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Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males.

CONTEXT: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. OBJECTIVE: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. DESIGN: This was a double-blind, placebo-controlled, crossover study. SETTING: This was a hospital-based study. PARTICIPANTS: Male volunteers (n = 6) were recruited. INTERVENTIONS: Each volunteer received a 90-min i.v. infusion of kisspeptin-54 (4 pmol/kg x min) and a control infusion of saline (0.9%) in random order. MAIN OUTCOME MEASURE: Plasma LH, FSH, and testosterone concentrations were measured. RESULTS: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 +/- 1.5 vs. saline, 4.2 +/- 0.5 U/liter, P < 0.001; mean 90-min FSH: kisspeptin, 3.9 +/- 0.7 vs. saline, 3.2 +/- 0.6 U/liter, P < 0.001; mean 180-min testosterone: kisspeptin, 24.9 +/- 1.7 vs. saline, 21.7 +/- 2.2 nmol/liter, P < 0.001). The plasma half-life of kisspeptin-54 was calculated to be 27.6 +/- 1.1 min. The mean metabolic clearance rate was 3.2 +/- 0.2 ml/kg x min, and the volume of distribution was 128.9 +/- 12.5 ml/kg. CONCLUSION: Elevation of plasma concentrations of kisspeptin in human males significantly increases circulating LH, FSH, and testosterone levels. Kisspeptin infusion provides a novel mechanism for hypothalamic-pituitary-gonadal axis manipulation in disorders of the reproductive system.

Adult↗

[Effect of single physical exercise on formation, fixation, and reproduction of temporal associations in rats].

The effects of submaximal and maximal physical exercise on the formation, fixation and subsequent reproduction of temporary relations were compared before or immediately after training. Physical exercise before training, that impairs the formation of temporary relations, led to relatively moderate disorders in their fixation and reproduction. During physical exercise immediately after training, disorders of fixation and subsequent reproduction of temporary relations are more pronounced. It is suggested that disorders of the formation and fixation of the temporary relations caused by physical exercise are partially determined by changes in the brain content of biogenic amines.

Animals↗

Selected health risks caused by long-term, whole-body vibration.

The problem of a "vibration disease" caused by low-frequency whole-body vibration (wbv) is critically discussed. Disorders of the nervous, circulatory, and digestive systems are interpreted not to be predominantly wbv-specific, but to be related to the totality of working conditions. Long-term wbv exposure can probably contribute to the pathogenesis of disorders of female reproductive organs (menstrual disturbances, anomalies of position) and disturbances of pregnancy (abortions, stillbirths). Animal experiments suggest harmful effects on the fetus. WBV has a minor synergistic effect on the development of noise-induced hearing loss. Degenerative changes of the spine are more prevalent among wbv-exposed workers. Model calculations demonstrate an increased spinal load in pregnant women exposed to wbv or self-induced vibration, and illustrate a possibility for the comparison of data on stress, strain, and strength. The analysis of individual exposure-effect relationships is suggested as a future approach for evaluating potential occupation-related diseases.

Animals↗

Involvement of Bcl-2 family genes and Fas signaling system in primary and secondary male germ cell apoptosis induced by 2-bromopropane in rat.

Epidemiological surveys and animal experimental studies suggest that exposure to 2-bromopropane (2-BP) could result in reproductive and hematopoietic disorders. The objectives of this study were to investigate the role of apoptosis in 2-BP-induced testicular toxicity and whether this process involves Bcl-2 family genes and the Fas signaling system. Rats were injected percutaneously with 1350 mg/kg 2-BP for 1 to 5 days and then were euthanized at 6 or 12 h after one dose, 6 h after two, three, or five doses, and 2 or 9 days after the final treatment. Light and electron microscopic analyses, TUNEL staining of DNA fragments, agarose gel electrophoresis of low-molecular-weight DNA, and Western blotting analysis of Bcl-2 family proteins and Fas receptor and ligand were conducted. Two-day treatment resulted in selective degeneration of spermatogonia with marked nuclear chromatin condensation. DNA ladder formation on the agarose gel further validated the findings of TUNEL-stained apoptotic cells. The percentage of apoptotic-positive tubules and apoptotic cell index increased time dependently. 2-BP treatment resulted in two distinct morphological changes: an immediate effect on spermatogonia and secondary apoptosis of spermatocytes 9 days after treatment. Downregulation of Bcl-2 after the first or second injection of 2-BP and upregulation of Bax after the first treatment contributed to the initiation of primary apoptosis of spermatogonia. Expression of FasL was inhibited while expression of Fas increased after the 2-BP treatment and remained at levels about two times of the control. However, it increased about sixfold of the control by day 9 after final injection, which contributed to the induction of secondary apoptosis of spermatocytes. Our results indicate that 2-BP resulted in apoptotic death of testicular germ cells and that this process involves the Bcl-2 family genes and the Fas signaling system.

