Subsequent Reproductive Function Research Articles

Short and long-term menstrual, reproductive, and mental health outcomes after the intrauterine use of chitosan tamponade or the Bakri balloon for severe postpartum hemorrhage: an observational study

Objective This retrospective follow-up study analyzes the effect of intrauterine postpartum hemorrhage (PPH) therapy on menstrual, reproductive, and mental health outcomes. Methods All women who delivered at a university hospital between 2016 and 2021 with PPH and who needed intrauterine therapy were included. A questionnaire on well-being, menses, fertility, and reproductive outcomes was mailed to the patients. Those who did not reply were surveyed by telephone. Results A total of 214 women treated with chitosan-covered gauze (group A) and 46 women treated with a balloon tamponade (group B) were recruited, and their short-term courses were analyzed. For long-term follow-up, 71 women of group A (33%) and 21 women of group B (46%) could be reached. A total of 89% of group A and 95% of group B had regular menstrual bleeding in the most recent 12 months; 27% (group A) and 29% (group B) were trying to conceive again, and all of them did so successfully. There were 12 deliveries, 3 ongoing pregnancies, 3 miscarriages, and 2 terminations of pregnancies (TOP) in group A and 4 deliveries, 1 miscarriage, and 2 TOPs in group B. More than half of our study participants was sorted into grade II or III of the Impact of Events Scale, indicating they experienced clinical impacts in the form of psychological sequelae. One-quarter of patients had symptoms of post-traumatic stress disorder. Conclusion Chitosan gauze as well as balloon tamponade appear to have few adverse effects on subsequent menstrual and reproductive function. Women after PPH are at increased risk of long-term adverse psychological outcomes.

Single-cell transcriptome analysis of Bisphenol A exposure reveals the key roles of the testicular microenvironment in male reproduction.

Testicular development during juvenile is crucial for subsequent male reproductive function. However, it remains poorly understood about the contribution of the testis microenvironment to human germ cell maturation. Therefore, we systematically analyzed scRNA-seq transcriptome and found the dramatic changes in cell-type composition in human testis during puberty. Then we constructed cell-cell communication networks between germ cells and somatic cells in the juvenile testis, which may be achieved via immune-related pathways. Our results showed that maturation-promoting factors are the switches of the Sertoli cells that drive sperm maturation. Furthermore, we found that Bisphenol A(BPA) enhanced the maturation and growth of germ cells through the Sertoli cell's secretory protein. Finally, our results indicate Bisphenol A would lead to the dysregulation of secreted protein expression in Sertoli cells during spermatogenesis, which in turn has direct cytotoxicity to Sertoli cells. Bisphenol A is one of the underlying causes of non-obstructive azoospermia (NOA). In summary, our results reveal the reproductive toxicity and molecular mechanism of Bisphenol A in Sertoli cells and male reproduction. Provide a reference for the toxicity of Bisphenol A to human reproduction.

Establishment of immortalised cell lines derived from female Shiba goat KNDy and GnRH neurones.

Kisspeptin plays a critical role in governing gonadotrophin-releasing hormone (GnRH)/gonadotrophin secretion and subsequent reproductive function in mammals. The hypothalamic arcuate nucleus (ARC) kisspeptin neurones, which co-express neurokinin B (NKB) and dynorphin A (Dyn) and are referred to as KNDy neurones, are considered to be involved in GnRH generation. The present study aimed to establish cell lines derived from goat KNDy and GnRH neurones. Primary-cultured cells of female Shiba goat foetal hypothalamic ARC and preoptic area (POA) tissues were immortalised with the infection of lentivirus containing the simian virus 40 large T-antigen gene. Clones of the immortalised cells were selected by the gene expression of a neuronal marker, and then the neurone-derived cell clones were further selected by the gene expression of KNDy or GnRH neurone markers. As a result, we obtained a KNDy neurone cell line (GA28) from the ARC, as well as two GnRH neurone cell lines (GP11 and GP31) from the POA. Immunocytochemistry revealed the expression of kisspeptin, NKB and Dyn in GA28 cells, as well as GnRH in GP11 and GP31 cells. GnRH secretion from GP11 and GP31 cells into the media was confirmed by an enzyme immunoassay. Moreover, kisspeptin challenge increased intracellular Ca2+ levels in subsets of both GP11 and GP31 cells. Kisspeptin mRNA expression in GA28 cells, which expressed the oestrogen receptor alpha gene, was significantly reduced by 17β-oestradiol treatment. Furthermore, the transcriptional core promoter and repressive regions of the goat NKB gene were detected using GA28 cells. In conclusion, we have established goat KNDy and GnRH neurone cell lines that could be used to analyse molecular and cellular mechanisms regulating KNDy and GnRH neurones in vitro, facilitating the clarification of reproductive neuroendocrine mechanisms in ruminants.

