Hypothalamic Kiss1 and RFRP gene expressions are changed by a high dose of lipopolysaccharide in female rats.

Reproductive function is suppressed by several types of stress. Hypothalamic kisspeptin, which is a product of the Kiss1 gene, and GnIH/RFRP have pivotal roles in the regulation of GnRH and gonadotropins through their receptors Kiss1r and GPR147 in many species. However, alterations of these factors under stress conditions have not been fully evaluated. This study investigated the mechanisms of immune stress-induced reproductive dysfunction, especially focusing on the changes of Kiss1 and RFRP gene expression. Serum LH levels and hypothalamic Kiss1 and GnRH mRNA levels were decreased, while hypothalamic RFRP and GPR147 mRNA levels were increased by administration of a high dose of LPS (5mg/kg) in both ovariectomized and gonadal intact female rats. In this condition, Kiss1 and/or RFRP mRNA levels were positively and negatively correlated with GnRH expression, respectively. In contrast, hypothalamic Kiss1, RFRP, and GPR147 mRNA levels were not changed by administration of a moderate dose of LPS (500g/kg) in ovariectomized rats. Rats with high-dose LPS injection showed more prolonged fever responses and severe anorexia compared with rats with moderate-dose LPS injection, indicating that more energy was used for the immune response in the former. These results suggest that the underlying mechanisms of dysfunction of gonadotropin secretion are changed according to the severity of immune stress, and that changes of some reserved factors, such as kisspeptin and RFRP, begin to participate in the suppression of GnRH and gonadotropin in severe conditions. As reproduction needs a large amount of energy, dysfunction of gonadotropin secretion under immune stress may be a biophylatic mechanism by which more energy is saved for the immune response.


High adiponectin level in late postmenopausal women with normal renal function.

We examined whether high circulating adiponectin level is associated with renal function and is favorable for lipid and glucose metabolism in late postmenopausal women with normal renal function. We conducted a cross-sectional study in 115 postmenopausal women and divided the subjects into 2 groups (early postmenopausal women and late postmenopausal women). Serum levels of adiponectin, blood urea nitrogen, creatinine (Cr), glucose, insulin and lipid profiles were measured. Glomerular filtration rate (GFR) was estimated by age and Cr. Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women, and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women. Adiponectin level showed a negative correlation with eGFR and tended to have a negative correlation with eGFR after adjustments for age, BMI and bioavailable testosterone in all subjects, but adiponectin level did not show a significant correlation with eGFR in late postmenopausal women. Adiponectin level in late postmenopausal women showed a significant negative correlation with triglyceride (TG) and a positive correlation with high-density lipoprotein cholesterol (HDL-C) after adjustments for age and BMI. In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women.


A case of placenta percreta with massive hemorrhage during cesarean section.

We describe a case of a 39-year-old woman diagnosed with placenta percreta complicated by massive hemorrhage during a cesarean section. At 27 weeks of gestation, she underwent an emergency cesarean section under general anesthesia for vaginal bleeding and an intrauterine infection. Soon after delivery, a massive hemorrhage was encountered while attempting to separate the placenta percreta from the bladder wall. Although total abdominal hysterectomy and partial cystectomy were performed, massive hemorrhaging persisted. Bleeding was finally controlled following bilateral internal iliac artery embolization. We used a cell salvage device and a rapid infuser for hemodynamics stabilization. Total blood loss was 47,000 mL, and anesthesia time was 12 h and 47 min. The patient was discharged on the 32(nd) postoperative day without major complications. Placenta accreta can be associated with life-threatening hemorrhage and it is vital to plan accordingly preoperatively.

The Journal of Medical Investigation : JMI


Improvement in diagnostic performance of the revised total testosterone measuring system in Japanese women with polycystic ovary syndrome.

Hyperandrogenemia has become an important factor in the diagnosis of polycystic ovary syndrome (PCOS), in Japan as well as Western countries, since the Japanese PCOS diagnostic criteria were revised in 2007. The revised electrochemiluminescence immunoassay (ECLIA) reagent for total testosterone (T) (ECLusys TESTO II; New T assay), which has lower cross-reactivity with DHEA-S than the previous reagent (ECLusys TESTO I; Old T assay), has recently been developed. We studied the improvement between New and Old T assays in regards to the diagnostic performance of serum T for patients with PCOS. Serum T levels were measured in both normal women (Control, n=92) and PCOS patients (n=86). The rate of elevated T using each kit was significantly higher in the PCOS group than in the Control group, and significantly higher using New T assay (38/86, 44.2%) compared with Old T assay (26/86, 30.2%). A significant correlation was found between T level and body mass index, but not LH level. Furthermore, higher detection rates of hormonal abnormalities were seen in PCOS patients using combined measurement of both T and LH (63/80) compared with single measurement of either T (37/80) or LH (36/80). Therefore, the serum T assay is essential for the diagnosis of PCOS, and New T assay combined with the LH assay may improve the diagnostic process for PCOS. J. Med. Invest. 61: 65-71, February, 2014.


Effect of ultra-low-dose estradiol and dydrogesterone on arterial stiffness in postmenopausal women.

Abstract Background Ultra-low-dose estradiol is known to improve menopausal symptoms and increase bone mineral density. However, the effect of ultra-low-dose estradiol on vascular function has not been clarified. Objectives We examined the effects of ultra-low-dose estradiol on brachial-ankle pulse wave velocity (baPWV) and circulating markers of cardiovascular risk. Patients and methods Twenty-eight postmenopausal women were enrolled in this study. Fourteen women received oral estradiol (0.5 mg) and dydrogesterone (5 mg) every day for 12 months (ultra-low-dose group) as hormone replacement therapy (HRT) and 14 women as a control group did not receive HRT. The baPWV, lipid profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and vascular inflammatory markers were measured. Results The baPWV level significantly decreased in the ultra-low-dose group (p = 0.037), while the baPWV level did not significantly change in the control group. HOMA-IR tended to decrease in the ultra-low-dose group (p = 0.076). Systolic blood pressure and diastolic blood pressure did not change significantly in either group. Conclusion An HRT regimen using oral ultra-low-dose estradiol and dydrogesterone has an effect on arterial stiffness and insulin resistance.


Difference in the Ratio of High-Molecular Weight (HMW) to Total Adiponectin and HMW Adiponectin in Late Postmenopausal Women.

Objective: High-molecular weight (HMW) isoform level and HMW ratio have been shown to be better predictors of insulin sensitivity and metabolic syndrome than total adiponectin level. We examined the changes in circulating levels of HMW adiponectin and ratios of HMW to total adiponectin in women during the menopausal transition. Methods: We conducted a cross-sectional study in 217 healthy women and divided them into 4 stages: 58 women in premenopausal, 69 women in perimenpausal, 62 women in early postmenopausal and 28 women in late postmenopausal women. Serum levels of total adiponectin and HMW adiponectin were measured by an enzyme-linked immunosorbent assay. Results: In late postmenopausal women, HMW adiponectin level was significantly higher than that in perimenopausal women and the HMW to total adiponectin ratio was significantly lower than that in early postmenopausal women. In perimenopausal women, HMW adiponectin level was significantly lower than that in premenopausal women and HMW to total adiponectin ratio was significantly lower than the ratios in premenopausal and early postmenopausal women. Conclusion: The ratio of HMW to total adiponectin is low in late postmenopausal women, though both levels of total and HMW adiponectin were high after menopause in our cross-sectional study.

Journal of Endocrinological Investigation


Associations of estrogen and testosterone with insulin resistance in pre- and postmenopausal women with and without hormone therapy.

Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. Testosterone and sex hormone-binding globulin (SHBG) as well as estrogen are also associated with insulin resistance in women. However, to date, the associations of estradiol, testosterone and SHBG with insulin resistance according to estrogen level have not been clarified. We examined the associations of estradiol, testosterone and SHBG with insulin resistance in pre- and in postmenopausal women and postmenopausal women who had received hormone therapy to clarify whether the associations differ depending on the estrogen status. Twenty premenopausal women and thirty-two postmenopausal women were enrolled in this study. Fifteen postmenopausal women received oral conjugated equine estrogen (CEE) (0.625 mg) everyday for 12 months. Serum levels of estradiol, testosterone, SHBG and insulin and plasma levels of glucose were measured. Serum estradiol levels tended to have a negative correlation with homeostasis model assessment of insulin resistance (HOMA-IR) in premenopausal women but not in postmenopausal women. On the other hand, free testosterone levels tended to have a positive correlation with HOMA-IR in postmenopausal women but not in premenopausal women. Serum SHBG levels showed significant negative correlations with HOMA-IR in both pre- and postmenopausal women. SHBG level was significantly increased, free testosterone level was significantly decreased and HOMA-IR was significantly decreased at 12 months after CEE administration. However, there were no significant correlations of changes between estradiol, SHBG or free testosterone and HOMA-IR. The associations of sex steroid hormones with insulin resistance are different depending on the estrogen status.

International Journal of Endocrinology and Metabolism


Effectiveness and tolerability of hysterectomy for the local recurrence of cervical cancer after radiation therapy

子宮頸癌放射線療法後の局所再発に対する子宮摘出の有用性と安全性について

Modern Trends in Obstetrics & Gynecology


Developmental changes in the responsiveness of hypothalamic ER alpha mRNA levels to food deprivation.

Estrogen plays an important role in feeding and energy balance, and the critical role of estrogen in the control of appetite and energy balance is mediated by hypothalamic estrogen receptor (ER) alpha. In undernourished rodents, hypothalamic ER alpha mRNA expression are decreased. Responses of some hypothalamic factors to negative energy balance develop during the early neonatal period. In this study, we examined the developmental changes of fasting-induced alterations in hypothalamic ER alpha mRNA expression in female rats. ER alpha mRNA expression was reduced after a 12-h or 24-h fast at postnatal days 15 and 25, but not at day 5. Serum estradiol levels in postnatal day 25 rats were not changed by fasting. Although serum leptin levels were suppressed by fasting at all ages, hypothalamic ER alpha mRNA expression at postnatal day 25 was not changed by leptin administration after a 24-h fast. These data show that the sensitivity of hypothalamic ER alpha to negative energy balance may not be established in the early neonatal period, and that it develops by postnatal day 15. Decreased leptin levels might not be involved in the alterations of hypothalamic ER alpha mRNA expression in the undernourished condition.


