Purpose: We evaluated the role of tumor necrosis factor alpha (TNFα) in rat ovulation and granulosa cell death of ovarian follicles during the periovulatory stage.Methods: Immature rats primed with pregnant mare serum gonadotropin were injected intraperitoneally with human chorionic gonadotropin (hCG), and TNFα was injected into the bursa 48 h later. The total number of released oocytes was counted. Apoptosis was measured with terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) and the expression of cleaved caspase 3 and Bax/Bcl‐2. Autophagy was assessed by the expression of light chain protein 3 (LC3) and autophagosomes under transmission electron microscopy.Results: TNFα significantly decreased the number of released oocytes, and many unruptured follicles were observed. TUNEL analysis revealed a larger number of apoptotic cells, and the cleaved caspase 3 and Bax/Bcl‐2 increased more than that of the control 12 h after hCG administration. Furthermore, the expression of LC3 wwas significantly higher than that of the control, and autophagosomes were observed in the cytoplasm.Conclusions: Our data indicated that TNFα is an important mediator of ovulation in terms of decreasing the number of released oocytes and inducing granulosa cell death of unruptured follicles via apoptosis and autophagy for remodeling ovarian tissues.

It is known that metabolic disturbances suppress reproductive functions in females. The mechanisms underlying metabolic and nutritional effects on reproductive functions have been established based on a large body of clinical and experimental data. From the 1980s to 1990s, it was revealed that disrupted gonadotropin-releasing hormone (GnRH) secretion is the main cause of reproductive impairments in metabolic and nutritional disorders. From the late 1990s to early 2000s, it was demonstrated that, in addition to their primary functions, some appetite- or metabolism-regulating factors affect GnRH secretion. Furthermore, in the early 2000s, kisspeptin, which is a potent positive regulator of GnRH secretion, was newly discovered, and it has been revealed that kisspeptin integrates the effects of metabolic status on GnRH neurons. Recent studies have shown that kisspeptin mediates at least some of the effects of appetite- and metabolism-regulating factors on GnRH neurons. Thus, kisspeptin might be a useful clinical target for treatments aimed at restoring reproductive functions in individuals with metabolic or nutritional disturbances, such as those who exercise excessively, experience marked weight loss, or suffer from eating disorders. This paper presents a review of what is currently known about the effects of metabolic status on reproductive functions and their underlying mechanisms by summarizing the available evidence.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.

Polycystic ovary syndrome (PCOS) is frequently seen in females of reproductive age and is associated with metabolic disorders that are exacerbated by obesity. Although body weight reduction programs via diet and lifestyle changes are recommended for modifying reproductive and metabolic phenotypes, the drop-out rate is high. Thus, an efficacious, safe, and continuable treatment method is needed. Recent studies have shown that oxytocin (OT) reduces body weight gain and food intake, and promotes lipolysis in some mammals, including humans (especially obese individuals), without any adverse effects. In the present study, we evaluated the changes in endogenous OT levels, and the effects of acute and chronic OT administration on body weight changes, food intake, and fat mass using novel dihydrotestosterone-induced PCOS model rats. We found that the serum OT level was lower in PCOS model rats than in control rats, whereas the hypothalamic OT mRNA expression level did not differ between them. Acute intraperitoneal administration of OT during the dark phase reduced the body weight gain and food intake in PCOS model rats, but these effects were not observed in control rats. In contrast, chronic administration of OT decreased the food intake in both the PCOS model rats and control rats. These findings indicate that OT may be a candidate medicine that is efficacious, safe, and continuable for treating obese PCOS patients.

Oxytocin (OT) affects many behavioral, psychological, and physiological functions, including appetite and body weight regulation. Central and peripheral OT levels are markedly affected by gonadal steroids, especially estrogen, and the anorectic effects of estrogen are partially mediated by OT in rodents. In this study, the relationship between the estrogen milieu and serum OT levels was evaluated in women of reproductive age under physiological (n = 9) and supraphysiological estrogenic conditions (n = 7). Consequently, it was found that serum OT levels were increased in physiological (the ovulatory phase) and supraphysiological (on the day of the human chorionic gonadotropin trigger in an ovarian stimulation cycle) estrogenic conditions, and that serum OT levels were positively correlated with serum estradiol levels. On the other hand, serum OT levels were negatively correlated with serum progesterone levels, and there was no correlation between serum and follicular OT levels. These results suggest that OT levels may be positively and negatively regulated by estrogen and progesterone, respectively, in humans. However, the physiological roles of these actions of gonadal steroids on OT remain unclear.

Objectives : It has been suggested that the clinical outcomes of frozen-thawed embryo transfer (ET) are superior to those of fresh embryo transfer. We examined whether a freeze-all strategy is necessary for all embryo transfers, and, if not, to evaluate the conditions in which the pregnancy rates of fresh embryo transfer and frozen-thawed ET did not differ. Methods : Patients who underwent blastocyst transfer at Tokushima University Hospital between 2008 and 2019 were enrolled. The clinical outcomes and clinical characteristics of 1,022 patients that underwent fresh embryo transfer and 1,728 patients that underwent frozen-thawed ET were examined retrospectively. We considered the factors that influenced the pregnancy outcomes of fresh embryo transfer. Results : The frozen-thawed ET group exhibited significantly higher pregnancy, live-birth, and miscarriage rates than the fresh embryo transfer group. In the fresh embryo transfer group, a high progesterone level on the day of the human chorionic gonadotropin (hCG) trigger and lower grade embryos were risk factors for a low pregnancy rate. However, in the cases in which the progesterone level was < 1.0 ng / mL the pregnancy rate was equal to that of frozen-thawed ET. Conclusions : A freeze-all strategy is not necessary for embryo transfers, but should be employed in cases involving pre-ovulatory progesterone elevation. J. Med. Invest. 69 : 224-229, August, 2022