Yiliyasi Mayila

Relationship between serum anti-Mullerian hormone and clinical parameters in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is an ovulatory disorder that affects 6-10% of women of reproductive age. Serum AMH level may be an additional factor, or surrogate of PCOM, in the diagnostic criteria of PCOS. We evaluated the correlations between the serum AMH level and various endocrine and metabolic features in PCOS using the latest fully automated assay. Serum AMH level was compared between 114 PCOS patient (PCOS group) and 95 normal menstrual cycle women (Control group). Correlations between serum AMH level and various endocrine and metabolic factors were analysed in PCOS group. The serum AMH level was significantly higher in the PCOS group (8.35±8.19 ng/mL) than in the Control group (4.99±3.23 ng/mL). The serum AMH level was independently affected by age and the presence of PCOS on multiple regression analysis. Ovarian volume per ovary (OPVO) showed the strongest positive correlation (r=0.62) with the serum AMH level among related factors. On receiver operating characteristic (ROC) curve analysis, the cut-off value of AMH for the diagnosis of PCOS was 7.33 ng/mL, but this value did not have high efficacy (sensitivity 44.7%, specificity 76.8%). A cut-off value of 10 ng/mL had a high specificity of 92.6%, although the sensitivity was low (24.6%). The serum AMH level was elevated and reflected ovarian size in PCOS patients. The serum AMH level could be a surrogate for ultrasound findings of the ovaries in PCOS and might be useful for estimating ovarian findings without transvaginal ultrasound in the diagnosis of PCOS.

Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome

Hypersecretion of luteinizing hormone (LH) is a common endocrinological finding of polycystic ovary syndrome (PCOS). This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of gonadotropin-releasing hormone (GnRH). We evaluated the relationship between the hypothalamic-pituitary-gonadal axis (HPG axis) and kisspeptin using a rat model of PCOS induced by letrozole. Letrozole pellets (0.4 mg/day) and control pellets were placed subcutaneously onto the backs of 3-week-old female Wistar rats. Body weight, vaginal opening and vaginal smear were checked daily. Blood and tissues of ovary, uterus and brain were collected at 12-weeks of age. An hypothalamic block was cut into anterior and posterior blocks, which included the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), respectively, in order to estimate hypothalamic kisspeptin expression in each area. The letrozole group showed a similar phenotype to human PCOS such as heavier body weight, heavier ovary, persistent anovulatory state, multiple enlarged follicles with no corpus luteum and higher LH and testosterone (T) levels compared to the control group. Kisspeptin mRNA expression in the posterior hypothalamic block including ARC was higher in the letrozole group than in the control group although its expression in the anterior hypothalamic block was similar between groups. These results suggest that enhanced KNDy neuron activity in ARC contributes to hypersecretion of LH in PCOS and might be a therapeutic target to rescue ovulatory disorder of PCOS in the future.

The effects of chronic testosterone administration on hypothalamic gonadotropin-releasing hormone regulatory factors (Kiss1, NKB, pDyn and RFRP) and their receptors in female rats

Abstract The effects of androgens on gonadotropin-releasing hormone (GnRH) secretion in females have not been fully established. To clarify the direct effects of androgens on hypothalamic reproductive factors, we evaluated the effects of chronic testosterone administration on hypothalamic GnRH regulatory factors in ovariectomized (OVX) female rats. Both testosterone and estradiol reduced the serum luteinizing hormone levels of OVX female rats, indicating that, as has been found for estrogen, testosterone suppresses GnRH secretion via negative feedback. Similarly, the administration of testosterone or estradiol suppressed the hypothalamic mRNA levels of kisspeptin and neurokinin B, both of which are positive regulators of GnRH, whereas it did not affect the hypothalamic mRNA levels of the kisspeptin receptor or neurokinin-3 receptor. On the contrary, the administration of testosterone, but not estradiol, suppressed the hypothalamic mRNA expression of prodynorphin, which is a negative regulator of GnRH. The administration of testosterone did not alter the rats’ serum estradiol levels, indicating that testosterone’s effects on hypothalamic factors might be induced by its androgenic activity. These findings suggest that as well as estrogen, androgens have negative feedback effects on GnRH in females and that the underlying mechanisms responsible for these effects are similar, but do not completely correspond, to the mechanisms underlying the effects of estrogen on GnRH.

