Ovarian Steroid Levels Research Articles

Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women

It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the age-related decline in immune function, known as immune senescence. Therefore, in this study, we determined the impact of menopause and estrogen therapy (ET) on lymphocyte subset frequency as well as the immune response to seasonal influenza vaccine in three different groups: 1) young adult women (regular menstrual cycles, not on hormonal contraception); 2) post-menopausal (at least 2 years) women who are not receiving any form of hormone therapy (HT) and 3) post-menopausal hysterectomized women receiving ET. Although the numbers of circulating CD4 and CD20 B cells were reduced in the post-menopausal group receiving ET, we also detected a better preservation of naïve B cells, decreased CD4 T cell inflammatory cytokine production, and slightly lower circulating levels of the pro-inflammatory cytokine IL-6. Following vaccination, young adult women generated more robust antibody and T cell responses than both post-menopausal groups. Despite similar vaccine responses between the two post-menopausal groups, we observed a direct correlation between plasma 17β estradiol (E2) levels and fold increase in IgG titers within the ET group. These findings suggest that ET affects immune homeostasis and that higher plasma E2 levels may enhance humoral responses in post-menopausal women.

Ovarian steroids involvement in maternal care in the native Thai hen (Gallus domesticus)

Maternal care in birds generally includes incubation, brooding and rearing behavior. The neuroendocrine regulation of such maternal behavior is not fully understood for many bird species. The aim of this study was to elucidate whether changes in the circulating levels of ovarian steroids might be associated with brooding behavior in the female native Thai chicken. Changes in the levels of ovarian steroids of rearing hens were compared with those of non-rearing ones. Plasma estradiol, progesterone, and testosterone levels were determined by enzyme-linked immunosorbent assays. The results revealed differences in circulating levels of ovarian steroids between hens rearing their chicks and those deprived of their young after hatching. The non-rearing hens had higher circulating estradiol, progesteron, and tertosterone levels than those of the rearing hens. These differences were significant during the first two weeks after hatching. The results of the present study demonstrate the inhibitory effect of brooding behavior on ovarian steroids in the native Thai chickens. Indeed, disruption of brooding behavior by removing the chicks from the hens increased circulating levels of ovarian steroids and reinitiated reproductive and egg laying activities.

Abstract T MP16: Impact of Circadian Clock Disruption on Infarct Volume in an Ischemic Stroke Model

Background: At perimenopause, women show increasing incidence of ischemic stroke and poor prognosis for recovery, suggesting that declining ovarian steroid levels alter the risk for neurovascular disease. Peripheral circadian clocks throughout the body may provide integral links between cycling levels of estrogen and neuroprotective responses. Circadian rhythm disruption may be a key factor coupling risk factors (ie, diabetes, obesity) to cardiovascular pathologies. Thus, the present study used an ischemic stroke model to determine whether environmental disruption of circadian rhythms in young adult female rats modulates estrous cyclicity and induces corresponding increases stroke volume and functional deficits similar to that observed in middle-aged females. Methods: Adult (5 mo) female rats were exposed for 8wks to either a fixed or shifted (12hr advance/5d) LD 12:12 cycle and then subjected to middle cerebral artery occlusion (MCAo). Pre and post sensorimotor testing was performed to assess functional deficits. Animals were terminated at 5d post MCAo. Brains processed for histological analysis of infarct volume. Before and after experimental manipulations, estrous cyclicity was assessed via vaginal smears in parallel groups of animals. Results: Circadian activity rhythms stably entrained to the fixed LD cycle but were severely disrupted in shifted LD rats. In contrast to the regular estrous cycles (~7d) in fixed LD animals, cyclicity was abolished and persistent estrous was evident in all shifted LD rats. Total infarct volume in shifted LD rats (0.47) was significantly increased (p<0.05) relative to that observed in fixed LD controls (0.27). Sensorimotor testing revealed a similar trend in which MCAo-induced functional deficits in shifted LD animals were greater than those in fixed LD rats. Conclusion: These results suggest that the loss of estrous cyclicity in young females due to circadian disruption exacerbates stroke outcomes, supporting the hypothesis that in females, middle-age may precipitate circadian disturbances that link reproductive aging to pathological changes in neuroprotective responses to injury. Supported by AHA 14GRNT18370013 to DE