[Development of a home care educational program for community physicians and other professionals-a trial in Kashiwa City].

From May to October 2011, we conducted an 8-day homecare educational program for physicians, dentists, pharmacists, visiting nurses, long-term care managers, and hospital staff in Kashiwa city, Chiba, which was primarily intended to increase home visits by physicians. The characteristics of the program were as follows: 1) active and busy community physician participation, 2) attendance of practical training by physicians, 3) interprofessional discussion, 4) recruitment of participants from the same city, 5) recommendation of participant recruitment by a community-level professional association such as Kashiwa City Medical Association. By comparison of the pre- and post-program questionnaires completed by participants, the motivation for homecare practice, knowledge about homecare, and interactions with other professionals have increased. We will further standardize and generalize this program in order to contribute to homecare promotion in Japan.

Japanese Journal of Cancer and Chemotherapy


Prepubertal exposure to glucocorticoid delays puberty independent of the hypothalamic Kiss1-GnRH system in female rats.

Secretion of glucocorticoids is widely known as a key endocrine response to stresses. Prenatal dexamethasone administration induces intrauterine growth retardation and delayed onset of puberty in female rats independent of the hypothalamic Kiss1-gonadotropin-releasing hormone (GnRH) system. The aim of this study was to evaluate the influence of chronic intracerebroventricular (central, CD) or subcutaneous (peripheral, PD) dexamethasone administration to prepubertal female rats on the onset of puberty and body weight change. Rats administered dexamethasone from day 25 to day 34 (CD and PD) showed significantly reduced body weight gain throughout the experimental period and delayed onset of vaginal opening compared with rats administered saline centrally (CS) or peripherally (PS). At 34 days old, hypothalamic Kiss1r mRNA levels were significantly lower with CD than with CS. No significant differences were seen between rats administered saline and rats administered dexamethasone with regard to hypothalamic Kiss1, GnRH and NPY mRNA levels or serum LH levels. Serum leptin concentrations were higher in CD and PD than in the controls (CS and PS). These results suggest that the delayed onset of puberty induced by prepubertal dexamethasone administration occurs independent of the hypothalamic Kiss1-GnRH system.

International Journal of Developmental Neuroscience


Association of circulating adiponectin with testosterone in women during the menopausal transition.

We examined (1) the change in circulating adiponectin in women during the menopausal transition and (2) the associations of adiponectin levels with estrogen, androgen and sex hormone-binding globulin (SHBG) in women during the menopausal transition. We conducted a cross-sectional study in 235 healthy women and divided them into 7 stages by menstrual regularity and follicle-stimulating hormone (FSH) level. Serum levels of adiponectin, estradiol, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and SHBG were measured. Levels of free and bioavailable testosterone were calculated by using total testosterone, albumin and SHBG. Serum adiponectin levels showed a U-curve, levels being low in early and late menopausal transition and gradually becoming higher after menopause. Adiponectin levels were negatively correlated with levels of free testosterone, bioavailable testosterone and DHEA-S and were positively correlated with SHBG in postmenopausal women for whom more than 1 year had passed since menopause. Adiponectin level was not correlated with estradiol level. Circulating adiponectin level shows a U-curve during the menopausal transition and adiponectin level is associated with levels of free and bioavailable testosterone and DHEA-S in postmenopause.


更年期障害 (特集 ホルモン補充療法の最新知識 : リスク・ベネフィットを今,どう考えるか)


Simultaneous recordings of pulsed wave Doppler signals in hepatic vein and descending aorta using dual Doppler: a novel method for evaluating fetal arrhythmias.


Changes in insulin sensitivity during GnRH agonist treatment in premenopausal women with leiomyoma.

The purpose of this study was to determine (1) the influence of estrogen deficiency induced by gonadotropin-releasing hormone (GnRH) agonist administration on insulin sensitivity as well as hormones and factors related to insulin resistance and (2) the differences in the influence for these parameters by the degree of basal insulin sensitivity. Thirty-five women diagnosed with leiomyoma were enrolled in this study. Serum levels of fasting glucose, insulin, sex steroid hormones, sex hormone-binding globulin (SHBG), vascular inflammatory markers and cytokines before and at 6months after commencement of GnRH agonist administration were examined. In all women, levels of insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly changed. However, in women who had a low HOMA-IR before treatment, levels of insulin, glucose and HOMA-IR showed significant increases and total testosterone level showed a significant decrease. In women who had a high HOMA-IR, levels of insulin, HOMA-IR and SHBG were significantly decreased and levels of highly sensitive C-reactive protein, soluble intercellular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 were significantly increased. Change in insulin sensitivity caused by GnRH agonist administration for premenopausal women with leiomyoma differs depending on baseline insulin sensitivity before treatment.


Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus.

The mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) is considered to act on gonadotropin-releasing hormone (GnRH) neurons and on the pituitary to inhibit gonadotropin release and synthesis. To understand the functional significance of this neuropeptide, we investigated the physiological changes in RFRP at mRNA and peptide levels, as well as at the mRNA level of its cognate receptor, G protein-coupled receptor 147 (GPR147), in the rat hypothalamus during development. We also investigated the effects of gonadal steroids on mRNA expression levels of these molecules. In male rats, mRNA expressions of both RFRP and GPR147 increased from postnatal days 12 and 16, peaking at postnatal days 35 and 42, respectively. However, their expressions fell at postnatal day 49. In female rats, mRNA expression of RFRP continued to increase throughout development; mRNA expression of GPR147 in female rats increased from postnatal day 16, peaking at postnatal day 28, but decreased from postnatal day 35. The hypothalamic contents of RFRP on postnatal days 28 and 42 were significantly higher than on postnatal day 4 in male rats, and those on postnatal day 42 were significantly higher than those on postnatal days 4 and 28 in females. Neither orchidectomy nor ovariectomy influenced mRNA expression levels of RFRP or GPR147 in the prepubertal period when endogenous sex steroid levels were low in males and females. Administration of estradiol-17β (E2) increased mRNA expression of RFRP in prepubertal females. These results suggest that the hypothalamic RFRP system changes during development. An ovarian sex steroid, E2, may stimulate mRNA expression of RFRP in the prepubertal period when the basal E2 concentration is low.


Harms of screening mammography for breast cancer in Japanese women.

BACKGROUND: The US Preventative Services Task Force assesses the efficacy of breast cancer screening by the sum of its benefits and harms, and recommends against routine screening mammography because of its relatively great harms for women aged 40-49 years. Assessment of the efficacy of screening mammography should take into consideration not only its benefits but also its harms, but data regarding those harms are lacking for Japanese women. METHODS: In 2008 we collected screening mammography data from 144,848 participants from five Japanese prefectures by age bracket to assess the harms [false-positive results, performance of unnecessary additional imaging, fine-needle aspiration cytology (FNA), and biopsy and its procedures]. RESULTS: The rate of cancer detected in women aged 40-49 years was 0.28%. The false-positive rate (9.6%) and rates of additional imaging by mammography (5.8%) and ultrasound (7.3%) were higher in women aged 40-49 years than in the other age brackets. The rates of FNA (1.6%) and biopsy (0.7%) were also highest in women aged 40-49 years. However, they seemed to be lower than the rates reported by the Breast Cancer Surveillance Consortium (BCSC) and other studies in the US. CONCLUSIONS: The results, although preliminary, indicate the possibility that the harms of screening mammography for Japanese women are less than those for American women.


単胎妊婦と双胎妊婦におけるカルシウム代謝ならびにビタミンDの動態の比較 (第22回婦人科骨粗鬆症研究会) -- (WORKSHOP 若年女性における骨の管理)

オステオポローシスジャパン : 日本骨粗鬆症学会雑誌

オステオポローシスジャパン : 日本骨粗鬆症学会雑誌


Roscovitine in combination with calcium ionophore induces oocyte activation through reduction of M-phase promoting factor activity in mice.

SummaryThe aim of the present study was to determine oocyte activation and change in M-phase promoting factor (MPF) activity induced by treatment with calcium ionophore and roscovitine in comparison with those induced by treatment with roscovitine alone and treatment with calcium ionophore and puromycin in mice. Freshly ovulated oocytes obtained from 6-8-week-old mice were divided into five groups (no activation treatment; 5 μM calcium ionophore A23187; 50 μM roscovitine; 5 μM calcium ionophore and 10 μg/ml puromycin; and 5 μM calcium ionophore and 50 μM roscovitine) and were incubated for 6 h. Oocyte activation, assessed by morphological changes, and changes in MPF activity in the five groups at 0, 2, 4 and 6 h of incubation were examined. Activated oocytes were defined as oocytes with at least one pronucleus. Oocytes treated with roscovitine alone were not activated during the 6-h incubation period. All of the oocytes in the calcium ionophore with puromycin group and in the calcium ionophore with roscovitine group were activated. The percentage activity of MPF in oocytes treated with roscovitine alone was decreased after 2 h and increased after 4 h of incubation. The percentage activity of MPF in oocytes treated with calcium ionophore and roscovitine was significantly decreased with suppression of MPF activity being maintained for 6 h, and this change was similar to that in oocytes treated with calcium ionophore and puromycin. Roscovitine with calcium ionophore is effective for induction of oocyte activation through suppression of MPF activity in mice.


Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats.

