Neonatal overfeeding reduces estradiol plasma levels and disrupts noradrenergic-kisspeptin-GnRH pathway and fertility in adult female rats.

This work evaluated the effects of neonatal overfeeding, induced by litter size reduction, on fertility and the noradrenaline-kisspeptin-gonadotrophin releasing hormone (GnRH) pathway in adult female rats. The litter size was adjusted to 3 pups with each mother in the small litters (SL) and 10 pups with each mother in the normal litters (NL). SL females exhibited metabolic changes associated with reproductive dysfunctions, shown by earlier vaginal opening and first estrus, later regular cyclicity onset, and lower and higher occurrences of estrus and diestrus phases, respectively, as well as reduced fertility, estradiol plasma levels, and mRNA expressions of tyrosine hydroxylase in the locus coeruleus, kisspeptin, and GnRH in the preoptic area in adult females in the afternoon of proestrus. These results suggest that neonatal overfeeding in female rats promotes reproductive dysfunctions in adulthood, such as lower estradiol plasma levels associated with impairments in fertility and noradrenaline-kisspeptin-GnRH pathway during positive feedback.

Long-term consequences of the absence of leptin signaling in early life.

Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.

Effects of chronic dietary petroleum exposure on reproductive development in polar cod (Boreogadus saida).

Increasing human activities in the Arctic raise the risk of petroleum pollution, thus posing an elevated risk for Arctic organisms to be chronically exposed to petroleum compounds. The endocrine disrupting properties of some of these compounds (i.e. polycyclic aromatic hydrocarbons [PAHs]) present in crude oil may have negative effects on the long and energy intensive reproductive development of polar cod (Boreogadus saida), an Arctic keystone species. In the present study, selected reproductive parameters were examined in feral polar cod exposed to crude oil via a natural diet (0.11, 0.57 and 1.14µg crude oil/g fish/day [corresponding to low, medium and high treatments, respectively]) for 31 weeks prior to spawning. Fish maturing in the current reproductive period made up 92% of the experimental population while 5% were immature and 3% were identified as resting fish. Phase I metabolism of PAHs, indicated by ethoxyresorufin-O-deethylase (EROD) activity, showed a dose-dependent increase in high and medium crude oil treatments at week 6 and 22, respectively. Decreasing EROD activity and increasing PAH bile metabolite concentrations over the experimental period may be explained by reproductive maturity stage. Significant alterations in sperm motility were observed in crude oil exposed males compared to the controls. The investigated somatic indices (gonad and hepatic), germ cell development and plasma steroid levels (estradiol-17ß [females], testosterone [males and females] and 11-ketotestosterone [males]) were not significantly altered by chronic dietary exposure to crude oil. The environmentally realistic doses polar cod were chronically exposed to in this study were likely not high enough to induce adverse effects in this ecologically important fish species. This study elucidated many baseline aspects of polar cod reproductive physiology and emphasized the influence of maturation state on biomarkers of PAH biotransformation (EROD and PAH bile metabolites).

Hypopituitarism in the elderly: a narrative review on clinical management of hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes dysfunction.

Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.

Endocrine Disruption throughout the Hypothalamus-Pituitary-Gonadal-Liver (HPGL) Axis in Marine Medaka (Oryzias melastigma) Chronically Exposed to the Antifouling and Chemopreventive Agent, 3,3'-Diindolylmethane (DIM).

Despite being proposed as a promising antifouling and chemopreventive agent, the environmental risks of 3,3'-diindolylmethane (DIM) are scarcely investigated. Therefore, this study used adult marine medaka (Oryzias melastigma) as a model organism to examine the toxicological effects and underlying mechanism of DIM throughout the hypothalamus-pituitary-gonadal-liver (HPGL) axis following 28 days of exposure to low DIM concentrations (0 and 8.46 µg/L). The results showed that altered gene transcription in the hypothalamus, pituitary, and gonads contributed to the great imbalance in hormone homeostasis. The lowered estradiol (E2)/testosterone (T) and E2/11-keto-testosterone (11-KT) ratios in female plasma resulted in decreased synthesis and levels of vitellogenin (VTG) and choriogenin in the liver and plasma, and vice versa in males. Subsequently, VTG and choriogenin deficiency blocked the reproductive function of the ovary as indicated by decreased fecundity and offspring viability, whereas in male medaka, DIM mainly targeted the liver and induced severe vacuolization. Proteomic profiling of plasma revealed that the sex-specific susceptibility to DIM could be attributed to the increased detoxification and oxidative defense in males. Overall, this study identified the endocrine disruption and reproductive impairment potency of DIM and first elucidated its mechanisms of action in medaka. The differential responses to DIM (estrogenic activities in the male but antiestrogenic activities in the female) provided sensitive biomarkers characteristic of each sex. Considering the chemical stability and potent endocrine disturbance at low concentration, the application of DIM either as an antifouling or chemopreventive agent should be approached with caution in marine environments.

