Normal Sexual Maturation Research Articles

The expression, regulation and signal transduction pathways of the mammalian gonadotropin-releasing hormone receptor

Normal mammalian sexual maturation and reproductive functions require the integration and precise coordination of hormones at the hypothalamic, pituitary, and gonadal levels. Hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator in this system; after binding to its receptor (GnRHR), it stimulates de novo synthesis and release of gonadotropins in anterior pituitary gonadotropes. Since the isolation of the GnRHR cDNA, the expression of GnRHR mRNA has been detected not only in the pituitary, but also in extrapituitary tissues, including the ovary and placenta. It has been shown that change in GnRHR mRNA is one of the mechanisms for regulating the expression of the GnRHR. To help understand the molecular mechanism(s) involved in transcriptional regulation of the GnRHR gene, the 5' flanking region of the GnRHR gene has recently been isolated. Initial characterization studies have identified several DNA regions in the GnRHR 5' flanking region which are responsible for both basal expression and GnRH-mediated homologous regulation of this gene in pituitary cells. The mammalian GnRHR lacks a C-terminus and possesses a relatively short third intracellular loop; both features are important in desensitization of many others G-protein coupled receptors (GPCRs), Homologous desensitization of GnRHR has been shown to be regulated by various serine-threonine protein kinases including protein kinase A (PKA) and protein kinase C (PKC), as well as by G-protein coupled receptor kinases (GRKs). Furthermore, GnRHR was demonstrated to couple with multiple G proteins (Gq/11, Gs, and Gi), and to activate cascades that involved the PKC, PKA, and mitogen-activator protein kinases. These results suggest the diversity of GnRHR-G protein coupling and signal transduction systems. The identification of second form of GnRH (GnRH-II) in mammals adds to the complexity of the GnRH-GnRHR system. This review summaries our recent progress in understanding the regulation of GnRHR gene expression and the GnRHR signal transduction pathways.Key words: gonadotropin-releasing hormone receptor, transcriptional regulation, desensitization, signal transduction.

Human leptin: from an adipocyte hormone to an endocrine mediator.

Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic-pituitary-adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic-pituitary-gonadal axis and on insulin metabolism, but also on the hypothalamic-pituitary-adrenal, thyroid and GH axes. Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation.

The expression, regulation and signal transduction pathways of the mammalian gonadotropin-releasing hormone receptor

Normal mammalian sexual maturation and reproductive functions require the integration and precise coordination of hormones at the hypothalamic, pituitary, and gonadal levels. Hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator in this system; after binding to its receptor (GnRHR), it stimulates de novo synthesis and release of gonadotropins in anterior pituitary gonadotropes. Since the isolation of the GnRHR cDNA, the expression of GnRHR mRNA has been detected not only in the pituitary, but also in extrapituitary tissues, including the ovary and placenta. It has been shown that change in GnRHR mRNA is one of the mechanisms for regulating the expression of the GnRHR. To help understand the molecular mechanism(s) involved in transcriptional regulation of the GnRHR gene, the 5' flanking region of the GnRHR gene has recently been isolated. Initial characterization studies have identified several DNA regions in the GnRHR 5' flanking region which are responsible for both basal expression and GnRH-mediated homologous regulation of this gene in pituitary cells. The mammalian GnRHR lacks a C-terminus and possesses a relatively short third intracellular loop; both features are important in desensitization of many others G-protein coupled receptors (GPCRs), Homologous desensitization of GnRHR has been shown to be regulated by various serine-threonine protein kinases including protein kinase A (PKA) and protein kinase C (PKC), as well as by G-protein coupled receptor kinases (GRKs). Furthermore, GnRHR was demonstrated to couple with multiple G proteins (Gq/11, Gs, and Gi), and to activate cascades that involved the PKC, PKA, and mitogen-activator protein kinases. These results suggest the diversity of GnRHR-G protein coupling and signal transduction systems. The identification of second form of GnRH (GnRH-II) in mammals adds to the complexity of the GnRH-GnRHR system. This review summaries our recent progress in understanding the regulation of GnRHR gene expression and the GnRHR signal transduction pathways.