Kisspeptin, which is the product of the kiss1 gene and its receptor kiss1r, have emerged as the essential gatekeepers of reproduction. The present study used gonadally intact female rats to evaluate fasting-induced suppression of the KiSS-1 system of anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) under normal physiological conditions. Starting on the day of estrous, one group of rats was subjected to 72 h of food deprivation, while the other group of rats was able to continue feeding ad libitum. The length of the estrous cycle was significantly longer in the food-deprived rats as compared to the feeding rats. At the end of the 72-h food deprivation period, all of the food-deprived rats were at the diestrous phase, with their serum concentrations of LH and leptin significantly lower than that observed in the feeding rats. In addition, as compared to the feeding rats, the expression levels of kiss1 mRNA were significantly lower in the food-deprived rats in the posterior hypothalamic block, which contained the ARC, but not in the anterior hypothalamic block, which contain the AVPV. However, both the kiss1r mRNA expression levels in the anterior and posterior hypothalamic blocks and the neurokinin B and neurokinin 3 receptor mRNA expression levels in the posterior hypothalamic block were not significantly different between the feeding and food-deprived rats. Thus, lower kiss1 mRNA levels in the ARC appear to be responsible for the fasting-induced inhibition of gonadotrophin secretion and subsequent prolongation of the estrous cycle.


高プロラクチン血症として管理されていたマクロプロラクチン血症の2症例

高プロラクチン血症として管理されていたマクロプロラクチン血症の2症例

Modern Trends in Obstetrics & Gynecology


当院におけるプラチナ耐性再発卵巣癌に対するドキシルの使用経験

当院におけるプラチナ耐性再発卵巣癌に対するドキシルの使用経験


骨盤内腫瘍の術後にたこつぼ心筋症を来した一症例

骨盤内腫瘍の術後にたこつぼ心筋症を来した一症例


Effect of immune stress on body weight regulation is altered by ovariectomy in female rats.

It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1β (IL1β) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1β mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1β mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1β synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency.


The possibility of vertical transmission of human papillomavirus through maternal milk

Human papillomavirus (HPV) DNA has been detected in the oral cavity of infants and breast cancer tissue, suggesting its vertical transmission through maternal milk. We determined whether HPV is detected in maternal milk and is vertically transmitted by breast-feeding. Informed consent was obtained, and maternal milk samples (n=80) were analysed for high-risk HPV DNA. In 43 women, this DNA was measured in the uterine cervix. In women with positive samples, this DNA was measured in the oral cavities of their children. The domain including HPV E6 and E7 was amplified by polymerase chain reaction using consensus primers, and HPV serotype determined by electrophoresis after restriction enzyme digestion. High-risk HPV-16 was detected in two of 80 samples (2.5%), and in these two cases, high-risk HPV was not detected in the uterine cervix or oral cavity of the child. It was concluded that the infection of HPV in maternal milk is rare (2/80); vertical transmission through maternal milk was not detected in this study (0/80). HPV infection through maternal milk may occur, but its likelihood is low.


Induction of circulating monocyte chemoattractant protein-1 in women with gonadotropin-releasing hormone agonist.

The aim of the present study was to determine the influence of acute estrogen deficiency induced by administration of a gonadotropin-releasing hormone (GnRH) agonist on circulating levels of cytokines and chemokines. Eighty-three women with uterine leiomyoma were assigned in open, parallel-group fashion to a no-treatment (control) group and a GnRH-agonist group. Serum levels of nine cytokines and chemokines as well as vascular inflammatory markers were measured. Serum levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-α (TNFα) in the GnRH-agonist group were increased significantly at 6 months. There were also significant differences in percentage changes in interleukin (IL)-6, IL8, MCP1, and macrophage inflammatory protein-1β (MIP1β) between the control and GnRH agonist groups. Soluble intercellular adhesion molecule-1 (sICAM1) and E-selectin levels showed significant increases in the GnRH agonist group at 6 months. Serum MCP1 concentrations showed weak correlations with levels of sICAM and E-selectin. We conclude that a hypo-estrogenic state due to administration of a GnRH agonist increases circulating levels of cytokines and chemokines, especially MCP1.


Changes in responsiveness of appetite, leptin and hypothalamic IL-1β and TNF-α to lipopolysaccharide in developing rats.

In addition to its role as a regulator of energy homeostasis, leptin plays a pivotal role in some immune/inflammatory responses. Synthesis and secretion of leptin are increased under immune stress conditions, and increased leptin may participate in the development of anorexia and fever. These actions are partially mediated by up-regulation of hypothalamic IL-1β. Leptin also protects against immune stress-induced lethality. On the other hand, the response and roles of leptin to immune stress conditions in the neonatal period have scarcely been examined. We hypothesized that 1. the response of leptin to immune stress would be suppressed in the early neonatal period, 2. hyporesponse of leptin in the early neonatal period would attenuate the anorectic response and increase the lethal rate under immune stress conditions and 3. supplementation of leptin in the early neonatal period would increase the anorectic response, whereas it would decrease the lethal rate under immune stress conditions. To test these hypotheses, we first examined the developmental changes in the responses of leptin and hypothalamic proinflammatory cytokines, i.e., IL-1β and TNF-α, to LPS-induced immune stress in female rats. We also examined the developmental changes in the anorectic response and lethality rate under LPS-induced immune stress conditions. Five- and 15-day-old rats showed no leptin response and a weak hypothalamic IL-1β response to LPS when compared with 25- and 42-day-old rats. Fifteen-day-old rats showed low anorectic responses and high lethality rates when compared with 25- and 42-day-old rats under LPS-induced immune stress conditions. We then examined whether administration of leptin affected the response to the anorectic and lethal effects of LPS in 15-day-old rats. Administration of leptin further attenuated body weight after LPS injection, but not after saline injection. On the other hand, administration of leptin did not affect survival rate. In addition, hypothalamic IL-1β mRNA levels were not affected by leptin administration. In conclusion, the absence of a leptin response may act to prevent immune stress-induced anorexia during the early neonatal period.


Differences in bone metabolism between singleton pregnancy and twin pregnancy.

The objective of this study was to examine the influence of twin pregnancy on calcium metabolism, including bone turnover markers and calcium-regulating factors, by comparison between singleton pregnancy and twin pregnancy in women during pregnancy and puerperium in cross-sectional and longitudinal studies. Women with singleton and twin pregnancies were recruited from the outpatient clinic of Tokushima University Hospital. In both cross-sectional and longitudinal studies, bone formation and resorption markers, mineral metabolism and calcium-regulating factors were measured at 10, 25, 30 and 36 weeks of pregnancy and at 4 days and 1 month postpartum in women with singleton and twin pregnancies. Urinary levels of cross-linked type I collagen N-telopeptides and C-terminal telopeptides of type I collagen in women with twin pregnancy were significantly higher than those in women with singleton pregnancy and those high levels were observed earlier than those in women with singleton pregnancy. In the cross-sectional study, serum levels of bone-specific alkaline phosphatase, calcium and phosphate in women with twin pregnancy were higher and the levels of 1,25-(OH)2 vitamin D and 25-(OH) vitamin D in women with twin pregnancy were lower than those in women with singleton pregnancy. Changes in bone metabolism in women with twin pregnancy are different from those in women with singleton pregnancy. Early and large increases in bone turnover markers allow women with twin pregnancy to meet high fetal demand for calcium during pregnancy.


The role of blood in early endometrial-peritoneal interactions in a syngeneic mouse model of endometriosis


Gene gun-mediated skin transfection with FL gene suppresses the growth of murine fibrosarcoma.

Particle-mediated transfection is known as an efficient method of non-viral gene transfer. Flt3 ligand (FL) is a growth factor for hematopoietic progenitors; it promotes the growth of dendritic cells (DC). DCs are powerful antigen-presenting cells (APCs) and show a remarkable capacity to stimulate antigen-specific T-cell responses. In this study, we intended to investigate the suppressive effect on tumor growth by gene gun-mediated transfer of FL in a murine model. C57BL/6J mice were injected intradermally with MCA205 cells. DNA (pNGVL-hFLex)-coated gold particles were delivered to the mouse skin surrounding the target tumor. The expression of FL was determined by RT-PCR. Analyses by immunohistochemistry and fluorescence-activated cell sorter (FACS) revealed an increase in the number of DC after treatment with FL. Gene gun-mediated pNGVL-hFLex transfer significantly inhibited the growth of the MCA205 tumor. FL transfer markedly increased the number of CD11c(+) DCs in the tumor tissue. Further, the FL-transfected mice exhibited a significantly higher number of CD80(+) MHC-II cells. We successfully performed FL therapy using an in vivo gene gun in order to effectively mobilize DCs in situ and induce suppressive immunity.

The Journal of Medical Investigation : JMI


View and present status of personnel involved in clinical trials: a survey of participants from the First Symposium of the Shikoku Collaborative Group for Promotion of Clinical Trials.

Clinical trials leading to drug approval (registration trials) play a central role in the drug development process. Since the introduction of the Good Clinical Practice (GCP) standard in 1997, the Japanese infrastructure for registration trials has improved. The contribution of support staff, including clinical research coordinators (CRCs), to clinical trials is now widely recognized in Japan. Quality issues and career development for these support staff are being increasingly emphasized. The Shikoku Collaborative Group for Promotion of Clinical Trials was organized in 2008 to address these issues through communication with the personnel involved in clinical trials in regional areas of Japan. To understand the views and present status of personnel involved in clinical trials, we used questionnaires to survey the participants of the First Symposium of the Shikoku Collaborative Group for Promotion of Clinical Trials held in August 2009. Group discussions and special lectures occurred at the symposium. The questionnaire began with questions about basic patient characteristics, followed by practical questions. Of 110 participants, there were 68 respondents (62%), including clinical trial support staff (clinical research coordinators [n=36, 53%], administrative officers [n=9, 13%]), and medical staff [n=23, 34%]). Among the support staff, 36 (80%) had more than 5 years of experience. The most common questionnaire answer selected for participation in the symposium was "willing to contact staff from other medical institutions or organizations" for support staff and "to obtain further knowledge concerning clinical trials" for medical staff. The overall view of the discussion ("Was the discussion satisfactory?") was favorable for 36 (53%) respondents. This survey revealed that the group discussion in the present symposium appears to be valuable for participants, using overall satisfaction as a surrogate. Based on the information obtained in the present study, further development of the clinical trial infrastructure, including training opportunities and career development for support staff, is required. Due to the limitations of this study, further analysis is warranted to determine the optimal strategy for training support staff.