Hormonal State Comparison (Progesterone, Estradiol, and Leptin) of Body Fat and Body Mass Indices in Mexican Women as a Risk Factor for Neonatal Physiologic Condition

Study ObjectiveDescribe the impact of teen pregnancy on later ovarian activity and metabolic hormones considering the concentration of current levels of ovarian steroids and leptin in a sample of Mexican females. DesignCross-sectional study in the maternity of the General Hospital of Atlacomulco and campus of the Autonomous University of the State of Mexico. Participants71women between the ages of 18 and 24, and 160 neonates seen between March 2010 and June 2012. Main Outcome MeasuresThe measurements obtained included anthropometric body composition (bioelectrical impedance), serum hormone quantification of ovarian steroids and leptin (immunoassays), and the Apgar scores, height, and weight in neonates. Statistical analysis included ANOVA, Student, and chi-square for P < .05. ResultsAdolescent mothers showed significantly lower concentrations of estradiol (P = .001) and progesterone (P = .001). However, higher levels of leptin in adolescent mothers were not statistically different compared with older mothers (P = .84). Also, leptin was correlated with all measures of adiposity. The mean birth weights (P = .001) and Apgar scores (P = .001) were lower in neonates of adolescent mothers than in neonates of adult mothers. There was no association between maternal age with the anthropometric variables studied. ConclusionsEarly reproduction represents a metabolic stress condition that modifies the long term ovarian activity and metabolic hormones, and impacts the morbidity-mortality of the mother and offspring in a later vital life cycle stage.

Estrous cycle fluctuations in sex and ingestive behavior are accentuated by exercise or cold ambient temperatures

This article is part of a Special Issue “Energy Balance”.In female Syrian hamsters (Mesocricetus auratus), low circulating levels of ovarian steroids are associated with increased food hoarding and decreased sexual motivation, but these effects are exaggerated in food-restricted females. To determine whether cold ambient temperature has the same effects as food restriction, groups of hamsters were fed ad libitum while they were housed at either 5°C or 22°C, and then tested for behavior for 90min on each day of the estrous cycle. In females housed at 22°C, high levels of sexual motivation and low levels of food hoarding were seen every day of the estrous cycle. In females housed at 5°C, high levels of sexual motivation were restricted to the periovulatory day. On the three nonestrous days, these females showed high levels of food hoarding, but not food intake. A separate cohort of females were provided with access to running wheels and housed at 22°C. They showed high levels of sexual motivation restricted to the periovulatory day, similar to the pattern of sexual motivation seen in cold-housed females. Unlike cold-housed females, those with running wheels showed low levels of food hoarding and high levels of food intake. Food restriction, cold housing, and access to wheels had no significant effect on plasma estradiol or progesterone concentrations, but significantly decreased plasma leptin concentrations. All three energetic challenges unmask estrous cycle fluctuations in sexual motivation that are obscured in laboratory conditions, i.e., isolation in a small cage with an overabundance of food.

Social stimulation and corticolimbic reactivity in premenstrual dysphoric disorder: a preliminary study.

BackgroundPremenstrual dysphoric disorder (PMDD), characterized by luteal phase-induced negative affect and loss of impulse control, often results in compromised social interactions. Although amygdala activation is generally linked to negative affect, increased amygdala reactivity to aversive stimuli in the luteal phase has not been consistently reported in PMDD. We tested the hypothesis that amygdala hyper-reactivity in PMDD is symptom specific, rather than generalized, and linked to socially relevant stimuli. Blood oxygenation level dependent signal changes during exposure to negative images with social and non-social content were evaluated in the mid-follicular and late luteal phase of the menstrual cycle. Fourteen women with PMDD and 13 healthy controls participated.ResultsWhen compared with healthy controls, women with PMDD in the luteal phase had enhanced reactivity to social stimuli compared to non-social stimuli in the amygdala and insula, but attenuated reactivity in the anterior cingulate cortex. Functional couplings between emotion processing and controlling areas were significantly different, being positive in women with PMDD and negative in healthy controls. Changes in progesterone levels in women with PMDD correlated positively with altered amygdala reactivity.ConclusionsSocially relevant aversive stimulation elicited enhanced activity in affective processing brain regions that were functionally coupled to compromised activity in cognitive control areas. Because increased reactivity correlated positively with alterations in ovarian steroid levels, data preliminary support the hypothesis that enhanced progesterone sensitivity in PMDD affects corticolimbic processing of social emotions.