Histopathological changes in Poecilia latipinna male gonad due to Tribulus terrestris administration.

Tribulus terrestris is a traditionally known non-toxic aphrodisiac herb for maleness. It was experimented recently to understand the effect and mechanism on mono sex production in Poecilia latipinna. It would help to develop a new eco-friendly way to masculinize P. latipinna, since males have higher commercial value than females. The different concentration (100, 150, 200, 250 and 300 mg/L) of T. terrestris extract and a control were tested for their effect on sex transformation/reversal in P. latipinna by immersing the newly born young ones in the respective concentrations for 2 mo. The obtained results indicate that a dose dependant masculinization is obtained due to T. terrestris administration, which improved the male proportion. Histological results revealed that the testes of fish treated with T. terrestris extract contained all stages of spermatogenesis, clearly demonstrating that the administration of T. terrestris extract to P. latipinna stimulated spermatogenesis. Thus, it is discernible that 0-d-old hatchlings of P. latipinna exposed to T. terrestris extract orient/reverse their sex more towards maleness besides yielding better growth and spermatogenesis which is a mandate for fancy fish industry.

Peripheral kisspeptin reverses short photoperiod-induced gonadal regression in Syrian hamsters by promoting GNRH release.

In seasonal breeders, reproduction is synchronised by day length via the pineal hormone melatonin. In short winter days (short day, SD), the Syrian hamster displays a complete gonadal atrophy together with a marked reduction in expression of kisspeptins (Kp), a family of potent hypothalamic stimulators of GNRH neurons. Both central and peripheral acute injections of Kp have been reported to activate the gonadotropic axis in mammals. The aim of this study was to determine if and how peripheral administration of Kp54 could restore gonadal function in photo-inhibited hamsters. Testicular activity of hamsters kept in SD was reactivated by two daily i.p. injections of Kp54 but not by chronic subcutaneous delivery of the same peptide via mini-pumps. Acute i.p. injection of Kp54-induced FOS (c-Fos) expression in a large number of GNRH neurons and pituitary gonadotrophs together with a strong increase in circulating testosterone. The activation of pituitary cells by Kp was inhibited by preadministration of the GNRH receptor antagonist acyline. Altogether, our results demonstrate that peripheral Kp54 activates the gonadotropic axis by stimulating GNRH release and indicate that an appropriate protocol of long-term systemic Kp administration can recrudesce a photo-inhibited reproductive axis.

Effects of chronic exposure to dispersed oil on selected reproductive processes in adult blue mussels (Mytilus edulis) and the consequences for the early life stages of their larvae.

Mussels (Mytilus edulis) were continuously exposed to dispersed crude oil (0.015-0.25mg/l) for 7 months covering the whole gamete development cycle. After 1 month exposure to 0.25 mg oil/l, the level of alkali-labile phosphates (ALP) and the volume density of atretic oocytes in female gonads were higher than those in the gonads of control females, indicating that oil affected the level of vitellogenin-like proteins and gamete development. Spawning of mussels was induced after 7 months oil exposure. Parental oil exposure did not affect subsequent fertilization success in clean seawater but this was reduced in 0.25 mg oil/l. Parental exposure to 0.25 mg oil/l caused both slow development and a higher percentage of abnormalities in D-shell larvae 2 days post-fertilization; reduced growth 7 days post-fertilization. These effects were greatly enhanced when larval stages were maintained at 0.25 mg oil/l. Similar studies are warranted for risk assessment prognosis.

Thalidomide treatment attenuates chemotherapy-induced gonadal toxicity.

The aim of this study was to investigate gonadal-protective properties of thalidomide in a mouse model of chemotherapy-induced ovarian failure. Administration of thalidomide before alkylating chemotherapy preserved ovarian follicles and lead to the resumption of normal estrous cyclicity.

Ultrastructural effects on gill, muscle, and gonadal tissues induced in zebrafish (Danio rerio) by a waterborne uranium exposure.