Effects of raloxifene on the production of cytokines in stimulated whole blood in ex vivo and in vitro studies.

The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10(-10)-10(-7) M and then stimulated with LPS or PHA. Concentrations of IL-1β, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1β, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (10(-9) M) inhibited LPS-stimulated production of IL-1β, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. Raloxifene therapy decreases the production of IL-1β, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene.


Effects of Japanese traditional medicines on circulating cytokine levels in women with hot flashes.

The effects of the Japanese traditional medicines keishibukuryogan and kamishoyosan on circulating cytokines were examined to clarify the difference in the actions of Japanese traditional medicines in women with hot flashes. Seven premenopausal, 51 perimenopausal, 45 spontaneously postmenopausal and 17 surgically postmenopausal women who had complained of hot flashes were enrolled in this study. Eighty women who hoped to receive Japanese traditional medicines were randomly assigned in open, parallel-group fashion to a keishibukuryogan group or kamishoyosan group. Forty women who did not want any treatment for hot flashes were followed up for 6 months as a control group. Serum levels of cytokines were measured using a multiplexed human cytokine assay. The proportions of responders in women treated with keishibukuryogan and kamishoyosan were 73.7% and 69.2%, respectively. Serum monocyte chemotactic protein-1 level in women treated with keishibukuryogan decreased significantly (P = 0.0037). On the other hand, concentrations of interleukin (IL)-6 and macrophage inflammatory protein-1β in women treated with kamishoyosan decreased significantly (P = 0.019 and P = 0.039, respectively). In both keishibukuryogan and kamishoyosan responder groups, serum IL-8 concentrations were reduced significantly (P = 0.021 and P = 0.014, respectively). Both treatments with keishibukuryogan and kamishoyosan reduce the circulating IL-8 level, which is involved in thermoregulation in perimenopausal women with hot flashes. In addition, keishibukuryogan decreases circulating monocyte chemotactic protein-1 level in postmenopausal women.


当科における子宮内膜症性嚢胞を伴う不妊症患者に対する手術療法の検討

当科における子宮内膜症性嚢胞を伴う不妊症患者に対する手術療法の検討

日本エンドメトリオーシス学会会誌

日本エンドメトリオーシス学会会誌


Psychological features of pregnant women predisposing to depressive state during the perinatal period

周産期の抑うつに影響を与える心理特性に関する検討


The impact of systematic para-aortic and pelvic lymphadenectomy on survival in patients with optimally debulked ovarian cancer.

The objective of this study was to verify the impact of systematic retroperitoneal lymphadenectomy on survival in patients with ovarian cancer.

The Journal of Obstetrics and Gynaecology Research


Prenatal diagnosis of closed spina bifida: a case report

胎児診断した潜在性二分脊椎の一例

Modern Trends in Obstetrics & Gynecology


骨盤内膿瘍に対する腹腔鏡手術の有用性

骨盤内膿瘍に対する腹腔鏡手術の有用性

骨盤内膿瘍に対する治療は，抗生剤による薬物療法が主体であるが，抗生剤無効例や，消化管から発生した膿瘍との鑑別を要する症例では外科的アプローチが必要となる．骨盤内膿瘍の場合，炎症による癒着が強いことが多く，手術は比較的難易度が高い．しかし，高度の炎症で疲弊した患者の負担を軽減するために，近年では腹腔鏡手術が積極的に導入されており，当院でも可能な限り腹腔鏡手術で対応している．抗生剤による治療が無効であった付属器膿瘍に対して腹腔鏡下手術を施行した4症例について報告する．4例とも輸血を要するような出血はなく，また他臓器損傷もなかった．術後は，速やかに炎症所見が改善し特に問題なく経過した． 骨盤内膿瘍に対する腹腔鏡手術は，ドレナージによりすみやかな炎症軽減が可能であり，かつ低侵襲であることから有用性は高い．一方で，(汎発性腹膜炎などで，)腸管麻痺を伴う症例では，腸管の膨隆のため腹腔鏡下の視野確保が困難であり，腹腔鏡手術の適応は慎重であるべきであると考える．


妊娠初期に捻転を起こし腹腔鏡下手術を行ったmassive ovarian edema の一例


Recombinant follicle-stimulating hormone (follitropin alfa) for ovulation induction in Japanese patients with anti-estrogen-ineffective oligo- or anovulatory infertility: results of a phase II dose response study


エクルーシス試薬テストステロンⅡ,LH,FSHの基準値の検討

エクルーシス試薬テストステロンⅡ,LH,FSHの基準値の検討

Japanese Journal of Medicine and Pharmaceutical Science


View of physicians on and barriers to patient enrollment in a multicenter clinical trial: experience in a Japanese rural area

Clinical trials in the general practice setting are important for providing evidence on the effectiveness and safety of different agents under various conditions. In conducting these trials, the participation of physicians and patient recruitment are important issues. Various investigations in the literature have reported views and attitudes of physicians on various types of clinical trials. Nevertheless, there is still little information concerning physicians participating in a clinical trial and among them, those who could not recruit any patients (unsuccessful physician recruiters). In 2003, we collaborated in a large-scale multicenter study of Japanese hypertensive patients (COPE Trial). In Tokushima University Hospital and 18 other medical institutions, we investigated the views and attitudes of unsuccessful physician recruiters in comparison with successful physician recruiters, using a questionnaire. The questionnaire was provided by mail to 47 physicians and 27 (57%) responded. The response rate was 79% for successful physician recruiters compared to 43% (P = 0.014) for unsuccessful physician recruiters. More successful physician recruiters (73%) than unsuccessful physician recruiters (42%) stated they had participated and enrolled patients in previous multicenter clinical trials. A significantly higher number of successful physician recruiters than unsuccessful physician recruiters (42%; P = 0.040) considered the presence of a support system with clinical research coordinators (CRC) as the reason for participation (80%). A large number of unsuccessful physician recruiters experienced difficulty in obtaining informed consent (67%), whereas a significantly smaller number of successful physician recruiters experienced such difficulty (20%; P = 0.014). The difficulties experienced by unsuccessful physician recruiters in the trial were as follows: inability to find possible participants (100%), difficulty in obtaining informed consent (58%), cumbersome procedures (58%), difficulty in long-term follow up (33%), and insufficient tools for explanation and obtaining informed consent (8%). This survey showed that successful physician recruiters consider a support system with CRC of value, and that they are skillful in obtaining informed consent. These views and attitudes may have originated from past experience involving clinical trials. In this regard, we need to develop an infrastructure to enlighten physicians on this support system for the promotion of clinical trials.


Consultation clinics for complementary and alternative medicine at Japanese university hospitals: An analysis at Tokushima University Hospital

Here, we report on a Consultation Clinic for Complementary and Alternative Medicine (CAM) which we established at Tokushima University Hospital in July of 2007 with the aim of providing person-to-person information on CAM, though not CAM therapy itself. In December of 2008, we received 55 applications for consultation, 37% concerning health foods, 37% Japanese herbal medicine (Kampo), and 26% various other topics. The consultants (nutritionists and pharmacists) communicated individually with 38 applicants; malignancies (26%) and cardiovascular disease (24%) were the main underlying concerns. To promote the quality of consultation, data was collected by means of focus group interviews concerning the perspective of the consultants. Safe and effective use of CAM requires a network of communication linking individuals, consultation teams, physicians, primary care institutions and university hospitals. To advance this goal, we plan to broaden the efforts described herein. Our findings indicate that the specific role of the consultation clinic in promoting the scientific use of CAM merits further study.


Neonatal LPS injection alters the body weight regulation systems of rats under non-stress and immune stress conditions.

It has been reported that prenatal immune stress induced by lipopolysaccharides or cytokines increases food intake and leads to obesity and other features of metabolic syndrome in adulthood. Using Sprague-Dawley rats, we evaluated whether neonatal LPS injection altered their body weight regulation systems under non-stress and immune stress conditions. On Day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) (PND(10)LPS) or saline (PND(10)Saline). After weaning, body weight was significantly elevated in PND(10)LPS compared with PND(10)Saline. Thereafter, the rats were injected with LPS (100 microg/kg, i.p.) or saline (used as a basal condition) from 7 to 8 weeks of age. Under basal conditions, cumulative food intake were significantly higher, serum leptin concentration was significantly increased, and hypothalamic NPY mRNA expression was significantly decreased in PND(10)LPS compared with PND(10)Saline. Under adult LPS injected conditions, body weight gain and cumulative food intake were suppressed in both the PND(10)LPS and PND(10)Saline groups compared with those observed under basal adult saline-injected conditions. The suppressive effects induced by adult LPS injection were less evident in the PND(10)LPS group than in the PND(10)Saline group. Adult LPS injection increased the serum leptin concentration in the PND(10)Saline rats, but not in the PND(10)LPS rats. In addition, adult LPS injection increased the mRNA expression of anorexinergic factors (IL-1beta, and TNF-alpha), and decreased that of the orexinergic factor NPY in both groups. However, the influence of adult LPS injection upon these factors was less evident in the PND(10)LPS group than in the PND(10)Saline group. These results suggest that neonatal LPS injection alters body weight regulation under both non-stress and immune stress conditions in male rats. Changes in the endocrine, neuropeptide, and cytokine regulation systems might be involved in these alterations.