Neonatally induced mild diabetes: influence on development, behavior and reproductive function of female Wistar rats

BackgroundNeonatal STZ treatment induces a state of mild hyperglycemia in adult rats that disrupts metabolism and maternal/fetal interactions. The aim of this study was investigate the effect of neonatal STZ treatment on the physical development, behavior, and reproductive function of female Wistar rats from infancy to adulthood.MethodsAt birth, litters were assigned either to a Control (subcutaneous (s.c.) citrate buffer, n = 10) or STZ group, (streptozotocin (STZ) - 100 mg/kg-sc, n = 6). Blood glucose levels were measured on postnatal days (PND) 35, 84 and 120. In Experiment 1 body weight, length and the appearance of developmental milestones such as eye and vaginal opening were monitored. To assess the relative contribution of the initial and long term effects of STZ treatment this group was subdivided based on blood glucose levels recorded on PND 120: STZ hyperglycemic (between 120 and 300 mg/dl) and STZ normoglycemic (under 120 mg/dl). Behavioral activity was assessed in an open field on PND 21 and 75. In Experiment 2 estrous cyclicity, sexual behavior and circulating gonadotropin, ovarian steroid, and insulin levels were compared between control and STZ-hyperglycemic rats. In all measures the litter was the experimental unit. Parametric data were analyzed using one-way or, where appropriate, two-way ANOVA and significant effects were investigated using Tukey’s post hoc test. Fisher’s exact test was employed when data did not satisfy the assumption of normality e.g. presence of urine and fecal boli on the open field between groups. Statistical significance was set at p < 0.05 for all data.ResultsAs expected neonatal STZ treatment caused hyperglycemia and hypoinsulinemia in adulthood. STZ-treated pups also showed a temporary reduction in growth rate that probably reflected the early loss of circulating insulin. Hyperglycemic rats also exhibited a reduction in locomotor and exploratory behavior in the open field. Mild hyperglycemia did not impair gonadotropin levels or estrous cylicity but ovarian steroid concentrations were altered.ConclusionsIn female Wistar rats, neonatal STZ treatment impairs growth in infancy and results in mild hyperglycemia/hypoinsulinemia in adulthood that is associated with changes in the response to a novel environment and altered ovarian steroid hormone levels.

Reshaping of T-lymphocyte compartment in adult prepubertaly ovariectomised rats: A putative role for progesterone deficiency

This study explores the role of ovarian hormones in the phenotypic shaping of peripheral T-cell pool over the reproductive lifespan of rats. For this purpose, 2-month-old prepubertally ovariectomised (Ox) rats, showing oestrogen and progesterone deficiency, and 11-month-old Ox rats, exhibiting only progesterone deficiency, were examined for thymus output, and cellularity and composition of major TCRαβ+ peripheral blood lymphocyte (PBL) and splenocyte subsets. Although ovariectomy increased thymic output in both 2- and 11-month-old rats, the count of both CD4+ and CD8+ PBLs and splenocytes increased only in the former. In the blood and spleen of 11-month-old Ox rats only the count of CD8+ cells increased. Although ovariectomy affected the total CD4+ count in none of the examined compartments from the 11-month-old rats, it increased CD4+FoxP3+ PBL and splenocyte relative proportions over those in the age-matched controls. The age-related differences in the cellularity and the major subset composition in Ox rats were linked to the differences in the ovarian steroid hormone levels registered in 2- and 11-month-old rats. The administration of progesterone to Ox rats during the seven days before the sacrificing confirmed contribution of this hormone deficiency to the ovariectomy-induced changes in the TCRαβ+ PBL and splenocyte pool from 11-month-old rats. The expansion of the CD8+ splenocyte subset in the 11-month-old Ox rats reflected increases in cellularity of memory and, particularly, naïve cells. This was due to greater thymic output of CD8+ cells and homeostatic proliferation than apoptosis in 11-month-old Ox rats when compared with age-matched sham-Ox control rats. The homeostatic changes within CD8+ splenocyte pool from 11-month-old Ox rats, most likely, reflected the enhanced splenic IL-7 and TGF-β mRNA expression. Overall, in adult female rats, circulating oestrogen and progesterone provide maintenance of T-cell counts, a diversity of T-cell repertoire, and the main T-cell subset composition in the periphery. Progesterone deficiency affects mainly the CD8+ lymphocyte compartment through increasing thymic CD8+ cell export and upsetting homeostatic regulation within the CD8+ splenocyte pool. These alterations were reversible through progesterone supplementation.

