| BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a rare congenital disorder due to an isolated deficiency or dysfunction of gonadotropin-releasing hormone (GnRH) neurons. IHH is characterized by delayed or absent sexual maturation and infertility associated with inappropriately low gonadotropin and sex steroid levels. In addition to IHH, constitutional delayed puberty is the most common diseases resulting in male delayed puberty disorders. CDP patients absent signs of sexual maturation by puberty age, with low serum gonadotropin and gonadal hormone levels, which are similar with IHH. Prolonged gonadal hormone deficiency in IHH patients may produce adverse effects on the endocrine homeostasis and metabolism. The hypothalamic-pituitary-adrenal (HPA) axis is essential for the regulation and maintenance of homeostasis. Gonadal hormone deficiency will inevitably lead to an imbalance of endocrine homeostasis, which may affect the HPA axis. Animal studies have shown that adrenocorticotropic hormone (ACTH) and corticosterone levels in male rats are increased by gonadectomy. But investigations on the influence of androgen deficiency on the basal HPA axis in humans are rare and still inconsistent. One of the main reasons for this is that previous studies have focused on healthy subjects by provisionally manipulating sex hormones to evaluate effects on the HPA axis. Therefore, the effects of prolonged androgen deficiency on the HPA axis in human males are unclear and limited to speculations based on observed in lower animals and healthy men. On the other hand, it is now established that low serum testosterone levels in men are associated with an increased risk of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Recently, a number of cross sectional studies have reported that patients with NAFLD increased clearance and decreased hepatic regeneration of cortisol and shown the association of NAFLD with chronic, subclinical compensatory activation of the HPA axis in humans. Furthermore, compensatory activation of the HPA axis may drive increased adrenal androgen secretion. Hence, we speculated there may be some correlation between NAFLD and the HPA axis. Glucocorticoids are regulated by the activities of 11 β-hydroxysteroid dehydrogenase 1(11β-HSD1) and the A-ring reductases (5a-and 5β-reductases). Changes in the expression of mRNAs of these enzymes have been reported in obese and NAFLD humans. However, in the condition of 1ong-term testosterone deficiency and NAFLD, the changes in the expression of glucocorticoid metabolizing enzymes are still unknown.ObjectivesAs compared with CDP, we characterized the clinical and hormone secretion features of IHH. We performed a retrospective case-control study involving 75 Chinese male IHH patients and 135 healthy controls after matching for gender and age. We measured serum basal ACTH and cortisol levels in male IHH patients and compare the patients with healthy controls. We compared serum basal ACTH, cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in IHH patients with NAFLD with patients without NAFLD. We also used castrated Sprague-Dawley (SD) rats to investigate the possible mechanism by which androgens may act to influence HPA function. We wanted to explore the relationship between prolonged androgen deficiency and basal HPA axis, and determined the associations of NAFLD and HPA axis in IHH, with the hope that a better and more comprehensive recognition of the change of basal HPA axis in IHH patients can be got, and the influence of IHH on the endocrine homeostasis and metabolism can be obtained.Methods1. Clinical data of 98 IHH patients and 35 CDP hospitalized male patients, who were admitted to the Chinese PLA General Hospital from January 2010 to October 2013, were retrospectively analysed, including age, bone age, anthropometry measurements, pubertal status, associated malformations, laboratory tests, basal and peak hormone levels. We compared the differences between the two diseases, summarized and analyzed the IHH patient specific clinical manifestations and clinical characteristics.2. We performed a retrospective case-control study involving 75 Chinese male IHH patients (mean age 21.39 ± 3.74 years, range 17-30 years) and 135 healthy controls after matching for gender and age. The present study measured serum basal ACTH and cortisol levels in male IHH patients and compare the patients with healthy controls to further characterize the basal HPA axis in human male with prolonged androgen deficiency. We also compared serum basal ACTH, cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in