Effects on the sexual maturation of the sediment-living amphipodMonoporeia affinis

The objective was to investigate whether sediment-living amphipods, i.e., Monoporeia affinis, were affected by endocrine disrupters in the same way as perch (Perca fluviatilis) and pike (Esox lucius) were observed to be affected in an earlier study. Surface sediments were collected at a reference site in Lake Malaren (Station 1), in a remote lake contaminated with an unidentified leakage water from a refuse dump (Station 2). The latter was compared to a sediment contaminated with heavy metals and PHOCs (polycyclic aromatic hydrocarbons and polychlorobiphenyls) from a sampling site located in the urban area of the city of Stockholm (Station 3). Amphipods were exposed to the contaminated sediments in soft-bottom microcosms in the laboratory during the periods for sexual maturation, mating, and embryogenesis. Three samplings were included; one at the start of the experiment, another after one month (to examine effects on gonad maturation), and a third after 3 months to investigate effects on fertilization success and embryogenesis. No effects were observed on organisms exposed to sediments from Station 1 and Station 3, while effects on sexual maturation on females and males of M. affinis were detected in sediment from Station 2. Females were more seriously affected. Nearly 50% of the females showed a delayed sexual development and 28% of these were immature, showing that the sexual maturation was interrupted due to contaminants in the sediment. In addition to the interrupted sexual maturation, other reproduction variables such as fertilization success and fecundity, were insignificantly (p=0.383) lower in Station 2 sediment and thus enforce the possibility of endocrine effect. Similar effects were observed on males in terms of a delayed sexual maturation and a lower number of secondary sexual characteristics, i.e., antennule segments, and chemical sensory organs, i.e., aesthetascs. Since effects were recorded on processes before mating we suggest that the contaminant(s) in the leakage water act as an endocrine disrupter by inhibiting the release of neural hormones controlling the normal sexual maturation in both female and male amphipods.

Effects on the sexual maturation of the sediment‐living amphipod Monoporeia affinis

The objective was to investigate whether sediment-living amphipods, i.e., Monoporeia affinis, were affected by endocrine disrupters in the same way as perch (Perca fluviatilis) and pike (Esox lucius) were observed to be affected in an earlier study. Surface sediments were collected at a reference site in Lake Mälaren (Station 1), in a remote lake contaminated with an unidentified leakage water from a refuse dump (Station 2). The latter was compared to a sediment contaminated with heavy metals and PHOCs (polycyclic aromatic hydrocarbons and polychlorobiphenyls) from a sampling site located in the urban area of the city of Stockholm (Station 3). Amphipods were exposed to the contaminated sediments in soft-bottom microcosms in the laboratory during the periods for sexual maturation, mating, and embryogenesis. Three samplings were included; one at the start of the experiment, another after one month (to examine effects on gonad maturation), and a third after 3 months to investigate effects on fertilization success and embryogenesis. No effects were observed on organisms exposed to sediments from Station 1 and Station 3, while effects on sexual maturation on females and males of M. affinis were detected in sediment from Station 2. Females were more seriously affected. Nearly 50% of the females showed a delayed sexual development and 28% of these were immature, showing that the sexual maturation was interrupted due to contaminants in the sediment. In addition to the interrupted sexual maturation, other reproduction variables such as fertilization success and fecundity, were insignificantly (p=0.383) lower in Station 2 sediment and thus enforce the possibility of endocrine effect. Similar effects were observed on males in terms of a delayed sexual maturation and a lower number of secondary sexual characteristics, i.e., antennule segments, and chemical sensory organs, i.e., aesthetascs. Since effects were recorded on processes before mating we suggest that the contaminant(s) in the leakage water act as an endocrine disrupter by inhibiting the release of neural hormones controlling the normal sexual maturation in both female and male amphipods. © 2000 John Wiley & Sons, Inc. Environ Toxicol 15: 518–526, 2000

Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero.

vom Saal et al. (Proc. Natl. Acad. Sci. 94, 2056-2061, 1997) have reported that low dose exposure (0.02-2 microg/kg/day) of CF1 mice to diethylstilbestrol (DES) in utero led to increases in the prostate gland weight when the pups reached 8 months of age. Nagel et al. (Environ. Health Perspect. 105, 70-76, 1997) reported similar effects in CF1 mice at 6 months of age after exposure in utero to low dose levels (2 and 20 microg/kg/day) of bisphenol A (BPA). vom Saal et al. (Toxicol. Indust. Health 14(1/2) 239-260, 1998) subsequently reported reduced sperm efficiency (daily sperm production per gram testes) in a subset of the BPA animals for which enlarged prostates had been observed. These three experiments have been repeated in a single experiment that was terminated when the offspring reached 6 months of age. No statistically significant effects on prostate weight or sperm efficiency were recorded for offspring of animals exposed to either DES (0.2 microg/kg/day) or BPA (2 and 20 microg/kg/day) in utero. Significant dam effects were seen for several of the assay parameters indicating that the litter, as opposed to the individual, should be considered as the statistical unit in such experiments. A statistically significant increase in body weight was recorded for the low dose BPA male offspring. Females from the study underwent normal sexual maturation and showed no significant differences in reproductive tissue weights at termination and the mean day of vaginal opening. The possible reasons for this failure to confirm the earlier reported effects for DES and BPA at these low doses are discussed.

Kallmann Syndrome and the Link between Olfactory and Reproductive Development

The sense of smell mediates communication with the external environment through the recognition of chemical cues. In mammals, olfactory chemosensation begins in sensory neurons located in the olfactory epithelium, which lines the olfactory turbinates inside the nose, and in the epithelium of the vomeronasal organ (VNO), a tubular structure that opens on the ventral aspect of the nasal septum. Neurons in the olfactory epithelium detect volatile odorants, providing information about the external milieu, whereas sensory neurons located in the VNO detect pheromones, nonvolatile chemical signals that trigger innate and stereotyped reproductive and social behaviors, as well as neuroendocrine changes. Olfactory and vomeronasal neurons project their axons to the main and the accessory olfactory bulbs, respectively, where they synapse with dendrites of mitral and tufted cells in specialized structures called “glomeruli” (Farbman 1992). The presence of a potentially functional VNO in humans has been recently documented, but whether humans use this system to process and to respond to chemical signals emitted by other members of the species remains controversial (Dulac and Axel 1995; Berliner et al. 1996; Herrada and Dulac 1997; Monti-Bloch et al. 1998; Stern and McClintock 1998). However, regardless of the role of the VNO as a sensory organ in our species, it is now clear from the study of the X-linked disorder Kallmann syndrome (MIM 308700, MIM 147950, and MIM 244200) that development of the olfactory and vomeronasal system is required for normal sexual maturation. Here, I review studies by neurobiologists, particularly those working in the developing chick, as well as the human genetic analysis that has brought this surprising connection to light.

Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism

Objective: To evaluate the clinical and hormonal responses of adolescent males with hypogonadotropic hypogonadism (HH) in response to gonadotropin replacement with the use of long-term combined hCG and FSH therapy. Design: Prospective clinical study. Setting: Clinical pediatric department providing tertiary care. Patient(s): Seven prepubertal males with isolated HH with a mean (±SD) age of 15.44 ± 1.97 years and seven prepubertal males with panhypopituitarism-associated HH with a mean (±SD) age of 18.1 ± 3.24 years were studied. Intervention(s): Human chorionic gonadotropin (1,000–1,500 IU IM) and FSH (75–100 IU SC) were administered every alternate day of the week until the total induction of puberty and spermatogenesis was achieved. Main Outcome Measure(s): Serum testosterone levels, testicular volume, penis length, and sperm count were evaluated after the administration of hCG and FSH. Result(s): All patients achieved normal sexual maturation and normal or nearly normal adult male levels of testosterone. The increase in testicular size was significant in both groups. Positive sperm production was assessed in four of five patients with isolated HH and in three of three patients with panhypopituitarism-associated HH. Conclusion(s): Long-term combined hCG and FSH therapy is effective in inducing puberty, increasing testicular volume, and stimulating spermatogenesis in adolescent males with isolated HH and panhypopituitarism-associated HH.

Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene.

We have investigated the largest family with PROP1 deficiency reported to date. Eight patients, aged 17-40 yr, in two sibships with possibly related mothers but no parental consanguinity were 109-137 cm in height (-8.8 to [minus]5.9 SD score) and sexually immature. None had received hormonal therapy. Affected individuals had similarities to and significant differences from patients with insulin-like growth factor I (IGF-I) deficiency due to GH receptor deficiency (GHRD) and normal thyroid function and sexual maturation. The differences from patients with GHRD include normal hand and foot length in seven of eight, normal arm span with relatively long legs, and persistence of extremely low levels of IGF-I into adulthood; similarities include the degree of growth failure, frequent but not uniform increased body weight for height or body mass index, and the presence of limited elbow extensibility and blue scleras in six of eight. Three patients had markedly increased sella turcica area for height age and bone age, determined from lateral skull films. The degree of sellar enlargement is variable in these two sibships. Serum GH concentrations were 0.1 ng/mL or less after clonidine ingestion. Other results were: IGF-I, 3-11 ng/mL (normal, 114-492); IGF-II, 185-299 ng/mL (normal, 358-854); IGF-binding protein-1 (IGFBP-1), 12-200 ng/mL (normal, 13-73); IGFBP-2, 60-384 ng/mL (normal, 55-480); and IGFBP-3, 400-600 ng/mL (normal, 2000-4000). The very low IGF-I and normal IGFBP-1 and -2 levels differ from findings in adults with GHRD. The GH-binding protein concentration was 58-799 pmol/L, with two patients above the normal range of 66-306. LH and FSH levels were very low, with no sex differences between serum levels of estradiol (3-6 pg/mL) and testosterone (3-10 ng/dL). PRL levels all were below normal. Serum concentrations of cortisol were normal. Serum T4 levels were uniformly low (<0.2-0.5; normal, 0.8-2.7 ng/dL), free T3 values were less than normal in seven of eight subjects, and total T3 concentrations were below normal in five of eight, but TSH levels were normal (0.58-2.18; normal, 0.4-4.2 mU/L). DNA specimens from affected individuals in each sibship were homozygous for a 2-bp deletion in exon 2 of the PROPI (Prophet of Pit-I) gene, which causes a shift of reading frames and results in a translational stop signal at codon 109. The mutant protein, when expressed in vivo lacks DNA-binding and transcriptional activation functions. The consequences of the PROPI abnormality in this and other kindreds include gonadotropin deficiency as well as the expected deficiencies in products of Pit-I-dependent somatotrophs, lactotrophs, and thyrotrophs. The severity of the hormone deficiency phenotype is compatible with the complete loss of PROP1 activity.

Sex, parturition and motherhood without oxytocin?