Myoma pseudocapsule - a biological and surgical structure to respect during myomectomy

Uterine fibroids affect almost one in two patients, causing many pelvic problems and requiring pharmacologic and surgical treatment. For many years, the importance of the fibroid was emphasized as uterine pathology, without focusing on the complex myometrial biology peripheral to fibroid. Moreover, the traditional surgical technique in fibroid removal has not been investigated for years. In recent years, on the contrary, morphological, neuroendocrine and anatomical studies have demonstrated the importance of a biological and surgical structure surrounding myoma, rich in neurotransmitters and neurofibres, the myoma pseudocapsule. This structure is formed in the womb peripheral to fibroid onset, it separates the fibroid from the myometrium and acts as a tissue regenerator after the removal of the fibroid from the uterus. The translation of scientific research on pseudocapsules into surgical practice has allowed us to identify new techniques of myomectomy, removing the myoma inside the pseudocapsule and promoting the pseudocapsules sparing surgery. All this to favor the subsequent biological process of uterine scarring and healing, by activating the neurotransmitters and neurofibres present in the myometrial fovea. The correct healing after fibroid removal restores the uterine anatomy, with a positive impact on subsequent reproductive function, reducing problems related to the muscle scar.

Postpartum Hemorrhage: Use of Bakri Balloon During Cesarean Delivery, a Case Report and Review

The American College of Obstetricians and Gynecologists recently revised the definition of postpartum hemorrhage (PPH) to a cumulative blood loss of >= 1,000 mL (or) blood loss associated with signs or symptoms of hypovolemia within 24 h of the birth process. PPH is one leading cause of maternal mortality across the world. Prompt identification of the risk factors is proven to be helpful in earlier detection of PPH and is critical in preventing severe complications and related maternal morbidity and mortality. In this case report, we discuss a 29-year-old patient who had PPH at the time of cesarean delivery. This was effectively controlled by placement of an intraoperative Bakri balloon. The purpose of this review was to discuss and describe the indications and technique of Bakri balloon at the time of cesarean delivery complicated by PPH. Bakri balloon tamponade is usually indicated as a second-line treatment for severe PPH only when initial trials of bimanual compression of the uterus and uterotonic drugs fail to control bleeding. This appears to have minimal adverse effects on subsequent menstrual and reproductive function when intrauterine balloon tamponade is used for the management of severe PPH. Early use of intrauterine balloon tamponade is a way of effectively limiting ongoing uterine blood loss while initiating other measures, and can be readily implemented by providers with minimal training. Bakri balloon tamponade can be a life-saving intervention at the time of PPH and can reduce the need for a hysterectomy. J Clin Gynecol Obstet. 2019;8(2):57-61 doi: https://doi.org/10.14740/jcgo556

Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data.

BACKGROUNDOverall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance.OBJECTIVE AND RATIONALEThe objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis.SEARCH METHODSFor identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. s were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches.OUTCOMESA total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues.WIDER IMPLICATIONSDirect experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal–human differences in susceptibility.

