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Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system.

We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-alpha and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.

Abortion, Spontaneous↗

The genetic basis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The disorder is characterized by clinical features of hyperandrogenism, menstrual irregularities and often central obesity and hyperinsulinaemia. PCOS may increase the risk for infertility, type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease and endometrial cancer, emphasizing the need for early diagnosis of the syndrome. The genetic basis of PCOS is unknown. There is a strong familial component but the mode of inheritance is uncertain and several candidate genes have been proposed to contribute to susceptibility. Not only genes involved in steroid hormone biosynthesis have been studied but also genes associated with the regulation of insulin secretion and action since hyperinsulinaemia is a characteristic of PCOS. So far there is evidence that INS VNTR (insulin variable number of tandem repeats) or CYP11alpha (cholesterol side chain cleavage) genes are associated with this syndrome. PCOS appears, however, to be an oligogenic disorder and more studies are necessary to define the genetic basis.

Cholesterol Side-Chain Cleavage Enzyme↗

Chronic orofacial pain: is the puzzle unraveling?

Conditions involving chronic orofacial pain represent a major health problem, and patients with persistent pain are difficult to manage successfully. These conditions are often comorbid with additional health issues such as sleep disturbances, cardiovascular, gastrointestinal and reproductive system complaints, weight loss or weight gain, swelling, numbness, sweating and flushing, and concerns regarding loss of libido, drive, attention, and memory. Neuroendocrine and autonomic pain-stress responsivity and the consequences of pain for sensory, motor, immune and reproductive functions, and mood seem to account for the broad range of comorbid complaints. Susceptibility to a particular response appears to explain intra-individual differences in disease expression. Understanding of these regulatory, mostly adaptive processes will support novel treatments to manage many troublesome comorbid complaints for which current approaches are unsatisfactory.

Adaptation, Physiological↗

The impact of reproductive events on the course of bipolar disorder in women.

BACKGROUND: Little is known about the impact of female reproductive hormones on the course of bipolar disorder. This study was designed to assess the influence of reproductive events and hormonal therapies on the course of bipolar disorder in women. METHOD: Fifty women with DSM-IV bipolar disorder completed a structured clinical interview to assess the impact of reproductive events on the course of their illness. RESULTS: The onset of bipolar disorder occurred before menarche in 32% (N = 16) of women; 18% (N = 9) experienced the onset within 1 year of menarche. Most women did not receive an accurate diagnosis of nor treatment for bipolar disorder until after they had children, and therefore the majority were not treated with mood stabilizers during or immediately after pregnancies. Of women with children, 20 (67%) of 30 experienced a postpartum mood episode. Of the women who had postpartum episodes after delivery of a first child, all had episodes after subsequent pregnancies. Having a postpartum mood episode after a first pregnancy significantly increased the risk of a postpartum episode after subsequent deliveries (p = .02). Postpartum episodes were almost exclusively depressive. Increased depressive symptoms during pregnancy were significantly associated with postpartum mood episodes (p = .01). Women who were not using hormone replacement therapy (HRT) were significantly more likely than those who were using HRT to report worsening of symptoms during perimenopause/menopause (p = .02). CONCLUSION: These data suggest that hormonal fluctuations are associated with increased risk of affective dysregulation and mood episodes in women with bipolar disorder.

Acute Disease↗

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy.

BACKGROUND: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. METHODS: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. RESULTS: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone-binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 mg. CONCLUSIONS: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.

Adolescent↗

[A specific disorder of Kanji writing observed in a learning-disabled child--cognitive-psychological and neuropsychological analysis].

We reported a learning-disabled child who demonstrated a specific disorder of Kanji writing. A right-handed 13-year-old boy had showed no abnormality in general intelligence (VIQ114 and PIQ 100 in WISC-R), but could write only 35% of Kanji, which he should have learned six years before. It was necessary to develop a new test battery to detect the symptom which had not been detected using current existing test batteries. In cognitive-psychology, this patient had a retrieval disorder of graphic forms of Kanji. In addition, he showed a disorder in reproduction of complex graphic forms which he was asked to remember. Therefore, it is likely that he had a disorder for both Kanji and complex graphic forms, which is similar to the syndrome of pure agraphia of Kanji in adults.

