Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus.

BACKGROUND: The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis. RESULTS: Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all P<0.005). The plasma FABP4 was 1.47±0.25 vs. 0.20±0.07 ng/ml in the GDM and control group, respectively (P<0.0001). Plasma PTEN was 6.46±1.57 vs. 4.72±0.82 ng/ml in the GDM and control group, respectively (P<0.0001). There was a positive relation between plasma FABP4 and PTEN when all blood samples, including GDM and control groups, were analyzed (P<0.05). The multiple-factor regression analysis revealed that plasma FABP4, TG, and PTEN were independent risk factors for increased insulin resistance. CONCLUSIONS: GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.

[Lipopolysaccharide, TNFα, IL-6, dexamethasone, and insulin increase the expression of GPR54 in the MCF7 breasr cancer cell line].

OBJECTIVE: To investigate the effects of different concentrations of lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), dexamethasone (Dex), and insulin on the mRNA and protein expressions of GPR54 in the MCF7 cell line in vitro. METHODS: MCF7 breasr cancer cells were cultured and treated with different concentrations of LPS (10 and 20 µg/ml), TNFα (20 and 100 ng/ml), IL-6 (10 and 20 ng/ml), Dex (10(-6) and 10(-7) mol/L), and insulin (0.01 and 0.1 IU/L). Those treated with culture fluid only served as controls. The mRNA and protein expressions of GPR54 were measured by real-time PCR and Western blot, respectively, after 6, 24, 48, and 72 hours of treatment. RESULTS: Compared with the blank con- trol, LPS (10 and 20 µg/ml), TNFα (20 and 100 ng/ml), IL-6 (10 and 20 ng/ml), Dex (10(-6) and 10(-7) mol/L), and insulin (0.01 and 0.1 IU/L) significantly increased the expressions of GPR54 mRNA (P < 0.05) and protein (P < 0.05). CONCLUSION: LPS, TNFα, IL-6, Dex, and insulin evidently increase the expression of GPR54 in the MCF7 cell line, indicating their influence on the function of gonads by regulating the GPR54 level.

Serum vitamin D is low and inversely associated with LDL cholesterol in the Kazak ethnic population: a cross-sectional study.

BACKGROUND: Accumulating evidence suggests that low concentrations of serum 25(OH)D is coupled with increased risks of hypertension, obesity, and cardiovascular disease. However, this relationship has not been established in populations with very low levels of 25(OH)D. Therefore, the aim of our study was to clarify the associations between 25(OH)D and blood pressure, obesity, sex, and lipid profiles in the Kazak ethnic population, who have an extremely low level of 25(OH)D. MATERIAL/METHODS: A multistage-cluster sampling survey was carried out for residents with Kazak ethnicity in Xinjiang, China. Anthropometric measurements of each participant were taken and the concentrations of 25(OH)D, calcium, alkaline phosphatase, and lipid profiles were measured. Individuals were classified into different groups in terms of vitamin D status, degree of adiposity, presence of hypertension, and other comorbidities. RESULTS: The madian concentration of 25(OH)D was 16.2 (11.8-20.5) ng/mL and the prevalence of vitamin D deficiency was 72.4% in this Kazak population (n=928, 59.0% women). Females had a lower 25(OH)D concentration than males - 14.6 (10.5-19.4) ng/mL vs. 17.7 (14.8-22.5) ng/mL, P<0.001. The subjects were classified into 3 groups according to their vitamin D status. There were significant differences in BMI (P=0.046), waist circumference (P=0.037), hip circumference (P=0.003), systolic BP (P=0.035), and LDL cholesterol (P=0.008) among the groups after adjustment for sex and age. On the other hand, there was no significant difference in vitamin D levels between groups with or without hypertension (P=0.586), and groups with or without obesity (P=0.639). A multifactor-regression analysis revealed that every increment of 1mg/dL in LDL cholesterol was associated with a 1.0 ng/mL decline in serum 25(OH)D. CONCLUSIONS: The insufficiency of vitamin D is highly prevalent in Kazaks. Sex, LDL cholesterol, and hip circumference are 3 variables strongly associated with serum 25(OH)D concentration. In a population with low levels of 25(OH)D, the negative relationship between obesity and serum 25(OH)D, a common finding from most previous studies, could not be established.

