Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction

Hogeveen, Kevin; Cousin, Patrice; Pugeat, Michel; Dewailly, Didier; Soudan, Benoı̂t; Hammond, Geoffrey L.

doi:10.1172/jci200214060

Cited by 20 publications

(24 citation statements)

References 35 publications

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“…Analysis of human SHBG transcripts in the germ cells of our transgenic mice by RT-PCR also indicate that some alternative exon 1 containing human SHBG transcripts lack exon 7 sequences. This type of alternatively spliced transcript would result in a premature termination of the open reading frame encoding an SHBG isoform, and this type of product would most likely fold abnormally and undergo rapid degradation, as shown recently (27) for a human SHBG variant encoded by an abnormal allele with a premature stop codon in exon 8. In addition, if human SHBG transcripts lacking exon 7 sequences produce a carboxyl-terminally truncated form of SHBG, this protein would lack consensus sites for N-glycosylation, and our Western blot analysis indicates that the immunoreactive human SHBG in the mouse germ cells is N-glycosylated.…”

Section: Discussionmentioning

confidence: 89%

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

Selva

Hogeveen²,

Seguchi

et al. 2002

Journal of Biological Chemistry

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Human sex hormone-binding globulin (SHBG) binds estradiol and testosterone with high affinity. Plasma SHBG is produced by hepatocytes, but the human SHBG gene is also expressed in the testis. Little is known about SHBG gene expression in the human testis, but human SHBG transcripts accumulate in a spermatogenic stagedependent manner in the testes of mice containing an 11-kb human SHBG transgene. We have now found that human SHBG transcripts containing an alternative exon 1 sequence are located specifically in the testicular germ cells of these transgenic mice, whereas murine SHBG transcripts are confined to Sertoli cells. In addition, we have detected immunoreactive human SHBG in the acrosome during all stages of spermiogenesis in mice containing an 11-kb human SHBG transgene. Western blots of germ cell extracts from these transgenic mice and from human sperm indicate that the immunoreactive human SHBG in the acrosome composes electrophoretic variants, which are 3-5 kDa smaller than the major electrophoretic isoforms of human SHBG in the blood. This apparent size difference is due in part to differences in glycosylation of plasma and acrosomal SHBG isoforms. The function of the human SHBG isoform in the acrosome is unknown, but it binds steroid ligands with high affinity. This is the first demonstration that human SHBG transcripts encode an SHBG isoform that remains within a cellular compartment.

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Section: Discussionmentioning

confidence: 89%

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

Selva

Hogeveen²,

Seguchi

et al. 2002

Journal of Biological Chemistry

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“…This difference in BT cal :BT meas between young and old men in our study population was observed when BT cal was calculated by using the algorithm by Vermeulen as well as when using the algorithm by Morris et al (21 ), with a significant (P Ͻ0.001) decrease in BT cal :BT meas from 2.38 for men older than 50 to 1.44 for men younger than 50 years. Although an increase in K s with age has been suggested (27 ) and some mutations in SHBG have been reported (28 ), they are unlikely to account for such a large discrepancy.…”

Section: Discussionmentioning

confidence: 93%

Age-Associated Discrepancy between Measured and Calculated Bioavailable Testosterone in Men

et al. 2007

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Background: Bioavailable testosterone (BT) concentration is considered the best marker for evaluating testicular function in men. The decrease of BT in older men is more pronounced than the decrease in total testosterone because of the parallel increase in sex hormone-binding globulin (SHBG) concentrations. Measurement of BT is therefore crucial for the diagnosis of hypoandrogenism in the aging male population. Methods: We compared BT concentrations measured by a specific RIA after ammonium sulfate precipitation (BT meas ) with those obtained by theoretical calculations (BT cal ) in plasma samples from 694 young men (14 to 49 years old) and 51 older men (50 to 81 years old). We based theoretical calculations on Vermeulen's simplified mass equation using total testosterone and SHBG concentrations. Results: BT cal and BT meas correlated significantly in young (Pearson r ‫؍‬ 0.87) and aging (r ‫؍‬ 0.89) men, but the BT cal :BT meas ratio differed markedly between the 2 groups (2.28 vs 3.48; P <0.001). Conclusions: In men, there is an age-associated discrepancy between calculated and measured BT concentrations. We suggest some hypotheses for the discrepancy, but additional studies will be performed to finally elucidate this difference in results and to determine the most appropriate method for BT measurements in older men.

