in a larger cohort of patients who underwent either in vitro fertilization or ovulation induction with intrauterine insemination at a US academic fertility center. DESIGN: Retrospective cohort study. SETTING: Single academic fertility center. PATIENT(S): Live singleton births from patients who underwent in vitro fertilization or ovulation induction between 2016 and 2020 at a single academic fertility center were included in this study. Patients were excluded if they had a missing prepregnancy AMH level, a pregnancy using donor oocytes or a gestational carrier, multiple gestations, a delivery before 20 weeks gestation, or a cerclage in place. INTERVENTION(S): AMH level. MAIN OUTCOME MEASURE(S): The primary outcome was the proportion of preterm delivery. Secondary outcomes included the rate of pregnancy-induced hypertension, gestational diabetes, and small for gestational age. RESULT(S): In the entire cohort (n = 875), 8.4% of deliveries were preterm. The mean AMH values were similar between those with term and preterm births (3.9 vs. 4.2 ng/mL). Similar proportions of patients with term and preterm deliveries had AMH levels greater than the 75th percentile (25% vs. 21%). The odds of preterm birth were similar by AMH quartile after adjusting for the history of preterm birth. Similarly, in the polycystic ovary syndrome (PCOS) cohort, there was no difference between mean AMH values of term and preterm births (n = 139, 9.6 vs. 10.0 ng/mL). The proportions of patients with PCOS with AMH levels greater than the 75th percentile were similar between those with term and preterm deliveries (25% vs. 22%). The odds of preterm birth were similar by the AMH quartile after adjusting for the history of preterm birth. CONCLUSION(S): Elevated AMH levels were not associated with an increased risk of preterm birth in patients who conceived after in vitro fertilization and ovulation induction, including patients with PCOS. Although studies suggest that AMH levels may help stratify the risk of preterm birth in this population, our findings indicate that further studies are needed before clinical application.

Long-acting gonadotropin-releasing hormone agonist trigger in fertility preservation cycles before chemotherapy.

BACKGROUND: Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for preserving fertility in patients with cancer, frequently both being offered to the same woman. As the first injection of GnRHa should be administered before chemotherapy, it is usually performed in the luteal phase of the urgent controlled ovarian stimulation (COS) cycle. The GnRHa flare-up effect on recently stimulated ovaries may cause ovarian hyperstimulation syndrome (OHSS) and this risk may discourage some oncologists to offer an ovarian function preservation method with proven efficacy. We suggest the long-acting GnRHa as an option to trigger ovulation for egg retrieval in oncological patients, whenever ovarian suppression during chemotherapy is planned. PATIENTS AND METHODS: We retrospectively analyzed prospectively collected data from all consecutive ovarian stimulation cases in oncological patients for oocyte cryopreservation from 2016 to 2021 in a single academic referral center. The COS was performed according to good clinical practice standards. Since 2020 long-acting GnRHa trigger was offered to all patients for whom ovarian suppression after cryopreservation was planned. All other patients served as controls, stratified for the triggering method used: highly purified chorionic gonadotrophin 10 000 UI or short-acting GnRHa 0.2 mg. RESULTS: Mature oocytes were collected, with the expected maturation rate, in all the 22 cycles triggered with GnRHa. The mean number of cryopreserved oocytes was 11.1 ± 4, with a maturation rate of 80% (57%-100%), versus 8.8 ± 5.8, 74% (33%-100%) with highly purified chorionic gonadotrophin and 14 ± 8.4, 80% (44%-100%) with short-acting GnRHa. No case of OHSS was observed after long-acting GnRHa triggering and by 5 days after egg retrieval most patients had reached luteinizing hormone levels showing suppression. CONCLUSIONS: Our preliminary data show that long-acting GnRHa is efficacious in inducing the final oocytes' maturation, reducing OHSS risk and suppressing ovarian function by the start of chemotherapy.

Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in "freeze-all" approach.