[Relationship between serum uric acid level and metabolic syndrome in Uygur children and adolescents with overweight or obesity].

OBJECTIVE: To study the relationship between serum uric acid (SUA) level and metabolic syndrome (MS) in Uygur children and adolescents with overweight or obesity. METHODS: A total of 173 Uygur children or adolescents who were either overweight or obese and 200 controls with normal body weight were included in the study. Body weight, height, waist circumference, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and SUA were measured. RESULTS: The overweight and obesity groups had significantly higher SUA levels (235 ± 42 and 285 ± 42 µmol/L respectively) than the control group (199 ± 32 µmol/L; P<0.01). The subjects with SUA levels of 300-349 µmol/L and ≥ 350 µmol/L had significantly higher incidence of MS, overweight/obesity, hypertension and dyslipidemia than those with SUA levels of <250 µmol/L and 250-299 µmol/L (P<0.01). There were significant differences in SUA levels between groups with different MS components. SUA level was significantly increased in groups with more MS components (P<0.01). Every 1 kg/m2 increment in body mass index (BMI) was associated with 5.74 µmol/L increase in SUA level, according to a multivariate regression analysis. CONCLUSIONS: Uygur children and adolescents who are either overweight or obese have higher SUA levels than those with normal body weight. The incidence of MS and its components rises with increasing SUA level. BMI has a positive relationship with SUA.

Clinical manifestations and spermatogenesis outcomes in Chinese patients with congenital hypogonadotropic hypogonadism caused by inherited or de novo FGFR1 mutations.

ABSTRACT: Fibroblast growth factor receptor 1 (FGFR1) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l-1, follicle-stimulating hormone (FSH) levels were 1.0 IU l-1, and testosterone levels were 1.3 nmol l-1. In contrast, the de novo group had LH levels of 0.2 IU l-1, FSH levels of 0.5 IU l-1, and testosterone levels of 0.9 nmol l-1, indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

[Clinical manifestations, therapeutic response to tyrosinase inhibitor and RET gene activating mutation in a patient with multiple endocrine neoplasia 2B].

OBJECTIVE: To explore the clinical manifestations, therapeutic response and RET gene mutation in a patient with multiple endocrine neoplasia 2B (MEN2B) characterized by medullary thyroid carcinoma (MTC), bilateral adrenal pheochromocytoma and multiple mucosal neuromas. METHODS: The clinical features, laboratory data and radiological manifestations of this patient were collected. Genomic DNA was extracted from her peripheral blood leukocytes and her parents. Tenth to sixteenth exons of RET proto-oncogene, including the flanking regions of introns, were amplified by polymerase chain reaction (PCR). And the mutations of RET proto-oncogene were identified by direct sequencing. RESULTS: MEN-2B was diagnosed by the clinical presentations, laboratory tests and radiological findings. Gene analysis confirmed heterozygous mis-sense mutation at codon 918 in exon 16 of RET proto-oncogene in which thymine was replaced by cytosine (ATG→ACG). Her thyroid medullary carcinoma was treated by radical operations and radiotherapy. Tyrosinase inhibitor sorafenib was administered for 2 months and watery diarrhea and cough were alleviated. The drug was withdrawn because of such intolerant side effects as hair loss and painful rashes. She had a survival time of over 14 years with multiple system tumor metastases. CONCLUSIONS: The mutation analysis of RET proto-oncogene confirmed the diagnosis of MEN2B in respect of molecular genetics. For patients with advanced MTC, tyrosinase inhibitors may relieve the symptoms and provide a new therapeutic choice.

[An analysis of hyperinsulinemia in Bartter syndrome].

