How alcohol affects insulin-like growth factor-1's influences on the onset of puberty: A critical review.

Alcohol (ALC) is capable of delaying signs associated with pubertal development in laboratory animals, as well as in humans. The normal onset of puberty results from a timely increase in gonadotropin-releasing hormone (GnRH) secretion, which is associated with a gradual decline in prepubertal inhibitory influences, and the establishment of excitatory inputs that increase GnRH release, which together drive pubertal development. In recent years, insulin-like growth factor-1 (IGF-1) has emerged as a pivotal contributor to prepubertal GnRH secretion and pubertal development, whose critical actions are interfered with by ALC abuse.

IGF-1 Influences Gonadotropin-Releasing Hormone Regulation of Puberty.

The pubertal process is initiated as a result of complex neuroendocrine interactions within the preoptic and hypothalamic regions of the brain. These interactions ultimately result in a timely increase in the secretion of gonadotropin-releasing hormone (GnRH). Researchers for years have believed that this increase is due to a diminished inhibitory tone which has applied a prepubertal brake on GnRH secretion, as well as to the gradual development of excitatory inputs driving the increased release of the peptide.

Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat.

The onset of puberty is the result of an increase in secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). This action is a result of not only the development of stimulatory inputs to its release, but also the gradual decrease in inhibitory inputs that restrain release of the peptide prior to pubertal onset. Dynorphin (DYN) is one of the inhibitory inputs produced in the medial basal hypothalamus (MBH); however, little is known about what substance(s) control its prepubertal synthesis and release.

Alcohol Delays the Onset of Puberty in the Female Rat by Altering Key Hypothalamic Events.

Background: Because alcohol (ALC) delays signs of pubertal development, we assessed the time course of events associated with the synthesis of critical hypothalamic peptides that regulate secretion of luteinizing hormone-releasing hormone (LHRH), the peptide that drives the pubertal process.

Methods: Immature female rats were administered either laboratory chow or BioServe isocaloric control or ALC-liquid diets from 27 through 33 days of age. On days 28, 29, 31, and 33, animals were killed by decapitation and tissue blocks containing the medial basal hypothalamus (MBH) and the rostral hypothalamic area (RHA) were isolated and stored frozen until assessed by Western blot analysis.

Regulation of Kisspeptin Synthesis and Release in the Preoptic/Anterior Hypothalamic Region of Prepubertal Female Rats: Actions of IGF-1 and Alcohol.

Background: Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone-releasing hormone (LHRH). Insulin-like growth factor-1 (IGF-1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF-1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons.

Alcohol and Puberty: Mechanisms of Delayed Development.

Adolescence represents a vulnerable period for developing youth. Alcohol use and misuse are especially problematic behaviors during this time. Adolescents are more sensitive to alcohol and less tolerant of its detrimental effects than are adults.

Influences of manganese on pubertal development.

The onset of puberty is the result of complex neuroendocrine interactions within hypothalamic region of the brain, as well as from genetic and environmental influences. These interactions ultimately result in the increased synthesis and release of luteinizing hormone-releasing hormone (LHRH). Manganese (Mn) is an essential environmental element known for years to be involved in numerous mammalian physiological processes, including growth and reproductive function.

Improvements in oocyte competence in superovulated mice following treatment with cilostazol: Ovulation of immature oocytes with high developmental rates.

Exogenous administration of superovulatory hormones negatively affects oocyte competence in mammals. Phosphodiesterase 3A inhibitors were found to improve competence of oocytes matured in vitro in several species, including humans. This study was therefore designed to define oocyte maturation synchronization and competence, in vivo, using superovulated mice treated with cilostazol, a selective phosphodiesterase 3A inhibitor.

Manganese-Stimulated Kisspeptin Is Mediated by the IGF-1/Akt/Mammalian Target of Rapamycin Pathway in the Prepubertal Female Rat.

Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway.

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones.

Aims: Since manganese (Mn) is capable of stimulating the hypothalamic-pituitary unit and advancing female puberty, we assessed the possibility that this element might overcome some of the detrimental effects of prepubertal alcohol (ALC) exposure on the hypothalamic control of pituitary function.

Main Methods: Rats received either saline or Mn (10mg/kg) daily by gastric gavage from day 12 to day 31. After weaning, all rats were provided Lab Chow diet ad libitum until day 27 when they began receiving either the Bio Serv control or ALC diet regime.

Differential Effects of Alcohol on Excitatory and Inhibitory Puberty-Related Peptides in the Basal Hypothalamus of the Female Rat.

Background: An increase in development of excitatory inputs along with a decline in inhibitory inputs ultimately govern the timely increased secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH) at the time of puberty. As chronic alcohol (ALC) exposure acts at the hypothalamic level to suppress LHRH secretion and delay puberty, we assessed its ability to differentially affect the expression of key puberty-related proteins.

