Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway.

Premature ovarian failure (POF) caused by chemotherapy is a growing concern for female reproductive health. The use of metformin (MET), which has anti-oxidative and anti-inflammatory effects, in the treatment of POF damaged by chemotherapy drugs remains unclear. In this study, we investigated the impact of MET on POF caused by cyclophosphamide (CTX) combined with busulfan (BUS) and M1 macrophages using POF model mice and primary granule cells (GCs). Our findings demonstrate that intragastric administration of MET ameliorates ovarian damage and alleviates hormonal disruption in chemotherapy-induced POF mice. This effect is achieved through the reduction of inflammatory and oxidative stress-related harm. Additionally, MET significantly relieves abnormal inflammatory response, ROS accumulation, and senescence in primary GCs co-cultured with M1 macrophages. We also observed that this protective role of MET is closely associated with the AMPK/PPAR-γ/SIRT1 pathway in cell models. In conclusion, our results suggest that MET can protect against chemotherapy-induced ovarian injury by inducing the expression of the AMPK pathway while reducing oxidative damage and inflammation.

Danggui Shaoyao San protects cyclophosphamide-induced premature ovarian failure by inhibiting apoptosis and oxidative stress through the regulation of the SIRT1/p53 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: It has been reported that apoptosis and oxidative stress are related to cyclophosphamide (CYC)-induced premature ovarian failure (POF). Therefore, anti-apoptotic and anti-oxidative stress treatments exhibit therapeutic efficacy in CYC-induced POF. Danggui Shaoyao San (DSS), which has been extensively used to treat gynecologic diseases, is found to inhibit apoptosis and reduce oxidative stress. However, the roles of DSS in regulating apoptosis and oxidative stress during CYC-induced POF, and its associated mechanisms are still unknown. AIM OF THE STUDY: This work aimed to investigate the roles and mechanisms of DSS in inhibiting apoptosis and oxidative stress in CYC-induced POF. MATERIALS AND METHODS: CYC (75 mg/kg) was intraperitoneally injected in mice to construct the POF mouse model for in vivo study. Thereafter, alterations of body weight, ovary morphology and estrous cycle were monitored to assess the ovarian protective properties of DSS. Serum LH and E2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was employed for examining ovarian pathological morphology and quantifying follicles in various stages. Meanwhile, TUNEL staining and apoptosis-related proteins were adopted for evaluating apoptosis. Oxidative stress was measured by the levels of ROS, MDA, and 4-HNE. Western blot (WB) assay was performed to detect proteins related to the SIRT1/p53 pathway. KGN cells were used for in vitro experiment. TBHP stimulation was carried out for establishing the oxidative stress-induced apoptosis cell model. Furthermore, MTT assay was employed for evaluating the protection of DSS from TBHP-induced oxidative stress. The anti-apoptotic ability of DSS was evaluated by hoechst/PI staining, JC-1 staining, and apoptosis-related proteins. Additionally, the anti-oxidative stress ability of DSS was measured by detecting the levels of ROS, MDA, and 4-HNE. Proteins related to SIRT1/p53 signaling pathway were also measured using WB and immunofluorescence (IF) staining. Besides, SIRT1 expression was suppressed by EX527 to further investigate the role of SIRT1 in the effects of DSS against apoptosis and oxidative stress. RESULTS: In the in vivo experiment, DSS dose-dependently exerted its anti-apoptotic, anti-oxidative stress, and ovarian protective effects. In addition, apoptosis, apoptosis-related protein and oxidative stress levels were inhibited by DSS treatment. DSS treatment up-regulated SIRT1 and down-regulated p53 expression. From in vitro experiment, it was found that DSS treatment protected KGN cells from TBHP-induced oxidative stress injury. Besides, DSS administration suppressed the apoptosis ratio, apoptosis-related protein levels, mitochondrial membrane potential damage, and oxidative stress. SIRT1 suppression by EX527 abolished the anti-apoptotic, anti-oxidative stress, and ovarian protective effects, as discovered from in vivo and in vitro experiments. CONCLUSIONS: DSS exerts the anti-apoptotic, anti-oxidative stress, and ovarian protective effects in POF mice, and suppresses the apoptosis and oxidative stress of KGN cells through activating SIRT1 and suppressing p53 pathway.