OBJECTIVE: To analyse hyperinsulinemia in Bartter syndrome. METHODS: Twenty-three cases of Bartter syndrome [age (27 ± 9) years; fasting serum potassium (2.8 ± 0.5) mmol/L], 20 patients of aldosterone-producing adenoma [APA, age (45 ± 11)years, fasting serum potassium (3.0 ± 0.4) mmol/L], 20 patients of idiopathic hyperaldosteronism [IHA, age (51 ± 11) years, fasting serum potassium (3.4 ± 0.2) mmol/L] were diagnosed in Peking Union Medical College Hospital from September 2003 to May 2008. All patients underwent 3-hours oral glucose tolerance test (3hOGTT), postural stimulation test and calculated HOMA-insulin resistance (HOMA-IR) and HOMA-insulin sensitivity (HOMA-IS) by Homeostasis model. RESULTS: The insulin area under curve[(229.0 ± 162.4) mIU×L(-1)×h] was significantly higher than APA group [(121.2 ± 81.1) mIU×L(-1)×h, P < 0.05] and were similar to the aged-matched patients with IHA [(227.7 ± 158.6) mIU×L(-1)×h]. But HOMA-IR in Bartter group were similar to APA group (1.96 ± 1.14 vs 1.41 ± 0.91), and HOMA-IR in APA group was lower than IHA group (1.96 ± 1.14 vs 2.40 ± 1.60, P < 0.05). There was no deference in HOMA-IS among three groups, but APA group had lower level. In all three groups, the peak of insulin secretion was delayed. CONCLUSION: Bartter syndrome patients commonly present with hyperinsulinemia.

[Clinical values of triptorelin stimulating test in assessing hypothalamus-pituitary-gonad axis function in male patients with hypothalamus-pituitary-gonad axis disorders].

OBJECTIVE: To investigate the clinical values of luteinizing hormone-releasing hormone (LHRH) α (triptorelin) stimulating test in the differential diagnoses of hypothalamus-pituitary-gonad axis (HPGA) disorders. METHODS: A total of 229 male patients with various HPGA disorders were recruited for triptorelin stimulating test. And all patients were followed up for 12 - 48 months until a definite diagnosis was made. The values of triptorelin stimulating test in the differential diagnoses of HPGA disorders were assessed by examining the close relationship between LHmax and the final clinical diagnosis. RESULTS: (1) LH levels rose steady after an intramuscular injection of triptorelin 100 µg and the time of LHmax appeared at 45 - 60 min. (2) LHmax < 4 U/L indicated the function of HPGA was not activated. LHmax in the range of 4 - 12 U/L indicated the patients might have constitutional delayed puberty development. LHmax > 12 U/L indicated the fulfilled puberty development. CONCLUSION: Triptorelin stimulating test can precisely evaluate the functions of HPGA in various HPGA disorders and provide valuable information for the differential diagnoses in constitutional delayed puberty development, hypogonadotropic hypogonadism, central and peripheral precocious puberty disorders.

[Clinical values of single or repeated triptorelin stimulating test in the differential diagnosis between idiopathic hypogonadotropic hypogonadism and constitutional delayed puberty].

OBJECTIVE: To investigate the values of single or repeated luteinizing hormone (LH) releasing hormone analogue (triptorelin) stimulating test in the differential diagnosis between idiopathic hypogonadotropic hypogonadism (IHH) and constitutional delayed puberty (CDP). METHODS: Male patients (n = 133) without puberty onset after the age of 14 were recruited for triptorelin stimulating test and were followed up for 24 - 48 months until the diagnosis were confirmed: 86 were IHH and the other 47 were CDP. Repeated triptorelin stimulating tests were conducted in 9 IHH patients and 13 CDP patients one year after the first stimulating tests with an attempt to evaluate the dynamic change of hypothalamus-pituitary-testis axis function. The relationship between the final diagnosis and the peak LH value (LH(max)), and the changes of repeated LH(max) were investigated. RESULTS: In the single triptorelin stimulating test, LH(max) was (1.9 +/- 1.2) U/L in IHH group, which was significantly lower than that in CDP group [(13.7 +/- 8.3) U/L] (P < 0.01); 75 IHH patients (87.2%) had a LH(max) lower than 4 U/L, while only 2 CDP patients (4.3%) had a LH(max) lower than 4 U/L. When LH(max) < 4U/L was used as a criteria for the diagnosis of IHH, the single triptorelin stimulating test had a sensitivity of 87.2%, a specificity of 95.7%, and a positive predictive value of 97.4%. The repeated triptorelin stimulating tests performed one year later showed that the LH(max) in the 9 IHH patients increased from (4.7 +/- 2.5) U/L to (5.1 +/- 3.3) U/L (P = 0.78), while that in the 13 CDP patients increased from (10.7 +/- 3.3) U/L to (24.5 +/- 5.7) U/L (P < 0.05). CONCLUSIONS: A single triptorelin stimulating test is highly effective in differentiating IHH from CDP. For some patients without definitive diagnosis, a repeated triptorelin stimulating test performed one year later may provide more valuable information on the dynamic change of the hypothalamus-pituitary-testis axis function.

