Hypothalamic-pituitary-gonadal Axis Function Research Articles

Single microcystin exposure impairs the hypothalamic-pituitary-gonadal axis at different levels in female rats

Microcystin (MC) is most common cyanobacterial toxin. Few studies have evaluated the MC effects on the hypothalamic-pituitary-gonadal (HPG) axis and metabolic function. In this study, we assessed whether MC exposure results in HPG axis and metabolic changes. Female rats were exposed to a single dose of MC at environmentally relevant levels (5, 20 and 40 μg/kg). After 24 h, we evaluated reproductive and metabolic parameters for 15 days. MC reduced the hypothalamic GnRH protein expression, increased the pituitary protein expression of GnRHr and IL-6. MC reduced LH levels and increased FSH levels. MC reduced the primary follicles, increased the corpora lutea, elevated levels of anti-Müllerian hormone (AMH) and progesterone, and decreased estrogen levels. MC increased ovarian VEGFr, LHr, AMH, ED1, IL-6 and Gp91-phox protein expression. MC increased uterine area and reduced endometrial gland number. A blunted estrogen-negative feedback was observed in MC rats after ovariectomy, with no changes in LH levels compared to intact MC rats. Therefore, these data suggest that a MC leads to abnormal HPG axis function in female rats.

Polystyrene microplastics disrupt female reproductive health and fertility via sirt1 modulation in zebrafish (Danio rerio)

Microplastics (MPs) pollution poses an emerging threat to aquatic biota, which could hinder their physiological processes. Recently various evidence has demonstrated the toxic impacts of MPs on cellular and organismal levels, but still, the underlying molecular mechanism behind their toxicity remains ambiguous. The hypothalamic-pituitary-gonadal (HPG) axis regulates the synthesis and release of sex steroid hormones, and SIRT1 plays a vital role in this process. The current study aimed to elucidate the harmful effects of MPs on female reproduction via SIRT1 modulation. Healthy female zebrafish were exposed to different concentrations (50 and 500 µg/L) of polystyrene microplastics (PS-MPs). The results revealed a significant change in the gonadosomatic index (GSI) after exposure to PS-MPs. In addition, the decreased fecundity rate displayed an evident dosage effect, indicating that exposure to PS-MPs causes deleterious effects on fertilization. Furthermore, significantly enhanced levels of reactive oxygen species (ROS) and apoptotic signals through the TUNEL assay were evaluated in different treated groups. Moreover, morphological alterations in the gonads of zebrafish exposed to MPs were also observed through H&E staining. The subsequent change in plasma steroid hormone levels (E2/T ratio) showed an imbalance in hormonal homeostasis. Meanwhile, to follow PS-MPs’ effects on the HPG axis via SIRT1 modulation and gene expression related to steroidogenesis, SIRT1/p53 pathway was evaluated through qPCR. The altered transcription levels of genes indicated the plausible interference of PS-MPs on the HPG axis function. Our in-silico molecular docking study proves that PS-MPs efficiently bind and inhibit endocrine receptors and SIRT1. Thus, these findings add to our understanding of the probable molecular mechanisms of reproductive impairment caused by PS-MPs in zebrafish.

Subacute cadmium exposure disrupts the hypothalamic-pituitary-gonadal axis, leading to polycystic ovarian syndrome and premature ovarian failure features in female rats.

Cadmium (Cd), a toxic heavy metal, is a known endocrine disruptor that is associated with reproductive complications. However, few studies have explored the effects of Cd exposure on features of polycystic ovary syndrome (PCOS) and premature ovary failure (POF). In this study, we assessed whether doses found in workers occupationally exposed to Cd and subacute exposure result in hypothalamic-pituitary-gonadal (HPG) axis and other irregularities. We administered CdCl2 to female rats (100ppm in drinking water for 30 days) and then assessed Cd levels in the blood, HPG axis and uterus. Metabolic features, HPG axis function, reproductive tract (RT) morphophysiology, inflammation, oxidative stress (OS), and fibrosis were evaluated. Cd exposure increased Cd levels in the serum, HPG axis, and uterus. Cd rats displayed metabolic impairments, such as a reduction in adiposity, dyslipidemia, and insulin resistance (IR). Cd exposure also caused improper functioning in the HPG. Specifically, Cd exposure caused irregular estrous cyclicity, abnormal hypothalamic gene expression (upregulated - Kiss1, AR and mTOR; downregulated - Kiss1R, LepR and TNF-α), high LH levels, low AMH levels and abnormal ovarian follicular development, coupled with a reduction in ovarian reserve and antral follicle number was observed, suggesting ovarian depletion. Further, Cd exposure caused a reduction in corpora lutea (CL) and granulosa layer thickness together with an increase in cystic/atretic follicles. In addition, Cd exposure caused RT inflammation, OS and fibrosis. Finally, strong positive correlations were observed between serum, RT Cd levels, IR, dyslipidemia and estrous cycle length, cystic, atretic follicles, LH levels, and RT inflammation. Thus, these data suggest that subacute Cd exposure using doses found in workers occupationally exposed to Cd disrupt the HPG axis function, leading to PCOS and POF features and other abnormalities in female rats.

