The effects of ovariectomy and lifelong high-fat diet

In females, ovarian hormones play pivotal roles in metabolic, appetite, and body weight regulation. In addition, it has been reported that ovarian hormones also affect longevity in some species. Recently, it was found that the consumption of a high-fat diet aggravates ovariectomy-associated metabolic dysregulation in female rodents. The aim of this study was to investigate the hypothesis that long-term high-fat diet consumption and ovariectomy interact to worsen body weight regulation and longevity in female rats. At 21 days of age, female rats were weaned and randomly divided into two groups, one of which was given the high-fat diet, and the other was supplied with standard chow. At 23 weeks of age, each group was further divided into ovariectomized and sham-operated groups, and then their body weight changes, food intake, and longevity were measured until 34 months of age. The sham – high-fat diet rats exhibited greater body weight changes and higher feed efficiency than the sham – standard chow rats. On the other hand, the ovariectomized – high-fat diet and ovariectomized - standard chow rats displayed similar body weight changes and feed efficiency. The sham – high-fat diet and ovariectomized – standard chow rats demonstrated similar body weight changes and feed efficiency, indicating that the impact of ovariectomy on the regulation of body weight and energy metabolism might be similar to that of high-fat diet. Contrary to our expectations, ovariectomy and high-fat diet consumption both had small favorable effects on longevity. As the high-fat diet used in the present study not only had a high fat content, but also had a high caloric content and a low carbohydrate content compared with the standard chow, it is possible that the effects of the high-fat diet on body weight and longevity were partially induced by its caloric/carbohydrate contents. These findings indicate that the alterations in body weight and energy metabolism induced by ovariectomy and high-fat diet might not directly affect the lifespan of female rats

GnIH and Stress-Induced Reproductive Dysfunction

Physical and psychological stressors suppress hypothalamic–pituitary–gonadal axis activity and sexual behavior and consequently induce reproductive dysfunction. Recently, it has been shown that gonadotropin-inhibitory hormone (GnIH), also called RFamide-related peptide 3 (RFRP) in mammals, which is a potent inhibitory regulator of gonadotropin-releasing hormone (GnRH) and gonadotropin, is involved in stress-induced reproductive dysfunction. GnIH/Rfrp (the gene coding RFRP-3) expression and activity are increased by psychological and immune stress, and this alteration suppresses GnRH and gonadotropin secretion. Glucocorticoid acts as a mediator that interacts between stress and hypothalamic GnIH/RFRP-3. GnIH/RFRP-3 also plays important roles in stress-induced suppression of sexual behavior and infertility, and genetic silencing of GnIH/Rfrp completely recovers sexual behavior and fertility. This review summarizes what is currently known about the roles of GnIH in stress-induced reproductive dysfunction

Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats

Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone’s effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings

The effects of chronic testosterone administration on body weight, food intake, and fat weight were age-dependent

Previously, we showed that chronic testosterone administration increased body weight (BW) and food intake (FI), but did not alter fat weight, in young female rats. To examine our hypothesis that the effects of androgens on BW, FI and body composition might be age-dependent, the effects of chronic testosterone administration were evaluated in rats of different ages; i.e., young and middle-aged rats. Although chronic testosterone administration increased BW gain, FI, and feed efficiency in both young and middle-aged rats, it increased visceral fat weight in middle-aged rats, but not in young rats. Therefore, it is possible that testosterone promotes the conversion of energy to adipose tissue and exacerbates fat accumulation in older individuals. In addition, although the administration of testosterone increased the serum leptin level, it did not alter hypothalamic neuropeptide Y mRNA expression in middle-aged rats. On the contrary, the administration of testosterone did not affect the serum leptin levels of young rats. Thus, testosterone might induce hypothalamic leptin resistance, which could lead to fat accumulation in older individuals. Testosterone might disrupt the mechanisms that protect against adiposity and hyperphagia and represent a risk factor for excessive body weight and obesity, especially in older females

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

Effects of DHT injection

To clarify the direct effects of androgens, the changes in the hypothalamic levels of reproductive and appetite regulatory factors induced by chronic dihydrotestosterone (DHT) administration were evaluated in female rats. DHT treatment increased the BW and food intake of the ovariectomized rats, but not the estradiol (E2)-treated rats. DHT administration suppressed the expression of a hypothalamic anorexigenic factor. Although the kisspeptin (Kiss1) mRNA levels of the anterior hypothalamic block (the anteroventral periventricular nucleus, AVPV) were increased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the AVPV in the ovariectomized or E2-treated rats. Conversely, DHT administration reduced the Kiss1 mRNA levels of the posterior hypothalamic block (the arcuate nucleus, ARC) in the ovariectomized rats. Although the Kiss1 mRNA levels of the posterior hypothalamic block (ARC) were decreased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the ARC in these rats. Serum luteinizing hormone levels of these groups exhibited similar patterns to the Kiss1 mRNA levels of the ARC. These results showed that DHT affects the production of hypothalamic reproductive and appetite regulatory factors, and that these effects of DHT differ according to the estrogen milieu