[Gly14]-humanin exerts a protective effect against D-galactose-induced primary ovarian insufficiency in mice.

RESEARCH QUESTION: Is there a protective effect of the humanin derivative [Gly14]-humanin (HNG) on a D-gal-induced mouse model of primary ovarian insufficiency (POI), and what is the underlying mechanism? DESIGN: D-gal (200 mg/kg/day) was injected subcutaneously for 6 weeks to induce the mouse POI model. Mice treated with HNG were injected intraperitoneally with different concentrations for 6 weeks. Ovarian morphology, function, levels of sex hormones and states of oxidative stress in the ovary and body were evaluated. RESULTS: Compared with the D-gal group, 10 mg/kg HNG improved the abnormal ovarian morphology and oestrous cycle (P = 0.0036), increased the number of ovarian follicles (P = 0.0016) and litters (P = 0.0127), and increased the levels of oestrogen (P = 0.0043) and AMH (P = 0.0147). Antioxidant indicators in the ovaries and serum of mice, including total antioxidant capacity (P = 0.0004 and P = 0.0032, respectively), catalase (P = 0.0173 and P = 0.0103, respectively) and glutathione (both P < 0.0001) were significantly increased. The oxidation indicator malondialdehyde decreased significantly (all P < 0.01). Apoptosis of ovarian granulosa cells was significantly reduced (P = 0.0140) as was the expression of senescence-related proteins p53, p21 and p16 (all P < 0.01). The level of autophagy in ovarian tissue of mice treated with high increased (significantly increased LC3 protein [P < 0.0001] and significantly reduced p62 protein [P = 0.0007]). CONCLUSIONS: HNG inhibited D-gal-induced oxidative stress, apoptosis and ovarian damage, promoting ovarian autophagy. HNG may be a potential prophylactic agent against POI.

Fallo ovárico, una problemática para las mujeres en edad reproductiva y su relación genética / Ovarian failure, a problem for women in reproductive age and its genetic relationship

La insuficiencia ovárica primaria es una condición en la que las mujeres menores de 40años experimentan oligomenorrea o amenorrea durante 4meses o más; esta pérdida temprana de la función ovárica puede estar relacionada con una serie de etiologías, incluidos trastornos genéticos, autoinmunes, infecciones o causas iatrogénicas; no obstante, del 74 al 90% son idiopáticas. A pesar de ser una alteración poco prevalente, es de gran importancia clínica, ya que afecta en múltiples aspectos de la vida a todas las mujeres. En la actualidad se están desarrollando diferentes estudios con el fin de encontrar nuevos blancos moleculares para establecer nuevas terapias para el tratamiento de esta patología.(AU)

Primary ovarian failure is a condition in which women under 40 experience oligomenorrhea or amenorrhea for 4months or longer; this early ovarian function loss may be related to a series of etiologies, including genetic disorders, autoimmune diseases, infections or iatrogenic causes; however 74%-90% are idiopathic. Despite being a less prevalent disorder, it is of great clinical importance since it affects all women in multiple aspects of life. At present, different studies are being developed in order to find new molecular targets to establish new therapies for the treatment of this pathology.(AU)

MicroRNA-144-3p protects against chemotherapy-induced apoptosis of ovarian granulosa cells and activation of primordial follicles by targeting MAP3K9.

