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Abstract Context Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. Objective To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. Design In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. Results 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001). Conclusions In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.

Background Oxidative stress (OS), defined as an imbalance between excessive reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) production and antioxidant insufficiency, has been suggested to be involved in the pathogenesis of poor ovarian response (POR). Growth hormone (GH) can reduce OS in some cell types. This study investigated whether GH can improve OS and the in vitro fertilization and embryo transfer (IVF-ET) outcomes of poor ovarian responders. Methods This study enrolled 105 patients with POR and 58 patients without POR (controls) who were diagnosed according to the Bologna criteria and underwent conventional IVF-ET. Poor ovarian responders were randomly assigned to two groups: the POR-GH group, which received pretreatment with GH 4 IU/d on day 2 of the previous menstrual cycle before IVF until the trigger day, and the POR-C group, which received no pretreatment. OS markers in follicular fluid (FF), ROS levels in granulosa cells (GCs), and the IVF outcomes of the groups were compared. Results Endometrial thickness on trigger day, the number of cleaved embryos, the number of higher-quality embryos, and the rates of embryo formation, higher-quality embryo formation, implantation and clinical pregnancy were significantly increased in the POR-GH group compared with the POR-C group ( P  < 0.05). Moreover, compared to those in the non-POR group, FF malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI) and ROS levels in GCs were significantly higher, whereas superoxide dismutase (SOD) and the total antioxidant capacity (TAC) were significantly lower in the POR-C group ( P  < 0.05). Furthermore, compared with those in the POR-C group, the FF TAC was significantly increased in the POR-GH group, and TOS, OSI and intracellular ROS levels were significantly reduced ( P  < 0.05). Conclusions Pretreatment with GH alleviates OS and improves oocyte quality and IVF outcomes of poor ovarian responders. Trial registration Chinese Clinical Trial Registry. ChiCTR1900021269 . Registered 8 February 2019, http://www.chictr.org.cn/edit.aspx?pid=35837&htm=4 .

The effect of diminished ovarian reserves after undergoing hysterectomies with bilateral salpingectomies is one of the health concerns among reproductive-age women with benign gynecological diseases. Coenzyme Q10 (CoQ10), an antioxidant, is crucial in mitochondrial energy production, improving oocyte quality and quantity. This study compares the benefit of a 14-d preoperative (CoQ10) v. placebo on ovarian reserve by measuring anti-Müllerian hormone (AMH) in women undergoing hysterectomy with bilateral salpingectomy. A double-blinded, randomised, placebo-controlled trial was conducted. Forty-four women with benign gynecological diseases were randomised to receive either oral CoQ10 300 mg per d or placebo for 14 d before undergoing hysterectomy with bilateral salpingectomy. Serum AMH levels were collected for analysis before taking CoQ10 and 6 weeks postoperatively in each group. The baseline demographic, clinical characteristics and baseline AMH levels were comparable between the groups (1·47 (0·45, 2·49) v. 1·29 (0·47, 2·11), P = 0·763). The serum AMH levels after the surgery were significantly decreased from preoperative levels (median 0·99 (0·37, 1·63) v. 1·34 (0·57, 2·30)), P = 0·001. However, there was no significant difference in the AMH change between the CoQ10 group and the placebo group (AMH per cent change −28·2 % (64·09, −4·81) v. −20·07 % (–61·51, −2·92)), P = 0·99, respectively. Age, gynecological disease, operative time and blood loss were not significantly associated with the AMH change. There were no significant side effects or adverse operative outcomes among CoQ10 users. In conclusion, hysterectomy with bilateral salpingectomy led to a significantly decreased AMH level. However, pretreatment with CoQ10 for 2 weeks was ineffective in protecting an ovarian reserve.

Background To investigate the impact of Melatonin on follicular oxidative stress and assisted reproductive technology (ART) outcomes in women with diminished ovarian reserve (DOR). Method We put 68 women with DOR who were going through ART into a randomized controlled trial. Starting on the fifth day of their menstrual cycle, we gave them either 3 mg of Melatonin or a placebo every day before stimulating their ovaries. We obtained follicular fluid during oocyte retrieval, assessed it for oxidative stress indicators, and documented ART outcomes. Results Melatonin administration markedly enhanced the quantity of oocytes retrieved, fertilization rates, and embryo quality. In addition, Melatonin changed markers of oxidative stress, specifically the levels of reduced glutathione (rGSH) and total antioxidant capacity (TAC). The Melatonin group exhibited significantly elevated biochemical pregnancy rates. Conclusion Melatonin may improve the quality of oocytes and help with reproductive technology in women with low ovarian reserves, possibly by lowering oxidative stress in the follicles.

