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PubMed2026

miRNA-mediated control of TLR-NLR interplay in the uterus: A hidden corner of recurrent pregnancy loss.

Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are crucial pattern recognition receptors that initiate inflammatory responses and immunological activation upon detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPS) in the female reproductive tract, thereby maintaining homeostasis and supporting pregnancy success. Their signaling pathways play a significant role in reproductive disorders by mediating the immune response to various pathogenic stimuli. Recurrent pregnancy loss (RPL), defined as the natural ending of two or more pregnancies before 24 weeks of gestation, approximately half of these patients remain idiopathic without precise prognostic, diagnostic, and therapeutic plans. Emerging data point that microRNAs are essential for immunological control in the female reproductive tract. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA and preventing translation into protein. miRNAs play a role in many biological processes, including the development and differentiation of trophoblasts, the activation and implantation of embryos, immune tolerance, and the receptivity of the endometrium during implantation. Given their capacity to regulate up to 30 % of the human genome, miRNAs offer a promising avenue for understanding the immunopathogenesis of pregnancy complications. Recent research has detected differential expression of specific miRNAs in reproductive system pathologies. This review focuses on microRNAs and their association with idiopathic recurrent miscarriage, a condition characterized by considerable heterogeneity. Future studies identifying the precise mechanisms linking miRNA-mediated immune dysregulation in RPL immunopathogenesis could open the way for novel personalized therapeutic and diagnostic strategies.

Female↗
PubMed1995

The role of estrogen in turtle sex determination and the effect of PCBs.

In the current model of vertebrate sex determination and sexual differentiation, gonadal sex is fixed at fertilization by specific chromosomes, a process known as genotypic sex determination (GSD). Only after the gonad is formed do hormones begin to exert an influence that modifies specific structures that eventually will differ the sexes. Many egg-laying reptiles do not exhibit GSD but rather depend on the temperature of the incubating egg to determine the gonadal sex of the offspring, a process termed temperature-dependent sex determination (TSD). Research on TSD indicates that sex determination in these species is fundamentally different in at least one way. Gonadal sex is not irrevocably set by the genetic composition inherited at fertilization but depends ultimately on which genes encoding for steroidogenic enzymes and hormone receptors are activated during the midtrimester of embryonic development by temperature. Incubation temperature modifies the activity as well as the temporal and spatial sequence of enzymes and hormone receptors such that sex-specific hormone milieus, created in the urogenital system of the developing embryo, determine gonad type. Estrogen is the physiologic equivalent of incubation temperature and the proximate cue that initiates female sex determination. There is increasing evidence that some polychlorinated biphenyl (PCB) compounds are capable of disrupting reproductive and endocrine function in fish, birds, and mammals, including humans. Reproductive disorders resulting from exposure to these xenobiotic compounds may include reductions in fertility, hatch rate in fish and birds, and viability of offspring, as well as alterations in hormone levels or adult sexual behaviors, all of which have further implications, particularly in wildlife population dynamics. Research on the mechanism through which these compounds may be acting to alter reproductive function indicates estrogenic activity, by which the compounds may be altering sexual differentiation. In TSD turtles, the estrogenic effect of some PCBs reverses gonadal sex in individuals incubating at an otherwise male-producing temperature. Furthermore, certain PCBs are synergistic in their effect at very low concentrations.

Animals↗
PubMed2025

Nongenomic Stimulatory Effect of T3 on Calcium Dynamics in GnRH Neurons via Integrin αVβ3.

Many clinical studies have identified correlations between thyroid dysfunction and reproductive issues, yet the underlying mechanisms behind this interaction remain poorly understood. In this study, we investigated the effect of triiodothyronine (T3) on the activity of gonadotropin-releasing hormone (GnRH) neurons, a key regulator of the central reproductive axis. Dual labeling confirmed that GnRH neurons express thyroid receptor (TR)α and integrin αVβ3 receptors mediating genomic and nongenomic effects of thyroid hormones, respectively. Using calcium imaging in an ex vivo model, we show that T3 induces a rapid and sustained increase of calcium oscillation frequency in GnRH neurons. No change in response was detected after application of T4. The T3 stimulatory effect was not inhibited by a TR-specific antagonist (1-850) but was mimicked by membrane-impermeable T3-BSA, indicating a mechanism independent of nuclear TR signaling. In contrast, the blockade of membrane αVβ3 integrins (with cilengitide) prevented the T3-induced increase in GnRH neurons calcium peak oscillation frequency. Further investigation using modulators of intracellular calcium and calcium entry revealed that binding to αVβ3 integrin can induce distinct calcium responses depending on the ligand, with T3 triggering a complex response involving multiple channels and calcium sources, possibly with compensatory mechanisms. In sum, these results demonstrate for the first time a direct effect of thyroid hormones on GnRH neuronal activity, with T3 stimulating calcium oscillations through the nongenomic αVβ3 integrin pathway. Understanding this thyroid-reproductive axis interaction will help clarify the mechanisms linking thyroid dysfunction to reproductive disorders and pave the way for targeted therapeutic interventions.