Clinical outcome of various metformin treatments for women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is an ovulatory disorder and insulin resistance and diabetes are involved in its pathophysiology. Metformin, an anti‐diabetic agent, has been reported to be useful to induce ovulation.

Prenatal undernutrition disrupted the sexual maturation, but not the sexual behavior, in male rats

Exposure to various stressors, including psychological, metabolic, and immune, in the perinatal period induces long‐lasting effects in physiological function and increase the risk of metabolic disorders in later life. In the present study, sexual maturation and sexual behavior were assessed in prenatally undernourished mature male rats.

The effects of prenatal undernutrition and a high-fat postnatal diet on central and peripheral orexigenic and anorexigenic factors in female rats

Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.

Pilot study of the optimal protocol of low dose step-up follicle stimulating hormone therapy for infertile women

To evaluate the optimized protocol of low dose follicle‐stimulating hormone (FSH) therapy that has a starting dose of 50 IU/62.5 IU with a small increment dose (12.5 IU) for women with World Health Organization (WHO) II ovulatory disorder and unexplained infertility.

Effects of Low Energy Availability on Reproductive Functions and Their Underlying Neuroendocrine Mechanisms

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.

Prenatal undernutrition attenuates fasting-induced reproductive dysfunction in pre-pubertal male rats

Prenatal undernutrition affects various physiological functions, such as metabolic and reproductive functions, after birth, and such changes are associated with the pathogeneses of certain diseases. It has been hypothesized that these changes are predictive adaptive responses that help individuals to endure similar conditions in the postnatal period. Thus, we evaluated the effects of prenatal undernutrition on the responses of the body weight (BW) regulation system and reproductive functions to fasting in the pre‐pubertal period in male rats. Prenatally normally nourished and undernourished rats exhibited similar reductions in BW and visceral fat after 48 h fasting in the pre‐pubertal period. Furthermore, these two groups displayed similar fasting‐induced patterns of change in their hypothalamic levels of appetite regulatory factors; i.e., neuropeptide Y and pro‐opiomelanocortin. These results indicate that prenatal undernutrition had no marked effects on BW regulation in male rats. On the other hand, serum luteinizing hormone and testosterone levels were decreased by 48 h fasting in the prenatally normally nourished rats, whereas the levels of these hormones did not change in the prenatally undernourished rats. However, the hypothalamic mRNA level of kisspeptin 1 (Kiss1), which is a positive regulator of gonadotropin‐releasing hormone/gonadotropins, was reduced by fasting in both groups. These results indicate that prenatal undernutrition might attenuate fasting‐induced reproductive dysfunction in the postnatal period; however, these changes might not be induced by alterations in the hypothalamic Kiss1 system. Further studies are needed to clarify the mechanisms involved in these changes in reproductive function.

Prenatal undernutrition decreases the anorectic response to septic doses of lipopolysaccharides in adulthood in male rats

Prenatal undernutrition affects some physiological functions after birth, and such changes are associated with the pathogenesis of various diseases. Recently, we have reported that prenatally undernourished male rats exhibited stronger febrile and anorectic responses to immune stress induced by moderate‐dose lipopolysaccharide (LPS) treatment in adulthood. In the present study, we evaluated the effects of prenatal undernutrition on stress responses to the administration of a septic dose (3 mg/kg) of LPS in later life, mainly focusing on changes in hypothalamic proinflammatory cytokine expression. We also evaluated the expression of hypothalamic and peripheral reproductive factors because it has been suggested that the stress responses of reproductive functions are affected by prenatal and neonatal stress and nutritional conditions. As a result, we found that prenatal undernutrition attenuated the anorectic response to septic‐dose LPS treatment in adulthood in male rats. In addition, it attenuated the LPS‐induced suppression of serum testosterone levels and the changes in hypothalamic proinflammatory cytokine (interleukin (IL)‐1β, tumor necrosis factor‐α, and IL‐6) expression induced by septic‐dose LPS treatment in adulthood. These results suggest that prenatal undernutrition attenuates stress and reproductive responses under severe immune stress conditions. The downregulation of hypothalamic stress‐related factor expression might be involved in such attenuated stress responses, which could be one of the protective mechanisms used to prevent excessive immune responses and aid survival.