Our understanding of the functions of oxytocin in mammals has recently been challenged by findings in transgenic mice in which the oxytocin gene has been knocked out. Mammals generally have only two posterior pituitary nonapeptide genes, for oxytocin and vasopressin, while some marsupials do not express oxytocin but do express a closely related peptide, mesotocin, which acts at the oxytocin receptor (Acher et al. 1995). Birds have arginine vasotocin and mesotocin (Acher et al. 1995), while among other vertebrates a subclass of cartilaginous fishes evidently produces oxytocin (Michel et al. 1993). Mice homozygous for deletion of exon 1 of the oxytocin gene, containing the oxytocin nonapeptide sequence, were produced by homologous recombination in mouse embryonic stem cells. Offspring from matings of the heterozygotes were in the correct Mendelian frequency, indicating no lethal developmental defects in the homozygotes, which later showed normal sexual maturation, with both males and females showing sexual behaviour and normal fertility (Nishimori et al. 1996). Young and colleagues (1996) used gene targeting to generate a mouse with most of the first intron and the last two of the three exons of the oxytocin gene eliminated. The amount of oxytocin gene transcripts in the supraoptic and paraventricular nuclei of homozygotes was 1% of the wild-type level, with less than 0·4% of the wild-type content of oxytocin in the pituitary gland, and no oxytocin detectable in blood plasma by RIA. In both types of oxytocin gene disablement, the only evident defect was a complete failure of postpartum homozygotes to transfer milk to the suckling young, which consequently did not survive unless the mothers were treated with exogenous oxytocin. Thus parturition and maternal behaviour proceeded without oxytocin, although these processes were not studied in detail. These findings are surprising in view of the vast literature on a wide range of species suggesting important roles for oxytocin in regulating gonadal function, in expression of sexual behaviour, in parturition and initiation of maternal behaviour as well as in lactation. It is appropriate to consider whether the results from the oxytocin knockout mice arise from peculiarities in the roles of oxytocin in the mouse in comparison with other species, or indicate redundancy in the mechanisms in which oxytocin normally has an important role; apart that is, from the milk-ejection reflex in which there is no evident redundancy, at least in the mouse.

Success of glucocorticoid replacement therapy on fertility in two adult males with 21-CAH homozygote classic form

A normal gonadal maturation with normal fertility are some of the major goals of long-term replacement therapy in adult males with Congenital Adrenal Hyperplasia (CAH). We describe here two young men, G.O. (case A, 23 years old) and S.S.(case B, 24 years old), both with a well defined diagnosis of CAH due to 21-hydroxylase deficiency classic homozygote form (21-CAH). In case A the diagnosis of the 21-CAH classic virilizing form was made at 3 years of age. The patient has undergone glucocorticoid therapy and is now 170 cm tall; all his hormonal findings are within the normal range. The semen analysis has shown a good fertility potential, with a slight modification when the patient decided to discontinue the therapy. In case B the diagnosis of the 21-CAH salt wasting form was performed at 9 days of age. The patient was initially treated with i.v. normal saline solution and a daily i.m. injection of hydrocortisone and, subsequently, with mineral and glucocorticoid replacement therapy po. A satisfactory adult stature (165 cm) was attained. The patient is still on therapy, with a good hormonal profile. The semen analysis has shown an apparently normal fertility. In conclusion, our experience in adult males with 21-CAH, who have been administered prompt and adequate replacement therapy, shows that these patients can attain normal quality of life, satisfactory growth and development, normal sexual maturation and activity, and adequate sperm fertilizing ability, thereby supporting the usefulness of continuing this therapy during adult age.

Adult-onset idiopathic hypogonadotropic hypogonadism — A treatable form of male infertility: Nachtigall L.B.; Boepple P.A.; Pralong F.P.; Crowley W.F. Jr. USA New Engl J Med 1997 336/6 (410–415)