Animals↗

Applicability of radiosurgery with heavy ion beams to inactivate specific organs in living organisms.

It was the aim of the study to test the applicability of radiosurgery in inactivating a specific organ through local irradiation with heavy ion beams. Silkworms were exposed to whole-body or local irradiation with carbon ion beams ((12)C(5+), 18.3 MeV/u, range=1.1 mm). After irradiation at the wandering stage, no significant differences were observed regarding either survival or cocoon quality between locally irradiated larvae and controls. Only localized effects were seen, such as the deletion of wings and functional disorders of the reproduction primordium, depending on both irradiation dose and site. This observation was not true for whole-body irradiated larvae. After local irradiation of the hemopoietic organs at the 4th instar premolting stage, the hemocyte densities were clearly reduced and the hemopoietic organ capacity was disrupted. The change in hemocyte densities was accompanied by changes of hemolymph components. These results show that radiosurgery utilizing heavy ion beams can destroy a specific organ or tissue in a living organism.

Animals↗

A Risk Score for Polycystic Ovary Syndrome Based on Meta-Analysis and Machine Learning of Gut Microbiota Signatures.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder among reproductive-age women, in which emerging evidence suggests a substantial role played by the gut microbiota. To comprehensively evaluate gut microbiota alterations in PCOS and identify microbial biomarkers through integrated analysis, a systematic search of PubMed, Web of Science, and Embase was conducted for studies employing 16S rRNA gene sequencing of fecal samples from PCOS cohorts. Ten eligible PCOS cohorts, comprising 858 individuals, were included in the study, from which a risk score was derived using a 20-gene gut microbial signature associated with PCOS. Meta-analysis at the genus level identified that Subdoligranulum, NK4A214_group, and Collinsella significantly decreased, and Bacteroides increased in PCOS across multiple cohorts. Machine learning analysis identified a 20-genus microbial signature using the least absolute shrinkage and selection operator (LASSO) method, which was used to construct a risk score with an AUC of 0.835 in diagnosis prediction. Network analysis further identified Negativibacillus and Lachnospiraceae_UCG_010 as potential driver microbes in PCOS. The analysis in this study highlights key alterations in the gut microbiota across PCOS cohorts. The identified gut microbial signature and derived LASSO-based risk model offer novel insights and a potential tool for PCOS diagnosis.

Polycystic Ovary Syndrome↗

Toxicokinetics of chlorobiphenyls and associated physiological responses in marine mammals, with particular reference to their potential for ecotoxicological risk assessment.

For the conservation of marine mammals and their ecosystem, it is important to know whether or not they are exposed to intolerable levels of environmental pollutants. In some case studies on marine mammals, xenobiotics can be linked to reproductive and immunological disorders. Disturbed endocrine systems seem to be a common denominator, whereby metabolization systems dealing with xenobiotic as well as endocrine compounds are involved. Two sets of indicators are distinguished to evaluate the toxicity of organochlorine residues found in marine mammal tissues. These are (1) interactions of chlorobiphenyls with the cytochrome P450 enzyme system and (2) comparative physical and chemical blood parameters directly and indirectly obtained via functional immunoassays. Apart from the constitutive enzymes, the induction of each of the other 150 isoenzymes of the P450 system exhibits substrate (= compound) specificity and moreover organisms develop species and even organ specific induction profiles. Therefore, a specific enzyme profile for each compound in a given species/organ may exist. The biotransformation capacity, constitutive and/or induced, will be reflected in the extent to which biotransformation of the chlorinated biphenyls in question has occurred. This can be expressed in the ratio of the concentration of a given individual biphenyl to the concentration of a persistent reference individual biphenyl. Both these indicators will provide information on which compounds are most likely involved and to what extent. The directly obtained blood parameters include levels of vitamin A, steroid hormones and thyroxine. The blood parameters acquired via functional immunoassays include mitogen- and antigen-induced proliferative responses of peripheral blood mononuclear cells (PBMC) and natural killer (NK) activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Association between urinary incontinence and urinary tract infections, and fractures in postmenopausal women.