Menstrual and reproductive outcomes after use of balloon tamponade for severe postpartum hemorrhage

BackgroundThe use of intrauterine balloon tamponade to manage postpartum hemorrhage is increasing. However, there is lack of studies on the menstrual and reproductive outcomes after such treatment. The purpose of this study is to explore the menstrual and reproductive outcomes for patients who had been managed by intrauterine balloon tamponade for severe postpartum hemorrhage in her index pregnancy.MethodsAll patients who had delivered in United Christian Hospital from January 2011 to June 2016 with severe postpartum hemorrhage (PPH) (blood loss> = 1 L) were identified by the labour ward delivery registry and a comprehensive obstetric database. Patients who had intrauterine balloon tamponade inserted were compared with those managed solely by uterotonic agents as controls. Patients who had hysterectomy or additional procedures performed, such as compression sutures or uterine artery embolization were excluded from both groups. A questionnaire on menses, fertility and reproductive outcomes was mailed to both groups of patients. Those that had not replied within 4 weeks would receive a telephone survey.ResultsA total of 39 patients in the balloon tamponade group and 161 patients in the control group were recruited, which represented 87.0% of all eligible patients within the study period. The median follow up period was 45 months. All patients in the balloon tamponade group had return of menses after delivery. The majority of the patients (87.2%) in the balloon tamponade group had normal menstrual patterns in the 12 months after the index delivery as well as in the most recent 12 months. After excluding the patients with contraception, the subsequent pregnancy rate was 42.9% (9/21) in the balloon tamponade group compared to 45.9% (28/61) in the control group (p = 0.81). Among the 9 subsequent pregnancies in the balloon tamponade group, there were two miscarriages, one scar pregnancy, one induced abortion, while the remaining five were normal pregnancies with full term deliveries without intrauterine growth restriction. The majority of patients replied that they were satisfied with using Bakri balloon for PPH management in their index pregnancy.ConclusionsIntrauterine balloon tamponade for the management of severe PPH appeared to pose little adverse effects on subsequent menstrual and reproductive function.

Mini-Puberty and Growth.

* Abbreviation: IGF-1 — : insulinlike growth factor-1 Within the first few months of life, the human infant experiences a transient activation of the hypothalamo-pituitary-gonadal axis. First described in the 1970s, after the development of assay methodology sufficiently sensitive to detect low levels of hormones in blood,1 this process has been described as a “mini-puberty.” Its purpose remains unclear, but is most commonly thought to be an important developmental event related to subsequent reproductive function.2,3 Mini-puberty occurs in both sexes, with an increase in testosterone in boys and increase in both estradiol and testosterone in girls (testosterone concentrations in girls are ∼30% lower than those in boys at peak). Resultant effects on the reproductive organs include testicular, penile, and prostate growth in boys, uterine and breast enlargement in girls, and sebaceous gland and acne development in both sexes. Effects of this early activation of the hypothalamo-pituitary-gonadal axis are not confined to the reproductive organs, however. Recent evidence suggests that the androgen exposure of mini-puberty also predicts later sex-typed behavior.4,5 In this issue of Pediatrics , Kiviranti et al6 describe yet another effect of this neonatal androgen … Address correspondence to Kenneth C. Copeland, MD, 1200 N. Children’s Ave, Oklahoma University Physicians Building, Ste 4500, Oklahoma City, OK 73104. E-mail: kenneth-copeland{at}ouhsc.edu

Effect of Surgery for Endometrioma on Ovarian Function: A Different Point of View

Recent evidence in the literature suggests that surgical excision of the endometrioma wall may reduce ovarian reserve, which may have a negative effect on subsequent reproductive function. However, because of inconsistent results and methodologic flaws of anti-müllerian hormone (AMH) as a marker of ovarian reserve, antral follicle count may be a more accurate noninvasive marker than AMH. Evaluating ovarian reserve using antral follicle count rather than AMH may yield different conclusions insofar as postsurgical damage to the ovary. Surgery should be performed only by experienced surgeons, and the stripping technique currently is still the only one supported by strong scientific evidence. The dual function of surgery, that is, to improve fertility and reduce pain, cannot be minimized or undervalued.

