Growth hormone therapy in childhood-onset growth hormone deficiency: adult anthropometric and psychological outcomes

The current adult heights of hypopituitary children treated with recombinant human growth hormone (rGH) now range between −1.5 and −0.7 height standard deviations (HtSDS) of control populations. These height outcomes are markedly better than the ones observed following treatment with pituitary-derived human growth hormone (pGH) (between −4.7 and −2.0 Ht SDS). Although treatment with rGH has not yielded adult heights that are equal to genetic target heights, the discrepancy is much less now than in previous decades. Higher rGH dose, longer duration of treatment, early age at diagnosis, correction of height deficit prior to onset of puberty, and daily rGH injections have had beneficial effects on final adult heights. The current dosing regimens, (0.3–0.18 mg/kg/wK) have not had an adverse effect on bone maturation and have not stimulated an earlier onset of puberty. Although height gains in puberty are less than controls, a majority of treated subjects reach heights within the normal range for adults. Higher doses of rGH during puberty have been studied in limited numbers of adolescents with positive effects; however, standard dosing will likely continue to be used because of financial considerations and safety concerns. Further improvements in adult heights are likely to be reported when the youngest children who began rGH in 1985 complete their growth. Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) patients who, as children, had been treated with GH predominantly during the pGH era. Domains of functioning assessed include educational attainment, employment, and marital status. Although some studies have reported a generally positive adaptation, others have shown this group to exhibit marked deficits. Limited adult height outcomes in the pGH era of GH therapy has sometimes been used to account for poor outcomes. Variable behavioral findings are likely related to sample heterogeneity and disparate research methodologies and designs, most particularly the choice of control or comparison groups. In addition to summarizing this older literature, we report on a recently completed investigation in which the QOL adjustment of GHD patients is compared to that of same-sex siblings. Comparisons between GHD cases and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same-sex siblings. IGHD (isolated growth hormone deficiency) patients were functioning better than those with MPHD (multiple pituitary hormone deficiencies), but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.     

Renaturalizing the sexually dimorphic profiles of circulating growth hormone in hypophysectomized rats

Hypophysectomy resulted in a total elimination of measurable circulating growth hormone with an associated loss of body weight gain. The typical sexually dimorphic plasma growth hormone patterns: pulsatile profiles in male rats and tonic-like secretion in female rats, were lost. The male- and female-dependent profiles of plasma growth hormone, monitored from serial blood collections, were restored by administering the hormone through a single electrically controlled external pump attached to an indwelling catheter, and by implanting osmotic pumps intraperitoneally, respectively. Restoring the natural patterns of plasma growth hormone in animals devoid of pituitaries, re-initiated body growth. However, the body weight gains in both sexes of hypophysectomized rats were much greater when rat growth hormone was introduced to the animals in a masculine (pulsatile) pattern that appeared to be independent of pulse frequency, rather than in a continuous feminine profile. Subcutaneous injections, the most commonly reported method of administration, produced low-amplitude, long-lasting plasma peaks that were not as effective as pulse infusion in restoring growth. The procedure allows manipulation of the hormone profile (i.e. number of pulses/day, pulse amplitude, and through duration in the pulsatile pattern, and plasma concentration in the tonic pattern) in order to identify, and thus study the presumed salient components of the pattern regulating growth hormone responses.     

A sexually dimorphic pattern of growth hormone secretion in the elderly.

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.     

Intrinsic signals in the sexually dimorphic circulating growth hormone profiles of the rat

Male rats secrete growth hormone (GH) in episodic bursts every 3.5-4 h. Between the peaks, GH levels are undetectable. In females, GH secretory profiles are characterized as continuous because hormone concentrations are always measurable in the circulation. These gender differences in the circulating GH profiles are responsible, to varying degrees, for observed sexual dimorphisms ranging from body growth to the expression of hepatic cytochrome P450 (P450, CYP) isoforms. Using hypophysectomized rats in which restored gender-dependent plasma GH profiles were manipulated, we have investigated the importance of the interpulse period in the masculine episodic plasma GH profile in regulating expression (mRNA, protein and/or specific catalytic activity) of male-specific CYP2A2, 2C11, 2C13 and 3A2, female-specific CYP2C12 and female-predominant CYP2A1, 2C6 and 2C7. We observed that some isoforms were induced or suppressed by discerning the length of the GH-devoid interpulse period, others responded to the pulse amplitudes, still others recognized the mean circulating concentrations of GH and some were regulated by a combination of these signals. We conclude that concealed in the gender-dependent circulating GH profiles are numerous intrinsic signals, both inductive and repressive, individually "tailored" to be recognized by each isoform of P450. There would appear to be no one signal in each gender-dependent GH profile responsible, in toto, for the characteristic sexually dimorphic expression of some dozen hepatic P450s in male and female rats.     