Premature ovarian failure (POF) is defined by amenorrhea, ovarian atrophy, hypoestrogenism, elevated gonadotropin level, and infertility under the age of 40. POF is frequently induced by chemotherapeutic agents. However, the underlying mechanisms regarding chemotherapy-mediated damage to ovarian function are unclear. In this study, enhanced apoptosis of granulosa cells (GCs) and aberrant activation of primordial follicles were observed in a POF mouse model induced by cisplatin. We subsequently observed significant downregulation of miR-144-3p and upregulation of mitogen-activated protein kinase kinase kinase 9 (MAP3K9) in primary ovarian GCs from POF mice, as revealed by microarrays. Furthermore, MAP3K9 expression was higher in human ovarian granulosa cells (COV434) treated with cisplatin and was identified as a novel target of miR-144-3p. Functional analysis revealed that miR-144-3p attenuated cisplatin induced apoptosis of GCs via silencing MAP3K9 expression, which suppressed the activity of the downstream p38 mitogen activated protein kinase (MAPK) pathway. Meanwhile, miR-144-3p prevented premature primordial follicle depletion in cisplatin-induced POF mice through targeting Map3k9, which led to a decline in the phosphorylation and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase b (AKT) pathway. Taken together, this study revealed the protective effects of miR-144-3p on ovarian function and shed light on the epigenetic regulatory mechanism in the development of POF, which might provide new biomarkers for the ovarian reserve.

Berberine protects cyclophosphamide and busulfan-induced premature ovarian insufficiency in mouse model.

Premature ovarian insufficiency (POI) is a clinical syndrome that declines ovarian function in women. Berberine (BBR) is a compound with anti-inflammatory, antioxidant, and anti-apoptotic activities. However, the role of BBR on POI is still unknown. In this study, we investigated the role of BBR on ovarian function decline by establishing a POI mouse model using cyclophosphamide (CTX) and busulfan (BU). Our results showed that POI was attenuated by BBR, which was evidenced by enhanced body weight and ovarian weight, improved morphology of ovary, increased the number of healthy follicles, decreased the production of atretic follicles and restored serum hormone levels, including estradiol, anti-Müllerian hormone and follicle-stimulating hormone. In addition, we showed that germ cell function markers, mouse vasa homologue (MVH) and octamer-binding transcription factor 4 (OCT4) were enhanced by BBR, at both protein and mRNA levels. Furthermore, our results revealed that BBR inhibited inflammation and oxidative stress by reducing nuclear factor kappa B (NF-κB) and enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Taken together, we demonstrate that BBR can effectively improve ovarian function in POI mice, which is mainly mediated by reducing oxidative stress and inflammatory response. Our study also provides new strategy for POI treatment.

Zigui-Yichong-Fang protects against cyclophosphamide-induced premature ovarian insufficiency via the SIRT1/Foxo3a pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zigui-Yichong-Fang (ZGYCF) is a traditional Chinese medicine prescription for the treatment of infertility and premature ovarian insufficiency (POI). It is clinically used to regulate hormone levels, improve ovarian reserve and increase pregnancy rate. However, the exact mechanism of action is not yet clear. AIMS OF THE STUDY: This study aimed to explore the potential impact and mechanism of ZGYCF on POI, and provide a scientific basis for its clinical application. MATERIALS AND METHODS: UHPLC‒MS/MS was used to identify the main compounds of ZGYCF. Female 8-week-old C57BL/6N mice were randomized into four group containing the vehicle control (Veh) group, the cyclophosphamide (CTX) model group, the low-dose ZGYCF (CTX-ZG-L) group and the high-dose ZGYCF (CTX-ZG-H) group. A mouse POI model was induced with a single intraperitoneal injection of CTX, and the therapeutic effects of different doses of ZGYCF on POI were evaluated according to the ovarian weight coefficient, serum AMH, serum E2, ovarian histomorphology and follicle counts. After the dose screening experiment, the CTX-ZG-L group was renamed the CTX-ZG group and subjected to follow-up experiments. RNA-seq was used to explore the mechanism of POI and the therapeutic mechanism of ZGYCF on POI in Veh group, CTX group and CTX-ZG group. The mechanism of action of ZGYCF on POI were determined by measuring serum hormone level, histomorphology, follicle counts, protein expression and acetylation modification in groups of Veh, CTX, CTX-ZG and CTX-ZG-Nam (SIRT1 inhibitor). RESULTS: A total of 37 compounds in ZGYCF were identified. ZGYCF attenuated the morphological changes in ovarian tissue in POI model mice, increased serum AMH and E2 levels, reduced the damage to primordial follicles and other follicles at all stages, and protected ovarian reserve. RNA-seq results suggested that the genes expression of the PI3K signaling and apoptosis signaling pathways was increased in POI mice, while ZGYCF upregulated SIRT1 gene and the expression of estradiol, apoptosis inhibition and other signaling pathway genes. Immunohistochemical staining, TUNEL staining, Western blot analysis and immunoprecipitation results showed that in CTX group, SIRT1 expression and Foxo3a nuclei localization were decreased, while Ac-Foxo3a, p-AKT, p-Foxo3a and apoptotic markers were upregulated. After administration of ZGYCF, these conditions were reversed, however, after treatment with the SIRT1 inhibitor, the results were opposite to those of ZGYCF. CONCLUSIONS: Acetylated Foxo3a plays an important role in the occurrence of POI. ZGYCF improves the ovarian reserve of CTX-induced POI mice by activating SIRT1-mediated deacetylation of Foxo3a, and played a role in the treatment of POI. SIRT1 may be a novel target for ZGYCF to ameliorate POI.

