Manganese (Mn) is considered important for normal growth and reproduction. Because Mn can cross the blood brain barrier and accumulate in the hypothalamus, and because it has been suggested that infants and children are potentially more sensitive to Mn than adults, we wanted to determine the effects of Mn exposure on puberty-related hormones and the onset of puberty, and discern the site and mechanism of Mn action. We demonstrated that the central administration of manganese chloride (MnCl2) stimulated luteinizing hormone (LH) release in prepubertal rats. Incubation of medial basal hypothalamus (MBH) in vitro showed this effect was due to a Mn-induced stimulation of luteinizing hormone releasing hormone (LHRH). Further demonstration that this is a hypothalamic site of action was shown by in vivo blockade of LHRH receptors and the lack of a direct pituitary action of Mn to stimulate LH release in vitro. Chronic supplementation of low dose of MnCl2 caused elevated serum levels of LH, follicle stimulating hormone (FSH) and estradiol or testosterone. Importantly, Mn supplementation advanced the timing of puberty in both sexes. We investigated the mechanism by which Mn induces LHRH/LH release from the hypothalamus. Blocking the NMDA receptor, IGF1 receptor, or inhibiting nitric oxide synthase in vivo was ineffective in altering Mn-induced LH release. Dose-response, pharmacological blockade and nitrite assessments indicated that the lowest doses of Mn used stimulated LHRH release, but did not induce nitric oxide (NO) production, while only the highest dose of Mn stimulated NO. Conversely, a dose-dependent inhibition of Mn-induced LHRH release was observed in the presence of ODQ, a specific blocker of soluble guanylyl cyclase. Furthermore, Mn stimulated the release of cyclic GMP (cGMP) and LHRH from the same MBH, and a protein kinase G (PKG) inhibitor, KT5823, blocked Mn-induced LHRH release. Collectively, these data demonstrate that Mn can stimulate specific puberty-related hormones both acutely and chronically, and furthermore, suggest that low levels of Mn facilitate the normal onset of puberty. The principal action of Mn within the hypothalamus is to facilitate the activation of guanylyl cyclase, which subsequently stimulates the cGMP/PKG pathway resulting in the stimulation of prepubertal LHRH secretion.

Increased pulsatile release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) is critical for pubertal initiation of ovarian cycles in female mammals. Kisspeptin, a peptide product of the Kiss1 gene, is required for normal puberty. In Experiment 1, ovariectomized ewe lambs bearing subcutaneous estradiol implants were used to investigate Kiss1 gene expression in the preoptic area (POA) and hypothalamus during pubertal maturation of the reproductive neuroendocrine system. Brain tissue was collected from ewes at 25, 30, and 35 wk of age (n=6/group). Patterns of LH release in circulation were determined on the day before euthanasia and cells containing Kiss1-mRNA were identified by in situ hybridization. Mean concentrations of LH and the frequency of LH pulses increased (P < 0.01) as ewe lambs matured. In the POA/Periventricular area (PEV), the number of Kiss1-expressing cells was greater (P < 0.04) in 30- and 35-wk-old than in 25-wk-old ewe lambs. In the arcuate nucleus (ARC), although no significant changes in number Kiss1-expressing cells were observed among age groups, the number of Kiss1 cells increased (P < 0.02) with increased frequency of LH release. This resulted in greater (P < 0.01) number of Kiss1 cells in the ARC of ewes demonstrating elevated frequency (> 6 pulses/12 h) of LH pulses. In Experiment 2, 28-wk-old ewe lambs were used to determine the effects of intermittent injections of kisspeptin on the release of LH and stimulation of gonadal function in peripubertal ewe lambs. Ewe lambs were treated intravenously with saline (Controls; n=6) or kisspeptin (n=6) hourly for 24 h. Blood samples were collected throughout the experiment for hormone analysis. Kisspeptin-treated lambs had greater (P < 0.02) mean circulating concentrations of LH, and frequency and amplitude of LH pulses than controls. Four of six kisspeptin-treated ewe lambs exhibited LH surge and luteal activity in response to treatments. However, onset of regular estrous cycles was not established immediately following kisspeptin-induced ovulation and no difference in age at onset of puberty was observed between groups. In conclusion, activation of the hypothalamic kisspeptin system may support elevated episodic release of LH critical for establishment of normal estrous cycle during pubertal development.