Growth hormone therapy for children with chronic diseases

Growth disorders are commonly observed in children suffering from chronic diseases. The pathogenesis of growth failure is multifactorial. In chronic inflammatory diseases such as juvenile idiopathic arthritis and inflammatory bowel disease, growth is also affected by pro-inflammatory cytokines. Patients with chronic diseases might also become growth hormone (GH) deficient. However, normal or increased GH secretion with reduced plasma concentrations of insulin-like growth factor-I indicate a degree of GH insensitivity in some patients. Growth damage can increase with specific treatments, especially if glucocorticoids are used. GH therapy has been used to reduce the consequences of the disease and long-term steroid therapy in these patients. In this review, it is reported the encouraging results of GH treatment in growth-retarded children with chronic diseases, both in well defined indications as well in situations still under investigation.     

Growth hormone replacement therapy in growth hormone deficient children and adults: Effects on hemochrome

Several lines of evidence have suggested a role of the GH/IGF-I axis in the regulation of hemochrome. Many studies have been carried out in GH deficient children and adults about this topic, reporting predominantly a positive effect of recombinant human GH (rhGH) on red series, with no action on serum leucocytes and platelets counts. The aim of this study was to assess the impact of GH deficiency (GHD) and of rhGH replacement on blood cells count in 17 pre-pubertal children with idiopathic isolated GHD (11 males and 6 females, aged 9.1+/-0.8 yr) and in 18 patients with adult-onset GHD (12 males and 6 females, aged 47.9+/-3.0 yr). Evaluation of absolute and SD score (SDS) values of red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets and white blood cells was performed at baseline and after 12 months of rhGH treatment (0.045+/-0.001 mg/kg bw/day and 4.2+/-0.5 microg/kg bw/day for children and adults, respectively). At baseline, all patients showed low IGF-I levels. Effectiveness of rhGH therapy was documented by significant increase in height SDS, height velocity and serum IGF-I levels in children. In adults, adequacy of rhGH was demonstrated by significant increase in serum IGF-I and significant decrease in body fat. At baseline, about 25% of patients (4 of 17 children and 4 of 18 adults) showed normochromic normocytic anemia, while the other indices were normal. In 7 of the 8 anemic patients, normal levels of hemoglobin were restored on rhGH, while no change in all the other indices was observed. In conclusion, rhGH therapy at physiological doses has no effect on erythropoiesis in GHD children and adults with normal blood cells count, while in patients with normochromic normocytic anemia rhGH is able to restore normal hemoglobin levels.     

Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy

The most appropriate way to manage GH replacement in the transition period to adulthood in children treated with GH for GH deficiency (GHD) is controversial. The Growth Hormone Research Society suggests that the retesting of GH status at final height (FH) is unnecessary in the presence of severe organic GHD, and cranial irradiation falls into this etiological category. This recommendation has never been validated. To investigate whether patients diagnosed in childhood as GHD secondary to irradiation require retesting after FH, GH status has been reassessed in a large cohort of irradiated children treated with GH during childhood. Seventy-three children underwent biochemical assessment of GH status after irradiation and again at FH after GH therapy had been discontinued; 66 and 67 of the 73 patients underwent two provocative tests at the two time points, respectively. The characteristics of the cohort include a median age at irradiation of 5 yr (range, 1-11 yr), a median biological effective dose (BED) of irradiation to the hypothalamic pituitary axis of 54 Gy (range, 23-82 Gy), and a median time of GH status reassessment after FH of 0.4 yr (range, 0-8.4 yr). During childhood, patients with all degrees of GHD (peak GH responses to provocative test < 6.7 ng/ml) are treated, whereas in adulthood, only patients with severe GHD (peak GH responses to provocative test < 3 ng/ml) are considered for GH replacement. GH status has been grouped as follows: group 1, peak GH less than 3 ng/ml to both tests (severe GHD); group 2, one test with a peak GH less than 3 ng/ml and the other test with a peak of 3 ng/ml or greater; group 3, peak GH of 3-6.7 ng/ml to both tests; group 4, one test with a peak GH of 3-6.7 ng/ml and the other test with a peak of more than 6.7 ng/ml; and group 5, peak GH more than 6.7 ng/ml to both tests (normal GH status). In childhood, the number of patients in groups 1, 2, 3, and 4 were 33, 22, 17, and one, respectively. At retesting, severe GHD was diagnosed in 21 (64%) of 33 patients who were diagnosed in childhood with severe GHD (group 1) and 17 (44%) of 39 patients who were diagnosed in childhood with moderate GHD (groups 2 and 3). In total, 35 (48%) of 73 patients in the whole cohort and 12 (36%) of 33 patients with severe GHD in childhood did not fulfill the severe GHD biochemical criteria for GH replacement in adulthood. Using multiple linear regression, GH status at retesting is predicted by BED, age at irradiation, and use of chemotherapy. In conclusion, the diagnosis of severe GHD in childhood secondary to irradiation should not be taken as irrefutable evidence of permanent severe organic GHD, and our recommendation is that retesting of GH status at FH should be mandatory.     