Growth hormone cocktail improves hepatopulmonary syndrome secondary to hypopituitarism: A case report.

BACKGROUND: Metabolic associated fatty liver disease frequently occurs in patients with hypopituitarism and growth hormone (GH) deficiency. Some patients may develop to hepatopulmonary syndrome (HPS). HPS has a poor prognosis and liver transplantation is regarded as the only approach to cure it. CASE SUMMARY: A 29-year-old man presented with progressive dyspnea for 1 mo. At the age of 10 years, he was diagnosed with panhypopituitarism associated with pituitary stalk interruption syndrome. Levothyroxine and hydrocortisone were given since then. To achieve ideal height, he received GH treatment for 5 years. The patient had an oxygen saturation of 78% and a partial pressure of arterial oxygen of 37 mmHg with an alveolar-arterial oxygen gradient of 70.2 mmHg. Abdominal ultrasonography showed liver cirrhosis and an enlarged spleen. Perfusion lung scan demonstrated intrapulmonary arteriovenous right-to-left shunt. HPS (very severe) was our primary consideration. His hormonal evaluation revealed GH deficiency and hypogonadotropic hypogonadism when thyroid hormone, cortisol, and desmopressin were administrated. After adding with long-acting recombinant human GH and testosterone for 14 mo, his liver function and hypoxemia were improved and his progressive liver fibrosis was stabilized. He was off the waiting list of liver transplantation. CONCLUSION: Clinicians should screen HPS patients' anterior pituitary function as early as possible and treat them primarily with GH cocktail accordingly.

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing.

46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian structures. At least 30 genes related to 46,XY DSD have been found. However, the clinical phenotypes of patients with different gene mutations overlap, and accurate diagnosis relies on gene sequencing technology. Therefore, this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted next-generation sequencing (NGS) technology. Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital (Beijing, China). A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD. The incidence of these rare variants was approximately 69.0% (60/87). Twenty-five novel variants and 29 reported variants were identified. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance. The overall diagnostic rate was about 42.5% based on the pathogenic and likely pathogenic variants. Androgen receptor (AR), steroid 5-alpha-reductase 2 (SRD5A2) and nuclear receptor subfamily 5 Group A member 1 (NR5A1) gene variants were identified in 21, 13 and 13 patients, respectively. The incidence of these three gene variants was about 78.3% (47/60) in patients with rare variants. It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR, SRD5A2, and NR5A1 genes were the most common pathogenic genes in our cohort.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy in patients with congenital hypogonadotropic hypogonadism: a multicentre clinical study.