Manganese (Mn) is considered important for normal growth and reproduction. Because Mn can cross the blood brain barrier and accumulate in the hypothalamus, and because it has been suggested that infants and children are potentially more sensitive to Mn than adults, we wanted to determine the effects of Mn exposure on puberty-related hormones and the onset of puberty, and discern the site and mechanism of Mn action. We demonstrated that the central administration of manganese chloride (MnCl2) stimulated luteinizing hormone (LH) release in prepubertal rats. Incubation of medial basal hypothalamus (MBH) in vitro showed this effect was due to a Mn-induced stimulation of luteinizing hormone releasing hormone (LHRH). Further demonstration that this is a hypothalamic site of action was shown by in vivo blockade of LHRH receptors and the lack of a direct pituitary action of Mn to stimulate LH release in vitro. Chronic supplementation of low dose of MnCl2 caused elevated serum levels of LH, follicle stimulating hormone (FSH) and estradiol or testosterone. Importantly, Mn supplementation advanced the timing of puberty in both sexes. We investigated the mechanism by which Mn induces LHRH/LH release from the hypothalamus. Blocking the NMDA receptor, IGF1 receptor, or inhibiting nitric oxide synthase in vivo was ineffective in altering Mn-induced LH release. Dose-response, pharmacological blockade and nitrite assessments indicated that the lowest doses of Mn used stimulated LHRH release, but did not induce nitric oxide (NO) production, while only the highest dose of Mn stimulated NO. Conversely, a dose-dependent inhibition of Mn-induced LHRH release was observed in the presence of ODQ, a specific blocker of soluble guanylyl cyclase. Furthermore, Mn stimulated the release of cyclic GMP (cGMP) and LHRH from the same MBH, and a protein kinase G (PKG) inhibitor, KT5823, blocked Mn-induced LHRH release. Collectively, these data demonstrate that Mn can stimulate specific puberty-related hormones both acutely and chronically, and furthermore, suggest that low levels of Mn facilitate the normal onset of puberty. The principal action of Mn within the hypothalamus is to facilitate the activation of guanylyl cyclase, which subsequently stimulates the cGMP/PKG pathway resulting in the stimulation of prepubertal LHRH secretion.

The present study was performed in order to update available data on puberty in South African women gathered from studies among a variety of South African population groups and to compare our findings with these previous studies in order to identify any change. In addition, the children's social environment was evaluated to see if it had any influence on the timing of puberty. This study is important because a decrease in the age of onset of the various stages of puberty would be expected as the socio-economic status of the population increases. We would expect that once socio-economic and therefore nutritional equality between different communities exists, there would be little difference between the age at which children attain puberty. An absence in the trend toward a younger onset of puberty would be a cause for concern as this would imply that there has been no improvement in living conditions from the time of the original study. A relationship has also been shown to exist between an earlier age at menarche and an increased risk of breast cancer (Pike 1983), an increased risk of coronary heart disease (Colditz 1987), shorter adult height (Shangold 1989), earlier initiation of sexual activity (Soefer 1985), earlier first pregnancy, (Sandler 1984) and larger family size (Frisch 1978). This implies that as the age at which children pass through puberty decreases, it becomes increasingly important to introduce both sexual education and the availability of contraception at a correspondingly earlier age in order to avoid the tragedies of teenage pregnancies.

No description available.