International Journal of Developmental Neuroscience


Association of N-terminal pro B-type natriuretic peptide and sex hormone-binding globulin in non-obese peri- and postmenopausal women.

BACKGROUND: The relationships between N-terminal fragment proBNP (B-type natriuretic peptide) (NT-proBNP) and sex steroid hormones have not been fully elucidated. We examined these associations in pre-, peri- and postmenopausal women without known cardiovascular disease. We also examined the change in circulating NT-proBNP caused by a gonadotrophin-releasing hormone (GnRH) agonist in order to clarify the effect of acute hormone deficiency on NT-proBNP. METHODS: Forty-nine premenopausal women, 101 perimenopausal women and 108 postmenopausal women were enrolled in one study. Forty-four premenopausal women with leiomyoma were recruited for another study, and 22 of those women were treated with a GnRH agonist. Serum levels of NT-proBNP, estradiol, testosterone and sex hormone-binding globulin (SHBG) were measured. RESULTS: NT-proBNP concentrations showed significant inverse correlations with body mass index (BMI) in peri- and postmenopausal women. Serum NTproBNP concentrations showed significant positive correlations with SHBG in peri- and postmenopausal women. These significant correlations remained after adjustment for age and BMI. Serum NT-proBNP concentration was significantly decreased after GnRH agonist administration, while NT-proBNP concentration in the control group did not change significantly. Serum SHBG level was also significantly decreased after GnRH agonist administration. CONCLUSION: Circulating NT-proBNP levels are positively associated with SHBG levels in non-obese peri- and postmenopausal women, and this relationship was found under the condition of acute hormone deficiency induced by GnRH agonist treatment.


Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats.

Recent studies have suggested that intrauterine undernutrition is closely associated with the pathogenesis of diseases after birth. Perinatal undernutrition is known to disturb the development of reproductive function and delay the onset of puberty in some species. Using a rat model, we determined the effects of prenatal undernutrition on the development of the hypothalamic kisspeptin system and evaluated whether the alteration of the kisspeptin system contributes to the delayed onset of puberty induced by prenatal undernutrition. We also evaluated the effects of prenatal undernutrition on the developmental changes in serum leptin levels because leptin was a putative positive regulator of the hypothalamic kisspeptin system. We compared the timing of vaginal opening (VO) and the developmental changes in body weight, hypothalamic Kiss1 mRNA levels, and serum leptin concentrations between offspring with prenatal undernutrition (UN offspring) and normal nutrition (NN offspring). After birth, the UN offspring showed rapid growth and had caught up to body weight of the NN offspring by postnatal day 12. After postnatal day 16, the UN offspring showed significantly lower Kiss1 mRNA levels than the NN offspring, despite their significantly higher serum leptin levels (at days 20 and 28). The timing of VO in the UN offspring was delayed compared with that in the NN offspring, and chronic central injection of kisspeptin normalized the timing of VO in the UN offspring. These results suggest that decreased hypothalamic kisspeptin action contributes to the delayed onset of puberty in prenatally undernourished female rats. Increased leptin resistance in the kisspeptin system might be involved in these alterations.


Hypothalamic Ghrelin suppresses pulsatile secretion of luteinizing hormone via beta-endorphin in ovariectomized rats.

OBJECTIVES: Ghrelin, an endogenous growth hormone secretagogue, is a known accelerator of feeding behavior and suppresses pulsatile secretion of luteinizing hormone (LH) in ovariectomized rats. However, the mechanisms underlying this action remain unclear. We examined the effects of naloxone (NAL), a specific opioid antagonist, on the suppression of pulsatile LH secretion by ghrelin to determine whether beta-endorphin (beta-END) is involved in this suppressive effect. METHODS: Ghrelin was administered intracerebroventricularly, and NAL was injected intravenously in ovariectomized rats; then, serum LH concentrations were measured by radioimmunoassay in blood samples drawn every 6 min for 2 h to analyze pulsatile secretion. RESULTS: Administration of ghrelin significantly reduced mean LH concentration and pulse frequency. Coadministration of NAL with ghrelin significantly restored mean LH concentration and pulse frequency. CONCLUSION: Suppressive effect of intracerebroventricular injection of ghrelin on pulsatile LH secretion was mediated by beta-END, suggesting that hypothalamic ghrelin suppressed pulsatile gonadotropin-releasing hormone secretion via beta-END in female rats.


Interleukin-7 is associated with monocyte chemoattractant protein-1 and soluble E-selectin levels in peripheral blood of newly post-menopausal women.

Interleukin (IL-7), which is a regulator of development and homeostatic maintenance of T and B cells, is implicated in the induction of leukocyte-endothelial cell adhesion during inflammatory events. We hypothesized that circulating IL-7 is associated with cytokines and chemokines, vascular inflammatory markers and lipid profiles involved in regulating cell adhesion in post-menopausal women. Serum levels of 8 cytokines and chemokines were simultaneously measured in 200 post-menopausal women using a multiplexed human cytokine assay. C-reactive protein, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule and soluble E-selectin were measured as inflammatory markers. Serum IL-7 concentration was significantly correlated with serum MCP-1 concentration and the correlation remained after adjustment for age and body mass index (BMI). Serum IL-7 levels also showed significant positive correlations with serum levels of IL-10 and IL-6. In addition, the serum IL-7 concentration showed significant positive correlations with levels of soluble E-selectin and triglyceride after adjustment for age and BMI. We conclude that there is a relationship between circulating IL-7, MCP-1 and soluble E-selectin, and that IL-7 may be involved in regulating inflammatory cell adhesion together with MCP-1 and E-selectin in post-menopausal women.


Reproducibility of luteinizing hormone hypersecretion in different phases of the menstrual cycle in polycystic ovary syndrome.

AIM: We evaluated the reproducibility of an elevated luteinizing hormone (LH) level or elevated LH/follicle-stimulating hormone (FSH) ratio in different phases of the menstrual cycle in patients with polycystic ovary syndrome (PCOS). Furthermore, we evaluated the influence of cycle days and body mass index on LH levels using different days from menses or withdrawal bleeding. METHODS: Forty-three patients with PCOS and 37 controls were enrolled. All patients with PCOS had elevated LH levels and LH/FSH ratio, polycystic ovarian morphology and chronic anovulation at diagnosis. After their diagnoses, we measured serum LH and FSH in the early period and/or late period of the follicular phase. RESULTS: The rate of patients with elevated LH levels and LH/FSH ratio were significantly higher in the late phase than in the early phase in PCOS. In the early phase, only 52% of patients had elevated LH levels and LH/FSH ratio. We failed to demonstrate an inverse relationship between the LH level and BMI. Conclusions: LH levels of patients with PCOS were strongly influenced by the days from menses or withdrawal bleeding. In the early period, the reproducibility of elevated LH levels or LH/FSH ratio was poor even in patients previously diagnosed with them.

The Journal of Obstetrics and Gynaecology Research


Effects of oral and transdermal estrogen therapies on circulating cytokines and chemokines in postmenopausal women with hysterectomy.

OBJECTIVE: The aim of the present study was to determine the different effects of oral estrogen therapy (ET) and transdermal ET on changes in circulating levels of cytokines and chemokines in relationship to changes in markers of inflammation in postmenopausal women with hysterectomy. METHODS: Fifty-five postmenopausal women with hysterectomy were randomly assigned in open, parallel-group fashion to an oral ET group and a transdermal ET group. Serum levels of cytokines and chemokines were simultaneously measured using a multiplexed human cytokine assay. Serum concentrations of high-sensitive C-reactive protein, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, and E-selectin were measured as vascular inflammation markers. RESULTS: Both oral ET and transdermal ET significantly decreased serum interleukin (IL)-7 concentrations at 12 months (P=0.020 and P=0.015 respectively). Transdermal ET decreased serum concentrations of IL-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1beta (P=0.05, P=0.019, and P=0.029), but oral ET increased IL-8 level (P=0.025). There were significant differences in percentage changes in IL-8 and MIP-1beta between the oral and transdermal ET groups. Oral ET significantly decreased E-selectin level after 12 months. CONCLUSION: Transdermal ET reduces circulating levels of IL-8, MCP-1, and MIP-1beta, while both oral ET and transdermal ET reduce circulating level of IL-7.


Neonatal lipopolysaccharide exposure attenuates the homotypic stress-induced suppression of LH secretion in adulthood in male rat.

Neonatal immune challenges have a long-lasting influence on immune response. Using male Sprague-Dawley rats, we examined whether neonatal lipopolysaccharide (LPS) challenge alters the sensitivity of male reproductive function to adult LPS challenge and at which level (central or testes) the alteration occurs. We also examined the mRNA expression of proinflammatory cytokines in the hypothalamus and testes because they have a pivotal role in immune stress-induced suppression of gonadotropin secretion and testosterone synthesis. On day 10 after birth, all the pups were injected with LPS (100 microg/kg, i.p.) or saline. Thereafter, LPS (100 microg/kg, i.p.) or saline was injected in adulthood at 8 weeks of age. The serum LH concentration was decreased by LPS injection during adulthood in the neonatal saline-injected rats. This suppressive effect was not seen in the neonatal LPS-injected rats. The serum testosterone concentration was decreased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. The expression levels of KiSS-1, which encodes kisspeptin, known to have a crucial role in the regulation of gonadotropin secretion, and GnRH mRNA in the hypothalamus and LHbeta mRNA in the pituitary were not influenced by neonatal or adult LPS injection. On the other hand, the expression levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in the hypothalamus and testes were increased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. Furthermore, the expression levels of these factors in the hypothalamus after adult LPS injection were significantly lower in the neonatal LPS-injected rats than in the neonatal saline-injected rats. These findings indicate that neonatal LPS challenge reduces the sensitivity of male reproductive function to the suppressive effects of LPS, mainly at the central level. Attenuation of proinflammatory cytokine synthesis in the hypothalamus might be involved in this alteration.


