Clinical and molecular characterization of 10 Chinese children with congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency.

BACKGROUND: The clinical manifestations of nonclassical 11beta-hydroxylase deficiency are very similar to those of non-classical 21-hydroxylase deficiency. For this study, we investigated the relationship between the clinical and molecular features of congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency and reviewed the related literature, which are expected to provide assistance for the clinical diagnosis and analysis of congenital adrenal hyperplasia. METHODS: Clinical data for 10 Chinese patients diagnosed with congenital adrenal hyperplasia in our hospital from 2018 to 2022 were retrospectively analyzed. We examined the effects of gene mutations on protease activity and constructed three-dimensional structure prediction models of proteins. RESULTS: We describe 10 patients with 11beta-hydroxylase gene mutations (n = 5, 46,XY; n = 5, 46,XX), with 10 novel mutations were reported. Female patients received treatment at an early stage, with an average age of 2.08 ± 1.66 years, whereas male patients received treatment significantly later, at an average age of 9.77 ± 3.62 years. The most common CYP11B1 pathogenic variant in the Chinese population was found to be c.1360C > T. All mutations lead to spatial conformational changes that affect protein stability. CONCLUSIONS: Our study found that there was no significant correlation between each specific mutation and the severity of clinical manifestations. Different patients with the same gene pathogenic variant may have mild or severe clinical manifestations. The correlation between genotype and phenotype needs further study. Three-dimensional protein simulations may provide additional support for the physiopathological mechanism of genetic mutations.

[A randomized, double blind, placebo-controlled, parallel and multicenter study to evaluate the safety and efficacy of pioglitazone with sulphonylurea in type 2 diabetic patients].

OBJECTIVE: To evaluate the safety and efficacy of 30 mg pioglitazone hydrochloride combined with sulphonylurea in the treatment of type 2 diabetic patients. METHODS: A randomized, double blind, placebo-controlled, parallel group, multicenter study was performed. A total of 236 patients, who had fasting plasma glucose (FPG) 7.5 - 13.0 mmol/L and glycosylated hemoglobin A1c (HbA1c) 7.0% - 12.0%, treated with stable dosage of a sulphonylurea for at least 30 days previously, were randomized to receive placebo or pioglitazone 30 mg once daily for 16 weeks. The sulphonylurea and dosage remained unchanged. RESULTS: The patients who had been treated with pioglitazone 30 mg showed significant decrease than that in the placebo group on the average from baseline in FPG [(1.48 ± 2.08) mmol/L vs (-0.17 ± 1.92) mmol/L, P < 0.05], and in HbA1c [(0.92 ± 0.10)% vs (0.28 ± 0.11)%, P < 0.05]. Since fasting plasma insulin (FIns) levels decreased (0.24 ± 0.04) mU/L and (0.09 ± 0.04) mU/L in the two groups. The homeostatic model assessment insulin resistant (HOMA-IR) decreased 1.42 ± 2.90 and 0.46 ± 3.53 in two groups. The triglyceride level was decreased 0.36 mmol/L and 0.14 mmol/L, and the HDL-C level increased 0.17 mmol/L and 0.05 mmol/L in two groups. There were significant differences in two groups (all P < 0.05). CONCLUSIONS: The 16-week clinical study demonstrated that pioglitazone hydrochloride with a dosage of 30mg daily, could significantly improve the blood glucose control and enhance the insulin sensitivity, lower triglyceride and raise HDL-C level as an additional therapy to a stable-dose sulphonylurea in Chinese type 2 diabetic patients previously poorly controlled by single sulphonylurea therapy, and furthermore had good safety and compliance.

[Clinical and genetic analysis of 11ß-hydroxylase deficiency].