Animals↗
PubMed1999

Insulin action in the polycystic ovary syndrome.

Research on insulin action in PCOS has been intensive after the identification of insulin resistance as a feature of the syndrome in 1980. It is now clear that PCOS is a metabolic as well as a reproductive disorder and an important cause of type 2 diabetes mellitus in women. The cellular and molecular mechanisms of insulin resistance in PCOS are distinct from those in other insulin resistance syndromes. Elucidating these mechanisms promises to provide considerable insight into insulin receptor signal specificity. Conversely, insulin resistance is now known to have an important role in the pathogenesis of the reproductive disturbances of PCOS. It is thought that one or several genetic defects may cause both the insulin resistance and reproductive abnormalities characteristic of PCOS.

Androgens↗
PubMed1984

Rates of diagnosis of six diseases of Holstein cows during 15-day and 21-day intervals.

The lactations of 3,172 Holstein dairy cows were divided into intervals of 15 and 21 days. The numbers of new diagnosis of metritis, cystic ovary, miscellaneous reproductive disorders, mastitis, left displaced abomasum, and milk fever in each interval were counted. The numbers of cows at risk in each interval were also counted. A cow was at risk if she was still milking, in the herd, and a diagnosis had not already been made for that condition in that lactation. A cow was also only at risk of a reproductive diagnosis if she was not pregnant. For each interval, the incidence rate of new diagnosis was calculated by dividing the number of new diagnoses by the number of cows at risk.

Abomasum↗
PubMed2006

Huge leiomyoma in a woman with Down syndrome: a case report.

BACKGROUND: For patients with Down syndrome, the reproductive period is becoming longer in relation to the increasing lifetime. Thus, the possibility of reproductive disorders is also increasing. CASE: A 37-year-old woman with trisomy 21 was hospitalized with uterine myomatosis, which was spreading to the umbilicus. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed, and estrogen replacement was given after surgery. CONCLUSION: The incidence of solid tumors in Down syndrome patients is extremely rare or nonexistent. This case calls attention to reproductive pathology in long-lived women with Down syndrome.

Adult↗
PubMed1985

Effects of fluoride on screech owl reproduction: teratological evaluation, growth, and blood chemistry in hatchlings.

The effects on reproduction in screech owls (Otus asio) of chronic dietary sodium fluoride administration at 0, 40, and 200 ppm were examined. Fluoride at 40 ppm resulted in a significantly smaller egg volume, while 200 ppm also resulted in lower egg weights and lengths. Day-one hatchlings in the 200 ppm group weighed almost 10% less than controls and had shorter crown-rump lengths. No gross abnormalities were apparent. Skeletal clearing and staining revealed significantly shorter tibiotarsus lengths in the 40 ppm and 200 ppm groups and a shorter radius-ulna length in the 200 ppm group. By 7 days of age, body weights and lengths did not differ from controls, but the tibiotarsus in the 200 ppm group remained shorter. No significant differences were detected in hematocrit, hemoglobin, plasma calcium or alkaline phosphatase. Plasma phosphorus levels were higher in the 40 ppm group than in controls. These results, in combination with the findings of Pattee et al. [25], revealed significant impairment of overall reproduction, suggesting that sodium fluoride could cause slight to moderate reproduction disorders in owls in fluoride-polluted areas.

Abnormalities, Drug-Induced↗
PubMed1995

Isolation of Coxiella burnetii from dairy cattle and ticks, and some characteristics of the isolates in Japan.