LCZ696 (sacubitril/valsartan) mitigates cyclophosphamide-induced premature ovarian failure in rats; the role of TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway.

AIM: Cyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model. MAIN METHODS: Rats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1ß, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored. KEY FINDINGS: CP treatment significantly elevated levels of MDA, IL-18, IL-1ß, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone. SIGNIFICANCE: LCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.

Loss of p16 does not protect against premature ovarian insufficiency caused by alkylating agents.

BACKGROUND: Chemical agents such as alkylating agents (AAs) that are commonly used for the treatment of cancer cause great damage to the ovaries, thereby significantly increasing the risk of premature ovarian insufficiency (POI). However, the exact molecules underlying AA-induced POI remain largely obscure. Upregulation of the p16 gene may contribute to the progression of POI. As yet, no in vivo data from p16-deficient (KO) mice are available to demonstrate a critical role of p16 in POI. In the present study, we employed p16 KO mice to investigate whether loss of p16 could protect against POI caused by AAs. METHODS: WT mice and their p16 KO littermates received a single dose of BUL + CTX to establish an AA-induced POI mouse model. One month later, oestrous cycles were monitored. Three months later, some of the mice were sacrificed to collect sera for measurements of hormone levels and ovaries for measurements of follicle counts, the proliferation and apoptosis of granulosa cells, ovarian stromal fibrosis and vessels. The remaining mice were mated with fertile males for the fertility test. RESULTS: Our results showed that treatment with BUL + CTX significantly disrupted the oestrous cycles, increased the levels of FSH and LH while decreasing the levels of E2 and AMH, decreased the counts of primordial follicles and growing follicles while increasing the counts of atretic follicles, reduced the vascularized area in the ovarian stroma, and decreased fertility. All of these results were comparable between WT and p16 KO mice treated with BUL + CTX. In addition, ovarian fibrosis was not increased significantly in WT and p16 KO mice treated with BUL + CTX. Growing follicles with normal appearance had normally proliferating granulosa cells (without apparent apoptosis). CONCLUSION: We concluded that genetic ablation of the p16 gene did not attenuate ovarian damage or help preserve the fertility of mice challenged by AAs. This study demonstrated for the first time that p16 is dispensable for AA-induced POI. Our preliminary findings suggest that targeting p16 alone may not preserve the ovarian reserve and fertility of females treated with AAs.

Expert consensus on fertility preservation in hematopoietic stem cell transplantation in girls in China.