Prenatal malnutrition and subsequent foetal loss risk: Evidence from the 1959-1961 Chinese famine

AbstractBACKGROUNDScientists disagree on whether prenatal malnutrition has long-term influences on women's reproductive function, and empirical evidence of such long -term effects remains limited and inconsistent.METHODSUsing the retrospective pregnancy history of 12,567 Chinese women collected in a nationally representative sample survey in 2001, this study conducted difference-in-differences analyses to investigate the relationship between prenatal exposure to the 1959-1961 Great Leap Forward Famine in China and the subsequent risk of involuntary foetal loss, including miscarriage and stillbirth, and how this relationship changes between the rural and urban populations.RESULTSPrenatal exposure to the Great Leap Forward Famine had no long-term effect on women's risk of miscarriage. Such an exposure increased the risk of stillbirth among urban women but not among rural women.CONCLUSIONSThe results support the foetal origins hypothesis. The significant urban-rural difference in the effect of prenatal famine exposure on stillbirth suggests the presence of a long- term negative foetal origins effect and a strong selection effect caused by famine-induced population attrition.(ProQuest: ... denotes formulae omitted.)1. IntroductionScientists disagree on whether prenatal malnutrition has long-term influences on subsequent reproductive outcomes. On the one hand, the 'foetal origins' hypothesis and its straightforward extensions predict that prenatal malnutrition has a long-term negative influence on the female reproductive system by affecting the in utero development of the female foetus' organs that are responsible for the production and regulation of reproductive hormones (Drake and Walker 2004; Gardner, Ozanne, and Sinclair 2009; Lumey and Stein 1997; Lummaa 2003). On the other hand, based on the evolutionary life-history regulation theory, if prenatal malnutrition is associated with impaired health later in life, as predicted by the foetal origins hypothesis, an enhanced reproductive function is likely to present as a life-history compensation (Bateson et al. 2004; Painter et al. 2008). Both arguments are based on sound scientific theories; therefore the final adjudication depends on which argument is better supported by empirical evidence. Given the rampant poverty and malnutrition and high prevalence of involuntary foetal loss in many developing countries, testing the relationship between prenatal malnutrition and subsequent involuntary foetal loss risk is not only of important scientific value but also of significant policy relevance.Due to the legal and ethical restrictions on the use of human subjects in scientific research, empirical evidence on the relationship between prenatal malnutrition and subsequent reproductive function has mainly been derived from observational studies. A number of such studies showed that women's prenatal conditions, as measured by their birth weight, are negatively associated with their subsequent risk of foetal loss and preterm birth, and positively associated with babies' birth weight and chance of survival (Emanuel et al. 1992; Hackman et al. 1983; Klebanoff, Meirik, and Berendes 1989; Little 1987; Sanderson, Emanuel, and Holt 1995; Skjaerven, Wilcox, and Magnus 1997). However, due to the weaknesses of observational design, the causal nature of these findings remains unclear. More specifically, the observed association between women's birth weight and their subsequent reproductive outcomes may be the result of the causal mechanism articulated by the foetal origins hypothesis or the result of inadequate control of the common determinants of both women's birth weight and their reproductive outcomes that cannot be directly observed (Clarke 2005; Murnane and Willett 2010).Famine provides an 'experiment-like' opportunity to address this important question. Similar to a randomised experiment, the assignment of the famine 'treatment' condition (i. …

Physiology and Treatment of Retained Fetal Membranes in Cattle

Retained fetal membranes (RFM) in cattle have adverse effects on fertility and production. Understanding the pathophysiology and causes of RFM is important for managing this disease. The hormonal processes that lead to normal placental separation are multifactorial and begin before parturition. A variety of risk factors, including early or induced parturition, dystocia, hormonal imbalances, and immunosuppression, can interrupt these normal processes and result in retention of the placenta. Current research does not support the efficacy of many commonly practiced treatments for RFM. Systemic administration of antibiotics can be beneficial for treating metritis after RFM, but antibiotic administration has not been shown to significantly improve future reproduction in cows with RFM. Collagenase injected into the umbilical arteries of retained placentas specifically targets the lack of placentome proteolysis and might enhance placental release. However, such therapy is costly and its benefits in terms of improving subsequent reproductive function have not been evaluated.