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“…38,39 In polycystic ovary syndrome, a decrease in sex hormone binding globulin leads to increased levels of free, metabolically active androgens. 40 Women with polycystic ovary syndrome, particularly in association with hyperandrogenism, have been shown to be at an increased risk for NAFLD. 41 The proportion of Mexican American children in San Diego who receive a diagnosis of NAFLD far exceeds the community's ethnic demographics.…”

Section: Discussionmentioning

confidence: 99%

Influence of Gender, Race, and Ethnicity on Suspected Fatty Liver in Obese Adolescents

Schwimmer¹,

McGreal²,

et al. 2005

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ABSTRACT. Objectives. Fatty liver is a common cause of liver disease in children. However, the epidemiology of pediatric fatty liver is limited to single-center case series of nonalcoholic fatty liver disease (NAFLD). Obesity and insulin resistance are major established risk factors for NAFLD. The role of gender, race, and ethnicity on the prevalence of fatty liver in obese children is unknown.Methods. We recruited obese 12th-grade participants from the Child and Adolescent Trial for Cardiovascular Health in California, Louisiana, Minnesota, and Texas. Serum samples were collected at school when the participants were well. Alanine aminotransferase (ALT) was measured by kinetic enzymatic assay, and ALT >40 U/L was defined as abnormal. Causes of abnormal ALT other than NAFLD were excluded by serum testing.Results. A total of 127 obese students (73 female, 54 male) had a mean BMI of 35.2 kg/m 2 . Unexplained ALT elevation was present in 23% of participants overall. The mean ALT for participants with normal values was 28 U/L and for participants with an abnormal ALT was 56 U/L. Abnormal ALT was significantly more prevalent in boys (44%) than in girls (7%). The prevalence of abnormal ALT differed significantly by race and ethnicity (Hispanic: 36%; white: 22%; black: 14%). Serum ALT value was significantly predicted by the combination of gender, race/ethnicity, and BMI. After controlling for gender and BMI, Hispanic ethnicity significantly predicted greater ALT than black race.Conclusions. In a national, school-based sample of obese adolescents, boys were 6 times more likely than girls to have an unexplained elevated ALT. Given that participants were well and causes of chronic liver disease were excluded, we speculate that obese adolescent boys have an increased prevalence of fatty liver compared with obese adolescent girls. This population-based study also supports the hypothesis that NAFLD is more common in Hispanic adolescents. These findings have implications for both disease screening and studies of fatty liver pathophysiology. N onalcoholic fatty liver disease (NAFLD) is regarded as the most common cause of liver disease in children. 1 NAFLD encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The most mild form is simple steatosis in which triglyceride accumulates within hepatocytes. A more advanced form of NAFLD, nonalcoholic steatohepatitis (NASH), includes inflammation and liver cell injury. NASH was first described in children in 1983, 2 and more recently, several investigators have reported that NASH may present with cirrhosis and end-stage liver disease in some children. [3][4][5][6] Established risk factors for NAFLD in children include obesity, insulin resistance, and type 2 diabetes. 5,7,8 Although most pediatric patients with NAFLD are obese, only a subset of obese children or adolescents will develop NAFLD. Gender is likely to be 1 important factor that modifies the risk for NAFLD. Early studies in adults suggested that women were more likely than men to...

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Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction

Cited by 20 publications

References 35 publications

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

A Human Sex Hormone-binding Globulin Isoform Accumulates in the Acrosome during Spermatogenesis

Age-Associated Discrepancy between Measured and Calculated Bioavailable Testosterone in Men

Influence of Gender, Race, and Ethnicity on Suspected Fatty Liver in Obese Adolescents

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