Changes in circulating cytokine levels in midlife women with psychological symptoms with selective serotonin reuptake inhibitor and Japanese traditional medicine.

OBJECTIVE: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms. METHODS: Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene's climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay. RESULTS: Greene's total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene's total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1beta and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly. CONCLUSION: Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1beta.


Raloxifene reduces circulating levels of interleukin-7 and monocyte chemoattractant protein-1 in postmenopausal women.

OBJECTIVE: The aim of the present study was to determine the effects of raloxifene on changes in circulating levels of cytokines and chemokines in relation to changes in lipid profiles and markers of inflammation in postmenopausal women. METHODS: Fifty-three postmenopausal women aged 45-65 years old were randomly assigned in open, parallel-group fashion to a control group or raloxifene group. Twenty-six women received oral administration of 60mg raloxifene every day and 27 women did not receive any drugs for 12 months. Serum cytokines levels were simultaneously measured using a multiplexed human cytokine assay. RESULTS: Serum IL-7 concentrations in women who received raloxifene were decreased significantly (p=0.014), and serum monocyte chemoattractant protein (MCP)-1 concentrations in women who received raloxifene were decreased significantly (p=0.0003) at 12 months. In the control group, serum levels of MCP-1 and IL-7 did not show significant changes. There were significant differences (p=0.032 and p=0.0024, respectively) in percentage changes in IL-7 and MCP-1 in the control group and in the raloxifene group. Levels of low-density lipoprotein cholesterol (LDL-C) and E-selectin were decreased significantly in women who received raloxifene, but the percentage changes in LDL-C and E-selectin over a period of 12 months were not significantly correlated with percentage changes in IL-7 and MCP-1 over the same period. CONCLUSION: Circulating levels of IL-7 and MCP-1 decrease in postmenopausal women who received raloxifene.


Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats.

A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.

International Journal of Developmental Neuroscience


Associations of endogenous sex hormones and sex hormone-binding globulin with lipid profiles in aged Japanese men and women.

BACKGROUND: The associations of endogenous estrogen with lipid profiles and insulin resistance were conflicting in both men and women. We determined the associations of serum estradiol level and free estradiol index (FEI) with lipid profiles and insulin resistance in aged Japanese men and women. METHODS: One hundred seventy-four men and 208 postmenopausal women aged from 50 to 85 y were included in this study. Lipid profiles, fasting glucose and insulin as well as estradiol, testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) in serum were measured. RESULTS: Serum estradiol concentration in men showed a significant and negative correlation with high density lipoprotein-cholesterol (HDL-C) concentration and a significant and positive correlation with triglyceride (TG) after adjustment for age and body mass index (BMI). In addition, estradiol level was positively correlated with insulin and HOMA index. In women, serum levels of estradiol and testosterone were not correlated with lipid profiles and insulin resistance. SHBG concentration was negatively correlated with TG after adjustment for age and BMI in women. CONCLUSION: Endogenous estradiol level is associated with unfavorable lipid profiles and insulin resistance in aged men. In aged women, SHBG level is associated with favorable lipid profiles.


Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats.

Gonadotropin-inhibitory hormone (GnIH), a newly discovered hypothalamic RFamide peptide, inhibits reproductive activity by decreasing gonadotropin synthesis and release in birds. The gene of the mammalian RFamide-related peptides (RFRP) is orthologous to the GnIH gene. This Rfrp gene gives rise to the two biologically active peptides RFRP-1 (NPSF) and RFRP-3 (NPVF), and i.c.v. injections of RFRP-3 suppress LH secretion in several mammalian species. In this study, we show whether RFRP-3 affects LH secretion at the pituitary level and/or via the release of GnRH at the hypothalamus in mammals. To investigate the suppressive effects of RFRP-3 on the mean level of LH secretion and the frequency of pulsatile LH secretion in vivo, ovariectomized (OVX) mature rats were administered RFRP-3 using either i.c.v. or i.v. injections. Furthermore, the effect of RFRP-3 on LH secretion was also investigated using cultured female rat pituitary cells. With i.v. administrations, RFRP-3 significantly reduced plasma LH concentrations when compared with the physiological saline group. However, after i.c.v. RFRP-3 injections, neither the mean level of LH concentrations nor the frequency of the pulsatile LH secretion was affected. When using cultured pituitary cells, in the absence of GnRH, the suppressive effect of RFRP-3 on LH secretion was not clear, but when GnRH was present, RFRP-3 significantly suppressed LH secretion. These results suggest that RFRP-3 does not affect LH secretion via the release of GnRH, and that RFRP-3 directly acts upon the pituitary to suppress GnRH-stimulated LH secretion in female rats.


Associations of circulating adiponectin with estradiol and monocyte chemotactic protein-1 in postmenopausal women.

OBJECTIVE: The aim of the present study was to clarify the association of serum adiponectin concentrations with serum 17beta-estradiol concentrations in pre-, peri-, and postmenopausal women. In addition, the associations of serum adiponectin with serum concentrations of proinflammatory and anti-inflammatory cytokines were examined in women during the menopausal transition. DESIGN: A total of 197 women were enrolled in this study: 33 premenopausal women, 80 perimenopausal women, and 84 postmenopausal women. Serum adiponectin concentration was measured by an enzyme-linked immunosorbent assay. Serum concentrations of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha, anti-inflammatory cytokine IL-10, and the chemokines IL-8, macrophage inflammatory protein-1beta and monocyte chemotactic protein-1 were measured by using a multiplexed human cytokine assay. RESULTS: Serum adiponectin concentration showed a significant negative correlation with serum estradiol concentration (r= -0.400, P=0.001) in postmenopausal women but not in pre- and perimenopausal women, and this correlation was significant after adjustment for age and body mass index. Serum adiponectin concentration also showed a significant negative correlation with serum monocyte chemotactic protein-1 concentration (r= -0.244, P=0.05) in postmenopausal women. CONCLUSION: An increase in adiponectin level due to a decrease in estradiol results in a reduction in monocyte chemotactic protein-1 level in postmenopausal women, suggesting that adiponectin may be associated with a protective role against insulin resistance and atherosclerosis, which occur in the postmenopausal stage.


Transition of leptin receptor expression during pubertal development in female rat pituitary.

Leptin is thought to play important roles in pubertal development and reproductive function in the female. Leptin receptor is expressed in various tissues including the pituitary and hypothalamus. We investigated the transition of leptin receptor (Ob-R) expression in female rat pituitary during pubertal development. Real-time RT-PCR was performed for long-form leptin receptor (Ob-Rb) and short-form leptin receptor (Ob-Ra) in the pituitary and cerebrum of the rats aged 4 (juvenile), 6 (pubertal), and 8 weeks (adult). Double immunohistochemical colocalization of Ob-R and luteinizing hormone (LH) was performed in pituitaries from 4-week-old female rats. Serum leptin concentrations of 4-, 6-, and 8-week-old rats were measured by radioimmunoassay. In the pituitary, expression of Ob-Rb mRNA in 4-week-old rats (1.00 +/- 0.16) was significantly higher than in 8-week-old rats (0.61 +/- 0.07, p<0.05), although expression of Ob-Ra mRNA did not differ among 4-, 6-, and 8-week-old rats. In cerebrum, Ob-Ra and Ob-Rb mRNA expressions did not differ significantly among 4-, 6-, and 8-week-old rats. Intense staining of Ob-R and colocalization of Ob-R and LH were seen in 4-week-old rat pituitary. On the other hand, serum concentrations of leptin in 6- and 8-week-old rats were significantly higher than those in 4-week-old rats (p<0.05, p<0.01, respectively). In conclusion, since the pituitary gonadotroph is a potential target of leptin, the juvenile rat pituitary might prepare for a subsequent increase of serum leptin concentration by expressing Ob-Rb.


Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women.

OBJECTIVE: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women. METHODS: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. RESULTS: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p<0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). CONCLUSIONS: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

Journal of Endocrinological Investigation


Associations of interleukin-6 with interleukin-1beta, interleukin-8 and macrophage inflammatory protein-1beta in midlife women.

OBJECTIVE: The aim of the present study was to determine the associations of interleukin (IL)-6 with other cytokines and chemokines and to compare these associations in peri- and postmenopausal women. METHODS: Ninety-nine perimenopausal and 92 postmenopausal women were enrolled in this study. Serum concentrations of IL-6, IL-1beta, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-alpha, interferon gamma, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, macrophage inflammatory protein (MIP)-1beta and monocyte chemotactic protein (MCP)-1 were measured simultaneously using a multiplexed cytokine assay. RESULTS: Among the 17 cytokines, IL-6, IL-1beta, IL-5, IL-7, IL-8, IL-10, MCP-1 and MIP-1beta were detected in serum in more than 50% of the women. Serum levels of IL-4 and MCP-1 in postmenopausal women were significantly higher than those in perimenopausal women. Serum IL-6 concentrations showed significant and positive correlations with serum concentrations of IL-1beta, IL-8, MIP-1beta, IL-7 and MCP-1 in women regardless of menopausal status, and these correlations were still significant after adjustment for age and body mass index. CONCLUSION: Serum IL-6 concentration was found to be closely associated with serum concentrations of IL-1beta, IL-8, MIP-1beta, IL-7 and MCP-1 in women regardless of menopausal status, suggesting that these cytokines act in concert with the progression of several symptoms and various diseases.


FKBP5, SERT and COMT mRNA expressions in the peripheral leukocytes during menstruation cycle in healthy reproductive females.