Growth hormone regulation of serum lipoproteins in the rat: different growth hormone regulatory principles for apolipoprotein (apo) B and the sexually dimorphic apo E concentrations

Growth hormone (GH) regulation of serum lipoproteins and apolipoproteins was studied using hypophysectomized (Hx) male and female Sprague-Dawley rats. Hypophysectomies were performed at 45 or 50 days of age. Hx rats were given replacement therapy with L-thyroxine (10 micrograms/kg/d) and hydrocortisone (400 micrograms/kg/d) unless otherwise specified. Bovine GH (bGH) was given either as two daily subcutaneous (SC) injections at 12-hour intervals or as a continuous SC infusion. Serum cholesterol and apolipoprotein (apo) E concentrations decreased after Hx of female rats. In contrast, Hx of male rats resulted in increased serum cholesterol concentrations and had no effect on serum apo E concentrations. There were no effects of Hx on high-density lipoprotein (HDL) apo E levels in male rats in contrast to female rats. bGH given twice daily to Hx male rats had no effect on HDL apo E levels, but a continuous infusion of bGH resulted in a marked increase in HDL apo E concentration, to levels above those of intact male rats. As previously observed in female rats, serum and HDL apo A-I concentrations decreased and serum and low-density lipoprotein (LDL) concentrations of apo B increased after Hx of male rats. Treatment with L-thyroxine and hydrocortisone reduced the serum concentrations of apo B. bGH given alone resulted in even lower concentrations of apo B. Serum concentrations of cholesterol and apo E were unaffected by replacement therapy with L-thyroxine and hydrocortisone. Treatment with bGH alone had similar effects on serum cholesterol, apo E, and apo B concentrations as treatment with L-thyroxine, hydrocortisone, and bGH in combination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood

There are well-recognized sex differences in many pituitary endocrine axes, usually thought to be generated by gonadal steroid imprinting of the neuroendocrine hypothalamus. However, the recognition that growth hormone (GH) cells are arranged in functionally organized networks raises the possibility that the responses of the network are different in males and females. We studied this by directly monitoring the calcium responses to an identical GH-releasing hormone (GHRH) stimulus in populations of individual GH cells in slices taken from male and female murine GH-eGFP pituitary glands. We found that the GH cell network responses are sexually dimorphic, with a higher proportion of responding cells in males than in females, correlated with greater GH release from male slices. Repetitive waves of calcium spiking activity were triggered by GHRH in some males, but were never observed in females. This was not due to a permanent difference in the network architecture between male and female mice; rather, the sex difference in the proportions of GH cells responding to GHRH were switched by postpubertal gonadectomy and reversed with hormone replacements, suggesting that the network responses are dynamically regulated in adulthood by gonadal steroids. Thus, the pituitary gland contributes to the sexually dimorphic patterns of GH secretion that play an important role in differences in growth and metabolism between the sexes.     

Growth hormone suppression after an oral glucose load in children

BACKGROUND: GH nonsuppression after oral glucose is diagnostic for GH excess, but normative data are lacking in children. Adult data cannot be extrapolated to children given the pubertal increase in GH concentration. In addition, because GH levels are higher in pubertal girls than boys, nadir GH may differ across gender. OBJECTIVE: Our objective was to determine whether nadir GH during an oral glucose tolerance test (OGTT) is gender and pubertal stage specific. We hypothesized that nadir GH would be higher in girls, and at the pubertal stage known to correspond with peak height velocity (Tanner 2-3 in girls and Tanner 3-4 in boys) and maximal GH concentrations. SUBJECTS/ METHODS: A 2-h OGTT using 2.35 g/kg oral glucose (maximum 100 g) was performed in 64 girls and 43 boys, 9-17 yr (10th-90th percentiles for body mass index). Girls were grouped as group 1 (Tanner 1), group 2 (Tanner 2-3), and group 3 (Tanner 4-5), and boys as group 1 (Tanner 1-2), group 2 (Tanner 3-4), and group 3 (Tanner 5). RESULTS: Nadir GH was higher in girls than boys, and in group 2 girls and boys than the other two groups. The upper limit for nadir GH was highest in group 2 girls (1.57 ng/ml), and lower for the other two groups of girls (0.64 ng/ml), and for boys (0.50 ng/ml). All but one girl, and all boys suppressed to less than 1.0 ng/ml. There were 16 girls and five boys who had a nadir GH of more than 0.3 ng/ml. CONCLUSION: GH suppression after oral glucose is gender and pubertal stage specific.     