BACKGROUND: Pulsatile gonadotropin-releasing hormone (GnRH) therapy may restore function of the hypothalamus-pituitary-gonad axis and induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). The study sought to test the reliability of a newly developed Innopump® hormone pump, and to confirm the efficacy and safety of pulsatile GnRH therapy (by Innopump® hormone pump) in CHH patients. METHODS: From November 2017 to November 2018, 28 male patients with CHH were treated with pulsatile GnRH at Peking Union Medical College Hospital, Beijing Chaoyang Hospital, and Shandong Provincial Hospital. A prospective, self-controlled, 7-day clinical trial was conducted. The primary outcome measures were the efficacy and safety of pulsatile GnRH therapy (which was administered via the Innopump® hormone pump). The secondary outcome measures included total serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels. RESULTS: All of the patients participated the clinical study. For 7 days, a dosage prescribed by doctors was accurately administered by the Innopump® hormone pump, and recorded by the pump. During the treatment, LH and FSH levels gradually increased to 2.66±1.74 and 5.05±3.03 IU/L, respectively. Upper respiratory tract infection in 1 patient and slight nausea in another patient were reported, which were confirmed to be unrelated to the pulsatile GnRH therapy. CONCLUSIONS: The Innopump® hormone pump was found to be reliable in drug administration, and to have an accurate alarming system. It effectively and safely treated patients with CHH. Pulsatile GnRH therapy may produce a physiological pattern of GnRH secretion, and re-establish pituitary-gonad axis function by increasing gonadotropin levels.

[A report of familial male-limited precocious puberty caused by a germ-line heterozygous mutation (M398T) in luteinizing hormone receptor gene].

OBJECTIVE: To clarify the possible gene mutations in luteinizing hormone(LH) receptor gene in a boy with LH independent precocious puberty and probe the mechanism the of diseases caused by LH receptor activating mutations. METHODS: (1) Describe the clinical manifestations and laboratory data in a 5-year-old boy with LH independent precocious puberty. (2) Peripheral leukocytes were collected from the proband, his parents and other 20 normal puberty developed males. PCR and direct DNA sequence of 11 exons in LH receptors gene were conducted. RESULTS: (1) The proband was diagnosed to have LH independent precocious puberty according to the clinical symptoms and the laboratory tests. (2) A germ-line heterozygous point mutation in the 11 exon of LH receptor gene was found in the proband and his mother: c1193 T-->C leading to amino acid change with M398T, which causes consecutively an activation of the LH receptor. (3) Other nucleotide changes in the proband and other normal males include c935 A-->G (N312S) and c1065 -->C (same sense mutation). CONCLUSIONS: (1) A germ-line heterozygous point mutation in the LH receptor gene with M398T leads to consecutively activation of the LH receptor and LH independent precocious puberty. (2) The same point mutation does not have any influence on the puberty development, menstruation and productive functions of the proband's mother. (3) The LH receptor gene has possible polymorphism in the Han ethnic population.

[Clinical features of 9 patients with X-linked adrenal hypoplasia congenita caused by DAX1/NR0B1 gene mutations].

OBJECTIVE: To study the clinical features of 9 patients with X-linked adrenal hypoplasia congenita (AHC) by gene sequencing so as to provide diagnostic rationales. METHODS: The patients were 9 cases of X-linked AHC treated at our hospital from July 2007 to June 2009. The clinical manifestations were analyzed. The blood biochemistry tests and the hormone examinations including luteinizing hormone-releasing hormone (LHRH) stimulation tests and human chorionic gonadotropin (HCG) stimulation tests were conducted to evaluate the functions of gonads. And CT scans of adrenal glands and gene tests of DAX1/NR0B1 were performed. RESULTS: Nine AHC patients from 8 families were studied. All patients had DAX1/NR0B1 gene mutations. The main clinical features were: (1) some patients (3 families) had a family history of X-linked recessive inheritance; (2) the ages of onset were all below 10 years old (from 2 month after birth to 9 years old) and ages of being treated at our hospital were from 15 to 34 years old; (3) all patients had adrenocortical hypofunctions, but clinical situations were different, most of them had pigmentation (n = 9), nausea and vomiting (n = 8), hypotension (n = 6), Addisonian crisis (n = 4). Others were debility, hypoglycemia and cold susceptibility. Laboratory tests indicated that all patients had hyponatremia at the onset and higher blood adrenocorticotropic hormone level, lower blood 17-hydroxyprogesterone level compared to normal controls; (4) none of the patients had puberty and there was no responses to LHRH stimulation tests, 3 of them had normal responses to HCG stimulation tests; (5) small bilateral adrenal glands were displayed on CT scans. CONCLUSIONS: The main clinical features of X-linked AHC are adrenocortical hypofunction and hypogonadotropic hypogonadism. But the phenotypes vary greatly in different patients. So male children with adrenal cortical hypofunction should be suspected of X-linked AHC and DAX1/NR0B1 gene tests should be performed. The sexual development of the patients also should be followed up.