Adolescent↗

Organophosphorus poisoning and anaesthesia.

Organophosphorus compounds, used as insecticides and agents of chemical warfare, are a major global cause of health problems. These irreversible inhibitors of cholinesterase produce three well-recognised clinical entities: the initial cholinergic phase, which is a medical emergency often requiring management in an intensive care unit; the intermediate syndrome, during which prolonged ventilatory care is necessary; and delayed polyneuropathy. In addition, disturbances of body temperature and endocrine function, electrolyte imbalances, immunological dysfunction and disorders of reproduction have been reported in animals and man. Vocal cord paralysis, pancreatitis, cardiac arrhythmias and a wide range of neuropsychiatric disorders are known to follow acute and chronic exposure to organophosphorus compounds. As a result of the inhibition of plasma cholinesterase, there can be increased sensitivity to drugs hydrolysed by this enzyme, e.g. suxamethonium and mivacurium. The inhibition of acetylcholinesterase causes dysfunction at the neuromuscular junction which can produce altered responses to nondepolarizing neuromuscular blockers. Anaesthetists may encounter patients exposed to organophosphorus compounds either following acute poisoning, trauma (warfare) or as patients with a wide range of nonspecific disorders presenting for surgery. The traditional use of oximes and atropine in treatment has failed to reduce the morbidity and mortality associated with poisoning. The roles of agents that have reduced the toxicity of organophosphorus compounds in animal experiments are discussed as potential therapeutic agents. There is an urgent need for accurate information on the problems associated with exposure to organophosphorus compounds. This would best be achieved by collaborative research between technologically advanced countries and developing countries, where organophosphorus compounds are a leading cause of ill health.

Anesthesia↗

Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome.

UNLABELLED: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproductive age women characterized in its broadest definition by the presence of oligoamenorrhea and hyperandrogenism and the absence of other disorders. Defects of gonadotropin secretion, including an elevated LH level, elevated LH to FSH ratio, and an increased frequency and amplitude of LH pulsations have been described, but the prevalence of these defects in a large, unbiased population of PCOS patients has not been determined. Sixty-one women with PCOS defined by oligomenorrhea and hyperandrogenism and 24 normal women in the early follicular phase had LH samples obtained every 10 min for 8-12 h. Pool LH levels from the frequent sampling studies were within the normal range in the 9 PCOS patients (14.8%) who were studied within 21 days after a documented spontaneous ovulation. Excluding these post-ovulatory patients, 75.0% of the PCOS patients had an elevated pool LH level (above the 95th percentile of the normal controls), and 94% had an elevated LH to FSH ratio. In the anovulatory PCOS patients, pool LH correlated positively with 17-OH progesterone (R = 0.30, P = 0.03), but not with estradiol, estrone, testosterone, androstenedione, or DHEA-S. Pool LH and LH to FSH ratio correlated positively with LH pulse frequency (R = 0.40, P = 0.004 for pool LH, and R = 0.39; P = 0.005 for LH/FSH). There was also a strong negative correlation between pool LH and body mass index (BMI) (R = -0.59, P < 10(-5)). The relationship between BMI and LH secretion in the PCOS patients appeared to be strongest with body fatness, as pool LH was correlated inversely with percent body fat, whether measured by skinfolds (R = -0.61, P < 10(-5)), bioimpedance (R = -0.55, P < 10(-4)), or dual energy x-ray absorptiometry (DEXA) (R = -0.70, P = 0.001; n = 18 for DEXA only). By DEXA, the only body region that was highly correlated with pool LH was the trunk (R = -0.71, P = 0.001). The relationship between body fatness and LH secretion occurred via a decrease in LH pulse amplitude (R = -0.63, P < 10(-5) for BMI; R = -0.58, P < 10(-4) for bioimpedance; and R = -0.64, P = 0.004 for whole body DEXA), with no significant change in pulse frequency with increasing obesity (R = -0.17, P = 0.23 for BMI). IN CONCLUSION: 1) the prevalence of gonadotropin abnormalities is very high in women with PCOS selected on purely clinical grounds, but is modified by recent spontaneous ovulation; 2) the positive relationship between LH pulse frequency and both pool LH and LH to FSH ratio supports the hypothesis that a rapid frequency of GnRH secretion may play a key etiologic role in the gonadotropin defect in PCOS patients; 3) pool LH and LH pulse amplitude are inversely related to body mass index and percent body fat in a continuous fashion; and 4) the occurrence of a continuous spectrum of gonadotropin abnormalities varying with body fat suggests that nonobese and obese patients with PCOS do not represent distinct pathophysiologic subsets of this disorder.