Aims: Preconditioning before hematopoietic stem cell transplantation (HSCT) seriously damages the ovarian function and causes female infertility. This consensus focuses on the fertility preservation(FP) for girls needing HSCT, aim to make doctors in different disciplines aware of the importance, necessity and technique of ovarian protection.Materials and methods: Summarizing relevant literature and organizing multidisciplinary experts, including obstetrics and gynecology, reproductive medicine, oncology, pediatrics and hematology for full discussion.Results: Individuals exposed to HSCT in childhood are at higher risk of loss of fertility. Considering the high risk of premature ovarian insufficiency (POI) after conditioning and negative impact of POI on fertility, physical and mental health, it is absolutely necessary to protect fertility before HSCT conditioning. Ovarian tissue cryopreservation is the main fertility preservation option for these population.Conclusions: Fertility preservation before HSCT conditioning is crucial. Ovarian tissue cryopreservation is often the only option for these population.

Protective Effects of Antioxidants on Cyclophosphamide-Induced Ovarian Toxicity.

The most common limitation of anticancer chemotherapy is the injury to normal cells. Cyclophosphamide, which is one of the most widely used alkylating agents, can cause premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to their effects. Although little information is available about the pathogenic mechanism of cyclophosphamide-induced ovarian damage, its toxicity is attributed to oxidative stress, inflammation, and apoptosis. The use of compounds with antioxidant and cytoprotective properties to protect ovarian function from deleterious effects during chemotherapy would be a significant advantage. Thus, this article reviews the mechanism by which cyclophosphamide exerts its toxic effects on the different cellular components of the ovary, and describes 24 cytoprotective compounds used to ameliorate cyclophosphamide-induced ovarian injury and their possible mechanisms of action. Understanding these mechanisms is essential for the development of efficient and targeted pharmacological complementary therapies that could protect and prolong female fertility.

Melatonin Protects against Primary Ovarian Insufficiency by Activating the PI3K/Akt/mTOR Pathway and Inhibiting Autophagy.

OBJECTIVE: Primary ovarian insufficiency (POI), which refers to the occurrence of ovarian insufficiency before the age of 40, is indicated by menstrual cycle changes as a precursor and is accompanied by menstrual disorders, elevated gonadotropin levels, and decreased estrogen levels. The incidence of POI is reportedly increasing worldwide and this disease markedly reduces the quality of life and affects the physical and mental health of patients. Treatment options for POI include hormone replacement therapy; however, its efficacy remains unsatisfactory. Therefore, exploring hormonal drugs with superior curative effects and clarifying the molecular mechanism underlying POI pathogenesis could afford new directions for POI therapy. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were used to detect the effects of melatonin (MT) on cell survival and mortality. Flow cytometry was performed to examine the effect of MT on apoptosis. The impact of MT on autophagosome formation was examined using electron microscopy, whereas the expression of autophagy-related proteins and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway-related proteins following MT intervention was detected by western blotting. RESULTS: (1) MT exerted a protective effect on ovarian granulosa cells subjected to serum starvation. (2) MT inhibited serum starvation-induced apoptosis of ovarian granulosa cells. (3) MT inhibited serum starvation-induced autophagosome formation in ovarian granulosa cells. (4) MT inhibited the expression of autophagy-related proteins LC3II/I and Agt5. (5) MT suppressed autophagy in ovarian granulosa cells by activating the PI3K/Akt/mTOR signaling pathway. CONCLUSION: Collectively, our results demonstrate that MT can inhibit excessive autophagy in ovarian granulosa cells by activating the PI3K/Akt/mTOR pathway, thereby exerting its protective effect against POI.

Ovarian Reserve Disorders, Can We Prevent Them? A Review.

The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders.

Gonadotropin-releasing hormone agonist for the preservation of ovarian function in survivors of haematopoietic stem cell transplantation for haematological diseases.

