Congenital Hydrocephalus
Congenital Hydrocephalus
Object: Despite the investigations that have linked hydrocephalus to reproductive system abnormalities, no researchers have attempted to identify the pathophysiological mechanism of this relationship. Because the role of the hypothalamic gonadotrophin-releasing hormone (GnRH) system in the regulation of reproductive functions is well established, the authors used immunohistochemical and radioimmunoassay (RIA) techniques to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system.
Methods: Hypothalamic GnRH levels, fiber density, and cell types were studied in 21- and 50-day-old control and congenitally hydrocephalic Texas rats. Results of RIA indicated a significant (8.4%) increase in GnRH in 21-day-old hydrocephalic rats (9.17 ± 0.64 pg/ng total protein) compared with that in controls (0.97 ± 0.74 pg/ng total protein). In addition, the 50-day-old hydrocephalic animals had a significantly higher level of GnRH compared with age-matched controls (20.4 pg/ng compared with 1.88 ± 2.1 pg/ng total protein). This increase was accompanied by changes in the fiber appearance and a shift from low GnRH producing cells to high GnRH producing cells in the hydrocephalic animals; however, there was no significant difference in the fiber density between the control and hydrocephalic animals at 21 days. In addition, poor neurological scores correlated with the severity of hydrocephalus.
Conclusions: These results demonstrated that hypothalamic GnRH levels are significantly affected by fetal-onset hydrocephalus and that the mechanisms responsible for these effects may take place at the cellular rather than the gross structural level. Furthermore, they suggest that impairments in the GnRH system may be protracted in neonates and infants with hydrocephalus, and thus may be overcome by relatively early treatment with ventricular diversion. However, the clinical implications of GnRH perturbations in shunt-dependent patients must await a forthcoming study in shunted animals.
Authors of several case reports and investigations have linked hydrocephalus to reproductive system abnormalities, namely, amenorrhea and precocious puberty. Hydrocephalus-related amenorrhea and precocious puberty have been reported in the literature. A number of authors have suggested a relationship between precocious puberty and hydrocephalus. Moreover, the Gnrh system seems to be the mediator that links hydrocephalus to these reproductive abnormalities.
Despite these clinical data, no researchers have attempted to identify the pathophysiological mechanisms by which the GnRH system is affected. One possibility is that hydrocephalus impairs hypothalamic GnRH regulation by directly altering GnRH-containing neurons or the axonal tracts through which the peptide is transported. The peri- and paraventricular locations of the fiber tracts and the ME subject these structures to increased intracranial pressure and distention of the third ventricle. Most of the neurons that produce GnRH are situated anterior to the third ventricle, and thus may be relatively protected from the pressure and distortion caused by ventriculomegaly. Nevertheless, these cells could be affected retrogradely by direct influences on their axons.
The present study was undertaken to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system. Only one previous attempt has been made to evaluate the changes that occur in the hypothalamus during hydrocephalus, and this study was focused on vasopressin and prolactin alterations in the adult hamster. As described previously, the HTX rat model of inherited, fetal-onset aqueductal stenosis represents a particularly good experimental paradigm in which to study the effects of hydrocephalus on the developing brain. Obstructive hydrocephalus develops in the HTX rats subsequent to aqueductal stenosis between gestational Day 18 (in a 22-day gestation period) and postnatal Day 5. Ventriculomegaly develops progressively to reach severe proportions by Days 21 to 24, and untreated animals usually die by 4 to 6 weeks of age. In view of the probable association between infantile hydrocephalus and the GnRH system, we hypothesized that GnRH axons and neurons would be structurally modified and that GnRH protein would be increased in the hypothalamus of developing HTX rats. This information forms the groundwork for further studies on the pathogenesis of hydrocephalus-related reproductive disorders and on the effects of cerebrospinal fluid shunting.
Object: Despite the investigations that have linked hydrocephalus to reproductive system abnormalities, no researchers have attempted to identify the pathophysiological mechanism of this relationship. Because the role of the hypothalamic gonadotrophin-releasing hormone (GnRH) system in the regulation of reproductive functions is well established, the authors used immunohistochemical and radioimmunoassay (RIA) techniques to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system.
Methods: Hypothalamic GnRH levels, fiber density, and cell types were studied in 21- and 50-day-old control and congenitally hydrocephalic Texas rats. Results of RIA indicated a significant (8.4%) increase in GnRH in 21-day-old hydrocephalic rats (9.17 ± 0.64 pg/ng total protein) compared with that in controls (0.97 ± 0.74 pg/ng total protein). In addition, the 50-day-old hydrocephalic animals had a significantly higher level of GnRH compared with age-matched controls (20.4 pg/ng compared with 1.88 ± 2.1 pg/ng total protein). This increase was accompanied by changes in the fiber appearance and a shift from low GnRH producing cells to high GnRH producing cells in the hydrocephalic animals; however, there was no significant difference in the fiber density between the control and hydrocephalic animals at 21 days. In addition, poor neurological scores correlated with the severity of hydrocephalus.
Conclusions: These results demonstrated that hypothalamic GnRH levels are significantly affected by fetal-onset hydrocephalus and that the mechanisms responsible for these effects may take place at the cellular rather than the gross structural level. Furthermore, they suggest that impairments in the GnRH system may be protracted in neonates and infants with hydrocephalus, and thus may be overcome by relatively early treatment with ventricular diversion. However, the clinical implications of GnRH perturbations in shunt-dependent patients must await a forthcoming study in shunted animals.
Authors of several case reports and investigations have linked hydrocephalus to reproductive system abnormalities, namely, amenorrhea and precocious puberty. Hydrocephalus-related amenorrhea and precocious puberty have been reported in the literature. A number of authors have suggested a relationship between precocious puberty and hydrocephalus. Moreover, the Gnrh system seems to be the mediator that links hydrocephalus to these reproductive abnormalities.
Despite these clinical data, no researchers have attempted to identify the pathophysiological mechanisms by which the GnRH system is affected. One possibility is that hydrocephalus impairs hypothalamic GnRH regulation by directly altering GnRH-containing neurons or the axonal tracts through which the peptide is transported. The peri- and paraventricular locations of the fiber tracts and the ME subject these structures to increased intracranial pressure and distention of the third ventricle. Most of the neurons that produce GnRH are situated anterior to the third ventricle, and thus may be relatively protected from the pressure and distortion caused by ventriculomegaly. Nevertheless, these cells could be affected retrogradely by direct influences on their axons.
The present study was undertaken to determine the morphological and biochemical effects of hydrocephalus on the hypothalamic GnRH system. Only one previous attempt has been made to evaluate the changes that occur in the hypothalamus during hydrocephalus, and this study was focused on vasopressin and prolactin alterations in the adult hamster. As described previously, the HTX rat model of inherited, fetal-onset aqueductal stenosis represents a particularly good experimental paradigm in which to study the effects of hydrocephalus on the developing brain. Obstructive hydrocephalus develops in the HTX rats subsequent to aqueductal stenosis between gestational Day 18 (in a 22-day gestation period) and postnatal Day 5. Ventriculomegaly develops progressively to reach severe proportions by Days 21 to 24, and untreated animals usually die by 4 to 6 weeks of age. In view of the probable association between infantile hydrocephalus and the GnRH system, we hypothesized that GnRH axons and neurons would be structurally modified and that GnRH protein would be increased in the hypothalamus of developing HTX rats. This information forms the groundwork for further studies on the pathogenesis of hydrocephalus-related reproductive disorders and on the effects of cerebrospinal fluid shunting.
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