Background Poor ovarian response (POR) to controlled ovarian stimulation (COS) remains challenging, especially in advanced-age women with diminished ovarian reserve, resulting in low live birth rates. Many patients prefer to conceive with their eggs, underscoring the need for improved treatments. This study explores astaxanthin potential as a COS adjuvant to improve ovarian response and assisted reproductive technology (ART) outcomes, considering its impact on oxidative stress (OS), inflammation, and apoptosis, which are key factors in POR. Methods In this randomized, triple-blind, placebo-controlled trial, 60 infertile POR patients from POSEIDON Group 4 (the poorest prognosis category, age > 35 and poor ovarian reserve (anti-müllerian hormone < 1.2 ng/ml or antral follicle count < 5) undergoing intracytoplasmic sperm injection were enrolled. Patients were assigned to receive either 12 mg/day AST or placebo for eight weeks. All patients underwent a gonadotropin-releasing hormone antagonist regimen for COS. ART outcomes were compared between groups. Blood serum and follicular fluid (FF) were analyzed for OS markers (superoxide dismutase [SOD], total antioxidant capacity [TAC], and malondialdehyde [MDA]), and pro-inflammatory cytokines (interleukin-6 [IL-6], interleukin-8 [IL-8], and vascular endothelial growth factor [VEGF]) via enzyme-linked immunosorbent assay kits, and cell-free DNA [cfDNA] (apoptotic marker) via ALU quantitative polymerase chain reaction. Results After the intervention, the AST group exhibited a significant elevation in serum ( P  = 0.013) and TAC ( P  = 0.030), accompanied by a significant reduction in serum MDA ( P  = 0.005). No significant differences between AST and placebo groups were observed in OS markers in FF. AST group showed significant reductions in the serum IL-6 ( P  < 0.001), IL-8 ( P  = 0.001), and VEGF ( P  = 0.002) levels following AST therapy. In the AST group, FF levels of IL-6 ( P  = 0 < 001), IL-8 ( P  = 0.036), VEGF ( P  = 0.006), and cfDNA ( P  < 0.001) were significantly lower than in the placebo group. Between-group comparisons showed significant differences in the alterations of serum SOD ( P  = 0.027), IL-6 ( P  < 0.001), and IL-8 ( P  = 0.035) levels between AST and placebo groups. The AST group showed significant increases in the number of retrieved oocytes ( P  = 0.003), MII oocytes ( P  = 0.004), frozen embryos ( P  = 0.037), and high-quality embryos ( P  = 0.014) compared to the placebo group. Conclusion AST shows promise as a COS adjuvant therapy, potentially enhancing some ART outcomes in POR through alleviating OS, inflammation, and apoptosis. Trial registration Clinical trial registration number: IRCT20230223057510N1, URL: https://irct.behdasht.gov.ir/trial/68870 , registration date: 2023 March 16. Graphical Abstract

Background The use of progestin (P) during ovarian stimulation is effective in blocking the luteinizing hormone (LH) surge in women with normal ovarian reserve, however, its effects have not been determined in poor responders. This study aimed to explore the follicular dynamics in P-primed minimal stimulation in poor responders. Methods A total of 204 infertile women with diminished ovarian reserve were allocated into the medroxyprogesterone acetate (MPA) group or the natural-cycle control group in an alternating order. MPA (10 mg) was administered daily beginning from the early follicular phase and a low dose of hMG was added in the late follicular phase if the serum FSH level was lower than 8.0mIU/ml. When a dominant follicle reached maturity, triptorelin 100 μg and hCG 1000 IU were used for trigger, and oocytes were retrieved 34-36 h later.All viable embryos were cryopreserved for subsequent frozen embryo transfer. Natural cycle IVF was used as controls. Results Compared with the natural cycle group, the MPA group exhibited a larger pre-ovulatory follicle (18.7 ± 1.8 mm vs 17.2 ± 2.2 mm), a longer follicular phase (13.6 ± 3.6 days vs 12.3 ± 3.2 days), and higher peak oestradiol values (403.88 ± 167.16 vs 265.26 ± 122.16 pg/ml), while maintaining lower LH values ( P  < 0.05). The incidences of spontaneous LH surge and premature ovulation decreased significantly (1.0% vs 50%; 2% vs. 10.8%, respectively; P  < 0.05). A greater number of oocytes and viable embryos were harvested from the MPA group than from the natural cycle group ( P  < 0.05). Moreover,the clinical pregnancy rate was slightly higher in the MPA group than in the natural cycle controls, but the difference was not significant (11.8% vs 5.9%, P  > 0.05). Conclusion This study supported the hypothesis that P-primed minimal stimulation achieved ovulation control of the dominant follicle and did not adversely affect the quality of oocytes in poor responders. Therefore, P-priming is a promising approach to overcome premature ovulation in minimal stimulation for poor responders. Trial registration ChiCTR-OCH-14004176 . Registered on January 8, 2014.