Premenstrual dysphoric disorder and prefrontal reactivity during anticipation of emotional stimuli

Premenstrual disorder (PMDD) affects around 5% of women in childbearing ages. An increased sensitivity in emotion processing areas of the brain to variations in ovarian steroid levels has been suggested as part of the pathophysiology in PMDD, but prior neuroimaging studies of emotion processing are yet inconclusive. Previous behavioral studies of women with PMDD have, however, reported enhanced luteal phase startle responsivity during emotional anticipation. Here we used functional magnetic resonance imaging (fMRI) to investigate central neural circuitry activity during anticipation of, and exposure to, emotional stimuli across the menstrual cycle in women with and without PMDD. As compared to healthy controls, women with PMDD displayed significantly enhanced reactivity in the prefrontal cortex during anticipation of, but not exposure to, negative emotional stimuli during the luteal phase. In PMDD patients, BOLD reactivity during anticipation or viewing of negative emotional stimuli was not dependent on absolute levels of estradiol or progesterone. However, progesterone levels were positively correlated with emotion-induced reactivity in the dorsolateral prefrontal cortex to positive emotional stimuli. These findings suggest that cortical emotional circuitry reactivity during anticipation is altered in PMDD during the luteal phase, which might be part of the pathophysiology behind the emotional symptoms or lack of emotional control reported by women with PMDD.

Hyperprolactinemia changes the sulfated glycosaminoglycan amount on the murine uterus during the estrous cycle

To evaluate the effects of hyperprolactinemia on the sulfated glycosaminoglycans (GAGs) of the murine uterus. Experimental research. University biochemistry laboratory. Eighty female mice were divided into two groups of 40 animals each and treated with 0.2 mL of saline solution (controls, Ctr) and 200 μg of metoclopramide (experimental, HPrl). Treatments lasted for 50 consecutive days. The animals were divided into four subgroups of 10 animals each per treatment (Ctr and HPrl) and sacrificed according to the phase of the estrous cycle. The uterine horns were removed for biochemical analyses, and blood samples were collected for hormone measurements. Induced hyperprolactinemia. To quantify the sulfated GAGs, and PRL and sex steroid levels. The endometrium during the estrus phase was significantly thicker in the HPrl animals than in the Ctr mice. The levels of chondroitin and dermatan sulfate were significantly increased in the HPrl group than in the Ctr group during all phases except metestrus. The amounts of heparan sulfate were lower during estrus and diestrus and higher in the metestrus phase in HPrl than in Ctr animals. Serum PRL levels were increased whereas the levels of E2 and P were decreased in all phases in the HPrl group than in the Ctr group. The hyperprolactinemia changed the amounts of uterine sulfated GAGs. Our data suggest that these changes may not be correlated with ovarian steroid levels.

Effects of Ovarian Hormones on Internal Circadian Organization in Rats1

The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker driving rhythms in endocrine physiology. Gonadal steroid hormones affect behavioral rhythms and clock gene expression. However, the impact of fluctuating ovarian steroid levels during the estrous cycle on internal circadian organization remains to be determined. Further, it is not known if steroid hormone depletion, as in menopause, affects the timing system. To determine the influence of estrous cycle stage and steroid depletion on circadian organization, we measured clock gene expression in the SCN and peripheral tissues from cycling and ovariectomized (OVX) period1-luciferase (per1-luc) transgenic rats. The estrous cycle had modest effects on mean phase and phase distribution of per1-luc expression in the SCN. Surprisingly, peak per1-luc expression in the SCN was widely distributed mainly at night, regardless of cycle stage, an effect eliminated by OVX. Treatment of SCN tissue explants with ovarian steroids did not significantly affect per1-luc expression, suggesting that brain regions outside the SCN mediate the phasic effects of steroids. Our data demonstrate that estrous cycle stage has tissue-dependent effects on the phase of per1-luc expression, phase synchrony among oscillators, and the phase relationship between some peripheral clocks and the light-dark cycle. They also reveal that steroid hormone depletion following OVX alters the timing system, suggesting that the decline in hormone levels, common during the transition to menopause, may be associated with irregular internal circadian organization. This effect on the timing system could contribute to the behavioral and physiological changes associated with this transition.

Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients, while their effects on major internal organs in females are not fully understood. We treated female mice with Bu/Cy, and examined the histopathology of major internal organs on Day 30 after the treatment. The results show that Bu/Cy treatment affected the ovaries most extensively, while it had less effect on the spleen, lungs, and kidneys, and no effect on the heart, liver, stomach, and pancreas. To better understand the effect of Bu/Cy on the ovaries, we counted follicles, and determined the levels of ovarian steroids. The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60. Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%, respectively. Thus, there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF). The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

Sex differences in object-in-place memory of adult rats.

Male rodents typically display an advantage over female conspecifics in tasks that assess memory for the identity or location of objects. However, the performance of female rodents on object recognition and object location tasks often is enhanced by elevated levels of ovarian steroids. The novel object-in-place task, combines elements of object recognition and object location tasks used to assess rodent object memory. Until now, only male rats have been tested on the object-in-place task, therefore, a study was conducted to compare the performance of males to females under different hormone conditions. Rats were given a sample phase to study the locations of four objects in an open field. After various delays, a test phase was administered with the locations of two objects reversed. Increased investigation of moved objects indicates memory for these objects and their original locations. Rats were able to discriminate moved from unmoved objects after a brief 5-min delay, regardless of biological sex or hormone status. However, gonadally intact males, but not diestrous females, were able to discriminate object locations after a 30-min delay. In contrast, ovariectomized females treated with estradiol and progesterone discriminated moved from unmoved objects after a 60-min delay while ovariectomized vehicle-treated females and gonadally intact males did not. Results indicate that female rats outperform males on a memory task that combines object recognition and location but only when circulating levels of the ovarian steroids, estradiol and progesterone, are elevated and only when memory is challenged by an extended retention interval.

ACTH and Cortisol Response to Dex/CRH Testing in Women with and without Premenstrual Dysphoria during GnRH Agonist-Induced Hypogonadism and Ovarian Steroid Replacement

During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC). Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC. We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic. Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated. Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-μg patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed. Plasma cortisol and ACTH levels were evaluated. HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [area under the curve (t(74) = 3.1; P < 0.01)] and urinary free cortisol (t(74) = 3.2; P < 0.01) and ACTH compared with hypogonadism [area under the curve (t(74) = 2.4; P < 0.05)]. HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.

Serum and Follicular Fluid Ghrelin Levels Negatively Reflect Human Oocyte Quality and In Vitro Embryo Development

Adverse outcomes from assisted reproductive techniques may be related in part to the effects of metabolic dysregulation in women undergoing these procedures on oocyte quality and embryo development. Among the various molecules linking metabolic dysfunction with reproductive outcomes is a peptide called ghrelin. It has been hypothesized that ghrelin affects steroidogenesis and ovarian cellular function and may mediate the relationship between metabolism and oocyte quality. Addition of ghrelin in vitro to mice preimplantation embryos in culture prevents embryonic development. Previous studies have suggested that the relationship of ghrelin with oocyte/embryonic development may be mediated by insulin, and that the negative impact of obesity, diabetes, insulin, and other metabolic dysfunction on antiretroviral therapy outcomes may be associated with intrafollicular and serum ghrelin levels. This prospective cohort study investigated the effect of serum and follicular fluid (FF) levels of ghrelin in women undergoing assisted reproduction on ovarian steroidogenesis, oocyte quality, and embryo development. The participants were 31 normal weight women undergoing in vitro fertilization at a university-based center for assisted reproduction. Patients with polycystic ovary syndrome, hypothalamic amenorrhea, or other endocrinopathies were excluded. Successful cleavage was defined as 6 cells or more by day 3 after fertilization. After an overnight fast, serum and FF were collected from preovulatory follicles of each participant (n = 81). Levels of ghrelin, insulin, and ovarian steroids (estradiol, testosterone, and progesterone) were measured. In vitro fertilization outcomes assessed included oocyte maturity and embryo development. FF ghrelin levels correlated significantly with serum levels and were 13% lower (range: 3%–24%). Serum ghrelin levels did not correlate with the body mass index or exogenous gonadotropins. Levels correlated negatively with the cleavage rate and number of viable cleavage stage embryos. Successfully cleaved embryos and those with viable morphology were 3 to 4 times more likely to come from follicles with lower levels of ghrelin than higher levels; the odds ratios were 3.67 (95% confidence interval [CI], 1.02–13.14) and 3.46 (95% CI, 1.01–11.81), respectively. Levels of FF ghrelin were negatively correlated with FF insulin and progesterone, and positively with estradiol. FF insulin levels were 52% higher (absolute difference,1.88; 95% CI,0.31–3.45] mIU/mL) in follicles with successfully cleaved embryos compared with those that were not. These findings suggest that FF ghrelin is not produced de novo in the ovary, but seems to be a serum transudate. FF ghrelin correlates with local steroidogenesis and expression of FF insulin. The effects of serum and FF ghrelin on oocyte/embryo development may be mediated by insulin.