OBJECTIVE: To determine the incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders (25-35 follicles with a diameter of ≥12 mm on day of triggering) who received a gonadotropin-releasing hormone (GnRH) agonist to trigger final follicular maturation. METHODS: We used individual data from women who participated in four different clinical trials and were high responders to ovarian stimulation in a GnRH antagonist protocol in this retrospective combined analysis. All women were evaluated for signs and symptoms of OHSS using identical criteria based on Golan's system (1989). RESULTS: High responders (n = 77) were of different ethnicities. There were no differences in baseline characteristics between women with or without signs and symptoms of OHSS. Mean ± standard deviation baseline data were: age, 32.3 ± 3.5 years; anti-Müllerian hormone, 42.4 ± 20.7 pmol/L; antral follicle count, 21.5 ± 9.2. Before triggering, duration of stimulation was 9.5 ± 1.6 days and the mean number of follicles with a diameter of ≥12 mm and ≥17 mm was 26.5 ± 4.4 and 8.8 ± 4.7, respectively. Mean serum estradiol (17,159 pmol/l) and progesterone (5.1 nmol/l) levels were high at 36 h after triggering. Overall, 17/77 high responders (22%) developed signs and symptoms of mild OHSS which lasted 6-21 days. The most frequently prescribed medication was cabergoline to prevent worsening of OHSS. No severe OHSS occurred and no OHSS cases were reported as serious adverse events. CONCLUSIONS: High responders receiving GnRH agonist for triggering should be informed that they may experience signs and symptoms of mild OHSS.

Ovarian tissue cryopreservation can be combined simultaneously with oocyte retrieval after controlled ovarian hyperstimulation.

STUDY QUESTION: Can ovarian tissue cryopreservation (OTC) be performed after controlled ovarian hyperstimulation (COH)? SUMMARY ANSWER: Unilateral oophorectomy after transvaginal oocyte retrieval is feasible on stimulated ovaries during one surgical step. WHAT IS KNOWN ALREADY: In the fertility preservation (FP) field, the timeframe between patient referral and start of curative treatment is limited. Combining oocyte pick-up with ovarian tissue (OT) extraction has been reported to improve FP but COH applied before OT extraction is not currently recommended. STUDY DESIGN, SIZE, DURATION: This retrospective cohort-controlled study involved 58 patients who underwent oocyte cryopreservation immediately followed by OTC between September 2009 and November 2021. The exclusion criteria were a delay between oocyte retrieval and OTC of >24 h (n = 5) and IVM of oocytes obtained ex vivo in the ovarian cortex (n = 2). This FP strategy was performed either after COH (stimulated group, n = 18) or after IVM (unstimulated group, n = 33). PARTICIPANTS/MATERIALS, SETTING, METHODS: Oocyte retrieval followed by OT extraction on the same day was performed either without previous stimulation or after COH. Adverse effects of surgery and ovarian stimulation, mature oocyte yield and pathology findings of fresh OT were retrospectively analysed. Thawed OTs were analysed prospectively, for vascularization and apoptosis using immunohistochemistry, when patient consent was obtained. MAIN RESULTS AND THE ROLE OF CHANCE: No surgical complication occurred after OTC surgery in either group. In particular, no severe bleeding was associated with COH. The number of mature oocytes obtained increased after COH (median = 8.5 (25% = 5.3-75% = 12.0)) compared to the unstimulated group (2.0 (1.0-5.3), P < 0.001). Neither ovarian follicle density nor cell integrity was affected by COH. Fresh OT analysis showed congestion in half of the stimulated OT which was higher than in the unstimulated OT (3.1%, P < 0.001). COH also increased haemorrhagic suffusion (COH + OTC: 66.7%; IVM + OTC: 18.8%, P = 0.002) and oedema (COH + OTC: 55.6%; IVM + OTC: 9.4%, P < 0.001). After thawing, the pathological findings were similar between both groups. No statistical difference in the number of blood vessels was observed between the groups. The oocyte apoptotic rate in thawed OT was not statistically different between the groups (ratio of positive cleaved caspase-3 staining oocytes/total number of oocytes equal to median 0.50 (0.33-0.85) and 0.45 (0.23-0.58) in unstimulated and stimulated groups respectively, P = 0.720). LIMITATIONS, REASONS FOR CAUTION: The study reports FP from a small number of women following OTC. Follicle density and other pathology findings are an estimate only. WIDER IMPLICATIONS OF THE FINDINGS: Unilateral oophorectomy can be successfully performed after COH with limited bleeding risk and an absence of impact on thawed OT. This approach could be proposed to post pubertal patients when the number of mature oocytes expected is low or when the risk of residual pathology is high. The reduction of surgical steps for cancer patients also has positive implications for introducing this approach into clinical practice. STUDY FUNDING/COMPETING INTEREST(S): This work was made possible through the support of the reproductive department of Antoine-Béclère Hospital and of the pathological department of Bicêtre Hospital (Assistance Publique Hôpitaux de Paris, France). The authors have no conflict of interest to disclose in this study. TRIAL REGISTRATION NUMBER: N/A.