OBJECTIVE: Administration of GnRH agonist (GnRHa) prior to chemotherapy may decreases the risk of gonadal dysfunction in patients with tumors. However, relevant data in haematopoietic stem cell transplantation (HSCT) recipients has not yet been established. Hence, the present study was designed to evaluate the clinical efficacy of GnRHa cotreatment prior to myeloablative regimens on ovarian protection in female survivors of HSCT for haematological diseases. PATIENTS AND METHODS: Eligible patients were divided into a GnRHa group and a control group. Medical records regarding age at HSCT; diagnosis/indication for HSCT; pre- and posttransplantation serum sex hormone levels; menstruation and perimenopausal symptoms after HSCT were collected and compared. The primary and secondary outcome was the incidence of premature ovarian insufficiency (POI) symptoms associated with hypoestrogenism. RESULTS: A total of 330 patients were enrolled in the study: 19 patients were lost to follow-up, and clinical information was obtained in 311 patients. There was no significant difference in the primary outcome of follow-up between the two groups (78.50% [84 of 107] for the GnRHa group versus 83.33% [170 of 204] for the control group). The adjusted relative risks (RR) and 95% confidence interval (CI) were 1.19 and 0.73-1.93 (P = 0.487). Among patients who received cotreatment with GnRHa, 62.62% (67 of 107) complained of perimenopausal symptoms, which was significantly lower than the 74.51% (152 of 204) in the control group (adjusted RR: 1.46, 95% CI: 1.04-2.06, P = 0.031). CONCLUSION: GnRHa cotreatment may not decrease the POI rate in HSCT survivors. However, it may reduce perimenopausal symptoms in this population, suggesting a potential benefit of GnRHa in clinical practice and warrant further researches.

Melatonin Protects Against Cyclophosphamide-induced Premature Ovarian Failure in Rats.

This study was designed to understand the efficacy and molecular cues of melatonin in cyclophosphamide(CTX)-induced premature ovarian failure (POF) in rats. Female SD rats were used to evaluate the potential effects of melatonin on the ovarian hormonal status, follicular development, and granulosa cells in CTX-treated rats. Here, we found that pretreatment with melatonin before CTX administration preserved the normal sex hormone levels, improved follicular morphology, and granulosa cell proliferation, and reduced apoptosis, as compared to the CTX treatment alone. Additionally, melatonin also up-regulated CYR6 and CTGF at the mRNA and protein levels. A potential mechanism is that melatonin inhibits LATS1, Mps1-One binder (MOB1), and YAP phosphorylation, thereby activating the Hippo signal pathway to promote its downstream targets, CYR61 and CTGF. In conclusion, pretreatment with melatonin effectively protected the ovaries against CTX-induced damage by activating the Hippo pathway. This study lay the foundation for the clinical application of melatonin for cancer patients with CTX treatment.

Melatonin prevents cyclophosphamide-induced primordial follicle loss by inhibiting ovarian granulosa cell apoptosis and maintaining AMH expression.

Cyclophosphaty -45mide (Cyc) chemotherapy in young female cancer patients is associated with an increased risk of premature ovarian insufficiency (POI). This study was designed to investigate the protective role of melatonin (Mel) as an adjuvant against Cyc-induced POI. Female mice received a single intraperitoneal (i.p.) dose of Cyc (75 mg/kg). Mel protection was achieved in mice after i.p. injection of melatonin (50 mg/kg) every 24 h for four consecutive days prior to chemotherapy initiation and for 14 additional days. Ovarian reserve testing, hormonal assays for follicle-stimulating hormone, luteinizing hormone, and anti-Müllerian hormone (AMH), assessment of the oxidative stress status, and measurement of the relative expression of genes in PTEN/AKT/FOXO3a and mitochondrial apoptosis pathways were performed. The results showed that treatment with 50 mg/kg Mel significantly prevented Cyc-induced over-activation of primordial follicles by maintaining the plasma level of AMH and subsequently preventing litter size reduction in mice treated with Cyc chemotherapy. Importantly, Mel treatment significantly prevented ovarian granulosa cell loss by inhibiting the mitochondrial apoptotic pathway. Identifying the protective actions of Mel against Cyc-induced primordial follicle loss has important implications for fertility maintenance in young cancer patients undergoing chemotherapy.