Testicular germ cell development in relation to 5α-Androstenone levels in pubertal entire male pigs

Androstenone is a 16-androstene steroid pheromone produced in the Leydig cells in the testis, and considered to be one of the major compounds responsible for boar taint. In entire male pigs, progress of sexual maturation has been related to an increase in androstenone levels in fat. Onset of puberty and subsequent reproductive function involves genetic factors affected by the internal and external environment. In this study entire male cross-bred pigs were housed under two different light regimens in order to manipulate the onset of puberty. DNA flow cytometry (FCM) was used to study spermatogenesis and monitor the proportions of haploid (1n), diploid (2n), and tetraploid (4n) testicular cells, with conventional histological evaluation used as the reference technique. Agreement between these two methods was found to be good. The best fit model explained 34% of the variation in the androstenone concentrations. Sexual maturation in boars of 125-146 days of age, as assessed by DNA FCM, was not significantly associated with the variation in androstenone concentrations in adipose tissue when various independent variables (breed, age, light strategy, skatole concentrations in fat, and length of the bulbourethralis glands) were included in this model. These findings support the suggestion that selection against androstenone may be an option in the breeding of entire male pigs.

Origin and Ontogeny of Mammalian Ovarian Neurons

Mammalian ovaries contain sympathetic neurons expressing the low affinity neurotropin receptor (p75NTR). To date neither the role these neurons might play in ovarian physiology nor their embryological origin is known. Immunohistochemistry was used to detect postnatal changes in distribution and number of both p75NTR-positive and tyrosine hydroxylase-positive neurons in rhesus monkey ovaries. Pig fetuses were used to map the pathway of ovarian neuronal migration during embryonic development. Antiserum to p75NTR revealed the presence of isolated neurons and neurons clustered into ganglia in 2-month-old monkey ovaries. After 8 months, the neurons exhibited well-developed processes, and other than being more extensively interlaced, the localization and morphology did not change after 2 yr of age. Total number of p75NTR-positive neurons present decreased gradually between 2 months and 12 yr of age and declined markedly with reproductive aging. Conversely, the subpopulation of neurons immunoreactive to anti-tyrosine hydroxylase increased significantly at puberty and then declined with the loss of reproductive capacity. By d 21 of fetal life in the pig, p75NTR neurons had migrated medially from the neural crest to form the paraaortic autonomic ganglia. Some neurons migrated ventrally from the ganglia and then continued ventrolaterally to enter the genital ridge. By d 27, neurons had entered the developing ovary, and by d 35, the migration was complete with neurons demonstrating immunoreactivity to NeuN, a neuron-specific marker. Results demonstrate that p75NTR-expressing ovarian neurons originate from the neural crest and that a catecholaminergic subset is associated with pubertal maturation of the ovary and subsequent reproductive function.

A medical management of interstitial ectopic pregnancy: A 5‐year clinical study

Medical treatment of the rare interstitial ectopic pregnancy with methotrexate has been considered an alternative to surgical resection. To determine the treatment success rate with a single-dose intravenous methotrexate/folinic acid regimen and to identify predictors of treatment outcome. A 5-year audit (April 2000-August 2005) was carried out, collecting clinical imaging data and serum beta-human chorionic gonadotrophin (beta-hCG). Time taken for complete beta-hCG resolution was recorded, and a negative beta-hCG result was used as an endpoint of successful outcome. Of the 13 cases, two required urgent surgery for rupture on presentation. In the remaining 11 cases, intravenous methotrexate (300 mg) was used, with oral folinic acid rescue (15 mg x 4 doses). There were no side-effects. Complete beta-hCG resolution was achieved in 10 of the 11 medically treated cases (91% success rate), requiring 21-129 days. Successful outcome was seen with initial beta-hCG level as high as 106 634 IU/L and gestation sac as large as 6 cm and a live fetus. The methotrexate/folinic acid regimen used as a one-dose treatment is safe and effective for unruptured interstitial pregnancy, with no side-effects and the advantage of avoiding invasive surgery. Subsequent tubal patency and reproductive function are yet to be ascertained.