OBJECTIVE: To explore the clinical and genetic characteristics of two patients with 11 ß-hydroxylase deficiency (11 ß-OHD). METHODS: The clinical features and laboratory data were collected from the patients and their families. All exons of CYP11B1 gene were amplified by PCR. And the PCR product sequences were identified by a DNA analyzer. RESULTS: Two patients presented with juvenile hypertension with bilateral adrenal hyperplasia and congenital hypospadias, hypertension for 17 years and periodic hematuria for 3 months after dexamethasone therapy respectively. Steroid analysis showed the typical pattern of 11 ß-OHD: elevated plasma levels of adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol, androstenedione and testosterone and lowered levels of potassium, aldosterone and plasma renin activity (PRA). CT scan revealed the presence of bilateral nodular hyperplasia of adrenal glands. Sequencing analysis showed compound heterozygous mutations of [R453Q]+[R454C] at exon 8 in patient 1 and homozygous mutation of [R454C] at exon 8 in patient 2. CONCLUSION: 11 ß-OHD is the second major cause of congenital adrenal hyperplasia. The classic characteristics are hypertension with low a level of PRA, hypokalemia, female pseudohermaphroditism and male sexual precocity. 11 ß-OHD should be screened in the patients with juvenile onset hypertension accompanied by bilateral adrenal hyperplasia.

Osteocalcin Levels in Male Idiopathic Hypogonadotropic Hypogonadism: Relationship With the Testosterone Secretion and Metabolic Profiles.

Idiopathic hypogonadotropic hypogonadism (IHH) patients are characterized by the absence of puberty and varying degrees of deteriorated metabolic conditions. Osteocalcin (OC) could regulate testosterone secretion and energy metabolism, but it remains unknown whether such an effect exists in IHH patients. Our study is aimed to examine the relationship between serum OC levels with testosterone and its responsiveness to gonadotropin stimulation and metabolic profiles in male IHH patients. A total of 99 male patients aged 18-37 years and diagnosed with IHH were enrolled in the current study, and the relationships between OC and testicular volume, baseline total testosterone (TT), free testosterone (FT), and peak TT (Tmax) levels after human chorionic gonadotropin (hCG) stimulation, gonadotropin responsiveness index (GRI), which is calculated by dividing Tmax by testicular volume, as well as metabolic profiles, such as 2-h post-challenge glucose (2hPG) and fat percentage (fat%), were analyzed. The results showed that OC had an independent negative relationship with testicular volume (r = -0.253, P = 0.012) and a positive association with Tmax (r = 0.262, P = 0.014) after adjusting for confounders. In addition, OC was a major determinant of GRI (adjusted R 2 for the model = 0.164, P = 0.012), fat% (adjusted R 2 for the model = 0.100, P = 0.004), and 2hPG (adjusted R 2 for the model = 0.054, P = 0.013) in IHH patients. In conclusion, OC is associated with testosterone secretion upon gonadotropin stimulation, glucose metabolism, and fat mass variations in IHH. This study was registered at clinicaltrials.gov (NCT02310074).

A 2-way cross-over, open-labeled trial to compare efficacy and safety of insulin Aspart and Novolin R delivered with CSII in 21 Chinese diabetic patients.

BACKGROUND: Subcutaneous absorption is accelerated by the monomeric conformation of insulin Aspart, which provides good glycemic control with a lower risk of hypoglycemia and less body weight increase. In the present study we investigated the efficacy and safety of a rapid-acting human insulin analogue (insulin Aspart) delivered with continuous subcutaneous insulin infusion (CSII) into Chinese diabetic patients. METHODS: A total of 21 patients with type 1 or type 2 diabetes were recruited for the 2-way cross-over, open-labeled trial, and then randomized to Group A (n = 10, treated with insulin Aspart) or Group B (n = 11, treated with Novolin R). Insulin Aspart and Novolin R were administered by CSII. Capillary glucose concentrations were measured at 8 time points, pre-prandial and postprandial, bedtime (10 pm), midnight (2 am) every day during the treatment. RESULTS: The average capillary glucose profiles for the day were much better controlled in Group A than in Group B (P < 0.01). The blood glucose levels were particularly better controlled in Group A than in Group B at pre-breakfast ((6.72 +/- 1.24) mmol/L vs (7.84 +/- 1.58) mmol/L, P = 0.014), post-breakfast ((8.96 +/- 2.41) mmol/L vs (11.70 +/- 3.11) mmol/L, P = 0.0028), post-supper ((8.15 +/- 2.10) mmol/L vs (10.07 +/- 2.36) mmol/L, P = 0.008), bed time ((7.73 +/- 1.72) mmol/L vs (9.39 +/- 2.05) mmol/L, P = 0.007) and midnight ((6.32 +/- 1.16) mmol/L vs (7.48 +/- 1.36) mmol/L, P = 0.0049). There was no significant difference in the frequency of hypoglycemic episodes between the two groups. CONCLUSION: Insulin Aspart results in better control of blood glucose levels than regular human insulin (Novolin R) in diabetic patients during delivery by CSII.