Temperament and ovarian reproductive hormones in women: Evidence from a study during the entire menstrual cycle

Personality and temperament were hypothesized to function as important factors affecting life history strategies. Recent research has demonstrated the association between temperamental traits and reproduction in humans, however, the underlying mechanisms are still poorly understood.This study presents evidence for an association between temperamental traits and woman's fecundity, as indicated by levels of ovarian steroid hormones during the menstrual cycle. On a large sample of urban, reproductive age women (n=108) we demonstrated that activity, endurance and emotional reactivity are associated with levels of estrogen and with a pattern of change of progesterone levels. Women high in activity, high in endurance and low in emotional reactivity had up to twice as high estradiol levels and more favorable progesterone profiles as women low in activity, low in endurance and high in emotional reactivity. The temperamental traits we measured highly overlap with extraversion, neuroticism and negative emotionality that were reported to correlate with reproductive success. Our findings thus suggest a possible explanation for these relationships, linking personality and women's reproductive success through a hormonal pathway.

Neonatal Exposure to Bisphenol A Alters Rat Uterine Implantation-Associated Gene Expression and Reduces the Number of Implantation Sites

Endocrine disrupters have been associated with reproductive pathologies such as infertility and gynecological tumors. Using a rat model of early postnatal exposure to bisphenol A (BPA), we evaluated the long-term effects on 1) female reproductive performance, 2) uterine homeobox A10 (Hoxa10) and Hoxa10-target gene expression, and 3) ovarian steroid levels and uterine estrogen receptor α and progesterone (P) receptor expression. Newborn female rats received vehicle, BPA.05 (0.05 mg/kg · d), BPA20 (20 mg/kg · d), diethylstilbestrol.2 (0.2 μg/kg · d), or diethylstilbestrol 20 (20 μg/kg · d) on postnatal d 1, 3, 5, and 7. A significant decrease in the number of implantation sites was assessed in the xenoestrogen-exposed females. To address the molecular effects of postnatal xenoestrogen exposure on the pregnant uterus, we evaluated the expression of implantation-associated genes on d 5 of pregnancy (preimplantation uterus). All xenoestrogen-treated rats showed a lower expression of Hoxa10. In the same animals, two Hoxa10-downstream genes were misregulated in the uterus. β(3) Integrin, which is up-regulated by Hoxa10 in controls, was decreased, whereas empty spiracles homolog 2, which is down-regulated by Hoxa10, was increased. Furthermore a clear down-regulation of estrogen receptor α and P receptor expression was detected without changes in estradiol and P serum levels. The early exposure to BPA produced a lower number of implantation sites in association with a defective uterine environment during the preimplantation period. Alterations in the endocrine-regulated Hoxa10 gene pathways (steroid receptors--Hoxa10--β(3) integrin/empty spiracles homolog 2) could explain, at least in part, the BPA effects on the implantation process.

Influence of the estrous cycle on clock gene expression in reproductive tissues: Effects of fluctuating ovarian steroid hormone levels