Growth outcomes in individuals with idiopathic short stature treated with growth hormone therapy

The few studies that have evaluated the long-term height outcomes following growth hormone (GH) treatment in children with idiopathic short stature (ISS) have shown a growth response to GH treatment similar to that in GH-deficient children. A literature search of all randomized and nonrandomized studies of GH treatment in children with ISS from prepubertal years to adult height or near-adult height published over the last 10 years identified six publications (none was a classic meta-analysis). Several studies showed a dose-dependent response in height outcome. Overall, the younger the patient and the greater the difference in current height vs. parental height at start of treatment, the more substantial the gain in height. Height improvement ranged from 0.5 to 1.3 standard deviation score (SDS). The magnitude of height gain was substantial, even after adjustment for growth changes in control subjects (0.5 to 1 SDS), and it was comparable to that seen in other non-GH-deficient syndromes. Only two studies reported data from matched control subjects. Interestingly, there was no difference in height gain between familial short stature and non-familial short stature after adjusting for spontaneous height gain to adult age in non-GH-treated control subjects. To summarize, patients with ISS can benefit from GH treatment with respect to growth outcome, with results maintained into adulthood.     

Growth hormone (GH) secretion, GH-dependent gene expression, and sexually dimorphic body growth in young rats with chronic renal failure

Chronic renal disease results in growth failure in children. This study sought to determine the influences of early renal failure on body growth, growth hormone (GH) secretion, and GH-dependent hepatic gene expression. Neonatal animals were subjected to five-sixth nephrectomy (Nephr) and monitored during growth. Sham-operated male (Sham) and female (Fem) rats served as controls. Whereas Nephr of adult animals causes renal insufficiency, neonatal nephrectomy leads to frank renal failure. In male Nephr compared with Sham animals, GH half-life and GH pulse frequency increased by 1.55- and 1.33-fold, respectively, and GH secretory-burst size decreased by 80%. Approximate entropy analysis quantified more disorderly patterns of GH secretion in Nephr animals, which differed from Sham males, but not from Fem rats. Expression of liver P450 CYP2C11 mRNA, which is dependent upon the male GH pattern, became undetectable, whereas expression of liver P450 CYP2C12 mRNA, which is dependent upon the female GH pattern, increased multifold. Renal failure in young rats abrogates the male pattern of GH pulsatility, abolishes the sexual dimorphism of body weight gain, and induces a female pattern of hepatic gene expression. These data raise the possibility that disruption of pulsatile GH secretion contributes to the growth failure of renal disease.     

Growth hormone deficiency in children

The foundation for the diagnosis of growth hormone (GH) deficiency in childhood must be auxology, that is, the comparison of the child’s growth pattern to that of established norms for gender and ethnicity. It is only in those growing considerably more slowly than average that testing for GHD makes sense. Assessment of laboratory tests, whether static, for example, the measurement of growth factors or their binding proteins, or dynamic, for example, secretagogue-stimulated GH secretion is confirmatory. One must be cognizant of the assay used to determine GH, for there may be a 3-fold difference in the concentration of GH among commercially-available assays. Controversy still exists concerning the measurement of spontaneous GH release and whether sex-steroid priming is appropriate in prepubertal children. Imaging analysis may prove helpful in some children with congenital GHD or to detect a space-occupying lesion in the area of the hypothalamus and pituitary. The final diagnosis is based on multiple parameters and occasionally on a therapeutic trial of GH therapy to determine if there is a significant acceleration of growth velocity.     