Background Men with isolated gonadotropinreleasing hormone (GnRH) deficiency typically present with an absence of pubertal development. We describe an adult-onset form of idiopathic hypogonadotropic hypogonadism that develops after puberty. Methods We studied 10 men (age, 27 to 57 years) with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone on frequent blood sampling. All the men had otherwise normal anterior pituitary hormone secretion and sellar anatomy. We compared the results of semen analyses and measurements of testicular volume, serum testosterone, inhibin B, and gonadotropins in these men with the results in 24 men with classic GnRH deficiency before and during GnRHreplacement therapy and in 29 normal men of similar age. Results Serum gonadotropin concentrations in the men with adult-onset GnRH deficiency were similar before and during pulsatile GnRH administration to those in the men with classic GnRH deficiency. However, as compared with men with classic GnRH deficiency, men with adult-onset hypogonadotropic hypogonadism had larger mean ( � SD) testicular volumes (18 � 5 vs. 3 � 2 ml, P � 0.001), serum testosterone concentrations (78 � 34 vs. 49 � 20 ng per deciliter [2.7 � 1.2 vs. 1.7 � 0.7 nmol per liter], P � 0.004), and serum inhibin B concentrations (119 � 52 vs. 60 � 21 pg per milliliter, P � 0.001). Treatment with GnRH reversed the hypogonadism and restored fertility in each of the five men who received long-term therapy. Conclusions The recognition of adult-onset hypogonadotropic hypogonadism in men as a distinct disorder expands the spectrum of GnRH deficiency and identifies a treatable form of male infertility. (N Engl J Med 1997;336:410-5.) ©1997, Massachusetts Medical Society.

Pubertal growth, sexual maturation, and final height in children with IDDM. Effects of age at onset and metabolic control.

To evaluate growth and pubertal development in children with IDDM and the influence of the age at onset of IDDM and the degree of metabolic control on final height. We conducted a retrospective evaluation of 62 subjects followed longitudinally both clinically and metabolically from the onset of IDDM until final height was reached. Height at diagnosis was within the normal percentiles in boys (0.5 +/- 1.0 standard deviation score [SDS]) and girls (0.4 +/- 1.0 SDS), but above the genetic target height (-1.0 +/- 0.9 SDS in boys and -1.1 +/- 0.6 SDS in girls; P = 0.0001 for both comparisons). Although a lesser height gain was observed during the ensuing years, the final height reached by boys (-0.4 +/- 1.1 SDS) and girls (-0.4 +/- 0.9 SDS) was higher than the genetic target height. Blunted total pubertal growth was observed both in boys (24.5 +/- 3.6 cm) and girls (20.1 +/- 4.2 cm). The decrease in height gain was independent of the duration of IDDM, the degree of metabolic control, or the insulin requirement. The greater the height at diagnosis, with respect to the genetic target height, the lesser was the subsequent height gain to reach final adult height (r = 0.34, p < 0.01). BMI increased with age as normally occurs in healthy children, independent of the duration of disease and the degree of metabolic control. Pubertal development began and progressed normally both in boys and girls. In boys, a testicular volume of 4 ml was reached at a mean age of 12.1 +/- 0.9 years. In girls, breast enlargement occurred at a mean age of 10.4 +/- 1.2 years and the mean age of menarche was 12.8 +/- 1.4 years. Pubertal development and progression occurred independent of the age at onset of IDDM, the glycemic control, or the insulin requirement during the pubertal period. Children with IDDM have normal onset of puberty and normal sexual maturation. Even though final height falls within the normal percentiles, the diminished height gain after diagnosis requires further investigation.

Puberty occurring either spontaneously or induced precociously in rhesus monkey (Macaca mulatta) is associated with a marked proliferation of Sertoli cells.

The pubertal ontogeny of Sertoli cell proliferation in primates is controversial. In the study of the rhesus monkey presented here, we investigated this issue during normal sexual maturation and during precocious puberty induced experimentally with pulsatile GnRH treatment. Cell number was calculated by standard stereological methods employing volume fraction of either seminiferous tubule or, whenever possible, cell nuclei. In the first experiment, testes were collected from normal monkeys at three developmental phases: neonates (7-18 days old, n = 5); juveniles (approximately 17 mo old, n = 4); and adults (5 yr and older, n = 4). In the second experiment, tissue was obtained from an additional three untreated juvenile monkeys and from six other juveniles of comparable age that had been subjected to premature activation of the pituitary-testicular axis for 5 or 10 wk with pulsatile GnRH (1 microgram/min for 3 min every 3 h). The number of Sertoli cells in adults was 6-fold greater than that in neonatal and juvenile animals. A similar increase in number of this somatic cell type was also observed during experimentally induced puberty. A less dramatic proliferation of Sertoli cells occurred during the neonatal-juvenile transition. Although the increase in Sertoli cell number between the juvenile and adult stages of development was paralleled by a comparable change in Ad and Ap spermatogonia, proliferation of these stem spermatogonia during premature activation of the pituitary-testicular axis was less striking. These results lead to the suggestion that, in primates, the onset of puberty is associated with a rapid and substantial proliferation of Sertoli cells, which is subsequently followed by amplification of stem spermatogonia. They also indicate that while Sertoli cells and stem spermatogonia proliferate during infancy and juvenile development, these earlier changes appear to be more insidious than those at puberty.