Adolescent↗

Reproductive toxicity assessment of chronic dietary exposure to soy isoflavones in male rats.

Epidemiologic and experimental data suggest that consumption of diets that are rich in isoflavones may decrease cancer risk in the breast, prostate, and other tissues. Isoflavones such as genistein and daidzein are structurally similar to endogenous estrogens, and demonstrate both estrogenic and weak anti-estrogenic activities; these activities may underlie the impaired fertility and reproductive tract disorders reported in animals exposed to high doses of isoflavones. To identify possible effects of isoflavones on male fertility, we evaluated reproductive parameters in Wistar-Unilever rats receiving dietary exposure to PTI G-2535, a characterized mixture of soy-derived isoflavones containing 45% genistein, 23% daidzein, and 4% glycitein. Beginning at 10 weeks of age, rats received chronic dietary exposure to the soy isoflavone mixture (200 or 2000 mg/kg diet) for a minimum of 12 months. Controls received unsupplemented chow diet only for the same period. Dietary exposure to isoflavones induced no gross toxicity or alterations in body weight gain. Absolute and relative weights of the testis and epididymis in groups receiving high or low doses of isoflavones were comparable to those of controls, and histopathologic evaluations demonstrated that testicular morphology was similar in all study groups. Isoflavone exposure had no significant effects on spermatid count, sperm production, or sperm morphology in any group. These data suggest that the reproductive system of adult male rats is relatively insensitive to isoflavone toxicity at dose levels that demonstrate significant activity in cancer chemoprevention, and that male reproductive function is unlikely to be affected by long-term administration of isoflavones for cancer prevention or other purposes. The results of this study conducted in adult male rats differ from the significant alterations in reproductive parameters that have been reported in female rats receiving prenatal or juvenile exposure to isoflavones.

Animals↗

Female reproductive cycle and obsessive-compulsive disorder.

BACKGROUND: The aim of our study was to assess whether there is a relationship between reproductive cycle events and the initiation or changes in symptoms of obsessive-compulsive disorder (OCD). METHOD: Forty-six female outpatients meeting DSM-IV criteria for OCD completed a semistructured interview at our OCD unit to assess the relationship between reproductive cycle events and OCD. Dates of data collection were from January 2001 to December 2003. RESULTS: In our sample, OCD onset occurred in the same year as menarche in 22% (N = 10), at pregnancy in 2% (N = 1), at postpartum in 7% (N = 3), and at menopause in 2% (N = 1). Worsening of preexisting OCD was reported by 20% of patients (9/45) at premenstruum, 8% (1/12) at pregnancy, 50% (6/12) at postpartum, and 8% (1/12) at menopause. The number of premenstrual mood symptoms, which included anxiety, irritability, mood lability and depressed mood, was associated with both premenstrual worsening of OCD (OR = 5.1, p < .01) and onset or worsening of OCD at postpartum (OR = 2.7, p < .05). Patients with an onset or worsening of OCD at postpartum also more frequently reported pre-menstrual worsening of OCD and previous history of major depressive disorder, including postpartum depression (p < or =.05 for all). CONCLUSION: In a substantial number of patients, the onset or worsening of OCD was related to reproductive cycle events, especially at menarche and postpartum. Certain women with OCD seem to be vulnerable to worsening of OCD at different reproductive periods that imply hormonal fluctuations, and premenstruum and post-partum were the 2 reproductive events with a greater vulnerability. Those patients whose OCD symptoms appeared to be related to reproductive events also exhibited a greater history of mood symptoms (premenstrual depression and major depressive episodes).

