Primary Glucocorticoid Resistance Preliminary Study Of The Clinical Treatment Of The Syndrome And Its Pathogenesis

History and clinical findings: Primary glucocorticoid resistance syndrome (PGRS) is a rare condition characterized by hypercortisolism without Cushing's syndrome. This report describes a 7 year-old boy of PGRS with pseudo-precocious puberty and galactorrhea as the main manifestation. His height was 135 cm and body weight was 31 kg. Pigmentation could be seen in the skin, mammary areola and penis. He had hirsutism, low hair line, coarse voice, Tanner stage 3 pubic hair, penis in adult form, accelerated linear growth, and advanced bone age (13 yr), but normal (for age) testes. Furthermore, he had mammoplasia and galactorrhea. There were no features of glucocorticoid (GC) excess.Investigation: Serum cortisol concentration were 1445 nmol/L, 1294 nmol/L, 777 nmol/L, 199.3 nmol/L at 0800, 1200,1600 and 2400 h respectively. Plasma adrenocorticotropic hormone (ACTH) were normal or a little higher (43.9～80 ng/L). Urinary-free cortisol (UFC) is normal (55.5～62.4μg/24h).Serum estradiol (E₂) was 13.31pg/mL, progesterone (P) was 0.21ng/mL, testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were very low (T＜0.02 ng/mL, LH＜0.1 mIU/mL, FSH＜0.1 mIU/mL). Serum DHEA-sulfate (DHEAS) was 60μg/dL, urinary dehydroepiandrosterone (DHEA) level was elevated (0.96～3.2 mg/mL). Serum prolactin (PRL) level was high (58.7～183.9 ng/mL). Gonadotrophin hormone-releasing hormone (GnRH) stimulation test was negative. Serum cortisol responded normally to insulin-induced hypoglycemia. However, serum cortisol and plasma ACTH concentration was suppressed to more than 50% by 0.5 mg dexamethasone (Dex). Hepatic function was impaired (ALT 1426 IU/L, AST 611 IU/L) with no definite causes. The diagnosis of PGRS was made.Treatment and follow-up: The patient received a treatment of 0.75～1.0 mg/d Dex. Because of galactorrhea, bromocriptine was given 1.25～3.75 mg/d. After 12 months follow-up, the pigmentation relieved and galactorrhea disappeared. No advanced development of the external genitalia and breast was found. The acceleration of the bone age was also slowed down. But he still had obviously hirsutism. No side effect of taking Dex was found.Discussion and conclusion: In this case, the molecular mechanism may relate to the abnormality of the glucocorticoid receptor (GR) or the glucocorticoid (GC) signal transduction, altering tissue sensitivity to GC. Compensatory elevations in circulating ACTH concentrations lead to increased production of adrenal androgenic steroids and their corresponding clinical manifestations such as pseudo-precocious puberty and hirsutism. The impairment of hepatic function may also have relation to the increased production of adrenal androgens. However, the mechanism of galactorrhea and high circulating PRL concentration is still unclear. The aim of treatment in glucocorticoid resistance is to suppress the excessive secretion of ACTH and the increased production of adrenal androgens. The administration of synthetic GC with minimal intrinsic mineralocorticoid activity, such as Dex, provides a rational treatment for PGRS. Long-term Dex treatment should be individualized and carefully titrated based on the clinical manifestations and biochemical profile in order to control the clinical manifestations of the disease. Objective: Determination for the binding capacity and dissociation characters of glucocorticoid receptor (GR) in a boy with primary glucocorticoid resistance syndrome (PGRS) and his family members by radioligand binding assay to investigate the possible mechanism for PGRS.Methods: Isolation of the peripheral blood mononuclear cells (PBMCs) by Ficoll density gradient centrifugation. Using ³H-Dexamethasone (³H-Dex) as a labeled-ligand, we investigated the GR binding capacity and dissociation characters by radioligand binding assay and Scathard analysis.Results: The GR binding capacity (18.4 fmol/10⁶ cells) and affinity (Kd value: 8.6 nmol/L) of the patient were within the 95% of the control group (15.7±2.96 fmol/10⁶ cells, Kd value: 12.54±2.56 nmol/L). The same result was found in his family members. No significant differences in the family's GR binding capacity (18.7±7.08 fmol/10⁶ cells) and affinity (Kd value: 10.6±4.78 nmol/L) were found while compared with the normal control subjects.Conclusion: We found that the GR binding capacity and affinity of the patient were normal. The molecular mechanism of PGRS in this case may relate to other abnormalities of the GR or glucocorticoid signal transduction. Objective: Determination for the thermolability of glucocorticoid receptor (GR) in a boy with primary glucocorticoid resistance syndrome (PGRS) and his parents by radioligand binding assay to investigate the possible mechanism for PGRS.Methods: Isolation of the peripheral blood mononuclear cells (PBMCs) by Ficoll density gradient centrifugation. Using ³H-Dexamethasone (³H-Dex) as a labeled-ligand and reacting at 40℃, we investigated the GR binding capacity by radioligand binding assay and Scathard analysis. Compared to the results at 24℃which we had done before, this research evaluated the GR thermolability of the patient.Results: When the GR binding capacity (5.07 fmol/10⁶ cells) at 40℃of the patient was compared with the result of 24℃(18.4 fmol/10⁶ cells), the percentage was 27.51%. The percentage of the control group was 69.93±6.30% and the difference was distinguishable. The percentages of his parents were 47.21% and 44.19% respectively, and the difference between his parents and control group was also distinguishable.Conclusion: We found that the GR binding capacity at 40℃of the patient was significantly decreased. The GR binding capacity at 40℃of his parents were also decreased compared to the control group. The mechanism of PGRS in this case may relate to the increased GR thermolability.