Effect of seminiferous tubule size on hCG-induced regeneration of peritubular Leydig cells in hypophysectomized, EDS-treated rats.

Following their selective destruction 3 weeks previously by administration of ethane dimethanesulphonate (EDS) the regenerative capacity of Leydig cells was assessed in relation to seminiferous tubule morphology in hypophysectomized adult rats administered 7 daily injections of 100 iu hCG. Total Leydig cell volume per testis in hCG-treated rats (30.2 +/- 3.2 microliters, mean +/- SEM) was significantly (p < 0.01) greater than in the testes of rats at 3 and 4 weeks after EDS-treatment (7.6 +/- 0.7 and 22.7 +/- 1.4 microliters, respectively). Regeneration of Leydig cells in hCG-treated rats significantly (p < 0.05) favoured peritubular locations (18.6 +/- 2.8 microliters/testis) compared to central or perivascular sites of origin (11.6 +/- 1.2 microliters/testis). Partial restoration of spermatogenesis occurred in hCG-treated rats (tubule diameters usually > 250 microns) and a significant inverse correlation was found between peritubular Leydig cell percentage, or total volume per testis, and the volumetric proportion of seminiferous tubules (r = -0.94, p < 0.001) or the seminiferous epithelium (r = -0.73 to -0.79, p < 0.05-0.01). No significant (p > 0.4-0.9) correlation existed between centrally-regenerated Leydig cells and these parameters. The results show that in response to hCG stimulation, Leydig cells are more likely to develop around smaller seminiferous tubules, suggesting that hCG alone cannot mimic the expected pattern of Leydig cell regeneration (central and peritubular origins) which occurs during normal sexual maturation or at 3-4 weeks after EDS treatment. It is concluded that other factors, possibly FSH, are required for typical Leydig cell development which in turn may be influenced by local cellular growth factors originating from either the seminiferous tubules or the adjacent intertubular tissue.

Developmental abnormalities of the gonad and abnormal sex hormone concentrations in juvenile alligators from contaminated and control lakes in Florida.

The reproductive development of alligators from a contaminated and a control lake in central Florida was examined. Lake Apopka is adjacent to an EPA Superfund site, listed due to an extensive spill of dicofol and DDT or its metabolites. These compounds can act as estrogens. Contaminants in the lake also have been derived from extensive agricultural activities around the lake that continue today and a sewage treatment facility associated with the city of Winter Garden, Florida. We examined the hypothesis that an estrogenic contaminant has caused the current failure in recruitment of alligators on Lake Apopka. Supporting data include the following: At 6 months of age, female alligators from Lake Apopka had plasma estradiol-17 beta concentrations almost two times greater than normal females from the control lake, Lake Woodruff. The Apopka females exhibited abnormal ovarian morphology with large numbers of polyovular follicles and polynuclear oocytes. Male juvenile alligators had significantly depressed plasma testosterone concentrations comparable to levels observed in normal Lake Woodruff females but more than three times lower than normal Lake Woodruff males. Additionally, males from Lake Apopka had poorly organized testes and abnormally small phalli. The differences between lakes and sexes in plasma hormone concentrations of juvenile alligators remain even after stimulation with luteinizing hormone. Our data suggest that the gonads of juveniles from Lake Apopka have been permanently modified in ovo, so that normal steroidogenesis is not possible, and thus normal sexual maturation is unlikely.