OBJECTIVE: The association between urinary disorders, such as ongoing urinary incontinence (UI), history of urinary incontinence (HIST-UI) and urinary tract infections (UTI), and fractures in peri- and postmenopausal women was assessed in an epidemiological study. SUBJECTS AND METHODS: The sample consisted of 10000 women from seven birth cohorts, born between 1900 and 1940, who were investigated regarding urinary disorders, fractures and reproductive history by means of a postal questionnaire. RESULTS: The overall response rate was 74.6%. The respondents (n = 7459) represented 53% of the total population from the respective birth cohorts. There was a significant independent correlation between UI, HIST-UI and UTI, respectively, and fractures after the age of 30. In subjects with HIST-UI, tobacco smokers compared to non-smokers had significant more fractures in both the 1930 and 1940 birth cohorts (P < 0.01). Logistic multiple regression in the 1930 and 1940 cohorts demonstrated that age (P < 0.001), HIST-UI (P < 0.001) and tobacco smoking (P < 0.05), respectively, had an independent explanatory value for fractures. CONCLUSION: The prevalence of fractures increased with increasing age, in smokers compared to non-smokers and in women with a history of UI.

Age Factors↗

Analysis of microarray experiments of gene expression profiling.

The study of gene expression profiling of cells and tissue has become a major tool for discovery in medicine. Microarray experiments allow description of genome-wide expression changes in health and disease. The results of such experiments are expected to change the methods employed in the diagnosis and prognosis of disease in obstetrics and gynecology. Moreover, an unbiased and systematic study of gene expression profiling should allow the establishment of a new taxonomy of disease for obstetric and gynecologic syndromes. Thus, a new era is emerging in which reproductive processes and disorders could be characterized using molecular tools and fingerprinting. The design, analysis, and interpretation of microarray experiments require specialized knowledge that is not part of the standard curriculum of our discipline. This article describes the types of studies that can be conducted with microarray experiments (class comparison, class prediction, class discovery). We discuss key issues pertaining to experimental design, data preprocessing, and gene selection methods. Common types of data representation are illustrated. Potential pitfalls in the interpretation of microarray experiments, as well as the strengths and limitations of this technology, are highlighted. This article is intended to assist clinicians in appraising the quality of the scientific evidence now reported in the obstetric and gynecologic literature.

Algorithms↗

The development and pilot-testing of a training curriculum in adolescent medicine and health.

PURPOSE: To select and propose a set of knowledge, attitudes, and skills essential for the care of adolescents; to encourage the development of adolescent health multidisciplinary networks; and to set up training programs in as many European countries as possible. METHODS: The curriculum was developed by 16 physicians from 11 European countries with various professional specializations. In line with modern guidelines in medical education, it is a modular, flexible instrument which covers the main teaching areas in the field, such as basic skills (i.e. setting, rights and confidentiality, gender and cultural issues) as well as specific themes (i.e. sexual and reproductive health, eating disorders, chronic conditions). It consists of 17 thematic modules, each containing detailed objectives, learning approaches, examples, and evaluation methods. RESULT: Two international one-week summer schools were used to assess the feasibility and appropriateness of the curriculum. The overall evaluation was good, with most of the items surpassing three on a four-point Likert scale. However, it pointed to several aspects (process and content) which will need to be refined in the future, such as an increase in interactive sessions (role playing), and a better mix of clinical and public health issues.

Adolescent Medicine↗

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development.

The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

Animals↗

Interactions among endocrine control systems in the regulation of ovarian function.

During sequential physiologic maturation of an individual follicle, the number of granulosa cells increases in excess of 1000-fold, while intra-ovarian concentrations of sex steroids escalate by 100-fold. The recent development of several in vitro ovarian systems has permitted a more extensive and direct assessment of specific mechanisms that control growth and steroidogenesis in granulosa and thecal cells. For example, estradiol and follicle stimulating-hormone seem to promote the production by ovarian cells of low-molecular-weight growth factors, that may participate in granulosa cell proliferation. Luteinizing hormone stimulates the de novo synthesis of prostacyclin by granulosa cells in vitro. Prostacyclin, in turn, may regulate the microvasculature of the maturing follicle and directly stimulate steroidogenesis. The effects of individual hormones are markedly modified by other intraovarian endocrine factors, and by the precise status of cytodifferentiation of the ovarian cells. For example, the actions of prolactin on granulosa-cell steroidogenesis are influenced strikingly by both agonistic and antagonistic interactions between prolactin and estradiol, as well as by the level of granulosa-cell cytodifferentiation attained in vivo. Similar bihormonal intrafollicular interactions are recognizable between estrogen and follicle-stimulating hormone in the early follicle, and between estradiol and luteinizing hormone in the maturing follicle. These interactions are susceptible to more precise examination under defined in vitro conditions. Overall, recent advances in biomedical research continue to elucidate basic molecular mechanisms of hormone action in ovarian cell physiology. Such advances are likely to continue to provide important insights into the pathophysiology of clinical disorders of human reproduction.