[Adrenal lesions in patients of multiple endocrine neoplasia type 1].

OBJECTIVE: To investigate the prevalence and characteristics of adrenal lesions in Chinese multiple endocrine neoplasia type 1 (MEN-1) patients. METHODS: Adrenal CT scan and clinical manifestations were retrospectively reviewed in 32 consecutive MEN-1 patients who were evaluated at our hospital during January 1986 to December 2009. RESULTS: Adrenal lesions were identified in 16 of 32 (50%) MEN-1 patients. Five (31.3%) patents with adrenal involvement showed bilateral lesions, including bilateral adenoma (n=1), bilateral hyperplasia (n=2) and adenoma and hyperplasia on each side (n=2). Unilateral adrenal lesion was presented in 11 (68.7%) patients. Among which, 63.6% had adenomas with a mean diameter of 2.3 cm (0.8-4.0 cm) and the remainder was of hyperplasia or enlargement. In two patients, functioning adrenal abnormalities were detected including Cushing adenoma (n=1) and aldosterone-secreting adenoma (n=1). CONCLUSIONS: The prevalence of adrenal lesion in MEN-1 patient is similar between China and western countries. These tumors are mostly benign, small and nonfunctioning. Taking into account a high incidence of adrenal carcinoma in previous foreign studies, routine screening and close surveillance are still recommended for adrenal lesions in MEN-1 patients.

Metabolic Effects of Testosterone Replacement Therapy in Patients with Type 2 Diabetes Mellitus or Metabolic Syndrome: A Meta-Analysis.

BACKGROUND: Testosterone replacement therapy (TRT) is commonly used for the treatment of hypogonadism in men, which is often associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (Mets). Recent compiling evidence shows that TRT has beneficial metabolic effects on these patients. OBJECTIVE: A meta-analysis has been conducted to evaluate the effects of TRT on cardiovascular metabolic factors. METHODS: We conducted a systemic search on PubMed, Embase, Cochrane Library, Wanfang, and CNKI and selected randomized controlled trials (RCTs) to include. The efficacy of TRT on glycemia, insulin sensitivity, lipid profile, and body weight was meta-analyzed by Review Manager. RESULTS: A total of 18 RCTs, containing 1415 patients (767 in TRT and 648 in control), were enrolled for the meta-analysis. The results showed that TRT could reduce HbA1c (MD = -0.67, 95% CI -1.35, -0.19, and P=0.006) and improve HOMA-IR (homeostatic model assessment of insulin resistance) (SMD = -1.94, 95% CI -2.65, -1.23, and P < 0.0001). TRT could also decrease low-density lipoprotein (SMD = -0.50, 95% CI -0.82, -0.90, and P=0.002) and triglycerides (MD = -0.64, 95% CI -0.91, -0.36, and P < 0.0001). In addition, TRT could reduce body weight by 3.91 kg (MD = -3.91, 95% CI -4.14, -3.69, and P < 0.00001) and waist circumference by 2.8 cm (MD -2.80, 95% CI -4.38, -1.21 and P=0.0005). Erectile dysfunction (measured by IIEF-5) did not improve, while aging-related symptoms (measured by AMS scores) significantly improved. CONCLUSIONS: TRT improves glycemic control, insulin sensitivity, and lipid parameters in hypogonadism patients with T2DM and MetS, partially through reducing central obesity.

Gonadotropin treatment for male partial congenital hypogonadotropic hypogonadism in Chinese patients.

Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.

[Testosterone replacement in hypogonadotropic hypogonadal young male improves insulin sensitivity].