Effects of testosterone injection

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

Pregnancy outcomes of women who received conservative therapy for endometrial carcinoma or atypical endometrial hyperplasia

Case: Approximately 3%‐25% of cases of endometrial carcinoma (EC) or atypical endometrial hyperplasia (AH) occur in women aged <40 years and conservative treatment with high‐dose medroxyprogesterone acetate (MPA) is administered to women who wish to preserve their fertility. Here is reported the pregnancy outcomes of patients with EC or AH who received MPA therapy at Tokushima University Hospital, Tokushima, Japan. The frequency of pregnancy and live births among the patients with EC or AH who received conservative treatment, followed by fertility treatment, were analyzed retrospectively. Outcome: Twelve patients underwent fertility examinations and received fertility treatment immediately after the completion of conservative treatment for EC or AH. One patient had the complication of severe diabetes and total embryo cryopreservation was performed before her diabetes was treated. Among the other 11 patients, 8 (72.7%) became pregnant at least once and 6 (54.5%) experienced at least 1 live birth. Three patients (25.0%) suffered disease recurrence during or after the infertility treatment and all of the recurrences occurred in the EC cohort. Conclusion: When patients with EC or AH wish to preserve their fertility, it is recommended that prompt and effective fertility treatment, including assisted reproductive technology, should be initiated just after conservative treatment because EC and AH exhibit relatively high recurrence rates among conservatively treated patients

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

Purpose: 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. Methods: Anovulatory women with WHO group II ovulatory disorder (ovulation induction [OI] patients, n = 29), and with an unexplained infertility (ovarian stimulation [OS] patients, n = 21) were enrolled. The protocol of low dose step‐up FSH therapy was optimized for the starting dose as 50 IU (body mass index [BMI] < 20 group) and 62.5 IU (BMI ≥ 20 group) with the increment dose of 12.5 IU. Study outcomes were ovulation, monofollicular development and other variables. Results: In the OIpatients, the ovulation rate was 100% (BMI < 20 group) and 90.9% (BMI ≥ 20 group). Monofollicular development was 80.0% (BMI < 20) and 77.3% (BMI ≥ 20). The pregnancy rate was 60% (3/5 BMI < 20) and 18.2% (4/22 BMI ≥ 20). There was no multiple pregnancy. In the OSpatients, the ovulation rate was 100%. Monofollicular development was 85.7% (BMI < 20) and 76.6% (BMI ≥ 20). No pregnancy was achieved in the OSpatients. Conclusion: Optimized protocol of low dose FSH therapy setting a starting dose 50 IU/62.5 IU by BMI with an increment dose of 12.5 IU was safe and highly effective in WHO group II anovulatory patients. However, this protocol seemed uneffective for patients with unexplained infertility

生殖補助医療を行っている患者において卵胞液中のキスペプチン濃度は卵成熟および性腺ホルモン値と関連している

Purpose: To assess the kisspeptin concentrations in follicular fluid and their relationship with clinical outcomes during assisted reproductive technology. Methods: Thirty-nine patients who were aged 24-40 years and underwent oocyte retrieval for in vitro fertilization/intracytoplasmic sperm injection participated in this study. In 65 follicular fluid samples that had been obtained from 30 patients and their blood samples, the kisspeptin levels were measured in order to investigate the correlations with their gonadal hormone levels. Venous blood samples were collected from 14 patients to investigate their plasma kisspeptin levels across different phases of assisted reproductive technology. Results: The follicular fluid kisspeptin level was significantly higher than that of the plasma level and was positively associated with the follicular fluid estradiol concentration and with the serum estradiol and number of mature oocytes. In the plasma, the maximum concentration of kisspeptin was observed on the day of ovum pick-up and on the day of embryo transfer during ovarian stimulation for assisted reproductive technology. Conclusion: Kisspeptin was present in the follicular fluid and the plasma kisspeptin concentration was affected by ovarian stimulation. Kisspeptin appears to affect oocyte maturation and ovulation