Methods: ALC was administered to female rats from days 27 to 33, at which time animals were killed and tissues collected for protein expression.

Alcohol alters insulin-like growth factor-1-induced transforming growth factor β1 synthesis in the medial basal hypothalamus of the prepubertal female rat.

Background: Insulin-like growth factor-1 (IGF-1) and transforming growth factor β1 (TGFβ1) are produced in hypothalamic astrocytes and facilitate luteinizing hormone-releasing hormone (LHRH) secretion. IGF-1 stimulates release by acting directly on the LHRH nerve terminals and both peptides act indirectly through specific plastic changes on glial/tanycyte processes that further support LHRH secretion. Because the relationship between these growth factors in the hypothalamus is not known, we assessed the ability of IGF-1 to induce TGFβ1 synthesis and release and the actions of alcohol (ALC) on this mechanism prior to the onset of puberty.

Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats.

Evidence suggests that environmental substances regulating estrogenic pathways during puberty may be detrimental to the developing mammary gland (MG). Manganese (Mn) is a trace mineral required for normal physiological processes. Prepubertal exposure to Mn induces precocious puberty in rats, an event associated with early elevations in puberty-related hormones, including estradiol (E).

Actions and interactions of alcohol and transforming growth factor β1 on prepubertal hypothalamic gonadotropin-releasing hormone.

Background: Alcohol (ALC) diminishes gonadotropin-releasing hormone (GnRH) secretion and delays puberty. Glial transforming growth factor β1 (TGFβ1) plays a role in glial-neuronal communications facilitating prepubertal GnRH secretion. We assessed the effects of acute ALC administration on TGFβ1-induced GnRH gene expression in the brain preoptic area (POA) and release of the peptide from the medial basal hypothalamus (MBH).

Cilostazol administered to female mice induces ovulation of immature oocytes: a contraceptive animal model.

Aims: Both Cilostamide and Org 9935 are phosphodiesterase 3A (PDE3A) inhibitors that were evaluated in rodents and monkeys for their non-steroidal contraceptive properties. Although both compounds inhibited oocyte maturation, an adverse effect on heart rate was observed. Cilostazol (CLZ, Pletal) is a safe PDE3A inhibitor that was recently reported to block pregnancy in naturally cycling mice.

In vitro effects of cilostazol, a phosphodiesterase 3A inhibitor, on mouse oocyte maturation and morphology.

Inhibition of phosphodiesterase 3A (PDE3A) in oocytes has been reported to arrest oocyte maturation and to increase intra-oocyte cyclic adenosine monophosphate levels. Although many PDE3A inhibitors have been found to arrest oocyte maturation in different species, including humans, the most commonly prescribed PDE3A inhibitor named cilostazol (CLZ) has not yet been fully evaluated in reproduction. The present study was designed to investigate the potential inhibitory effects of CLZ on oocyte maturation and morphology in vitro.

Early life manganese exposure upregulates tumor-associated genes in the hypothalamus of female rats: relationship to manganese-induced precocious puberty.

Prepubertal exposure to low, but elevated levels of manganese (Mn) can induce increased secretions of puberty-related hormones resulting in precocious pubertal development in female rats. These events are due to an action of the element within the hypothalamus to induce the secretion of gonadotropin-releasing hormone (GnRH). Because of these prepubertal effects of Mn and because precocious puberty is a serious neuroendocrine disorder, we have assessed whether early life exposure to this environmental element is capable of precociously upregulating the expression of a select group of genes previously associated with tumor growth or suppression, and that have more recently been shown to increase at the normal time of puberty.

Hypothalamic actions and interactions of alcohol and IGF-1 on the expression of glial receptor protein tyrosine phosphatase-β during female pubertal development.

Background: Hypothalamic glial-neuronal communications are important for the activation of luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. As we have shown that alcohol (ALC) diminishes prepubertal LHRH secretion and delays puberty, we first assessed the effects of short-term ALC administration on the basal expression of a specific gene family involved in glial-neuronal communications. Second, as insulin-like growth factor-1 (IGF-1) is a critical regulator of LHRH secretion and the pubertal process, we then assessed whether IGF-1 could induce the expression of these signaling genes and determine whether ALC can block this affect.

Manganese induces IGF-1 and cyclooxygenase-2 gene expressions in the basal hypothalamus during prepubertal female development.

Precocious puberty is a significant child health problem, especially in girls, because 95% of cases are idiopathic. Our earlier studies demonstrated that low-dose levels of manganese (Mn) caused precocious puberty via stimulating the secretion of luteinizing hormone-releasing hormone (LHRH). Because glial-neuronal communications are important for the activation of LHRH secretion at puberty, we investigated the effects of prepubertal Mn exposure on specific glial-derived puberty-related genes known to affect neuronal LHRH release.