Circadian rhythms in physiology and behavior are known to be influenced by the estrous cycle in female rodents. The clock genes responsible for the generation of circadian oscillations are widely expressed both within the central nervous system and peripheral tissues, including those that comprise the reproductive system. To address whether the estrous cycle affects rhythms of clock gene expression in peripheral tissues, we first examined rhythms of clock gene expression ( Per1, Per2, Bmal1) in reproductive (uterus, ovary) and non-reproductive (liver) tissues of cycling rats using quantitative real-time PCR ( in vivo) and luminescent recording methods to measure circadian rhythms of PER2 expression in tissue explant cultures from cycling PER2::LUCIFERASE (PER2::LUC) knockin mice ( ex vivo). We found significant estrous variations of clock gene expression in all three tissues in vivo, and in the uterus ex vivo. We also found that exogenous application of estrogen and progesterone altered rhythms of PER2::LUC expression in the uterus. In addition, we measured the effects of ovarian steroids on clock gene expression in a human breast cancer cell line (MCF-7 cells) as a model for endocrine cells that contain both the steroid hormone receptors and clock genes. We found that progesterone, but not estrogen, acutely up-regulated Per1, Per2, and Bmal1 expression in MCF-7 cells. Together, our findings demonstrate that the timing of the circadian clock in reproductive tissues is influenced by the estrous cycle and suggest that fluctuating steroid hormone levels may be responsible, in part, through direct effects on the timing of clock gene expression.

Ovarian Tissue Autologous Transplantation to the Upper Extremity for Girls Receiving Abdominal/Pelvic Radiation: 20-year Follow-up of Reproductive Endocrine Function

Objective Upper-extremity ovarian autologous transplantation was first used for girls undergoing abdominal/pelvic radiation therapy; long-term follow-up is provided. Design A case series. Setting Tertiary pediatric medical center. Patients Girls with Wilms tumor with planned abdominal/pelvic radiation therapy. Interventions Subjects 1, 2, and 3 (ages 5, 2, and 1 year) presented with a Wilms tumor and underwent surgical resection. Each patient underwent ovarian autotransplantation to move ovarian tissue out of the radiation field. Subjects 1 and 2 had thin slices from 1 ovary placed in the arm. Subject 3 had a free transfer of the entire ovary into an axilla. Follow-up was obtained for the subsequent 20-25 years for all 3 subjects. Outcome Measures Pubertal, menarcheal, and menstrual history, and hormonal serum levels. Results All subjects survived and experienced spontaneous pubertal development and menarche. Data were available for follow-up for 20-25 years. Subjects 1 and 2 showed spontaneous follicular development of the autotransplanted ovarian tissue. They had fluctuating gonadotropin and estradiol levels until age 29 and 26, respectively; spontaneous menses until age 29 and 26; and cessation of spontaneous menses with elevated gonadotropins and low estradiol levels at age 30 and 26. Subject 3 had severe monthly axillary pain, and the ovary was transferred back to the pelvis. She then had ovarian dysfunction with intermittent spontaneous ovarian activity until age 25. Conclusions Ovarian autotransplantation to the upper extremity resulted in long-term sex steroid production for spontaneous puberty, menarche, follicular development, and menses with fluctuating gonadotropin and ovarian sex steroid levels and follicular activity that lasted for 13-15 years.

Lower levels of prepulse inhibition in luteal phase cycling women in comparison with postmenopausal women

Menopause denotes the end of the reproductive period in a woman's life and is characterized by gradually declining plasma levels of ovarian hormones. Mounting evidence suggests that prepulse inhibition (PPI) is sensitive to fluctuations in estradiol and progesterone. Deficits in PPI are associated with conditions characterized by increased levels of ovarian steroids, such as the mid-luteal phase of the menstrual cycle and the third trimester of pregnancy. The aim of the current study was to further elucidate ovarian steroid-related effects on PPI by examining 43 women with regular menstrual cycles, 20 healthy postmenopausal women without hormone replacement treatment (HRT) and 21 healthy postmenopausal women with ongoing estradiol-only or estradiol and progesterone therapy (EPT). Cycling women were tested during the late luteal phase of the menstrual cycle while postmenopausal women were tested on any arbitrary day. The PPI was measured by electromyography. Cycling women exhibited lower levels of PPI than postmenopausal women (p<0.05). There were no differences in PPI between postmenopausal HRT users and non-users. However, postmenopausal women with estradiol serum concentrations in the cycling range had lower PPI than postmenopausal women with low estradiol concentrations (groupxPPI interaction, p<0.05). In conclusion, the results further suggest a role for the ovarian steroids in PPI regulation as PPI is increased in postmenopausal women in comparison to regularly menstruating women examined during the late luteal phase. Furthermore, postmenopausal women with estradiol levels in the cycling range had lower PPI than postmenopausal women with low estradiol levels.