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern and is highly heritable; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern and is highly heritable; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Our large, accurately phenotyped cohort of patients with familial self-limited DP is a unique resource with a relatively homogeneous genetic composition. I have utilised this cohort to investigate the genetic variants segregating with the DP trait in these pedigrees. Whole exome sequencing in eighteen probands and their relatives, and subsequent targeted sequencing in an extended subgroup of the cohort, has revealed potential novel genetic regulators of pubertal timing. In ten unrelated probands, I identified rare mutations in IGSF10, a gene that is strongly expressed in the nasal mesenchyme during embryonic migration of gonadotropin-releasing hormone (GnRH) neurons. IGSF10 knockdown both in vitro and in a transgenic zebrafish model resulted in perturbed GnRH neuronal migration. Loss-of-function mutations in IGSF10 were also identified in five patients with absent puberty due to hypogonadotropic hypogonadism (HH). Additionally, I have identified and investigated one rare, pathogenic mutation in HS6ST1 - a gene known to cause HH - in one family with DP, and two rare variants in FTO - a gene implicated in the timing of menarche in the general population - in 3 families. Further potentially pathogenic variants have emerged from investigating candidate genes identified from microarray studies (LGR4, SEMA6A and NEGR1) and from related clinical phenotypes (IGSF1). Our large, accurately phenotyped cohort of patients with familial self-limited DP is a unique resource with a relatively homogeneous genetic composition. I have utilised this cohort to investigate the genetic variants segregating with the DP trait in these pedigrees. Whole exome sequencing in eighteen probands and their relatives, and subsequent targeted sequencing in an extended subgroup of the cohort, has revealed potential novel genetic regulators of pubertal timing. In ten unrelated probands, I identified rare mutations in IGSF10, a gene that is strongly expressed in the nasal mesenchyme during embryonic migration of gonadotropin-releasing hormone (GnRH) neurons. IGSF10 knockdown both in vitro and in a transgenic zebrafish model resulted in perturbed GnRH neuronal migration. Loss-of-function mutations in IGSF10 were also identified in five patients with absent puberty due to hypogonadotropic hypogonadism (HH). Additionally, I have identified and investigated one rare, pathogenic mutation in HS6ST1 - a gene known to cause HH - in one family with DP, and two rare variants in FTO - a gene implicated in the timing of menarche in the general population - in 3 families. Further potentially pathogenic variants have emerged from investigating candidate genes identified from microarray studies (LGR4, SEMA6A and NEGR1) and from related clinical phenotypes (IGSF1).

Thesis (Ph. D.)--University of Chicago, Department of Psychology, Committee on Human Development, June 2003. / Includes bibliographical references. Also available on the Internet.

Angus-sired heifers were allotted by age (mean=4 mo), BW (mean=135 kg), and sire (n=4) to either a control (n=10) or infected group (n=11; 600 metacercariae of Fasciola hepatica, intraruminally) to test our hypothesis that puberty is delayed by experimental fascioliasis. Blood samples were collected biweekly for analysis of steroid hormone concentrations. At 2-wk intervals, BW was recorded, and samples were collected for analysis of liver enzymes and serum proteins and fecal egg counts. A radiotelemetry system (HeatWatch??) was used to detect estrus and ovulation was confirmed by an elevation in serum progesterone (P4) after estrus. Heifers were artificially inseminated (AI) at the second observed estrus. Serum &#947;-glutamyl transpeptidase (GGT) and aspartate aminotransferase (AST) increased (p<0.0008) between day 0 and 112 in the infected group. Serum estradiol (E2) and P4 concentrations did not differ (p>0.1) between treatment groups. Mean age at puberty was 10 days later (p>0.1) in the infected group. Conception rate did not differ between control and infected heifers. The HeatWatch?? data were used to compare mounting activity during estrus in pubertal and gestating heifers. Mean duration of estrus was longer (p<0.01) for the second than for the pubertal estrus, though total mount duration and number of mounts did not differ. Number of mounts at second estrus was greater (p<0.05) for heifers that conceived (n=9). Mean duration of estrus and total mount duration at second estrus were not associated with pregnancy outcome. Estrus events were detected in all nine heifers during pregnancy (total=73). A majority (75%) of the interestrus intervals during gestation was <17 d. Number of mounts (p=0.035) and total duration of mounts (p=0.022) at second estrus were predictive of number of mounts during gestation. Experimental infection of Fasciola hepatica did not alter serum steroid hormone concentration or delay pubertal development in heifers. Estrus duration was longer for the second estrus compared to the pubertal estrus, and the number of mounts received during the second estrus was greater in heifers that did conceive to AI. Estrus events were detected in each heifer during pregnancy; however, a normal interestrus interval occurred in only 10% of the estrus events.

Thesis (Ph. D.)--UCLA, 2007. / Vita. Includes bibliographical references (leaves 124-146).

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 123-137). Available also in a digital version from Dissertation Abstracts.