Low temperatures during early development influence subsequent maternal and reproductive function in adult female mice

Challenging conditions early in development can have enduring effects into adulthood. The effects of low temperatures were examined on subsequent sex-specific morphology (anogenital distance [AGD]), maternal care, and reproductive performance in adult female mice. Dams (F 0) were maintained either in (1) standard laboratory room temperatures (21 ± 2 °C) or (2) low temperatures (10 ± 2 °C) throughout gestation. Their progeny (F 1) either remained in the temperature condition in which they were conceived or were switched to the other temperature condition at 2 days of age until weaning. Reproductive performance and maternal behaviors were assessed in adulthood. F 0 dams that were maintained in low temperatures bore larger litters as compared to F 0 animals housed in standard temperatures throughout their pregnancy. In contrast, mean litter size was reduced for all groups of F 1 females that experienced low temperatures. Infant mortality was elevated in litters of F 1 females that were exposed to low temperatures both before and after birth. Prenatal exposure to low temperatures was associated with reduced responsiveness towards the nursing young and decreased maternal aggression in F 1 animals. Prenatally treated F 1 females had longer, male-like AGDs on Day 2 following birth compared to animals not subjected to experimental manipulations. Our results indicate that exposure to low temperatures during early development impairs reproductive function and is associated with important fitness costs as evidenced by reduced offspring survival. Our findings also suggest that chronic low temperatures experienced only after birth may have less deleterious effects than exposure to a combination of pre- and postnatal or prenatal treatments alone.

Childhood exposure to the 1944–1945 Dutch famine and subsequent female reproductive function

Childhood caloric restriction may lead to permanent changes in the hypothalamo-pituitary-gonadal axis, which could lead to impaired female reproductive ability. We assessed the effect of childhood exposure to the 1944-1945 Dutch famine on subsequent female reproductive function. This was a population-based cohort study in Utrecht, The Netherlands. Between 1983 and 1985, 6030 women born between 1932-1941 were classified by questionnaire according to their famine exposure experiences. Dates of marriage, first and second childbirth, and information on a medical reason for having no children or fewer children than wanted were available from questionnaires, as well as ages and type of menopause. Severe famine exposure during childhood significantly decreased chances of first and second childbirth at any given time after marriage or first childbirth [adjusted hazard ratios (HR) 0.86, 95% confidence interval (CI) 0.76-0.96; and HR 0.87, 95% CI 0.78-0.97, respectively). Risk of a medical reason for having no or fewer children than wanted was increased in the severely exposed (odds ratio 1.88; 95% CI 1.29-2.74), as was the risk of a surgical menopause (HR 1.53; 95% CI 1.27-1.84). Our findings support the presence of longstanding modest effects of childhood famine exposure on reproductive function in women.

Effects of endocrine disrupting compounds on the pathology and oestrogen receptor α and β distribution in the uterus and cervix of ewe lambs

A number of chemicals have been classed as endocrine disrupting compounds due to their ability to mimic the actions of endogenous hormones in vivo and in vitro. The objective of this experiment was to determine the pathological changes and oestrogen receptor (ER) distribution in the cervix and uterus of prepubertal ovariectomised ewe lambs following exposure to a range of compounds with a predominantly oestrogenic effect. Lambs were exposed to diethylstilbestrol (0.175 mg/kg biweekly), bisphenol-A (3.5 mg/kg biweekly) or octylphenol (3.5 mg/kg biweekly) for 6 weeks. Following sacrifice, uterine and cervical tissue pathology was assessed. The endometrial and myometrial areas were quantified and the distribution of ERα and ERβ assessed by immunohistochemistry. No differences were observed between control and octylphenol-exposed lambs in uterine gross pathology and histopathology. Uteri from bisphenol-A- and diethylstilbestrol-exposed lambs were heavier than both control and octylphenol-exposed lambs. In the bisphenol-A-exposed lambs, endometrial oedema accounted for a significant increase in the endometrial cross-sectional area over the other groups. Uteri from animals exposed to diethylstilbestrol showed variable pathology including oedema and cellular proliferation. Keratinisation of the cervical epithelium was observed in both bisphenol-A- and diethylstilbestrol-exposed lambs. Exposure to diethylstilbestrol and bisphenol-A was associated with a diffuse intracellular distribution of ERα and ERβ in the uterine endometrium. This was in addition to the strong cytoplasmic staining of uterine epithelial cells and nuclear staining of specific sub-epithelial cells observed in all groups. We conclude that a 6-week exposure of lambs to bisphenol-A and diethylstilbestrol altered the uterocervical environment and has the potential to disrupt subsequent reproductive function. Pathological changes could not be detected in the uterus or cervix of lambs exposed to octylphenol.