Experiments on adult zebrafish (Danio rerio) were conducted to assess histopathological effects induced on gill, muscle, and gonadal tissues after waterborne uranium exposure. Although histopathology is often employed as a tool for the detection and assessment of xenobiotic-mediated effects in aquatic organisms, few studies have been dedicated to the investigation of histopathological consequences of uranium exposure in fish. Results showed that gill tissue architecture was markedly disrupted. Major symptoms were alterations of the secondary lamellae epithelium (from extensive oedema to desquamation), hyperplasia of chloride cells, and breakdown of the pillar cell system. Muscle histology was also affected. Degeneration and disorganization of myofibrillar sarcomeric pattern as well as abnormal localization of mitochondria within muscle and altered endomysial sheaths were observed. Morphological alterations of spermatozoa within the gonadal tissue were also noticed. This study demonstrated that uranium exposure induced a variety of histological impairments in fish, supporting environmental concerns when uranium contaminates aquatic systems.

Endocrine alteration and other biochemical responses in juvenile turbot exposed to the Prestige fuel oil.

Juvenile turbot (Scophthalmus maximus) were exposed to different concentrations of the Prestige fuel oil through the diet. The effects on hepatic biotransformation enzymes, namely, 7-ethoxyresorufin O-deethylase (EROD), catalase, and phase II activities - UDP-glucuronosyltransferases (UGT) and cytosolic sulfotransferases (SULT) -, were monitored after 42-day exposure. Additionally, potential alterations on the endocrine system of juvenile turbot were assessed by measuring circulating levels of testosterone and 17beta-estradiol in plasma, together with gonadal P450 aromatase activity and the glucuronidation of testosterone by liver microsomal fractions. Fluorescent aromatic compounds (FACs) in bile were determined as an indicator of exposure to polycyclic aromatic hydrocarbons (PAHs). EROD activity increased in a dose dependent manner, and a positive correlation between levels of FACs in bile and EROD activity was observed. A significant increase in UGT activity was observed in fish exposed to medium and high fuel doses, whereas SULT cytosolic activity was not responsive to exposure. Exposure to the Prestige fuel oil sharply reduced circulating levels of testosterone in plasma. The obtained results suggest the ability of the Prestige fuel oil to alter hepatic biotransformation enzymes and to disrupt endogenous hormone levels in juvenile turbot, with unknown consequences in terms of sexual differentiation and reproduction.

Chemical contaminants, health indicators, and reproductive biomarker responses in fish from rivers in the Southeastern United States.

Largemouth bass (Micropterus salmoides) and common carp (Cyprinus carpio) were collected from 13 sites located in the Mobile (MRB), Apalachicola-Flint-Chattahoochee (ARB), Savannah (SRB), and Pee Dee (PRB) River Basins to document spatial trends in accumulative chemical contaminants, health indicators, and reproductive biomarkers. Organochlorine residues, 2,3,7,8-tetrachlorodibenzo-p-dioxin-like activity (TCDD-EQ), and elemental contaminants were measured in composite samples of whole fish, grouped by species and gender, from each site. Mercury (Hg) and polychlorinated biphenyls (PCBs) were the primary contaminants of concern. Concentrations of Hg in bass samples from all basins exceeded toxicity thresholds for piscivorous mammals (>0.1 microg/g ww), juvenile and adult fish (>0.2 microg/g ww), and piscivorous birds (>0.3 microg/g ww). Total PCB concentrations in samples from the MRB, ARB, and PRB were >480 ng/g ww and may be a risk to piscivorous wildlife. Selenium concentrations also exceeded toxicity thresholds (>0.75 microg/g ww) in MRB and ARB fish. Concentrations of other formerly used (total chlordanes, dieldrin, endrin, aldrin, mirex, and hexachlorobenzene) and currently used (pentachlorobenzene, pentachloroanisole, dacthal, endosulfan, gamma-hexachlorocyclohexane, and methoxychlor) organochlorine residues were generally low or did not exceed toxicity thresholds for fish and piscivorous wildlife. TCDD-EQs exceeded wildlife dietary guidelines (>5 pg/g ww) in MRB and PRB fish. Hepatic ethoxyresorufin O-deethylase (EROD) activity was generally greatest in MRB bass and carp. Altered fish health indicators and reproductive biomarker were noted in individual fish, but mean responses were similar among basins. The field necropsy and histopathological examination determined that MRB fish were generally in poorer health than those from the other basins, primarily due to parasitic infestations. Tumors were found in few fish (n=5; 0.01%); ovarian tumors of smooth muscle origin were found in two ARB carp from the same site. Intersex gonads were identified in 47 male bass (42%) representing 12 sites and may indicate exposure to potential endocrine disrupting compounds. Comparatively high vitellogenin concentrations (>0.35 mg/mL) in male fish from the MRB, SRB, and PRB indicate exposure to estrogenic or anti-androgenic chemicals.

Gonadotropins: a cohesive gender-based etiology of Alzheimer disease.

While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.

A protective effect of vitamin E and selenium in ameliorating the immunotoxicity of malathion in chicks.