ObjectiveThis study aimed at improving fertility rates among infertile women with poor ovarian reserve.MethodsThis was a randomized clinical trial conducted in the outpatient clinic of a tertiary hospital. We recruited infertile women with poor ovarian reserve. The study population was divided into 2 groups, each of 25 participants. Both had induction of ovulation for three consecutive cycles. Study group took DHEA supplementation 25 mg/8 h for two consecutive cycles before induction of ovulation. Both groups were compared for outcomes of induction. Baseline ovarian reserve tests and antral follicle count (AFC) were done for both groups before induction of ovulation. The study group repeated these baseline tests after DHEA treatment to compare ovarian reserve before and after DHEA supplementation. Outcome measures were the number of mature follicles at the time of ovulation, the number of gonadotrophin ampoules needed for induction of ovulation, the duration of ovarian stimulation, E2 level at the day of HCG injection.ResultsThe study group baseline investigations after DHEA treatment showed a statistically significant improvement compared to the control group. The outcomes of induction of ovulation in the study group showed a statistically better response than the control group.ConclusionDHEA may help many poor responders so better considered for poor responder patients.Trial registration numberPACTR201911829230395.

Background Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. Methods We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. Results Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy ( P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. Conclusions Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. Trial registration The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492 , and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140 . This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

Ionizing radiation may cause irreversible ovarian failure, which, therefore, calls for an effective radioprotective reagent. The aim of the present study was to evaluate the potential radioprotective effect of N-acetylcysteine (NAC) on ionizing radiation induced ovarian failure and loss of ovarian reserve in mice. Kun-Ming mice were either exposed to X-irradiation (4 Gy), once, and/or treated with NAC (300 mg/kg), once daily for 7 days before X-irradiation. We examined the serum circulating hormone levels and the development of ovarian follicles as well as apoptosis, cell proliferation, and oxidative stress 24 hours after X-irradiation. In addition, morphological observations on the endometrial luminal epithelium and the fertility assessment were performed. We found that NAC successfully restored the ovarian and uterine function, enhanced the embryo implantation, improved the follicle development, and altered the abnormal hormone levels through reducing the oxidative stress and apoptosis level in granulosa cells while promoting the proliferation of granulosa cells. In conclusion, the radioprotective effect of NAC on mice ovary from X-irradiation was assessed, and our results suggested that NAC can be a potential radioprotector which is capable of preventing the ovarian failure occurrence and restoring the ovarian reserve.

We propose a novel method, the epinephrine compression method (Epi-pledget), as a hemostasis method for ovarian cystectomy. A total of 179 patients undergoing laparoscopic ovarian cystectomy with stripping were randomly allocated into three groups: the bipolar coagulation group, the Epi-pledget group, and the coagulation after Epi-pledget (Epi & Coagulation) group. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) by ultrasonography were measured to determine the preservation of ovarian function. To evaluate the postoperative ovarian cellular proliferative activity and tissue damage in a mouse model, we operated on the ovaries of mice with an artificial incision injury and applied two hemostatic methods: coagulation and Epi-pledget. Eight weeks after surgery, the AMH rate significantly decreased in the bipolar coagulation group compared with the Epi-pledget group. The AFC decline rate was also significantly greater in the coagulation group than the Epi-pledget group. Specifically, patients with endometrioma had a significantly greater decline of serum AMH in the coagulation group than the Epi-pledget group. In a histopathological analysis in mice, the Epi-pledget group showed ameliorated fibrotic changes and necrotic findings in the injured lesion compared with the bipolar coagulation group. The Epi-pledget method for ovarian stripping has an additional benefit of maximizing the preservation of the ovarian reserve, especially for the endometriotic ovarian cyst type.