Coxiella burnetii was isolated from raw milk (36/214, 16.8%) and uterus swab samples (13/61, 21.3%) originating from dairy cattle with reproductive disorders, aborted bovine fetus samples (2/4, 50%), mammary gland samples (4/50, 8%) originating from healthy dairy cattle, and tick samples (4/15, 26.7%) originating from 2 pastures. Fifty-nine strains had various degrees of pathogenicity, high (8; 13.6%), moderate (28; 47.5%) and low (23; 39%), for guinea pigs. The results of isolation suggested a high prevalence of Coxiella infection in dairy cattle with reproductive problems in Japan. Twelve strains (7, 2 and 3 strains from cattle, ticks and humans, respectively) and the reference Nine Mile strain of phases I and II were propagated in both yolk sacs of embryonated hen eggs and Buffalo green monkey (BGM) cell cultures. Protein profiles of these strains were similar to those of the reference strain of phase I. Lipopolysaccharide (LPS) profiles of 12 strains were similar to those of the reference strain of phase I and different from those of the reference strain of phase II. The LPS profiles of 12 strains suggested that these strains are associated with an acute form of Q fever.

Acute Disease↗
PubMed2004

Prediction of the reproductive status of cattle on the basis of milk progesterone measures: model description.

Reproductive management, in particular timely oestrus detection, is important for profitable dairy production. The aim of this study was to develop a biological model to predict reproductive state on the basis of milk progesterone measures. A number of additional inputs were incorporated to make use of other known effectors of reproductive performance that are not reflected in progesterone levels. These are: days from calving, breed, parity, signs of behavioural oestrus, insemination dates, pregnancy determinations, energy status, body fat status, milk urea content and reproductive disorders associated with calving. A dynamic, deterministic model was developed. It is designed to run each time a new trigger input (progesterone, behavioural oestrus, inseminations, pregnancy determinations) occurs using the current and previous values and can run in the absence of the additional inputs. The milk progesterone values are smoothed using an extended Kalman filter before being processed in the biological component of the model. The model predicts the reproductive status of the cow, which can be one of three mutually exclusive states: postpartum anoestrus, oestrus cycling, and potentially pregnant. The other model outputs are all reproductive status specific with the exception of days to next sample (DNS), which is calculated in each model run regardless of reproductive status. DNS is designed to feedback to the sampling system so that the frequency of milk sampling (i.e. progesterone measurement) can be varied according to the predicted likelihood of a future reproductive event, such as onset of oestrus cycling. The other model outputs are: risk of prolonged postpartum anoestrus, risk and type of ovarian cyst, onset of oestrus, likelihood of a potential insemination succeeding, and likelihood of being pregnant (following oestrus). The model was evaluated using three simulated datasets consisting of a timeseries of progesterone values centred on each of the three reproductive statuses and including relevant additional information. Test runs were carried out on the full datasets and then on reduced data. The data reductions were made by using only those values that would have been available if the model days to next sample function was used to control sampling frequency. The sensitivity of the model to noise in the raw progesterone data was examined by adding 1, 2, or 3 residual standard deviations (1.85 ng/ml) random variation to the original data and evaluating model performance. The model was found to be able to readily identify and distinguish reproductive states. A reduction in sampling frequency to 36% of original sample resulted in an average increase in days to detection of oestrus of 0.36. The addition of 1 S.D. noise did not cause additional oestruses to be detected and all oestruses were correctly identified. However, when 2 or 3 S.D. noise were added, the model found on average 1.4 and 3 extra oestruses. It was concluded that reproductive status can be predicted from milk progesterone values using a biological model and that such a model is robust to reductions in sampling frequency number and to a doubling in the random variation in the raw progesterone values. It therefore has the potential to provide the basis for a useful reproductive management tool.

Anestrus↗
PubMed2006

A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70-5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98-6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95-6.17) and preterm birth (OR 1.75; 95% CI: 1.16-2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25-4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03-9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.

Birth Weight↗
PubMed1992

The effect of experimental infection with Corynebacterium pseudotuberculosis on reproduction in adult ewes.

Fifteen ewes were inoculated subcutaneously with 2 x 10(6) cells of Corynebacterium pseudotuberculosis seven days before mating, during the embryonic stage of gestation and during the fetal stage of gestation. The clinical signs, antibody response and the consequences of the infection on reproduction were studied. None of the ewes showed any change in general condition during pregnancy. The effects of experimental infection during gestation were evident after incubation periods that ranged from 25 to 140 days after inoculation and were dependent on the time of the inoculation in relation to the period of gestation. Ewes inoculated before gestation can resolve infection. Ewes inoculated during the embryonic stage were severely affected and some aborted. In others lambs were stillborn or, if born alive, infected. Ewes inoculated during the fetal stage of gestation did not show reproductive disorders although some remained chronically infected.