MON-LB037 The Impact of Maternal Testosterone and Western-Style Diet on the Fetal Hypothalamic-Pituitary-Gonadal Axis

Polycystic ovary syndrome (PCOS) is a common fertility disorder affecting 5-10% of reproductive-age women. PCOS is associated with elevated androgens, obesity, and increased risk for diabetes. Evidence from animal models indicates that elevated androgens during pregnancy programs PCOS-like characteristics in female offspring, suggesting an early developmental origin of the disease whereby predisposition to PCOS may be transmitted from mother to daughter. However, many of the findings in animal models are associated with maternal levels of androgens that are much higher than those found in PCOS women and that can result in virilization of female offspring. To address this, our group previously developed a more translational model in which peripubertal female rhesus macaques were chronically treated with testosterone (T) implants to achieve modestly elevated serum androgen levels (1.35 ng/mL) in the presence and absence of an obesogenic western-style diet (WSD). After 3 years of treatment, animals were mated and fetal tissue was collected from pregnancies at gestational day 135 (GD 135, early third trimester). At GD135 the hypothalamic-pituitary-gonadal (HPG) axis is active during the so-called “mini-puberty,” and several adult disorders of the HPG axis are often preceded by evidence of a dysfunction during “mini-puberty.” Therefore, alterations in fetal HPG axis function could indicate a predisposition for future HPG dysfunction in adulthood. The current study examined the HPG axis in these fetuses to determine whether T, WSD, or the combination (T+WSD) predisposes offspring to reproductive dysfunction. Although the impact of maternal factors on the HPG axis may be greater in female offspring, there was insufficient sample size to separate by sex; therefore, offspring of both sexes were included in the initial analysis. The infundibular nucleus of the hypothalamus was dissected and assessed for expression of key reproductive neuroendocrine hormones by quantitative PCR. Several hypothalamic neuropeptides showed differential expression with maternal androgen exposure, including TAC3, KISS1R, and PDYN which are all critical components of the GnRH pulse generator. Examination of pituitary function through assessment of circulating gonadotropins revealed a modest decrease in the LH:FSH ratio with T treatment, regardless of diet. Preliminary examination of the testes found variation in histology. Control ovaries also had wide variability in follicle cohorts, making it difficult to draw conclusions about T and/or WSD effects on the gonads. These findings suggest that prenatal T exposure may result early changes in the HPG axis that begin in the hypothalamus and are reflected in a reduced ratio of LH to FSH secreted from the pituitary. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Testosterone-cortisol dissociation in children exposed to prenatal maternal stress, and relationship with aggression: Project Ice Storm.

Prenatal maternal stress (PNMS) has been associated with postnatal behavioral alterations that may be partly explained by interactions between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Yet it remains unclear whether PNMS leads to enduring HPA-HPG alterations in the offspring, and whether HPA-HPG interactions can impact behavior during development, in particular levels of aggression in childhood. Here we investigated the relationship between a marker for HPG axis function (baseline testosterone) and a marker for HPA axis response (cortisol area under the curve) in 11½-year-olds whose mothers were exposed to the 1998 Quebec ice storm during pregnancy (n = 59 children; 31 boys, 28 girls). We examined (a) whether the degree of objective or subjective PNMS regulates the testosterone-cortisol relationship at age 11½, and (b) whether this testosterone-cortisol relationship is associated with differences in aggressive behavior. We found that, at lower levels of subjective PNMS, baseline testosterone and cortisol reactivity were positively correlated; in contrast, there was no relationship between these hormones at higher levels of subjective PNMS. Cortisol response moderated the relationship between testosterone and aggression. These results support the notion PNMS may explain variance in fetal HPA-HPG interactions, and that these interactions may be associated with aggressive behavior in late childhood.