Gonadotropins as pharmacological agents in assisted reproductive technology and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy associated with subfertility/infertility and pregnancy complications. Most PCOS women opt for assisted reproductive technologies (ART) for successful conception; however, optimization of the relative doses of the gonadotropins [follicle-stimulating hormone (FSH), luteinizing hormone (LH)/human chorionic gonadotropin (hCG)] for appropriate steroidogenesis, without causing ovarian hyperstimulatory syndrome (OHSS), is challenging. Embryonic factors probably do not contribute to pregnancy loss in PCOS women, albeit hormonal imbalance impairs the metabolic microenvironment critical for oocyte maturation and endometrial receptivity. Certain clinical studies have confirmed the role of metabolic corrections in increasing the rate of pregnancy in PCOS women. This review focuses on the impact of untimely high LHCGR and/or LH levels on oocyte/embryo quality, pregnancy outcomes in ART, and exploring LHCGR as a potential drug target in PCOS women.

Computational screening of FDA-approved drugs to identify potential aromatase receptor inhibitors for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common cause of infertility without ovulation. Aromatase inhibitors were first proposed as new ovulation-inducing drugs in anovulatory women with an inadequate response to clomiphene. Letrozole is an aromatase inhibitor used as an ovulation inducer in infertile women due to PCOS. However, there is no definitive treatment for women with PCOS and the treatments are mostly symptomatic. In this study, we intend to introduce alternative drugs to letrozole using the library of FDA-approved drugs and evaluate the interaction of these drugs with the aromatase receptor. For this aim, molecular docking was performed to identify interactions of FDA-approved drugs with essential residues in the active site of the aromatase receptor. 1614 FDA-approved drugs were docked with aromatase receptor using AutoDock Vina. Molecular dynamics (MD) simulation study was also performed for 100 ns to verify the stability of the drug-receptor complexes. MMPBSA analysis evaluate the binding energy of selected complexes. Finally, acetaminophen, alendronate, ascorbic acid, aspirin, glutamine, hydralazine, mesalazine and pseudoephedrine drugs showed the best results in interaction with aromatase receptor based on computational studies. These drugs can be introduced as an alternative to letrozole for treating PCOS.Communicated by Ramaswamy H. Sarma.

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger and freeze-all strategy in GnRH antagonist protocol; case report and literature review.

Ovarian hyperstimulation syndrome (OHSS) is characterized by increased vascular permeability, hemoconcentration and fluid leakage to the third space. The vast majority of OHSS cases occur following ovarian stimulation for IVF. This potentially lethal iatrogenic condition is one of the most serious complications of assisted reproductive technologies. We report one case of severe early OHSS after GnRH agonist trigger in a GnRH antagonist protocol and freeze-all approach without the administration of any hCG for luteal-phase support in a 34-year-old case of PCO with 7 years primary infertility. After oocyte retrieval the patient was seen at the emergency unit of the hospital with abdominal distension, pain, anuria, dyspnea, and OHSS symptoms. The diagnosis was OHSS with severe ascitis. She was admitted to the Intensive care unit (ICU). She was managed with oxygen by mask, intravenous fluids, anticoagulant and albumen, we performed a two-time vaginal ascites puncture, resulting in the removal of 7800mL of clear fluid in Intensive Care Unit with full recovery. This case study presents the clinical manifestations, investigation, progress, management, outcome and preventive measures. The patient was managed with no complications. Clinicians have to be aware that even the sequential approach to ovarian stimulation with a freeze-all approach and GNRH analog triggering does not completely eliminate OHSS in all patients.