6-Ketoprostaglandin F1 alpha↗

Intensive hormone monitoring in women with unexplained infertility: evidence for subtle abnormalities suggestive of diminished ovarian reserve.

OBJECTIVE: To determine hormone levels across the menstrual cycle in women with rigorously defined unexplained infertility. DESIGN: Prospective study. SETTING: National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the following rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months' duration, with no male factor, anatomic or functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); (3) ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles and normal hormonal screens, and were matched for age and BMI with patients. MAIN OUTCOME MEASURE(S): Daily gonadotropin and steroid hormone levels across the menstrual cycle. RESULT(S): Basal FSH and LH levels in the early, middle and late follicular phases were increased significantly in the group with unexplained fertility compared with the normal controls. The mean (+/-SD) early follicular FSH levels were 7.0 +/- 0.57 mIU/mL in the unexplained-infertility group and 4.7 +/- 0.37 mIU/mL (conversion factor to SI units, 1.00) in the normal controls, respectively. There was no difference between groups over the periovulatory or luteal phase. Midluteal mean (+/-SD) P levels were lower in the unexplained-infertility group than in the normal controls (13.7 +/- 1.6 versus 24.0 +/- 3.2 ng/mL [conversion factor to SI units, 3.180]). Mean E2 concentrations were elevated in the group with unexplained infertility versus normal controls in the early through the late follicular phase but reached significance only in the midfollicular phase. Mean prolactin levels were elevated consistently across the menstrual cycle in the unexplained-infertility group compared with those in normal controls but reached significance only in the early and late follicular and midluteal phases of the cycle. Cortisol concentrations were similar between the two groups. CONCLUSION(S): These data indicate that there are subtle alterations in various hormones measured across the menstrual cycle in women with unexplained infertility compared with those in normal controls, suggesting a diminished ovarian reserve.

Adult↗

Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan.

OBJECTIVE: To evaluate the luteal phase in women with rigorously defined unexplained infertility. DESIGN: Prospective study. SETTING: National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months duration, with no male factor, anatomic-functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); [3] ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles, normal hormonal screen, and were matched for age and BMI to patients. MAIN OUTCOME MEASURE(S): Pattern of follicular growth rate and luteal phase hormonal profile. RESULT(S): Women with unexplained infertility did not differ in menstrual cycle characteristics, follicular growth rate or mean preovulatory follicle diameter, or endometrial biopsy dating. The mean levels of P tended to be lower in the unexplained infertility group throughout the luteal phase, but only the midluteal interval reached statistical significance. Luteal phase mean integrated P or urinary PDG levels of unexplained infertility women did not differ from those of fertile controls. The ratio of integrated E2:P also was significantly greater in women with unexplained infertility than in fertile controls. CONCLUSION(S): Women with rigorously defined unexplained infertility have subtle hormonal anomalies during the luteal phase when compared with fertile controls.

Adult↗

The first finding of antibodies to Encephalitozoon cuniculi in cows in Slovakia.

The presence of antibodies against Encephalitozoon cuniculi in cows was observed by the method of indirect immunofluorescence (IFAT). The animals reacting at the titre 1:64 and more were considered positive. Of the total number of 55 sera examined, 20 were positive at the titre 1:64, from which four were positive at the titre 1:256 also. Our results indicate that it is very important to carry out screening examinations in large-scale breeding of cattle due to the persistent high percentage of bovine abortions and disorders in the reproductive cycle of unknown etiology.

Abortion, Veterinary↗

Rationale for treatment of endometritis in the dairy cow.