Middle cerebral artery occlusion 25?years after cranial radiation therapy in acromegaly: a case report

We report a case of ischemic stroke in a 43 year-old woman with no traditional cardiovascular risk factors and a history of cranial surgery and cranial radiation therapy (CRT) for a GH-secreting pituitary macroadenoma. The neurological work-up on this patient disclosed several cerebral ischemic lesions and demonstrated the occlusion of the right middle cerebral artery together with the narrowing of the right carotid artery; post-radiation brain damage was also visible by nuclear magnetic resonance. We postulate the existence in this patient of a radiation-induced vascular damage, which is a well recognized process thoroughly described in in vitro studies. We remark that life-long follow-up of acromegalic patients receiving CRT is essential so that early diagnosis of radiation-induced vascular injury can be made.     

Growth hormone releasing hormone plus arginine stimulation testing in young adults treated in childhood with cranio-spinal radiation therapy

OBJECTIVE: Growth hormone deficiency (GHD) secondary to cranio-spinal radiation therapy (CSRT) is a complication seen in medulloblastoma survivors. The standard for diagnosis of adult GHD is a peak GH < 3 microg/l by the insulin tolerance test (ITT). However, insulin tolerance testing exposes patients to the risks of hypoglycaemia. Recent studies suggest that the GH releasing hormone + arginine (GHRH + ARG) test can identify GHD in cranially irradiated patients at longer time intervals after radiation. We evaluated the GHRH + ARG stimulation test compared to the ITT in young adults diagnosed with medulloblastoma during childhood. PATIENTS: We evaluated 10 young adult patients (age range 17-26 years) who were treated with CSRT during childhood for medulloblastoma, and who had resultant childhood-onset GHD. MEASUREMENTS: Subjects underwent GH provocative testing with the ITT and the GHRH + ARG test. IGF-I and IGFBP3 levels were also measured at baseline. RESULTS: Insulin tolerance testing and GHRH + arginine stimulation were performed at a mean +/- SD 14 +/- 4.4 years after cranial radiation. All patients failed the ITT with median peak GH 0.40 microg/l (range < 0.05-2.2). GHRH + arginine gave higher peak GH levels with a mean of 7.9 +/- 5.7 microg/l (P = 0.003). Four patients had peak GH > 9 microg/l and were between 7.8 and 19.6 years from cranial radiation. There was no correlation of peak GH levels with time interval since CSRT. Thirty-three per cent of subjects had normal IGF-I; neither IGF-I nor IGFBP3 standard deviation scores (SDS) correlated with ITT results. CONCLUSIONS: Using a GHRH + arginine cut-off for GHD of 9 microg/l, four patients would have been misclassified as GH sufficient, despite being > 7 years (with two patients being nearly 20 years) out from CSRT. These findings suggest that the pituitary GH-producing cells of young adults continue to maintain responsiveness to GHRH + arginine more than 5-10 years after cranial irradiation.     

Neonatal imprinting predetermines the sexually dimorphic, estrogen-dependent expression of galanin in luteinizing hormone-releasing hormone neurons.

The incidence of colocalization of galanin (GAL) in luteinizing hormone-releasing hormone (LHRH) neurons is 4- to 5-fold higher in female than male rats. This fact and the finding that the degree of colocalization parallels estradiol levels during the estrous cycle suggest that GAL is an estrogen-inducible product in a subset of LHRH neurons. To analyze further this paradigm we evaluated the effects of gonadectomy and steroid replacement therapy in male and female rats. Ovariectomy resulted in a significant decrease in the number of cells colocalizing LHRH and GAL, whereas estradiol replacement to such animals restored the incidence of colocalization to that observed in controls. In males, however, estradiol treatment failed to enhance the incidence of colocalization of GAL and LHRH, indicating, therefore, that the colocalization of these peptides is gender-determined. This possibility--i.e., gender-specific determination of LHRH neurons coexpressing GAL--was evaluated by neonatal manipulation of hypothalamic steroid imprinting. As mentioned above, male rats did not respond to estrogen or testosterone by increasing GAL/LHRH colocalization as females did. Neonatally orchidectomized rats, whose hypothalami have not been exposed to testosterone during the critical period, when treated with estrogen in adulthood showed an increase in colocalization of GAL and LHRH similar to that seen in female animals. These observations indicate that the colocalization of LHRH/GAL is neonatally determined by an epigenetic mechanism that involves the testis. In summary, this sex difference in the incidence of colocalization of GAL and LHRH represents a unique aspect of sexual differentiation in that only certain phenotypic characteristics of a certain cellular lineage are dimorphic. The subpopulation of LHRH neurons that also produces GAL represents a portion of the LHRH neuronal system that is sexually differentiated and programed to integrate, under steroidal control, a network of LHRH neurons that could synchronize their activity to control the estrous cycle in rats.