bims-ovagas 2026-04-05 papers

Syst Biol Reprod Med. 2026 Dec;72(1): 211-240

Molecular mechanisms of folliculogenesis and oogenesis.

Folliculogenesis is a complex, multi-stage process crucial for the establishment and maintenance of female fertility through the production of a developmentally competent oocyte. Folliculogenesis, including follicular formation, activation, growth and maturation, relies on a finely tuned spatiotemporal crosstalk between germ cells, somatic cells, and the hypothalamic-pituitary-ovarian axis. This work provides a comprehensive overview of the cellular dynamics and molecular mechanisms underlying each stage of follicular development. A particular emphasis is placed on the interaction of growth factors, transcriptional networks, signaling pathways and endocrine cues that collectively govern follicular fate and oocyte quality. Disruptions in these interactions lead to emergence of pathological conditions such as premature ovarian insufficiency and age-related infertility. We further highlight the dual aspects of oocyte maturation, nuclear and cytoplasmic, as major determinants of developmental competence, and explore the role of spindle dynamics, organelle redistribution and epigenetic reprograming in this process. The bidirectional communication between oocytes and cumulus cells, mediated by paracrine signaling and jap junctions, is underscored as a pivotal regulator of oocyte metabolic activity, redox homeostasis, and meiotic competence. A better understanding of the oocyte-cumulus cell interaction offers new approaches for refining the in vitro maturation systems and improving assisted reproductive technologies. A special attention is given to the emerging use of cumulus cell-derived biomarkers for noninvasive assessment of oocyte quality and prediction of preimplantation embryo development. Taken together, this article presents an integrated framework to guide future research in reproductive biology, regenerative medicine, and fertility preservation.

Keywords: Follicle; cumulus cells; developmental competence; meiosis; oocyte; spindle

DOI: https://doi.org/10.1080/19396368.2026.2631558

Mol Hum Reprod. 2026 Mar 30. pii: gaag018. [Epub ahead of print]

Exogenous Putrescine Supplementation Improves Cyclophosphamide-induced Premature Ovarian Insufficiency in Mice.

Chenxi Zhao, Cong Xu, Qian Zhang, Yuyi Wang, Siyuan Xie, Chao Gao, Yugui Cui, Wei Wu.

The incidence of premature ovarian insufficiency (POI) is gradually increasing, and currently no clinical treatments are available to restore ovarian function in POI patients, which severely affects the physical and mental health of young women with fertility needs. Putrescine is a type of polyamine found in the human body and different foods, and research has shown that adding putrescine to drinking water can reduce embryo resorption rates in aged mice. Polyamines are also closely related to apoptosis, with ovarian granulosa cells (GCs) apoptosis considered an important factor in follicular atresia, which may lead to POI. Therefore, we investigated putrescine's actions in POI. We generated a drug-induced POI mouse model by intraperitoneally injecting cyclophosphamide (Cy) into animals. Putrescine was then added to their drinking water to explore its effects on ovarian function in mice. In vitro, we added 4-hydroxycyclophosphamide (4-HC) and putrescine to a GCs line to examine the specific mechanisms underpinning putrescine actions. We discovered that putrescine improved ovarian function and fertility in Cy-induced POI mice and ameliorated GC apoptosis via P53 signaling. These findings provide potential therapeutic strategies for patients with POI.

Keywords: P53; apoptosis; cyclophosphamide; fertility; granulosa cells; premature ovarian insufficiency; putrescine

DOI: https://doi.org/10.1093/molehr/gaag018

J Autoimmun. 2026 Apr 02. pii: S0896-8411(26)00030-2. [Epub ahead of print]160 103552

Autoimmune modulation of immune-endocrine-metabolic regulation of ovarian reserve: A cohort study of 803 women.

Ae Ra Han, Monira Alzahrani, Thanh V Luu, Svetlana Dambaeva, Joanne Kwak-Kim.

Anti-Müllerian hormone (AMH) is an early functional marker of diminished ovarian reserve and premature ovarian insufficiency (POI), yet the immunologic context underlying AMH variation remains incompletely defined. Because ovarian autoimmunity constitutes a distinct subset of POI, anti-ovarian antibody (AOA) status may modulate the immune-endocrine-metabolic mechanisms that govern follicular function. In this retrospective observational cohort study, 803 women evaluated for reproductive failure between 2018 and 2024 were stratified by AOA status into AOA-positive (n = 135) and AOA-negative (n = 668) groups. Serum AMH was assessed together with endocrine and metabolic parameters, including 25-hydroxy vitamin D (VitD), thyroid-stimulating hormone (TSH), dehydroepiandrosterone sulfate (DHEAS), plasminogen activator inhibitor-1 (PAI-1), homocysteine, HbA1c, and androgen indices, as well as peripheral immune markers comprising lymphocyte subsets, natural killer (NK) cell cytotoxicity, and T helper (Th) 1/Th2 cytokine producing Th cell ratios. Age-adjusted AMH ratios (aaAMH ratios) were calculated using a validated polynomial model based on U.S. reference data. Multivariable regression and generalized additive models (GAM) were applied to evaluate both linear and nonlinear associations between biological variables and ovarian reserve. Age was inversely associated with AMH and excluded from adjusted models. In AOA-negative women, aaAMH ratios demonstrated significant nonlinear associations with NK cell proportion and B-1a cells, suggesting preserved but complex immune regulatory dynamics. Conversely, in AOA-positive women, several markers showed significant linear associations with aaAMH ratios, including homocysteine (Hcy), PAI-1, HbA1c, and the IFN-γ/IL-10 Th1/Th2 cytokine-producing Th cell ratio. The GAM explained substantially greater deviance in AOA-positive women than in AOA-negative women, indicating a distinct systemic regulatory pattern. A composite model integrating metabolic and immune markers yielded an area under the curve of 0.786 for identifying women at risk of markedly reduced ovarian reserve. These findings reveal fundamentally different immune-endocrine-metabolic signatures of ovarian dysfunction according to ovarian autoimmunity and support the concept that peripheral immune profiles reflect immune-mediated modulation of follicular function in autoimmune POI.