Endometritis is an inflammation of the uterine lining that is commonly initiated at parturition. The degree of its effect on fertility varies with the severity of the inflammation, the time required for resolution of endometrial lesions, and the extent of permanent changes that impair endometrial gland functions and/or alter the uterine and/or oviductal environment. The primary nonspecific organisms associated with endometrial pathology are Corynebacterium pyogenes and the gram-negative anaerobes. The majority of postpartum dairy cows have some degree of endometritis but resolve it by 40 to 50 days post partum. Cows with certain periparturient disorders involving the reproductive tract and/or a defective host immune mechanism may acquire persistent infections that impair subsequent fertility. Not all infertile cows or all cows with positive uterine cultures have endometritis. Cows recovering from C. pyogenes endometritis may require 1 month after clearance of the organism for fertility to be restored. These cows, as well as many cows with slightly delayed uterine involution at 30 days post partum, do not benefit from antimicrobial therapy. The effect of endometritis varies between herds. It is associated with prolongation of calving intervals that can vary from less than 2 weeks to 2 months or more. The cost of days open beyond 80 to 110 days post partum is currently estimated to be $2.00 to $2.25 per day. Evaluation of the bovine genital tract is best conducted by a rectal examination combined with a vaginal speculum examination. Cows selected for therapy for endometritis should meet the strict requirements of a grossly enlarged uterus and a severely abnormal uterine discharge. Induction of estrus is the treatment of choice whenever possible. When antimicrobial therapy is indicated, tetracycline is recommended for intrauterine use during the early postpartum period when mixed bacterial populations are present. Commonly used doses are 2 to 3 gm. For systemic signs of illness, systemic administration of penicillin has been recommended. Twice daily doses of 5000 to 10,000 IU of penicillin per kg may be necessary to maintain therapeutic blood concentrations. Systemic administration of an antimicrobial is necessary to achieve therapeutic concentrations in the oviducts, cervix, and vagina. With chronic endometritis due to C. pyogenes, intrauterine administration of 1 to 1.5 X 10(6) IU of procaine penicillin G has been recommended. Multiple daily treatments are desirable. Milk from treated cows should be tested for penicillin before it is added to bulk tank milk. It still is not clear whether antimicrobial therapy is cost effective.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Diagnosis and Treatment of the Causes of Chronic Pelvic Pain

Ten years of clinical evaluations of women with chronic pelvic pain resulted in concern that diagnostic laparoscopic surgery is performed too frequently in these patients. Of 500 women, the pain was due to urologic, myofascial, musculoskeletal, gastrointestinal, or psychologic causes in 30%, rather than to disorders of the reproductive organs. Laparoscopy would be inappropriate in these patients. By providing women with appropriate therapy of nongynecologic pain, those whose pain is due to gynecologic sources can be treated more appropriately. In approximately 70% of these latter patients, endometriosis is the primary finding. A paradigm for the diagnosis and the cost-effective treatment of women with chronic pelvic pain of gynecologic cause was developed.

Journal Article↗

Sole disorders in conventionally managed and organic dairy herds using different housing systems.

Records of claw trimmings were analysed in seven organic and six conventional Danish herds (a total of 974 cows). The housing systems represented were tie stall systems, loose housing system with slatted floor (one organic herd), and deep litter systems (deep straw bedding). Occurrence of sole disorders was analysed separately for cows in first lactation and for cows in later lactations. Three different responses (acute haemorrhage, sole ulcer in one leg and sole ulcer in two or more legs) were analysed using three binomial logistic regression analyses for each group. Herd analysed as a fixed effect was a strong risk factor for all kinds of sole ulcer. Lactation stage was a risk factor for acute haemorrhage in both groups of cows, and for sole ulcer in first parity cows. In general, there was a strong positive association between the period 61-120 d post partum and the presence of sole disorders. Breed was associated with acute haemorrhage in cows in second and later parities, and sole ulcer in one leg only in first parity cows in an interaction with lactation stage in both conditions. Danish Friesian cows were strongly associated with sole disorder, although the combination of lactation stage from 61 to 120 d post partum in cows of other dual purpose breeds was positively associated with the presence of sole ulcer in one leg only in first parity cows. The time of year for claw trimming was a risk factor for acute haemorrhage in first parity cows, with the period from December to January most strongly associated with acute haemorrhage. Previous disease treatment was a risk factor for sole ulcer in two or more legs in second and later parities. Udder related disorders and disorders other than reproductive problems were positively associated with the occurrence of sole ulcer. Body weight at calving was associated with acute haemorrhage in cows in second and subsequent parities. Body weight lower than the mean herd level by > 50 kg was negatively associated with acute haemorrhage.

Analysis of Variance↗