Factors influencing the number of mature oocytes and cryopreservable blastocysts in hyperresponder patients triggered with a GnRH analog.

PURPOSE: This study aimed to investigate which patient and cycle characteristics may affect the number of mature oocytes and cryopreservable blastocysts in the GnRH analog trigger cases. METHODS: This was a retrospective cohort study of 2749 GnRHa trigger cycles in patients at risk of OHSS, including a group of PGT patients, between 2011 and 2020 at Istanbul Memorial Hospital, ART and Reproductive Genetics Center. Patient and cycle characteristics were evaluated using the Generalized Linear Mixed Model (GLMM). The number of mature oocytes and the number of cryopreservable blastocysts were evaluated. RESULTS: A one-unit increase in female age, daily gonadotropin dose, E2 level on day 2, and LH level on trigger day significantly decreased the number of mature oocytes retrieved (p < 0.001) and the number of cryopreservable blastocysts as p < 0.001, p < 0.001, p < 0.001, and p = 0.003, respectively. The duration of GnRH antagonist use also decreased the number of mature oocytes retrieved (p < 0.001) but not the number of cryopreservable blastocysts. CONCLUSION: The GLMM used in our study showed that a one-unit increase in female age, daily gonadotropin dose, E2 level on day 2, and LH level on trigger day significantly decreased the number of mature oocytes retrieved and the number of cryopreservable blastocysts.

Risk factors for clinical pregnancy loss after IVF in women with PCOS.

RESEARCH QUESTION: Which factors are associated with the risk of clinical pregnancy loss in women with polycystic ovary syndrome (PCOS) undergoing IVF? DESIGN: Case-control study nested in a multicentre randomized trial comparing live birth rates between fresh and frozen embryo transfer in women with PCOS. Women with the outcome of clinical pregnancy loss were selected as the case group, those with live birth as the control group. Parameters before IVF treatment and variables during ovarian stimulation and embryo transfer were compared. RESULTS: Women with clinical pregnancy loss had higher maternal body mass index (BMI, P = 0.010), anti-Müllerian hormone (AMH, P = 0.032), 2-h glucose concentration after 75 g oral glucose tolerance test (OGTT, P = 0.025), and a higher proportion of fresh embryo transfers (P = 0.001). There were significant interactions between the types of transfer and antral follicle count (AFC, P = 0.013), 2-h glucose concentration after OGTT (P = 0.024) on clinical pregnancy loss in PCOS, indicating that these factors may have different effects on pregnancy loss after fresh versus frozen embryo transfer. When the multivariable logistic regression analysis was stratified by the fresh or frozen embryo transfer, AFC (adjusted odds ratio [aOR] 1.03, 95% confidence interval [CI] 1.01-1.05) was a risk factor for clinical pregnancy loss after fresh embryo transfer, while 2-hour glucose concentration after OGTT (aOR 1.13, 95% CI 1.01-1.25) was associated with clinical pregnancy loss in frozen embryo transfer (FET) cycles. CONCLUSIONS: In women with PCOS, fresh embryo transfer, higher BMI, AFC and 2-h glucose concentration after OGTT were risk factors for clinical pregnancy loss. FET may be a better choice to decrease the risk of clinical pregnancy loss, especially for those with higher AFC. During FET, 2-h glucose after OGTT appears to be associated with clinical pregnancy loss and warrants close monitoring.

More follicle-stimulating hormone may not improve outcomes, but can it be counterproductive?

Many studies have sought to explore the impact of high-dose gonadotropin on stimulation outcomes based on a hypothesis that higher doses of follicle-stimulating hormone may harm the quantity or quality of oocytes and, therefore, be counterproductive. Herein, we describe the results of a narrative review aimed at elucidating any harm associated with "excess" follicle-stimulating hormone dosing in poor-to-moderate responders. Additionally, we sought to describe the outcomes associated with mild ovarian stimulation, with an eye toward determining whether this approach is superior. We concluded that there is no apparent harm to higher-dose gonadotropin stimulation for poor-to-moderate responders. Simultaneously, we did not find compelling data to suggest that mild stimulation is superior. Finally, we close by presenting data that suggest that more gonadotropin may be beneficial in specific clinical scenarios.