The adolescent with diabetes

Successful treatment of Type 1 insulin dependent deabetes (IDDM) may be of particular importance during adolescence for the achievement of normal growth and sexual maturation and to reduce the risk of long term micro-vascular complications. Yet it is during adolescence that a deterioration in glycaemic control, as judged by serial glycosylated haemoglobin (HbA1) concetrations, is most often encountered. The reasons behind this deterioration in glycaemic control are complex and include both psychological and physiological factors. This article will concentrate on four areas which encompass many of the problems and controversies surrounding the care of adolescents with diabetes.

Transforming growth factor-α gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation

Hypothalamic injury causes female sexual precocity by activating luteinizing hormone-releasing hormone (LHRH) neurons, which control sexual development. Transforming growth factor-α (TGF-α) has been implicated in this process, but its involvement in normal sexual maturation is unknown. The present study addresses this issue. TGF-α mRNA and protein were found mostly in astroglia, in regions of the hypothalamus concerned with LHRH control. Hypothalamic TGF-α mRNA levels increased at times when secretion of pituitary gonadotropins—an LHRH-dependent event—was elevated, particularly at the time of puberty. Gonadal steroids involved in the control of LHRH secretion increased TGF-α mRNA levels. Blockade of TGF-α action in the median eminence, a site of glial-LHRH nerve terminal association, delayed puberty. These results suggest that TGF-α of glial origin is a component of the developmental program by which the brain controls mammalian sexual maturation.

Evaluation of the role of germ cells in regulating the route of secretion of immunoactive inhibin from the rat testis.

During normal sexual maturation of the male rat there is a progressive change in the route of secretion of inhibin by the Sertoli cell, from a predominantly basal route of secretion in prepuberty to a predominantly apical route of secretion in adulthood. This change may be monitored by comparing the levels of inhibin in testicular (TV), spermatic and peripheral (PV) venous blood and the levels in testicular interstitial fluid (IF). This study has assessed the role of germ cells in effecting this change by assessing (a) the effect of total germ cell depletion by X-irradiation of the males in utero, and (b) the effect of selective germ cell depletion in adulthood using the testicular toxicant, methoxyacetic acid (MAA). Female rats were X-irradiated on day 20 of gestation to produce male offspring whose testes were germ-cell deficient. Blood and IF samples were collected from groups of these offspring and age-matched controls at 35 and 100 days of age. In blood and IF samples, inhibin concentrations were significantly higher at 35 days of age than at 100 days. The absence of germ cells in X-irradiated animals did not affect the age-related fall in inhibin levels, nor the change in the predominant route of secretion of inhibin from the testis into blood. Testosterone was almost undetectable in 35-day-old controls, but was raised significantly by 100 days of age. In X-irradiated animals, testosterone levels were increased significantly at 35 days of age, and the levels in most samples were increased even more substantially by 100 days of age. However, PV levels of testosterone in 100-day-old X-irradiated animals were significantly lower than in controls. LH and FSH levels were raised in X-irradiated animals compared with their age-matched controls, but FSH levels in X-irradiated animals still fell with age, as in the controls. The role of specific germ cell types in regulating the route of secretion of inhibin from the normal adult testis was studied after depletion (80-100%) of pachytene and later spermatocytes by a single oral administration of MAA (650 mg/kg) to adult rats. At 3 days after MAA treatment, coincident with the loss of pachytene spermatocytes, plasma inhibin levels were increased significantly in blood and IF samples, and this was associated with a dramatic change in the route of secretion of inhibin from the testis, with increased secretion of this peptide via the base of the Sertoli cell into IF and TV blood.(ABSTRACT TRUNCATED AT 400 WORDS)

Testosterone Therapy for Pubertal delay

Testosterone Therapy for Pubertal delay