OBJECTIVE: To evaluate the effect of testosterone replacement therapy in patients with hypogonadotrophic hypogonadism (HH) on insulin sensitivity and high sensitivity C reactive protein (hsCRP). METHODS: 21 males with HH, aged 15 - 30, and 18 age, and BMI-matched healthy males underwent detection of homeostasis model assessment insulin resistance index (HOMA-IR). Second, the values of weight, abdominal circumstance, grips strength, body composition, total testosterone (TT), fast blood glucose and insulin, serum lipid profile, and hsCRP were compared before and after 9-month testosterone replacement therapy in the HH patient group. RESULTS: (1) Before treatment the TT level of the HH patients WAS (0.9 +/- 0.6) nmol/L, significantly lower than that of the healthy control group (18.8 +/- 3.2) nmol/L. The fast insulin level of the HH patients was (16.0 +/- 9.8) mIU/L, significantly higher than that of the control group [(8.4 +/- 3.3) mIU/L, P = 0.018]. The HOMA-IR of the HH patient was 3.7 +/- 2.4, not significantly different from that of the control group (1.8 +/- 0.7, P = 0.021). (2) After testosterone therapy, the fast insulin level of the HH patients decreased from (16.0 +/- 9.8) mIU/L to (12.1 +/- 7.4) mIU/L (P = 0.03); the HOMA-IR decreased from (3.7 +/- 2.4) to (2.7 +/- 1.7) (P = 0.045); and the total cholesterol, LDL-c, HDL-c, and Triglyceride all decreased, but not significantly (all P > 0.05). The hsCRP decreased from (1.49 +/- 1.18) mg/L to (0.70 +/- 0.56) mg/L (P = 0.025). CONCLUSION: Short period of testosterone replacement therapy in young HH male patients significantly improves the insulin sensitivity and decreases the risk of cardiovascular disease.

Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1.

OBJECTIVE: Wolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now. METHODS: We performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described. RESULTS: Six patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10-19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1. CONCLUSION: Our series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

Predictive factors for pituitary response to pulsatile GnRH therapy in patients with congenital hypogonadotropic hypogonadism.

Pulsatile gonadotropin-releasing hormone (GnRH) may induce spermatogenesis in most patients with congenital hypogonadotropic hypogonadism (CHH) by stimulating gonadotropin production, while the predictors for a pituitary response to pulsatile GnRH therapy were rarely investigated. Therefore, the aim of our study is to investigate predictors of the pituitary response to pulsatile GnRH therapy. This retrospective cohort study included 82 CHH patients who received subcutaneous pulsatile GnRH therapy for at least 1 month. Patients were categorized into poor or normal luteinizing hormone (LH) response subgroups according to their LH level (LH <2 IU l-1 or LH ≥2 IU l-1) 1 month into pulsatile GnRH therapy. Gonadotropin and testosterone levels, testicular size, and sperm count were compared between the two subgroups before and after GnRH therapy. Among all patients, LH increased from 0.4 ± 0.5 IU l-1 to 7.5 ± 4.4 IU l-1 and follicle-stimulating hormone (FSH) increased from 1.1 ± 0.9 IU l-1 to 8.8 ± 5.3 IU l-1. A Cox regression analysis showed that basal testosterone level (ß = 0.252, P = 0.029) and triptorelin-stimulated FSH60min(ß = 0.518, P = 0.01) were two favorable predictors for pituitary response to GnRH therapy. Nine patients (9/82, 11.0%) with low LH response to GnRH therapy were classified into the poor LH response subgroup. After pulsatile GnRH therapy, total serum testosterone level was 39 ± 28 ng dl-1 versus 248 ± 158 ng dl-1 (P = 0.001), and testicular size was 4.0 ± 3.1 ml versus 7.9 ± 4.5 ml (P = 0.005) in the poor and normal LH response subgroups, respectively. It is concluded that higher levels of triptorelin-stimulated FSH60minand basal total serum testosterone are favorable predictors of pituitary LH response to GnRH therapy.