Organochlorines Affect the Major Androgenic Hormone, Testosterone, in Male Polar Bears (Ursus Maritimus) at Svalbard

Normal sexual development and subsequent reproductive function are dependent on appropriate testosterone production and action. The regulation of steroid hormones, including androgens, can be influenced by both biological and environmental factors, including environmental chemicals. Concentrations of organochlorines are considerably greater in Svalbard polar bears than in polar bears from other regions. Between 1995 and 1998, samples were collected from 121 male polar bears (Ursus maritimus) from the Svalbard area. In this study, testosterone concentration variations were described for male polar bears during different seasons and for all age groups. To study possible relationships between plasma testosterone concentrations and biological factors, such as age, axial girth, and extractable plasma fat, and organochlorine contaminants including hexachlorocyclohexanes, hexachlorobenzene, chlordanes, p,p′–DDE, and 16 individual polychlorinated biphenyl (PCB) congeners, identical statistical analyses were performed on the total population and a subsample of reproductively active adults. Of the biological factors, axial girth showed a significant positive relationship and percentage extractable fat and a significant negative relationship with the testosterone concentrations. Both the Σpesticides and ΣPCBs made significant negative contributions to the variation of the plasma testosterone concentration. The continuous presence of high concentrations of organochlorines in male polar bears throughout their life could possibly aggravate any reproductive toxicity that may have occurred during fetal and early postnatal development.

Overexpression of glutamic acid decarboxylase-67 (GAD-67) in gonadotropin-releasing hormone neurons disrupts migratory fate and female reproductive function in mice.

gamma-Aminobutyric acid (GABA) inhibits the embryonic migration of GnRH neurons and regulates hypothalamic GnRH release. A subset of GnRH neurons expresses GABA along their migratory route in the nasal compartment before entering the brain, suggesting that GABA produced by GnRH neurons may help regulate the migratory process. To examine this hypothesis and the possibility that persistence of GABA production by GnRH neurons may affect subsequent reproductive function, we generated transgenic mice in which the expression of glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA synthesis, is targeted to GnRH neurons under the control of the GnRH gene promoter. On embryonic d 15, when GnRH neurons are still migrating, the transgenic animals had more GnRH neurons in aberrant locations in the cerebral cortex and fewer neurons reaching the hypothalamic-preoptic region, whereas migration into the brain was not affected. Hypothalamic GnRH content in mutant mice was low during the first week of postnatal life, increasing to normal values during infantile development (second week after birth) in the presence of increased pulsatile GnRH release. Consistent with these changes, serum LH and FSH levels were also elevated. Gonadotropin release returned to normal values by the time steroid negative feedback became established (fourth week of life). Ovariectomy at this time demonstrated an enhanced gonadotropin response in transgenic animals. Although the onset of puberty, as assessed by the age at vaginal opening and first ovulation, was not affected in the mutant mice, estrous cyclicity and adult reproductive capacity were disrupted. Mutant mice had reduced litter sizes, increased time intervals between deliveries of litters, and a shorter reproductive life span. Thus, GABA produced within GnRH neurons does not delay GnRH neuronal migration, but instead serves as a developmental cue that increases the positional diversity of these neurons within the basal forebrain. In addition, the results suggest that the timely termination of GABA production within the GnRH neuronal network is a prerequisite for normal reproductive function. The possibility arises that similar abnormalities in GABA homeostasis may contribute to syndromes of hypothalamic amenorrhea/oligomenorrhea in humans.

Effect of diethylstilbestrol on reproductive function

Objective: To review the effects of in utero exposure to diethylstilbestrol (DES) on müllerian development and subsequent reproductive function. Design: The literature on DES and reproductive function was reviewed and summary data are presented. The studies were identified through the computerized MEDLINE database and a manual search of relevent bibliographies. Result(s): In utero exposure to DES resulted in reduced fertility and increased rates of ectopic pregnancy, spontaneous abortion, and preterm delivery. Conclusion(s): An understanding of the reproductive performance of women who were exposed to DES in utero is useful for counseling these patients regarding their risks and treatment options.