Keywords: Anti-müllerian hormone; Anti-ovarian antibody; Immune-endocrine interaction; Natural killer cells; Ovarian autoimmunity; Premature ovarian insufficiency

DOI: https://doi.org/10.1016/j.jaut.2026.103552

Recent Adv Inflamm Allergy Drug Discov. 2026 Mar 26.

Inflammation-Driven Pathogenesis of Polycystic Ovary Syndrome: Integrating Endocrine Imbalance, Reproductive Impairments, and Tissue-Level Change.

Manthan Suthar, Vitalii Kaliberdenko.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age, classically defined by hyperandrogenism, ovulatory dysfunction and polycystic ovaries morphology. Recent findings now support that low-grade chronic inflammation is a key player in PCOS pathophysiology, explaining hormonal, metabolic, and reproductive dysfunction.
OBJECTIVE: The objective of this narrative review is to update the readership regarding the role of inflammation as a driver in the pathogenesis of PCOS, particularly at points where inflammatory and endocrine, reproductive, and tissue levels intersect.
METHOD: We performed a narrative review using published, peer-reviewed, and library-recorded sources available in databases such as PubMed, Scopus, and Web of Science. Keywords relevant to PCOS, fibrosis, endocrine dysfunction, inflammation and reproductive impairment were employed. studies were chosen to be included in this review based on their relevance, quality and concentration on inflammatory pathways and tissue-level changes in PCOS. Results were synthesised thematically in order to synthesize understanding mechanisms between the molecular, endocrine and clinical levels.
RESULTS: There is evidence that insulin resistance, hyperandrogenism, and dysfunction of the hypothalamic-pituitary-ovarian axis are associated with pro-inflammatory cytokines and immune dysregulation and oxidative stress. Inflammatory signaling also plays a role in follicular development, ovarian tissue remodeling and adipose tissue function. These elements of an feed-forward loop maintain the endocrine and metabolic features of Conclusion: Inflammation seems to be a primary determinant in the pathogenicity of PCOS and not mere secondary phenomenon. The identification of the development of inflammation opens the possibility of novel treatment paradigms including anti-inflammatory treatments such as those used for PCOS patients presenting with reproductive and metabolic abnormalities.

Keywords: Chronic Inflammation; Cytokines; Extracellular Matrix; Fibrosis; Follicular Arrest; Hyperandrogenism; Insulin Resistance; Ovarian Remodeling; Polycystic Ovary Syndrome (PCOS)

DOI: https://doi.org/10.2174/0127722708420885260130135852

bioRxiv. 2026 Mar 25. pii: 2024.10.05.616758. [Epub ahead of print]

Progressive hypothalamic neuroinflammation after ovariectomy in mice parallels age-related transcriptomic changes in the female human hypothalamus.

Jordana C B Bloom, Encarnación Torres, Sidney A Pereira, Liliana Arvizu-Sanchez, Audrey N Fontes, Hadine Joffe, David C Page, Victor M Navarro.

The hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized. Here, we performed a comprehensive temporal characterization of the mouse hypothalamus following ovariectomy (OVX), combining physiological measurements with bulk RNA-sequencing of the posterior hypothalamus (PH) and preoptic area (POA) at short-term (14 days) and long-term (4 months) post-OVX. Serum LH levels rose progressively and then declined, while core temperature peaked early and subsequently normalized, recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans. Transcriptomic analysis revealed time-dependent activation of inflammatory pathways, glial markers, and KNDy neuron-related gene networks, with the most pronounced changes emerging at 4 months post-OVX, particularly in the PH. Immunofluorescence confirmed increased NKB release, declining KNDy neuronal activity, and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal. To contextualize these findings, we analyzed publicly available human hypothalamic RNA-seq data across chronological age. Age-related transcriptomic patterns in women, including progressive inflammatory signaling, glial activation, and altered KNDy gene expression, showed significant correlation with the OVX mouse model, particularly at the pathway level. These findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal, identify conserved neuroinflammatory signatures across species, and provide a preclinical platform for testing interventions targeting menopausal-associated hypothalamic dysfunction.

DOI: https://doi.org/10.1101/2024.10.05.616758

J Ovarian Res. 2026 Apr 02.

Interconnected cell death pathways: central mechanisms and therapeutic targets in impaired follicular development of polycystic ovary syndrome.

Shuang Ma, Chang Sun, Yasong Wang, Xuanning Zhang, Hongying Kuang.

Keywords: Ferroptosis; Inflammasome; Ovarian microenvironment imbalance; Polycystic ovary syndrome; Programmed cell death; Pyroptosis

DOI: https://doi.org/10.1186/s13048-026-02054-5