There have been several evidences that the mRNA expressions in the peripheral leukocytes may indicate not only physical but also psychological states. The purpose of this study is whether the mRNA expressional changes in the leukocytes are related to the mental states across the menstrual cycle in reproductive healthy female subjects. Thirty-eight female subjects (22.4+/-1.4 year-old) were participated in this study at three menstruation cycle periods (menstrual, follicular and luteal phase). The FKBP5 (FK506-binding protein gene), SERT (serotonin transporter gene) and COMT (catechol-o-methyltransferase gene) mRNA expressions in the leukocytes were determined with hormonal data. The psychological changes were assessed with self-rating hospital anxiety and depression scale (HADS). Only one thirds of subjects (n=12) had regular menstrual cycles during the experiment. So we analyzed the data from these 12 subjects. The anxiety score of each subject was changed across the menstrual cycle (Friedman test: P<0.05). The FKBP5 mRNA expression was significantly lower in the follicular phase than in the other phases but no changes were seen in either SERT or COMT mRNA expressions among the phases. In conclusion, there are differences of HADS anxiety score and FKBP5 mRNA expression in the leukocytes across the menstrual cycle but there is no correlation between anxiety scores and FKBP5 mRNA.


Circulating osteoprotegerin is associated with age and systolic blood pressure, but not with lipid profile or fasting glucose, in postmenopausal women.

OBJECTIVE: Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis and osteoclast activation, has been reported to be linked to vascular biology. The aim of this study was to clarify the relationships between circulating OPG and the risk factors for vascular disorders in postmenopausal women. DESIGN: Eighty Japanese postmenopausal women were enrolled in this cross-sectional study. Clinical parameters (age, number of years since menopause, body mass index, systolic and diastolic blood pressure); serum concentrations of OPG, creatinine, calcium, and phosphorus; serum lipid profile; plasma glucose; and bone mineral density of the L2-4 vertebral bodies were determined for each woman. RESULTS: In rank-order correlation analysis, serum OPG concentrations had significant positive correlations with age (r = 0.29, P = 0.03), systolic blood pressure (r = 0.45, P < 0.01), diastolic blood pressure (r = 0.34, P < 0.01), and serum creatinine (r = 0.29, P = 0.04). Serum OPG concentration also had a marginally significant negative correlation with bone mineral density of the L2-4 vertebral bodies (r = -0.25, P = 0.06). However, serum OPG did not correlate with body mass index, serum lipid profile, or plasma glucose. The correlation of serum OPG with systolic blood pressure persisted after adjustment for both age and serum creatinine. CONCLUSIONS: These results suggest that increased circulating OPG in postmenopausal women is closely related to higher systolic blood pressure, which could cause atherosclerosis.


Decreased expression of kisspeptin mediates acute immune/inflammatory stress-induced suppression of gonadotropin secretion in female rat.

Kisspeptin and its corresponding receptor, the G protein-coupled receptor 54, play an important role in reproductive systems. It has been suggested that reproductive disorders in metabolically disrupted animals are caused by the alteration of hypothalamic KiSS-1 systems. Immune/inflammatory challenge is also known to disrupt reproductive function. However, the effects of immune/inflammatory challenge on KiSS-1 systems have not been investigated. In this study, we showed that lipopolysaccharide (LPS) injection decreased hypothalamic KiSS-1 mRNA expression as well as plasma LH levels in ovariectomized rats. Indomethacin completely blocked the suppressive effects of LPS on LH secretion and KiSS-1 mRNA level. Furthermore, we showed that i.v. injection of kisspeptin increased plasma LH levels in LPS-administrated rats to the same degree as in saline-injected rats. These results suggest that KiSS-1 systems are sensitive to immune/inflammatory challenge conditions and transmit these signals into the central reproductive system.


Differences in sensitivity to cold in Japanese men and postmenopausal women aged > or =50 years.

Sensitivity to cold is associated with several factors, such as aging, sex, and body composition. However, no previous studies have examined the differences in sensitivity to cold in men and women or the association of hormonal levels with sensitivity to cold. The aim of the present study was to clarify both the change in sensitivity to cold with aging and the difference in sensitivity to cold between men and women. Associations were also examined between circulating hormonal concentrations and the changes with aging and differences in sensitivity. This population-based cohort study enrolled healthy Japanese men and women aged > or = 50 years. A standardized 210-item health questionnaire was used to obtain information on symptoms of sensitivity to cold. Serum concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG) were measured. Of the 154 men and 180 women enrolled in this study, more women than men had sensitivity to cold. Whereas the percentage of men who had sensitivity to cold significantly increased with aging (P < 0.05), the percentage of women who had sensitivity to cold was already high (23.7%) at 50 to 60 years of age and did not change with aging. In men, advancing age and low body mass index (BMI) were significantly associated with sensitivity to cold (P < 0.05); however, age and BMI in women were not similarly associated. In addition, the effect of sex after adjustment for age was significant (P < 0.05), and there was also a numeric but nonsignificant effect of sex after adjustment for BMI. In men, low serum levels of the gonadal hormone FSH were significantly associated with sensitivity to cold in logistic analysis, but this association was nonsignificant after multivariate analysis. Serum concentrations of gonadal hormones and SHBG in women were not associated with sensitivity to col. The association of age with sensitivity to cold was different in men and women; the association of BMI with sensitivity to cold might be different in men and women. In addition, these changes in sensitivity to cold were not associated with circulating hormonal concentrations.


Estradiol suppresses NMU mRNA expression during sexual maturation in the female rat pituitary.

Neuromedin U (NMU) suppresses food intake and gonadotropin secretion. However, the developmental transition of NMU expression in the pituitary gland and the regulation of NMU expression are unclear. The objective of this study was to examine the transition of the expression of NMU mRNA in the pituitary glands of female rats from the juvenile period to the mature period of development. Furthermore, factors such as estradiol, insulin, leptin, and inhibin A, whose expressions change throughout puberty and which affect gonadotropin secretion in pituitary cell culture, were examined. In the pituitary gland, the expression of NMU mRNA was significantly lower in 8-week-old rats than in 4- and 6-week-old rats. In the pituitary cell culture, the expressions of NMU mRNA in the estradiol- and insulin-treated groups were significantly lower than in the control group. These results suggest that the expression of NMU mRNA in the female rat pituitary is reduced as the rats develop from the pubertal to the mature period. Additionally, the reduction of NMU expression in the pituitary may be related to the increases in serum estradiol and insulin levels that occur during the pubertal period, which may negate NMU suppression of gonadotropin secretion.

International Journal of Developmental Neuroscience


閉経後婦人の血中osteoprotegerin濃度と心血管病変の危険因子との関係の検討


Associations of adiponectin with sex hormone-binding globulin levels in aging male and female populations.

Changes with aging in serum gonadal hormones, sex hormone-binding globulin (SHBG) and adiponectin, which are involved in insulin resistance and metabolic syndrome, are different in men and women. We examined the relationships of serum adiponectin concentrations with serum concentrations of hormones and SHBG in men and women. One hundred fifty-four men and 180 women aged from 50 to 85 years were included in the cross-sectional study. Serum concentrations of testosterone, estradiol, dehydroepiandrosterone-sulfate, SHBG and adiponectin were measured in men and women. Serum adiponectin concentration showed a significant positive correlation with serum SHBG concentration in men and women (r=0.404, p<0.0001 and r=0.348, p<0.0001, respectively). Multiple regression analysis also showed that SHBG was the significant predictor for adiponectin in men and women. Serum adiponectin concentration in men showed a significant positive correlation with total testosterone concentration, but that in women was not significantly correlated with total testosterone concentration. Both adiponectin and SHBG concentrations in men (r=-0.222, p=0.0051 and r=-0.334, p<0.0001, respectively) and women (r=-0.281, p=0.0014 and r=-0.251, p=0.0048, respectively) showed significant negative correlations with the homeostasis model assessment (HOMA) index. Correlations between adiponectin and SHBG were significantly positive in both men and women, and both adiponectin and SHBG might be involved in insulin resistance in both sexes.


切迫早産管理が骨代謝に与える影響の検討(第1報)

切迫早産管理が骨代謝に与える影響の検討(第1報)


Prescribing patterns during pregnancy at Tokushima University Hospital

The purpose of this study was to investigate the drugs prescribed for pregnant women at Tokushima University Hospital in Japan, and to evaluate the risks associated with the use of these drugs during pregnancy according to the pregnancy risk classification systems of the PDA, ADEC and that used in manufacturers' package inserts. Of 496 female outpatients who gave birth at Tokushima University Hospital, 81% had been prescribed at least one drug, and the mean was 4.0 drugs per patient. Analysis of the prescriptions revealed a pattern of drug use very different from that in other countries, in that Kampo (Japanese herbal) medicines were also prescribed. For more than half of the oral drugs prescribed, risks were not given in the PDA and/or ADEC pregnancy risk systems. In addition, there was no listing of pregnancy risks in the package inserts of 20 drugs. We therefore consider it to be very important to develop a globally harmonized system for evaluating the risks associated with prescription drugs taken during pregnancy.

Japanese Journal of Pharmaceutical Health Care and Sciences


Association of serum cytokine concentrations with psychological symptoms in midlife women.

The purpose of the present study was to clarify the association of serum cytokine concentrations, determined using a multiplexed cytokine assay, with psychological symptoms in midlife women. Fifty-three peri- and post-menopausal women with and without psychological symptoms in Greene's climacteric scale were enrolled in this study. Levels of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Serum interleukin (IL)-6 concentration in women with psychological symptoms (2.71+/-047 pg/ml) was significantly (p=0.009) higher than that in women without psychological symptoms (0.98+/-0.18 pg/ml). Serum IL-8 concentration in women with psychological symptoms (33.4+/-8.17 pg/ml) was also significantly (p=0.022) higher than that in women without psychological symptoms (7.87+/-1.64 pg/ml). In addition, serum IL-10 concentration in women with psychological symptoms (0.74+/-0.26 pg/ml) was significantly (p=0.048) higher than that in women without psychological symptoms (0.07+/-0.04 pg/ml). Tumor necrosis factor (TNF)-alpha in serum was detected only in women with psychological symptoms. Serum IL-2 concentration in women with psychological symptoms tended (p=0.066) to be higher than that in women without psychological symptoms. No significant differences were found between levels of other cytokines in women with and without psychological symptoms. Psychological stress manifested as climacteric symptoms in midlife women may be associated with increases in serum concentrations of IL-6, IL-8, IL-10, and TNF-alpha.