Adolescent↗

Regulation of Wolffian duct development.

Wolffian ducts (WDs) are the embryonic structures that form the male internal genitalia. These ducts develop in both the male and female embryo. However, in the female they subsequently regress, whereas in the male they are stabilised by testosterone. The WDs then develop into separate but contiguous organs, the epididymis, vas deferens and seminal vesicles. Recently, considerable progress has been made in identifying genes that are involved in these different stages of development which is described in this review. In addition, WD development in (atypical forms of) cystic fibrosis and intersex disorders, such as the complete androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase deficiency and LH-receptor defects, is discussed. The apparent increase in male reproductive tract disorders is briefly discussed from the perspective of the potential endocrine-disrupting effects of the numerous chemicals in the environment to which the developing male foetus can be exposed.

Androgens↗

Reproductive dysfunction in women with epilepsy.

Reproductive endocrine disorders, such as polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, premature menopause, and hyperprolactinemia, are reported to be more common in women with epilepsy than in the general female population. Epilepsy itself may affect reproductive endocrine function. For example, the prevalence of PCOS appears to be high even among women with epilepsy who do not take antiepileptic drugs (AEDs). However, AEDs also induce various changes in endocrine function. The hepatic enzyme-inducing AEDs phenytoin and carbamazepine (CBZ) have been shown to increase serum levels of sex hormone-binding globulin (SHBG). This increase leads in time to a diminished estradiol:SHBG ratio and decreased bioactivity of estradiol, which may result in menstrual disorders in some women receiving long-term CBZ treatment. Enzyme-inducing AEDs also can reduce the efficacy of oral contraceptives. In women with epilepsy who are treated with valproate (VPA), especially in those who have gained weight during treatment, polycystic ovaries, hyperandrogenism, and menstrual disorders appear to be common. After the start of VPA therapy in a woman with epilepsy, the length of the menstrual cycles and body weight should be monitored. Transvaginal ultrasonography of the ovaries is indicated if the menstrual cycles are prolonged and serum testosterone levels are elevated, especially if there is associated weight gain. The endocrine effects of the new AEDs have not been widely studied. However, treatment with these agents should be considered in women who develop reproductive endocrine dysfunction during treatment with the older AEDs.

Adolescent↗

Studies of the reproduction function in hyper- and hypoadrenocorticism.

The investigation was carried out on 66 patients with hypo- or hyperfunctional syndromes of adrenocorticism, hospitalized and treated by our team. The patients were grouped into 5 lots according to their diseases. Lot one consisted of 34 female patients with Cushing's syndrome, lot two of 10 males with Cushing's syndrome, lot three of 10 males with Addison's disease and lot four, of 6 females with androgenic hypercorticism. The morphofunctional disorders of reproduction were followed up clinically and by complex hormone assays, before and after treatment. The incidence of these disorders is very high, and the results of clinical observations and of laboratory data demonstrate that both the excess of adrenocortical hormones and the decrease in their circulating level have a negative influence on the reproduction function or represent a risk factor in cases of pregnancy. By the curative treatment of the adrenal cortex a preventive treatment of abortion and/or sterility is achieved.

Adrenal Insufficiency↗

The problem: shiftwork.

Shiftwork, particularly that including night work, causes disruption of biological rhythms and perturbation of the social and family life that can negatively affect performance efficiency, health, and social relations. Adverse effects can manifest themselves in the short term as sleep disturbances, shiftlag syndrome, psychosomatic troubles, errors, and accidents; in the long term, there is an increased risk for gastrointestinal, psychoneurotic, and cardiovascular diseases, and women shiftworkers can be more vulnerable in relation to their reproductive function and family duties. A high interindividual variability is recorded in both short-term adjustment and long-term tolerance, being connected to individual factors as well as to work organization (shift schedules in particular) and social conditions.

Accidents, Occupational↗