A study was conducted to determine whether a combination of vitamin E and selenium was able to counteract the immunosuppressive effects of chronic toxicity of malathion in chicks. The chicks were divided into three groups. The first group received malathion 10 mg/kg body weight; the second group received the same dose of malathion but was supplemented with vitamin E and selenium for 60 days; and the third group served as the control. The concentration of total immunoglobulins and circulatory immune complexes decreased following the administration of malathion, whereas the supplementation of the diet with vitamin E and selenium partially counteracted this effect. The histopathological changes in the bursa of Fabricius due to malathion were consistent with these findings. Supplementation with vitamin E and selenium partially ameliorated the degenerative changes in the bursa of Fabricius.

Biochemical and histological responses in mussel (Mytilus edulis) exposed to North Sea oil and to a mixture of North Sea oil and alkylphenols.

Several environmental chemicals are suspected to be responsible for adverse health effects on the reproductive system in various organisms. During this work, environmentally relevant concentrations of North Sea oil were used alone or in combination with alkylphenols and additional PAH to study the effect on vitellogenin-like protein expression and gonadal development in mussels. North Sea oil (0.5 ppm) induced the expression of phospho-proteins in both sexes indicating that some compounds are oestrogen-mimics. This induction was not seen in samples dosed with the mixture but signs of toxic effects were observed in the gonads. Indeed, numerous degenerating ovarian follicles in females and foci, similar to vertebrate melanomacrophage centres, were observed in testes.

The GPR54 gene as a regulator of puberty.

BACKGROUND: Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. METHODS: We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. RESULTS: Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus. CONCLUSIONS: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.

Isolation of gonadal mutations in adult zebrafish from a chemical mutagenesis screen.

A mutagenesis screen was conducted on zebrafish using N:-ethyl N:-nitrosourea as a mutagen and an F2 crossing scheme to obtain homozygous mutants in the F3 generation. Whole abdomens of 3-mo-old F3 zebrafish progeny were fixed and mass-embedded in paraffin blocks. Blocks were cut with a microtome to obtain cross-sections of the entire body cavity that included the ovaries and testes. Slides of the cross-sections were analyzed for alterations in gonadal structure and gametogenesis and were compared with gonads of wild-type fish. A total of 125 mutagenized genomes in 81 families were screened and 11 mutations were observed that produced visible phenotypes in only one sex per family. Male mutations included testes without mature sperm that contained either predominantly spermatocytes or spermatogonia. Female mutations included ovaries containing 1) degenerating oocytes surrounded by hypertrophied follicle walls or stroma, 2) extrafollicular tissue proliferation, 3) proliferating postovulatory follicle walls, and 4) large numbers of degenerating preovulatory and postovulatory oocytes. While past screens on zebrafish have concentrated on early developmental mutations, the results of this study demonstrate for the first time that mutagenesis can be used with zebrafish to study reproduction in adult animals.

Evaluation of a Tier I screening battery for detecting endocrine-active compounds (EACs) using the positive controls testosterone, coumestrol, progesterone, and RU486.

After previously examining 12 compounds with known endocrine activities, we have now evaluated 4 additional compounds in a Tier I screening battery for detecting endocrine-active compounds (EACs): a weak estrogen receptor (ER) agonist (coumestrol; COUM), an androgen receptor (AR) agonist (testosterone; TEST), a progesterone receptor (PR) agonist (progesterone; PROG), and a PR antagonist (mifepristone; RU486). The Tier I battery incorporates 2 short-term in vivo tests (5-day ovariectomized female battery; 15-day intact male battery) and an in vitro yeast transactivation system (YTS). The Tier I battery is designed to identify compounds that have the potential to act as agonists or antagonists to the estrogen, androgen, progesterone, or dopamine receptors; steroid biosynthesis inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis); or compounds that alter thyroid function. In addition to the Tier I battery, a 15-day dietary restriction experiment was performed using male rats to assess confounding due to treatment-related decreases in body weight. In the Tier I female battery, TEST administration increased uterine weight, uterine stromal cell proliferation, and altered hormonal concentrations (increased serum testosterone [T] and prolactin [PRL]; and decreased serum FSH and LH). In the male battery, TEST increased accessory sex gland weights, altered hormonal concentrations (increased serum T, dihydrotestosterone [DHT], estradiol [E2], and PRL; decreased serum FSH and LH), and produced microscopic changes of the testis (Leydig cell atrophy and spermatid retention). In the YTS, TEST activated gene transcription in the yeast containing the AR or PR. In the female battery, COUM administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height, and increased serum PRL concentrations. In the male battery, COUM altered hormonal concentrations (decreased serum T, DHT, E2; increased serum PRL) and, in the YTS, COUM activated gene transcription in the yeast containing the ER. In the female battery, PROG administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height and altered hormonal concentrations (increased serum progesterone and decreased serum FSH and LH). In the male battery, PROG decreased epididymis and accessory sex gland weights, altered hormonal concentrations (decreased serum T, PRL, FSH, and LH; increased serum progesterone and E2), and produced microscopic changes of the testis (Leydig cell atrophy). In the YTS, PROG activated gene transcription in the yeast containing the AR or PR. In the female battery, RU486 administration increased uterine weight and decreased uterine stromal cell proliferation. In the male battery, RU486 decreased epididymis and accessory sex gland weights and increased serum FSH and LH concentrations. In the YTS, RU486 activated gene transcription in the yeast containing the ER, AR, or PR. Dietary restriction data demonstrate that confounding due to decrements in body weight are not observed when body weight decrements are 10% or less in the Tier I male battery. In addition, minimal confounding is observed at body decrements of 15% (relative liver weight, T3, and T4). Hence, compounds can be evaluated in this Tier I at levels that produce a 10% decrease in body weight without confounding of the selected endpoints. Using the responses obtained for all the endpoints in the Tier I battery, a distinct "fingerprint" was produced for each type of endocrine activity against which compounds with unknown activity can be compared. These data demonstrate that the described Tier I battery is useful for identifying EACs and they extend the compounds evaluated to 16.

Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor.

Cerivastatin is a new but structurally distinct 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"). It effectively decreases low-density lipoprotein (LDL) cholesterol at 1% of the doses of other currently available statins. The toxicology of cerivastatin was evaluated in a comprehensive program of studies including: (1) single- and multiple-dose toxicity studies in rats, mice, minipigs, dogs, and monkeys; (2) reproductive toxicity studies in rats and rabbits; (3) in vitro and in vivo mutagenicity assays in rats and mice; and (4) carcinogenicity studies in rats and mice. In addition, studies were undertaken to investigate the effects of cerivastatin on lens opacity, testicular tissue, and hemorrhage in dogs. Oral administration of single and multiple doses of cerivastatin over periods ranging from 4 weeks to 24 months was generally well tolerated. Adverse effects were similar to those observed with other statins and primarily involved the liver and muscle tissue. At the high doses used in the toxicologic studies, cerivastatin caused elevations in serum transaminases and creatine phosphokinase levels as well as some degeneration of muscle fibers in rats, mice, dogs, and minipigs. In dogs, the species most sensitive to statins, cerivastatin caused erosions and hemorrhages in the gastrointestinal tract, bleeding in the brain stem with fibroid degeneration of vessel walls in the choroid plexus, and lens opacity. Apart from minor morphologic changes in the testicular tissue of dogs--the only organ for which a comparably low margin of safety was observed--cerivastatin had no significant effects on the male or female reproductive system. Cerivastatin also caused no primary embryotoxic or teratogenic effects. With the exception of cerivastatin-induced effects on the eyes and testicles, administration of mevalonic acid reversed the toxicologic effects of cerivastatin, indicating that the toxic effects were related to its mode of action and not to any intrinsic toxicity of the molecule itself. There was no evidence that cerivastatin had any mutagenic effects and, in contrast to other statins, high doses of cerivastatin did not induce tumors in rats. The main metabolite of cerivastatin was well tolerated systemically in all animals, including dogs. Overall, cerivastatin has a similar toxicologic profile to other statins and is a well-tolerated HMG-CoA reductase inhibitor.

Steroidogenic factor 1 acts at all levels of the reproductive axis.

The conversion of cholesterol into steroid hormones occurs through the sequential actions of the cytochrome P450 steroid hydroxylases. Attempts to understand the mechanisms responsible for the temporal and spatial expression patterns of these enzymes led to the identification of a shared regulator, termed steroidogenic factor 1 (SF-1). SF-1 coordinately regulates the steroid hydroxylase genes and thus functions as a global mediator of steroidogenesis. Of greater significance, recent studies using a knockout mouse model have further implicated SF-1 in a variety of processes ranging from development of the steroidogenic organs to the normal function of gonadotropes and the development of the ventromedial hypothalamic nucleus. A fundamental aspect of elucidating the role of SF-1 at all levels of the reproductive axis is to identify its cell-specific target genes. The recent purification and cloning of the steroidogenic acute regulatory (StAR) protein has provided an intriguing new candidate through which SF-1 acts to mediate its effects on reproductive competence. These studies yield novel insights into the processes of steroidogenesis, endocrine development, and reproductive function.