Abortion, Veterinary↗
PubMed2006

Steroid biosynthetic enzyme activities in leachate-exposed female perch (Perca fluviatilis) as biomarkers for endocrine disruption.

Studies have shown that adult female perch in a freshwater lake, Molnbyggen, Sweden, have a reproductive disorder caused by unidentified endocrine disrupting compounds (EDCs) leaching from a local refuse dump. The adverse effects include shallow open sores, low ratio of sexually mature individuals, low gonadosomatic index and low circulating levels of androgens. We hypothesised that the low androgen levels could be a result of impaired production and/or stimulated excretion of androgens by EDCs. From October 2000 to November 2001, at time-points important in the perch reproductive cycle, adult female perch were collected in Molnbyggen and in the reference lake, Djursjön. The activities of three key enzymes in androgen biosynthesis: 17alpha-hydroxylase (17OHlase), 17,20-lyase (lyase) and 17beta-hydroxysteroid dehydrogenase (17betaHSD) were determined in head kidney or ovary. The relationship between enzyme activities and plasma steroid concentrations was examined. Ovarian histopathology and the determination of brain aromatase activity were also included in the study. Similar 17OHlase, 17betaHSD and aromatase activities were found in Molnbyggen females and reference fish throughout the year. Head kidney 17OHlase showed a positive correlation to cortisol levels (r=0.754; p<0.001) but not to androgen levels. Molnbyggen females exhibited lower ovarian lyase activity during vitellogenesis than reference fish. Atretic oocytes were on most occasions more frequent in sexually immature than in sexually mature females. The results suggest that neither 17OHlase, 17betaHSD nor aromatase is the target for EDCs disrupting the androgen homeostasis of exposed female perch. Further investigation is needed to establish the role of decreased ovarian lyase activity in endocrine homeostasis, but the possibility of increased excretion of androgens should also be examined.

17-Hydroxysteroid Dehydrogenases↗
PubMed1991

Using reproductive effect markers to observe subclinical events, reduce misclassification, and explore mechanism.

Biological markers of effect, in general less widely available than exposure markers, do exist in the field of reproduction and increasingly are being used in epidemiological studies. Several such markers, including semen quality, menstrual hormones, early pregnancy loss, and placental abnormalities, are cited as examples. We argue the value of effect markers for detecting subclinical events that are critical for reproductive performance. Such studies can extend knowledge of the true frequency and determinates of reproductive disorders. A second portion of the paper deals with the role of effect markers in reducing disease misclassification. With a hypothetical early pregnancy study as a case in point, we illustrate the degree and direction of bias associated with several different protocols and encourage epidemiologists to weigh these quantitative considerations in deciding on study design. Finally, we discuss uses of biological markers to explore mechanisms, drawing on experience in an ongoing reproductive study that is testing a hypothetical pathway from maternal psychosocial stress to reduced fetal growth using urine catecholamine levels as a physiological marker of exposure and placental vascular abnormalities as a marker of effect.

Biomarkers↗
PubMed1991

Reproductive physiology: recent advances of clinical interest.

Several new developments in the field of reproductive endocrinology were published in 1990. Research on inhibin and related peptides appears to be particularly active and developments in this area may provide fundamental new information for the understanding and treatment of reproductive disorders. Exogenous androgens were found to be useful as a pharmacologic form of reversible male contraception. Interesting new data were also published regarding hypothalamic physiology, ovulation induction procedures, and the endocrinology of pregnancy.

Activins↗
PubMed1999

Molecular biology and reproduction.

Modern molecular biology has provided unique insights into the fundamental understanding of reproductive disorders and the detection of microorganisms. The remarkable advances in DNA diagnostics have been expedited by the development of polymerase chain reaction (PCR) and the ability to isolate DNA and RNA from many different sources such as blood, saliva, hair roots, microscopic slides, paraffin-embedded tissue sections, clinical swabs, and even cancellous bone. These technical advances have been bolstered by the development of an increasing number of effective screening techniques to scan genomic DNA for unknown point mutations. The continued development of technology will ultimately result in automated DNA (desoxyribonucleic acid) diagnosis for the practicing clinician. The continuing expansion of information concerning the human genome will place an increasing emphasis on bioinformatics and the use of computer software for analyzing DNA sequences. With the automation of DNA diagnosis and the use of small samples (500 nanograms), the direct examination of the DNA of a patient, fetus, or microorganism will emerge as a definitive means of establishing the presence of the specific genetic change that causes disease. A knowledge of the precise pathology at the molecular level has and will provide important insights into the biochemical basis for many human diseases. A firm knowledge of the DNA alterations in disease and expression patterns of specific genes will provide for more directed therapeutic strategies. The refinement of vector technology and nuclear transplantion techniques will provide the opportunity for directed gene therapy to the early human embryo. This presentation is designed to acquaint the reader with current techniques of testing at the DNA level, prototype mutations in the reproductive sciences, new concepts in the molecular mechanisms of disease that affect reproduction, and therapeutic opportunities for the future. It is hoped that future refinement of these techniques combined with the ability to maintain genetic modification of these cells with recombinant vector technology will provide a definitive therapy for many single gene disorders, such as sickle cell anemia and thalassaemia. It is truly the challenge of the next century to decipher how these legions of newly discovered genes work, and to create a molecular language that can extend across all organisms.