Evaluation of the Relationship of Intracranial Pressure with the Levels of Hypothalamic-Pituitary-Gonadal Axis Hormones on Prognosis in Severe Brain Injury

Objective: Head traumas have an important place among all traumatic injuries and it is an important public health problem worldwide. Novel methods predicting prognosis may contribute to a decrease in the mortality and morbidity rates. Materials and Methods: Continuous intracranial pressure (ICP) measurements, initial cerebral computed tomography (CT) and measurement of the hypothalamic-pituitary-gonadal (HPG) axis hormones between the 0th and 4th days were performed in 15 adult male patients with severe head trauma. The relationship of these parameters with the short-term results of the patients on the 15th day was evaluated. Additionally, provocation tests were carried out to evaluate the HPG axis function. Results: High ICP and compression of basal cisterna increased mortality and they were found to affect prognosis (p=0.009 and p=0.033, respectively) No statistically significant association was found between midline shift and prognosis. No relationship was found between mortality and mean basal hormone values on the 0th day and between the 1st and 4th days. Conclusion: ICP measurement values and the presence of compression of basal cistern on the initial brain CT can be used to predict the prognosis in severe head injury but there is no significant relationship between hypophyseal hormone values and prognosis.

Effects of early-developmental stress on growth rates, body composition and developmental plasticity of the HPG-axis

In altricial songbirds, food restriction in early development has adverse effects on various physiological systems. When conditions improve birds can accelerate growth, but this compensatory strategy is associated with long-term adverse consequences. One system affected by altered growth rates is the hypothalamic–pituitary–gonadal (HPG) axis. Here, we subjected European starlings, Sturnus vulgaris, to an unpredictable food manipulation from 35 to 115days of age. We assessed the effects of the treatment by measuring overall body mass and body composition during and following the treatment period (i.e., accelerated growth). In adulthood, we measured the long-term effects of the treatment on overall body mass, testis volume, and HPG axis function in both sexes by quantifying androgen levels before and after a gonadotropin-releasing hormone (GnRH) challenge. During the treatment period, treatment birds had less body fat than controls. Following the treatment period, treatment birds weighed more than controls, but these gains were attributed to changes in lean mass. In adulthood, treatment males had lower baseline androgen levels, but there was no difference in peak androgen levels compared to controls. Treatment females did not differ from controls on any of the androgen measures. However, females that accelerated growth faster following the termination of the treatment had lower integrated androgen levels. When faced with limited developmental resources, birds may alter the developmental trajectory of physiological systems as a compensatory strategy. Such a strategy may have long-term consequences on endocrine regulation that could affect courtship and reproductive behaviors.

Variation in maternal urinary cortisol profiles across the peri-conceptional period: a longitudinal description and evaluation of potential functions.