The effectiveness of zinc supplementation in men with isolated hypogonadotropic hypogonadism.

A multicenter, open-label, randomized, controlled superiority trial with 18 months of follow-up was conducted to investigate whether oral zinc supplementation could further promote spermatogenesis in males with isolated hypogonadotropic hypogonadism (IHH) receiving sequential purified urinary follicular-stimulating hormone/human chorionic gonadotropin (uFSH/hCG) replacement. Sixty-seven Chinese male IHH patients were recruited from the Departments of Endocrinology in eight tertiary hospitals and randomly allocated into the sequential uFSH/hCG group (Group A, n = 34) or the sequential uFSH plus zinc supplementation group (Group B, n = 33). In Group A, patients received sequential uFSH (75 U, three times a week every other 3 months) and hCG (2000 U, twice a week) treatments. In Group B, patients received oral zinc supplementation (40 mg day-1 ) in addition to the sequential uFSH/hCG treatment given to patients in Group A. The primary outcome was the proportion of patients with a sperm concentration ≥1.0 × 106 ml-1 during the 18 months. The comparison of efficacy between Groups A and B was analyzed. Nineteen of 34 (55.9%) patients receiving sequential uFSH/hCG and 20 of 33 (60.6%) patients receiving sequential uFSH/hCG plus zinc supplementation achieved sperm concentrations ≥1.0 × 106 ml-1 by intention to treat analyses. No differences between Group A and Group B were observed as far as the efficacy of inducing spermatogenesis (P = 0.69). We concluded that the sequential uFSH/hCG plus zinc supplementation regimen had a similar efficacy to the sequential uFSH/hCG treatment alone. The additional improvement of 40 mg day-1 oral zinc supplementation on spermatogenesis and masculinization in male IHH patients is very subtle.

[Fasting serum free fatty acid, insulin sensitivity index and serum lipid levels in individuals with different body mass index and glucose tolerance].

OBJECTIVE: To investigate the relationship among fasting serum free fatty acid (FFA), insulin sensitivity index (ISI), serum triglyceride (TG) and total cholesterol (TC) levels in subjects with different body mass index (BMI) and glucose tolerance by using Bergman's minimodel method. METHODS: 26 normal control subjects, 39 obese subjects, 25 impaired glucose tolerance (IGT) subjects and 21 patients with newly diagnosed type 2 diabetes mellitus (DM) were recruited into this study. Serum FFA level was measured with radioimmunoassay and ISI was obtained by using Bergman's minimal model method. RESULTS: (1) In the four groups, serum FFA concentration of the control group was significantly lower than that of the other three groups, although there was no difference among the latter three. (2) ISI level of the control group was significantly higher than that of other three groups, while there was no difference among the latter three. (3) After adjusting with BMI, there was still significant difference in serum FFA levels between the control and the other three groups. (4) ISI, HOMAIR, BMI, waist hip ratio (WHR) and TG were all related to the concentration of serum FFA (r = -0.454, 0.213, 0.241, 0.336 and 0.414 respectively, P < 0.01, < 0.05, < 0.05, < 0.01 and < 0.01 respectively), while age, sex and serum TC levels were not related with serum FFA. (5) According to multivariate stepwise regression, ISI, BMI and TG were the major determinant factors for FFA (R(2) = 0.109, 0.212, 0.156, P < 0.001). CONCLUSIONS: Besides BMI, ISI and serum TG level are the major determinant factors that affect the concentration of serum FFA. As compared with the simple index HOMAIR, ISI level was more significantly related with serum FFA concentration. FFA levels are significantly different in various glucose tolerant states even after adjusting with BMI. FFA levels were obviously higher in subjects with IGT or type 2 diabetes mellitus.