Gonadotropin-releasing hormone agonists for ovarian protection during breast cancer chemotherapy: a systematic review and meta-analysis.

IMPORTANCE: The increasing trend of delaying childbirth means that more women are being diagnosed with breast cancer before having given birth to their desired number of children. Although chemotherapy can significantly improve the prognosis of this population, it also causes ovarian damage, including premature ovarian insufficiency and infertility. Gonadotropin-releasing hormone agonists (GnRHa) have shown promising fertility protective activity in premenopausal women, but their clinical usage remains controversial. OBJECTIVE: Here, we conducted a meta-analysis to assess the efficacy of GnRHa when administered concurrently with chemotherapy that included cyclophosphamide in the prevention of chemotherapy-induced ovarian damage in premenopausal women. EVIDENCE REVIEW: An extensive literature search was performed using the PubMed, Embase, and Cochrane databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were determined. FINDINGS: Eleven randomized controlled trials with a total of 1,219 participants were included in the analyses. A significantly higher number of women treated with GnRHa experienced the resumption of ovarian function after chemotherapy than those who did not receive this treatment (OR, 3.04; 95% CI, 1.87-4.94; P < 0.001). Regarding spontaneous pregnancy, a statistically significant difference was observed only in hormone receptor-negative participants (OR, 2.06; 95% CI, 1.03-4.11; P = 0.04). CONCLUSIONS AND RELEVANCE: When treating premenopausal women with breast cancer, the administration of GnRHa concurrently with chemotherapy appeared to improve the resumption rate of ovarian function; however, the spontaneous pregnancy rate only improved in hormone receptor-negative patients. Thus, the use of GnRHa during chemotherapy may represent a feasible strategy for preserving ovarian function in women with breast cancer.

Targeting signaling pathways involved in primordial follicle growth or dormancy: potential application in prevention of follicular loss and infertility.

INTRODUCTION: Premature ovarian failure (POF) is one of the important causes of infertility in females. To date, no efficient preventive pharmacological treatment has been offered to prevent POF. Therefore, it is necessary to focus on strategies that provide a normal reproductive lifespan to females at risk of developing POF. AREAS COVERED: Recently, attention has been drawn to discovering pathways involved in primordial follicle activation, as the inhibition of this process might maintain the stock of primordial follicles and therefore, prevent POF. In vitro and animal studies have resulted in the discovery of several of these pathways that can be used to develop new treatments for POF. These studies show crosstalk of these pathways at different levels. One of the important crossing points of many of these pathways involves anti-Mullerian hormone (AMH). Herein, we discuss different aspects of this topic by reviewing related published articles indexed in PubMed and Web of Science as of December 2021. EXPERT OPINION: Although the findings seem promising, most of the studies were conducted on animals, and the interaction between these factors and the possible outcomes of their administration in the long term are still unknown. Therefore, further investigation is necessary to assess these aspects.

First live birth in China after cryopreserved ovarian tissue transplantation to prevent premature ovarian insufficiency.

OBJECTIVE: This article reports the first live birth after cryopreserved ovarian tissue transplantation to prevent premature ovarian insufficiency in China. METHODS: A patient with myelodysplastic syndrome received ovarian tissue cryopreservation before hematopoietic stem cell transplantation, and six ovarian cortex strips were thawed and transplanted into her peritoneal pocket 2 years later. RESULTS: Pregnancy occurred spontaneously 27 months after grafting, and a healthy girl was born at 38 weeks gestation. Until now, the child has developed normally without any major diseases. CONCLUSIONS: We report the first live birth resulting from ovarian tissue cryopreservation and transplantation in China.