How do women's first morning urinary cortisol levels, a marker of stress axis activity, vary during the peri-conceptional period (the 12 weeks around conception)? First morning urinary cortisol follows an overall increasing trajectory across the peri-conceptional period, interrupted by 2 week-long decreases during the week preceding conception and the fifth week following conception. Later gestational stages (i.e. second and third trimesters) are characterized by increasing levels of circulating cortisol. This increase is hypothesized to constitute a response to the energy demands imposed by fetal growth, and the development of energy reserves in preparation for nursing and performing regular activities while carrying pregnancy's extra weight and volume. This study is based on a data set collected as part of a longitudinal, naturalistic investigation into the interactions between the stress (hypothalamic-pituitary-adrenal axis (HPAA)) and reproductive (hypothalamic-pituitary-gonadal axis (HPGA)) axes. Biomarkers of HPAA and HPGA function were quantified in first morning urinary specimens collected every other day from 22 healthy women who conceived a pregnancy during the study. We analyzed the longitudinal within- and between-individual variation in first morning urinary cortisol levels across the 12-week peri-conceptional period. Participants were recruited from two rural, aboriginal, neighboring communities in Guatemala. Cortisol, estradiol and progesterone metabolites (estrone-3-glucuronide and pregnanediol glucuronide, respectively) and hCG levels were quantified in first morning urinary specimens using immunoassays to determine time of conception and confirm pregnancy maintenance. Linear mixed-effects models with regression splines were used to evaluate the magnitude and significance of changes in cortisol trajectories. Overall, maternal first morning urinary cortisol increased from 6 weeks prior to conception (geometric mean ± SD = 58.14 ± 36.00 ng/ml) to 6 weeks post-conception (89.29 ± 46.76 ng/ml). The magnitude of the increase between the pre- and post-conception periods varied significantly between women (likelihood ratio test statistic = 8.0017, P = 0.005). The peri-conceptional period is characterized by an increasing cortisol trajectory (+1.36% per day; P = 0.007) interrupted by a week-long decline immediately prior to conception (-4.02% per day; P = 0.0013). After conception cortisol increased again (+1.73% per day; P = 0.0008) for 4 weeks, fell in the fifth week (-6.60% per day; P = 0.0002) and increased again in post-conceptional week 6 (+8.86% per day; P = 0.002). Maternal urinary cortisol levels varied with sex of the gestating embryo. During gestational week 2, mothers carrying female embryos (N = 10) had higher mean cortisol levels than those carrying male embryos (N = 9) (t(17) = 2.28, P = 0.04). Our results are based on a relatively small sample (n = 22) of women. However, our repeated-measures design with an average of 27 ± 8 (mean ± SD) data points per woman strengthens the precision of estimates resulting in high statistical power. Additionally, our study population's high degree of ethnic and cultural homogeneity reduces the effects of confounders compared with those found in industrialized populations. This higher level of homogeneity also increases our statistical power. However, since there may be small differences in absolute cortisol values among ethnic groups, the social and biological background of our sample may affect the generalizability of our results. General patterns of HPAA activity, however, are expected to be universal across women. Finally, as there is, to the best of our knowledge, no evidence to the contrary, we assumed that urinary cortisol levels reflect HPAA activity and that changes in gonadal steroids across the menstrual cycle do not affect the levels of free cortisol measured in urine. To our knowledge, this is the first longitudinal profile of basal maternal HPAA activity across the peri-conceptional period. A basic understanding of the normative (basal as opposed to stress-induced) changes in HPAA activity across this period is needed to accurately assess women's stress at this juncture. Importantly, changes in HPAA activity are likely to play a critical role in ovulation, fertilization, implantation, placentation and embryonic programing. Thus, this novel information should aid in the development of interventions aimed at preventing or moderating undesired effects of maternal physiological stress during the peri-conceptional period on reproductive outcomes as well as embryonic development. This research was funded by a CIHR IGH Open Operating grant (CIHR 106705) to P.A.N. and L.Z.; a Simon Fraser University (SFU) President's Start-up grant, a Community Trust Endowment Fund grant through SFU's Human Evolutionary Studies Program and a Michael Smith Foundation for Health Research Career Investigator Scholar Award to P.A.N.; an NSERC Discovery grant to L.Z.; a CIHR Post-Doctoral Fellowship to C.K.B. and an NSERC Undergraduate Student Research Award to H.M. and J.C.B. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests. Not applicable.

Gene dosage of Otx2 is important for fertility in male mice

Together, the hypothalamus, pituitary and gonads direct the development and regulation of reproductive function in mammals. Gonadotropin-releasing hormone (GnRH) expression is limited to ∼800 neurons that originate in the olfactory placode then migrate to the hypothalamus. Coordination of the hypothalamic–pituitary–gonadal (HPG) axis is dependent upon correct neuronal migration of GnRH neurons into the hypothalamus followed by proper synthesis and pulsatile secretion of GnRH. Defects in any one of these processes causes infertility. Otx2, the vertebrate homologue of Drosophila orthodenticle, is a transcription factor that has been shown to be critical for normal brain and eye development and is expressed in both the developing GnRH neurons and the pituitary, suggesting that this gene may play a critical role in development of the HPG axis. As Otx2-null mice are embryonic lethal, we have analyzed the reproductive capacity of heterozygous Otx2 mice to determine the contribution of Otx2 gene dosage to normal HPG axis function. Our data reveal that correct dosage of Otx2 is critical for normal fertility as loss of one allele of Otx2 leads to a discernible reproductive phenotype in male mice due to disruption of the migration of GnRH neurons during development.

Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I

GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19-32). All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2-14.2) up to the final height. Final height was very disappointing (≤ -5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow- up was 8.3 yr with the longest span of 17.2 yr. We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

Suicide attempt by jumping: A study of gonadal axis hormones in male suicide attempters versus men who fell by accident

Low plasma total testosterone (T) levels may influence the sense of well-being and produce depressive symptomatology, increasing the risk of suicide. In a previous study, we reported reduced serum T levels in male psychiatric patients after a suicide attempt. The reduction was more pronounced in subjects who used violent attempt methods, and we discussed the possible influence of stress of hospitalization, serious medical condition and treatment. In order to minimize the influence of such factors, we compared in this study the levels of plasma sex hormones of 15 psychiatric patients (10 suffering from schizophrenia and 5 from depression) who had attempted suicide by jumping with those of a group of 18 male subjects who were hospitalized after accidentally falling from a high height. Compared with a healthy control group of 40 males, both accident and attempt groups had lower T levels. The attempt group showed a trend toward lower T levels compared with levels in the accident group. In the accident group, luteinizing hormone (LH) levels were elevated compared with levels in healthy controls, indicating a normal function of the hypothalamic-pituitary-gonadal (HPG) axis. This was not the case for the attempt group, where low T levels were not accompanied by increases in LH. Cortisol and prolactin were similarly elevated in both patient groups, but were not related to the low T levels. The results indicate that male psychiatric patients who attempt suicide by violent methods may have low total plasma T levels, possibly due to a dysfunction of the HPG axis at the hypothalamic-pituitary level. Monitoring HPG axis function in future studies could prove to be a predictor of suicide at least for male psychiatric attempters, and could lead to preventive strategies.

Dynamic Nature of Alterations in the Endocrine System of Fathead Minnows Exposed to the Fungicide Prochloraz

The vertebrate hypothalamic-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms that maintain a dynamic homeostasis in the face of changing environmental conditions, including exposure to chemicals. We assessed the effects of prochloraz on HPG axis function in adult fathead minnows (Pimephales promelas) at multiple sampling times during 8-day exposure and 8-day depuration/recovery phases. Consistent with one mechanism of action of prochloraz, inhibition of cytochrome P450 (CYP) 19 aromatase activity, the fungicide depressed ex vivo ovarian production and plasma concentrations of 17beta-estradiol (E2) in female fish. At a prochloraz water concentration of 30 microg/l, inhibitory effects on E2 production were transitory and did not persist during the 8-day exposure phase. At 300 microg/l prochloraz, inhibition of E2 production was evident throughout the 8-day exposure but steroid titers recovered within 1 day of cessation of exposure. Compensation or recovery of steroid production in prochloraz-exposed females was accompanied by upregulation of several ovarian genes associated with steroidogenesis, including cyp19a1a, cyp17 (hydroxylase/lyase), cyp11a (cholesterol side-chain cleavage), and follicle-stimulating hormone receptor. In male fathead minnows, the 8-day prochloraz exposure decreased testosterone (T) production, possibly through inhibition of CYP17. However, as for E2 in females, ex vivo testicular production and plasma concentrations of T recovered within 1 day of stopping exposure. Steroidogenic genes upregulated in testis included cyp17 and cyp11a. These studies demonstrate the adaptability of the HPG axis to chemical stress and highlight the need to consider the dynamic nature of the system when developing approaches to assess potential risks of endocrine-active chemicals.

Effects of Maternal Undernutrition on the Hypothalamic–Pituitary–Gonadal Axis Function in Female Sheep Offspring

A study was conducted to evaluate the effects of maternal undernutrition on the hypothalamic-pituitary-gonadal axis in female sheep offspring. Pregnant ewes were fed to 100% throughout pregnancy (Control) or to 50% from 0 to 30 (R1) or from 31 to 100 days of gestation (R2). Female lambs were selected and fed to appetite throughout the study. At 2, 5.5 and 10 months of age a GnRH challenge was conducted. At the age of 10 months lambs were synchronized and blood samples were collected at 3 h intervals for 72 h following sponge removal. At slaughter (10 months) ovaries were removed and examined macroscopically. Maternal undernutrition did not affect the time of the onset of puberty, defined as the first increase in plasma progesterone concentrations >or=1 ng/ml. The magnitude of the pre-ovulatory gonadotrophin surge and the time to surge were unaffected by treatment. The LH and FSH response to GnRH challenge did not differ between groups at 2 and 5.5 months but at 10 months of age a higher (p < 0.05) FSH response was found in R1 group. Although the total number of visible follicles and corpora lutea did not differ between groups, a significant higher (p < 0.05) number of small (2-3 mm diameter) follicles in R1 group and a significant lower number (p < 0.05) of corpora lutea with diameter 8-11 mm and not even one with diameter >12 mm were detected in the ovaries of R2 lambs. In conclusion, maternal undernutrition during the first month of pregnancy resulted in increased pituitary sensitivity to GnRH and increased number of small follicles in the ovary, while during mid to late gestation resulted in a reduction of large corpora lutea in female offspring.

