Evidence of cancer therapy-induced chronic inflammation in the ovary across multiple species: A potential cause of persistent tissue damage and follicle depletion.

Chemotherapy and radiation treatments are known for deleterious effects on the ovary, which can result in prolonged recovery time before ovarian function resumes, including follicular growth after completion of these therapies. To better understand the protracted ovarian dysfunctions after chemotherapy and radiotherapy, we designed a comprehensive study to investigate the underlying mechanisms involved in chronic ovarian damage that prevent follicular development and/or to induce persistent follicle loss. Blood and ovarian samples were collected from reproductive age women, rhesus macaques, and mice after completion of chemotherapy and/or radiotherapy and from age-matched patients and animals without chemotherapy agent or radiation exposure to serve as controls. Serum levels of anti-Müllerian hormone and proinflammatory cytokines, monocyte chemoattractant protein 1 and IL6, were measured. Ovarian tissue was assessed for histopathology and inflammatory cell infiltration, e.g., macrophages and neutrophils, by immuohistochemistry. Serum anti-Müllerian hormone concentrations were lower, whereas proinflammatory cytokine concentrations were higher, in patients and rhesus macaques at ~1 year post-chemotherapy agent and/or radiation exposure compared with controls. The number of primordial follicles reduced in the mouse ovary > 5 weeks after a single injection of cyclophosphamide. Macrophage infiltration was observed in the ovarian cortex of humans and animals. These data suggest that chronic inflammation induced by chemotherapy agents and/or radiation treatment may be associated with persistent ovarian tissue damage, follicle depletion, and functional decline. Interventions that dampen the overactivated inflammatory response may further protect the ovary after completion of chemotherapy and radiotherapy to maintain follicle viability and support continued follicular development in female patients.

Vitamin D in follicular development and oocyte maturation.

Vitamin D (VD) is a secosteroid hormone synthesized predominantly in the skin upon UV light exposure, which can also be obtained from dietary sources. In target cells, the bioactive VD binds to specific VD receptor to regulate downstream transcription of genes that are involved in a wide range of cellular processes. There is an increasing recognition that the proper physiological levels of VD are critical for optimizing reproductive potential in women. The direct VD action in the ovary was first suggested in the 1980s. Since then, research has attempted to determine the role of VD in follicular development and oocyte maturation in animal models and clinical settings. However, data published to date are inconclusive due to the complexity in VD metabolism and the fact that VD actions are pervasive in regulating physiological functions in various systems, including the reproductive, endocrine and nervous systems that control reproduction. This review summaries in vitro, in vivo, and clinical evidence regarding VD metabolism and signaling in the ovary, as well as VD-regulated or VD-associated ovarian follicular development, steroidogenic function, and oocyte maturation. It is suggested that adequate animal models are needed for well-controlled studies to unravel molecular mechanisms of VD action in the ovary. For clinical studies, follicular development and function may be evaluated more effectively in a relatively homogeneous patient population under a well-controlled experimental design. A comprehensive understanding of VD-regulated folliculogenesis and oogenesis will provide critical insight into the impact of VD in female reproductive health.

Insulin-like growth factor 2 is produced by antral follicles and promotes preantral follicle development in macaques†.

Insulin-like growth factors (IGFs) are known for their involvement in endocrine and paracrine regulation of ovarian function. Although IGF2 is the predominant circulating and intraovarian form of IGFs in primate species, the stage-specific follicular expression, action, and regulation of IGF2 are not well defined. Therefore, experiments were conducted to investigate the follicular IGF production in response to steroid hormone regulation and the direct IGF actions on follicular development and function in vitro. Preantral follicles were isolated from rhesus macaque ovaries and cultured to the antral stage in media supplemented with follicle-stimulating hormone and insulin. Follicles were randomly assigned to treatment groups: (a) control, (b) trilostane (a steroid synthesis inhibitor), (c) trilostane + estradiol, (d) trilostane + progesterone, and (e) trilostane + dihydrotestosterone. Media was analyzed for IGF concentrations, which were correlated to follicle growth. Follicles produced IGF2, but not IGF1, at the antral stage. Steroid depletion decreased, whereas steroid replacement increased, IGF2 production by antral follicles. Media IGF2 levels correlated positively with antral follicle diameters. Macaque preantral follicles and granulosa cells were subsequently cultured without (control) and with recombinant human IGF2 supplementation. Follicle survival, growth, and paracrine factor production, as well as granulosa cell proliferation and gonadotropin receptor gene expression, were assessed. IGF2 addition increased follicle survival rates, diameters and inhibin B production, as well as granulosa cell proliferation. These data demonstrate that IGF2 produced by antral follicles, in response to steroid hormone regulation, could act as a paracrine factor that positively impacts preantral follicle development and function in primates.