Diagnostic performance of serum total testosterone for Japanese patients with polycystic ovary syndrome.

It is reported that the incidence of clinical and biochemical hyperandrogenism may be lower in Japanese patients with PCOS. Hyperandrogenism is included as a referential but not as an essential factor in the diagnostic criteria of the Japanese Society of Obstetrics and Gynecology (JSOG 1993). However, some patients with the typical clinical features of PCOS are not diagnosed with PCOS using JSOG 1993 criteria because they do not have a high LH level, which is defined as essential for diagnosis. In this study, we compared total testosterone (T) levels between Japanese patients with PCOS diagnosed using the JSOG 1993 criteria and normal menstrual women (controls). Fifty controls and 46 patients with PCOS were enrolled in this study. Furthermore, we evaluated the sensitivity and specificity of each cut-off value of T. The mean T level of patients with PCOS was significantly higher than that of the control (86 +/- 48 vs 68 +/- 46, P<0.01), and the prevalence rates of hyperandrogenism (T >114 ng/dL; defined as the mean +2SD of the control) were 10.2% in patients with PCOS and 4% in controls. The area under the ROC curve of T was 0.72, and there was no decision threshold to diagnose PCOS by T alone with both high sensitivity and high specificity. If the threshold is set as 110 ng/dL in order to gain high specificity, 94% of women whose serum level passed the threshold will be patients with PCOS. Although T should not be used as an independent essential factor of Japanese PCOS, it might be useful as a complementary factor in order to diagnose patients who have typical clinical features of PCOS but does not fulfill the JSOG 1993 criteria for PCOS.


Effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women.

The aims of our study were to evaluate the changes in bone turnover markers during pregnancy and puerperium as a longitudinal study and to elucidate the effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women. The study population comprised 27 Japanese pregnant women aged 23-40 years. All women were recruited for the longitudinal study from the outpatients clinic of the Department of Obstetrics and Gynecology, Tokushima University Hospital. Concentrations of serum bone-specific alkaline phosphatase (BAP), urinary cross-linked type I collagen N-telopeptides (NTx), serum NTx and urinary C-terminal telopeptide of type I collagen (CTx) were measured at 10, 26, 30 and 36 weeks of pregnancy and at 4 days and 1 month postpartum. In addition, we recruited 15 pregnant women (aged 25-35 years) who were treated by bed rest before 30 weeks of pregnancy for threatened premature delivery and compared bone turnover markers in these women with those in 22 normal pregnant women (aged 22-39 years). Concentrations of serum BAP, serum NTx, urinary NTx and urinary CTx were measured at 30 and 34 weeks of pregnancy and at 4 days and 1 month postpartum. In the longitudinal study, serum BAP concentration at 1 month postpartum was significantly higher than that at any stage of pregnancy and that at 4 days postpartum. Urinary concentration of NTx increased gradually during pregnancy and showed a peak at 36 weeks of pregnancy, followed by a decrease in the postpartum period. Serum NTx concentration and urinary CTx concentration showed the same patterns of change as that of urinary NTx concentration. In the comparison study, urinary concentrations of NTx and CTx at 30 and 34 weeks of pregnancy in women with bed rest were significantly (p<0.0001 and p<0.001, respectively) higher than those in normal pregnant women. Serum NTx concentration at 34 weeks of pregnancy in women with bed rest was also significantly (p=0.0029) higher than that in normal pregnant women. Serum BAP concentration at 34 weeks of pregnancy in women with bed rest was significantly (p=0.0038) higher than that in normal pregnant women, and these high levels were maintained during puerperium. Serum BAP concentration at 34 weeks of pregnancy was significantly correlated with duration of bed rest (r=0.767, p=0.0041). Immobilization due to bed rest during pregnancy is associated with increases in bone turnover markers in pregnant and postpartum women. Concentrations of bone resorption markers increased rapidly at the start of bed rest, while the concentration of a bone formation marker gradually increased toward puerperium.


The type 2 corticotrophin-releasing hormone receptor mediates orexin A-induced luteinising hormone suppression in ovariectomised rats.

Orexins are thought to be regulatory factors of the arousal and sleep patterns. They also affect immune, feeding, autonomic and neuroendocrine systems. We have previously shown that intracerebroventricular (i.c.v.) injection of orexin decreases pulsatile luteinising hormone (LH) secretion in ovariectomised (OVX) rats. However, the details of this mechanism have not been fully examined. Intracerebroventricular injection of orexin A also stimulates corticotrophin-releasing hormone (CRH) systems, which have been implicated in the stress-induced suppression of reproductive function. In the present study, we investigated the role of CRH systems in orexin-induced LH suppression. OVX rats were implanted with i.c.v. and intravenous (i.v.) cannulae. After i.c.v. injection of orexin and/or CRH receptor antagonists, blood samples were collected through the i.v. cannula at 6-min intervals for 120 min for LH measurement. Intracerebroventricular injection of orexin A or B (3 nmol/2.5 microl) suppressed pulsatile LH secretion. Coadministration of orexin A and alpha-helical corticotrophic-releasing factor (CRF), a nonselective CRH receptor antagonist (13 nmol/2.5 microl), or astressin(2)B, a selective type2 (CRH-R2) CRH receptor antagonist (28 nmol/2.5 microl), partly restored pulsatile LH secretion. Orexin B-induced LH suppression was not restored by alpha-helical CRF. In addition, i.c.v. injection of orexin A increased CRH and urocortin II (UcnII), but not Ucn mRNA levels, in the hypothalamus. These findings suggest that CRH-R2 mediates orexin A-induced LH suppression and it is possible that CRH and UcnII in the hypothalamus are involved in this pathway.


Changes in serum cytokine concentrations during the menopausal transition.

The purpose of the present study was to clarify the changes in serum concentrations of 17 cytokines in healthy women during the menopausal transition by using a multiplexed cytokine assay and to clarify the associations of these cytokines with serum estradiol concentration. Sixteen premenopausal, 54 perimenopausal and 52 postmenopausal women were enrolled in this study. Seventeen cytokines in serum samples were measured simultaneously using a Bio-Plex human cytokine 17-Plex assay. Serum IL-6 concentration showed a weak positive correlation with age (r=0.196, p<0.05). Postmenopausal women for whom less than 5 years had passed since menopause showed significant (p<0.05) increase in serum concentrations of IL-2, GM-CSF and G-CSF, while serum IL-4 concentration was significantly (p<0.05) increased in postmenopausal women for whom more than 5 years had passed since menopause. Serum estradiol concentration showed a significant negative correlation with serum IL-6 concentration and weak negative correlations with serum concentrations of IL-2, IL-8 and GM-CSF. We were able to simultaneously measure the levels of 17 cytokines using a highly sensitive cytokine assay, and we found that the changes in serum cytokine concentrations during the menopausal transition differed. We also found that serum IL-6 concentration during the menopausal transition was negatively correlated with serum estradiol concentration.


Association of serum undercarboxylated osteocalcin with serum estradiol in pre-, peri- and early post-menopausal women.

We investigated changes in serum concentration of undercarboxylated osteocalcin (ucOC), which is a sensitive marker of vitamin K status, and association of ucOC concentration with estradiol concentration in pre-, peri- and early post-menopausal women. The study population consisted of 193 pre-, peri- and post-menopausal Japanese women aged 39-66 yr. Serum ucOC concentration was measured to assess vitamin K status; serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) were measured as bone formation markers; and urine concentration of N-telopeptide was measured as a bone resorption marker. Serum estradiol and estrone concentrations were measured by a highly sensitive radioimmunoassay. Bone mineral density (BMD) was measured at the lumbar spine. Serum concentration of ucOC in peri-menopausal women was significantly (p=0.0005) higher than that in pre-menopausal women, while serum OC concentration in post-menopausal women for whom 1 yr had passed since menopause was significantly (p=0.0003, p=0.024, respectively) higher than the concentrations in pre-menopausal and peri-menopausal women. Serum ucOC concentration showed a significant negative correlation with estradiol concentration (r=-0.372, p<0.0001) and a significant positive correlation with serum FSH concentration (r=0.324, p<0.0001). Serum OC concentration was positively correlated with serum FSH concentration (r=0.317, p<0.001). The results showed that the change in ucOC concentration during the menopausal transition is different from that in OC concentration. In addition, serum ucOC concentration is closely associated not only with FSH concentration but also estradiol concentration.

Journal of Endocrinological Investigation


Change in serum undercarboxylated osteocalcin concentration in bilaterally oophorectomized women.

We investigated changes in serum undercarboxylated osteocalcin (ucOC) concentrations, bone turnover markers and spine bone mineral density (BMD) in women who had undergone bilateral oophorectomy during the premenopausal period. The study population comprised 141 bilaterally oophorectomized and 32 premenopausal women for a cross-sectional study. The longitudinal study consisted of 21 bilaterally oophorectomized women. Serum ucOC concentration, serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) as bone formation markers, urine N-telopeptide (NTx) concentration as a bone resorption marker and serum parathyroid hormone (PTH) concentration were measured. Serum concentration of ucOC in women at 1 month after bilateral oophorectomy was significantly (p<0.05) higher than that in premenopausal women and the high level was sustained after surgical menopause. On the other hand, serum OC concentration at 1 month after surgical menopause was not different from that in premenopausal women. In the longitudinal study, serum ucOC concentration at 1 month after surgical menopause was significantly (p<0.05) increased compared to that before bilateral oophorectomy, while serum OC concentrations before and at 1 month after surgical menopause were not significantly different. The results of this study showed that serum ucOC concentration rapidly increases in women after bilateral oophorectomy and that change in serum ucOC concentration after surgical menopause is different from change in serum OC concentration.