DNA↗
PubMed2003

Integrin receptors: the dynamic modulators of endometrial function.

Cell-cell and cell-extracellular matrix (ECM) interactions play a critical role in various developmental processes, including differentiation, proliferation and migration of cells. ECM proteins can influence cellular function thus creating a complex feedback mechanism. The adhesion of cells to each other, their ECM proteins and endothelial surfaces is mediated by a variety of membrane proteins collectively known as adhesion molecules. Adhesion molecules have been further divided into five subfamilies, the integrins, the selectins, the cadherins, the mucins and the immunoglobulin superfamily. Members of the integrin family of cell surface adhesion receptors are important mediators of cell-ECM contact. Integrin receptors are alpha beta heterodimers with a transmembrane segment, a short cytoplasmic domain and a large extracellular domain. The role of integrins in reproduction has been established. Several reasons make these molecules very attractive due to their constant involvement from egg to birth. They participate in sperm-egg interaction, fertilization, implantation and placentation in many species including humans. Integrins provide signals to individual cells essential for growth and development of different tissues. In the present review, we describe (1) the regulatory pathways for controlling expression of integrins in the endometrium, (2) various biomarkers and their role in endometrial function, (3) reproductive disorders in women related to aberrant integrin expression in the endometrium and (4) the functional significance of integrins available from gene knockout studies.

Animals↗
PubMed2004

Responses of domestic fowl to excess iodine: a review.

Typically, poultry diets contain 1-2 mg I/kg, but higher concentrations are sometimes used to enhance the I content of eggs. In addition to an increased deposition of I in the yolk, other often adverse responses occur, especially at exceptionally high concentrations. Excess I in grower diets can prevent sexual maturation in male and female fowl, and in layer diets will progressively reduce egg production until, by about 2500 mg I/kg diet, ovulation is inhibited and egg production ceases. Most I accumulates in the thyroid gland, and it is likely that the mechanism responsible for these reproductive disorders involves a modification of thyroid hormone activity. Simultaneous with the declining rate of lay, feed intake declines, egg weight and yolk-cholesterol contents decrease and body weight increases. Whereas fertility is unaffected in female breeders, hatch of fertile eggs is reduced, hatch time extended and embryonic mortality and dead-in-shell proportions increased. In contrast, male fertility is decreased because of an increased incidence of dead spermatozoa, although hatchability of eggs from normally fed hens is unaffected. All reproductive variables, together with feed intake and body weight, are normalised within about 7 d of returning to a diet with normal I levels. Excess I suppresses growth in meat-type chickens, but does not affect feed conversion efficiency. There are transient increases in plasma I and cholesterol concentration during excess I intake in all types of bird. The evidence for varying responses to different I sources is equivocal, but the consensus is that source is probably not important.

Animal Feed↗
PubMed2005

Effects of Wolbachia in the uzifly, Exorista sorbillans, a parasitoid of the silkworm, Bombyx mori.

The uzifly, Exorista sorbillans (Diptera: Tachinidae), a parasitoid of the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), harbours Wolbachia (Rickettsia) endosymbionts. Administration of 0.05 mg/ml oxytetracycline to the adult uziflies removed Wolbachia endosymbionts and resulted in different reproductive disorders, such as i) reduction in fecundity of uninfected females, ii) cytoplasmic incompatibility in crosses between infected males and uninfected females, iii) sterility in the crosses between both males and females from uninfected populations, and iv) sex-ratio distortion in uninfected females irrespective of the presence of Wolbachia in males. However, tetracycline treatment did not have much effect on longevity of the uzifly. These results suggest that the interaction of Wolbachia with its uzifly host is one of mutual symbiosis as it controls the reproductive physiology of its hosts.

Animals↗