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

Ovarian Aging and Menopause: Current Theories, Hypotheses, and Research Models

Aging of the reproductive system has been studied in numerous vertebrate species. Although there are wide variations in reproductive strategies and hormone cycle components, many of the fundamental changes that occur during aging are similar. Evolutionary hypotheses attempt to explain why menopause occurs, whereas cellular hypotheses attempt to explain how it occurs. It is commonly believed that a disruption in the hypothalamic-pituitary-gonadal axis is responsible for the onset of menopause. Data exist to demonstrate that the first signs of menopause occur at the level of the brain or the ovary. Thus, finding an appropriate and representative animal model is especially important for the advancement of menopause research. In primates, there is a gradual decline in the function of the hypothalamic-pituitary-gonadal (HPG) axis ultimately resulting in irregularities in menstrual cycles and increasingly sporadic incidence of ovulation. Rodents also exhibit a progressive deterioration in HPG axis function; however, they also experience a period of constant estrus accompanied by intermittent ovulations, reduced progesterone levels, and elevated circulating estradiol levels. It is remarkable to observe that females of other classes also demonstrate deterioration in HPG axis function and ovarian failure. Comparisons of aging in various taxa provide insight into fundamental biological mechanisms of aging that could underlie reproductive decline.

Clinical and molecular analysis of human reproductive disorders in Brazilian patients.

Several genes that influence the development and function of the hypothalamic-pituitary-gonadal-axis (HPG) have been identified. These genes encode an array of transcription factors, matrix proteins, hormones, receptors, and enzymes that are expressed at multiple levels of the HPG. We report the experience of a single Endocrinology Unit in the identification and characterization of naturally occurring mutations in families affected by HPG disorders, including forms of precocious puberty, hypogonadism and abnormal sexual development due to impaired gonadotropin function. Eight distinct genes implicated in HPG function were studied: KAL, SF1, DAX1, GnRH, GnRHR, FSHbeta, FSHR, and LHR. Most mutations identified in our cohort are described for the first time in literature. New mutations in SF1, DAX1 and GnRHR genes were identified in three Brazilian patients with hypogonadism. Eight boys with luteinizing hormone- (LH) independent precocious puberty due to testotoxicosis were studied, and all have their LH receptor (LHR) defects elucidated. Among the identified LHR molecular defects, three were new activating mutations. In addition, these mutations were frequently associated with new clinical and hormonal aspects, contributing significantly to the knowledge of the molecular basis of reproductive disorders. In conclusion, the naturally occurring genetic mutations described in the Brazilian families studied provide important insights into the regulation of the HPG.

Genes and male infertility: what can go wrong?

Genes and male infertility: what can go wrong?

Acute Re-Feeding Reverses Food Restriction-Induced Hypothalamic-Pituitary-Gonadal Axis Deficits1

Undernutrition has well-established effects on female reproduction. Here we describe the effects of food restriction on aspects of the hypothalamic-pituitary-gonadal (HPG) axis in the female musk shrew. We determined that acute re-feeding reverses deficits brought on by food restriction. Two days of food restriction led to an increase in proGnRH immunoreactive cells in the preoptic area relative to ad libitum-fed controls (AL). This increase was reversed by 90 min of ad libitum feeding in the re-fed females (RF). In addition, food-restricted (FR) females had significantly greater GnRH content in the median eminence than either the AL or RF females. After GnRH was administered, the majority of females in all food conditions ovulated, yet the FR females had significantly fewer corpora lutea than either the AL or RF animals. These data show that food restriction impairs HPG axis function in female musk shrews, and that some of these impairments can be rapidly reversed by acute re-feeding.