IHH patients with NAFLD with patients without NAFLD.3. Glucocorticoids metabolism was studied in male Sprague-Dawley rats (age lOwks,15 animals per group) 15wks after gonadectomy and high fat diet. Body weight and laboratory tests were monitored throughout life. Tail vein blood was taken at intervals of two weeks to detect blood glucose, lipids and biochemical indicators. The fat and muscle content of SD rats were analized by EnchoMRI in the 15th week. ACTH, CORT and DHEA levels were measured by ELISA assay. Abundances of mRNAs for steroid metabolizing enzymes were quantified in liver and adipose tissue.Results1. As compared with CDP, the arm span in more than half of IHH patients were greater than the height, the upper part in about 80% IHH patients were greater than the lower part (P<0.05). There were about 45% IHH patients with varying degrees of anosmia. Cryptorchidism and delayed bone age were significantly higher in IHH patients than in CDP patients (P<0.05). Both IHH and CDP patients were similar in terms of laboratory tests. Testicular volume of CDP patients were significantly greater than in patients with IHH (P<0.05), but the length of penis were no significant difference in the two groups. Basal T, LH and FSH levels were significantly lower in patients than in CDP patients (P<0.05). Serum basal ACTH and cortisol levels were significant higher in IHH patients than in CDP patients (P<0.05). For GnRH and HCG stimulation test, LH, FSH change value in CDP patients were significantly higher than in patients with IHH. The values of FSHmax/LHmax in IHH patients were higher than 1, and the values of FSHmax/LHmax in CDP patients were lower than 1 (P<0.05). When LHmax<10.51U/L was used as a criteria for the diagnosis of IHH, the GnRH stimulation test had a sensitivity of 88.6%, a specificity of 84.3%. When FSHmax<5.08U/L was used as a criteria for the diagnosis of IHH, the GnRH stimulation test had a sensitivity of 93.9%, a specificity of 70.0%.2. We observed higher serum basal ACTH levels and lower cortisol levels in male IHH patients than healthy subjects (p<0.05). IHH patients also showed higher metabolism parameters and higher prevalence rate of NAFLD than the controls (p<0.05). Serum basal ACTH and dehydroepiandrosterone sulfate (DHEAS) levels were significantly higher in IHH with NAFLD than in non-NAFLD groups (p<0.05). We also found that serum basal ACTH levels were positively correlated with NAFLD (r= 0.289, p<0.05) and triglyceride levels (r= 0.268, p<0.05) in IHH patients.3. Gonadectomy did not consistently alter weight gain, fasting blood glucose levels, or blood-lipid spectrum in rats fed by high-fat diets. Gonadectomy further increased the fat content (P<0.05) and increased ACTH and DHEA levels (P<0.05) in rats fed by high-fat diets. In liver, gonadectomy further suppressed 11β-HSD1 mRNA, 5β-reductase mRNA and GR mRNA, and further increased 5a-reductasel mRNA (P<0.05) in rats fed by high-fat diets than in rats fed by high-fat diets without gonadectomy. However, in adipose, gonadectomy further increased 11β-HSD1 mRNA and further suppressed 5α-reductase 1 and 50-reductase mRNA in rats fed by high-fat diets than in rats fed by high-fat diets without gonadectomy (P<0.05).Conclusion1. In IHH patients, the arm span is greater than the height, the lower part is greater than the upper part. Cryptorchidism and delayed bone age are common in IHH patients. As compared with CDP patients, serum basal testosterone, LH and FSH levels are lower in IHH patients. GnRH stimulation test shows the value of FSHmax/LHmax in IHH patients are greater than in CDP patients. GnRH stimulation test and HCG stimulation test have great value in identifying IHH and CDP patients. IHH patients have a higher serum basal ACTH and cortisol levels than in CDP patients.2. IHH patients showed higher serum basal ACTH levels and lower cortisol levels than matched controls. High-end normal ACTH levels are associated with NAFLD and triglyceride levels in male IHH patients. These preliminary findings provide evidence of the relationship between serum basal ACTH and NAFLD in male IHH patients.3. The high fat diet and gonadectomy induces complex changes in the regulation of the different components of the HP A axis. The NAFLD decreases 11β-HSD1 and increase 5a-reductase 1 in liver. By contrast, the high fat diet increases 11β-HSD1 and decrease 5a-reductase 1 in adipose tissue. Androgens tonically amplificate these effects. NAFLD have synergism with low serum testosterone in affecting the activity of the basal HPA axis. |
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