The Journal of Clinical Endocrinology & Metabolism Current Issue

• Two Novel Mutations of the TSH-{beta} Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
  

  Context: Patients with TSH-β subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening.

  Objective: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-β subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia.

  Results: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-β subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution.

  Conclusions: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.

  
  
  
• The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2a Caused by the Rare Intracellular RET Mutation S891A
  

  Background: Germline missense mutations of the RET protooncogene cause a clinical spectrum called multiple endocrine neoplasia (MEN) type 2. A strong genotype-phenotype correlation results in major implications for the clinical approach. More information on less common mutations is needed to advance specific guidance.

  Patients and Methods: We report individualized patient information on 36 carriers of the intracellular RET gene mutation S891A from three centers and clustered data of 38 former patients reported in the literature in nine additional studies.

  Results: S891A mutation accounts for up to 5% of all patients to date reported with RET mutations and 16% of those hitherto reported with intracellular mutations. S891A mutation caused medullary thyroid cancer (MTC) in 69.4%, pheochromocytoma in 2.8%, and parathyroid hyperplasia in 8.3% of the 36 patients of this case series and in 63.5, 4.1, and 4.1%, respectively, for the entire groups of 74 patients. The youngest age of onset for MTC in this group was 17 yr (median, 46 yr; range, 17–80 yr), for pheochromocytoma 46 yr (median, 46 yr), and for parathyroid hyperplasia 17 yr (median, 20 yr, range, 17–46 yr). Persistence of MTC was described in 14.3% of patients with available follow-up. Additional findings included corneal nerve thickening in three of 74 patients (4.1%).

  Conclusion: This intracellular mutation can initiate the full spectrum of MEN2a, initiates MTC at an early age, and causes recurrence and death if undertreated. We recommend stringent adherence to established guidance in MEN2a in this rare mutation.

  
  
  
• Resveratrol, a Red Wine Constituent, Blocks the Antimitogenic Effects of Estradiol on Human Female Coronary Artery Smooth Muscle Cells
  

  Context: Antimitogenic effects of estradiol on vascular smooth muscle cells (VSMCs) may be cardioprotective, and these effects are mediated by estrogen receptor--dependent and -independent mechanisms, with the latter involving the conversion of estradiol to 2-hydroxyestradiol/2-methoxyestradiol by CYP450. Because resveratrol inhibits CYP450 and is an estrogen-receptor- antagonist, resveratrol may abrogate the antimitogenic effects of estradiol.

  Objective: The objective of the study was to examine the interaction of pharmacologically relevant concentrations of resveratrol with estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol in human female coronary artery VSMCs.

  Methods and Results: In human female coronary VSMCs, resveratrol (0.1–10 µm) alone did not influence serum-induced DNA or collagen synthesis or cell proliferation or migration; however, resveratrol abrogated the inhibitory effects of estradiol, but not 2-hydroxyestradiol or 2-methoxyestradiol, on these responses. Resveratrol also abrogated the inhibitory effects of estradiol on positive growth regulators (cyclin A, cyclin D, MAPK phosphorylation) and the stimulatory effects of estradiol on negative growth regulators (p21, p27). In microsomes and cells, dietarily relevant levels of resveratrol (0.001–1 µm) inhibited the metabolism of estradiol to 2-hydroxestradiol/2-methoxyestradiol. Propylpyrazoletriol (estrogen receptor- agonist, 100 nmol/liter), but not diarylpropionitrile (estrogen receptor-β agonist, 10 nmol/liter), inhibited VSMC mitogenesis, and this effect was blocked by resveratrol (5 µmol/liter). Higher concentrations (>25–50 µm) of resveratrol, never attainable in vivo, inhibited VSMC growth, an effect blocked by GW9662 (peroxisomal proliferator-activated receptor- antagonist).

  Conclusion: In conclusion, dietarily relevant levels of resveratrol abrogate the antimitogenic effects of estradiol by inhibiting CYP450-mediated estradiol metabolism and blocking estrogen receptor-.

  
  
  
• Evidence for a Spatial and Temporal Regulation of Prostaglandin-Endoperoxide Synthase 2 Expression in Human Amnion in Term and Preterm Parturition
  

  Context: Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key enzyme involved in parturition. PTGS2 mRNA was found to be differentially expressed between placental amnion (amnion overlying the placental disc) and reflected amnion (amnion of the extraplacental chorioamniotic membranes) in term placentas.

  Objective: The aim was to evaluate the spatial and temporal regulation of PTGS2 expression in the amnion and the chorion-decidua.

  Design: PTGS2 expression was analyzed in the amnion and chorion-decidua obtained from 32 women: term not in labor (n = 12), term in labor (n = 12), and preterm labor (n = 8), by immunoblotting and densitometry. Prostaglandin E₂ (PGE₂) in the amnion and chorion-decidua was measured by a specific immunoassay.

  Results: Compared to preterm labor cases, PTGS2 expression increased at term before the onset of labor far more prominently in placental amnion (4.5-fold; P = 0.002) than in reflected amnion (1.4-fold; P = 0.007). There was a significant increase in PTGS2 expression in reflected amnion (2.9-fold; P < 0.01) but not in placental amnion with labor at term. PTGS2 expression was higher in reflected amnion than in chorion-decidua in labor at term (2.9-fold; P < 0.01). PTGS2 was barely detected in amnion and chorion-decidua with preterm labor. Expression of PGE₂ showed a good correlation with PTGS2 expression (r = 0.722; P < 0.001).

  Conclusion: PTGS2 expression in the amnion shows a distinct spatial and temporal regulation. Spontaneous labor at term and pathological preterm labor clearly differ in amniotic PTGS2 and PGE₂ abundance. Our observations underscore the biological significance of the amnion and amniotic fluid in human parturition.

  
  
  
• A Longitudinal Study of Serum Lipoproteins in Relation to Endogenous Reproductive Hormones during the Menstrual Cycle: Findings from the BioCycle Study
  

  Context: Exogenous estrogens have been shown to affect the lipid profile, leading to the hypothesis that endogenous estrogens may have similar effects.

  Objective: The objective of the study was to evaluate the association between endogenous estrogen and serum lipoproteins across the menstrual cycle.

  Design: This was a prospective cohort study.

  Setting: The study was conducted at the University at Buffalo, 2005–2007.

  Participants: Participants included 259 healthy, regularly menstruating women aged 18–44 yr.

  Main Outcome Measures: Serum levels of total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides measured up to eight times per cycle for up to two cycles were measured.

  Results: Total and LDL cholesterol were lower during the luteal phase as compared with the follicular phase (P < 0.001), and HDL levels were highest around ovulation (P < 0.001). More women were classified above the desirable range (LDL ≥130 mg/dl or total cholesterol ≥200 mg/dl) when measured during the follicular phase. Estradiol was positively associated with HDL in acute effects models [beta = 0.019, 95% confidence interval (CI) 0.015, 0.022] and inversely associated with total (beta = –0.017, 95% CI –0.020, –0.014) and LDL cholesterol (beta = –0.023, 95% CI –0.027, –0.018) and triglycerides (beta = –0.041, 95% CI –0.054, –0.029) in persistent effects models.

  Conclusions: Endogenous estrogen, like exogenous estrogen, appears to have beneficial effects on the lipid profile. Because lipoprotein cholesterol levels vary across the menstrual cycle, cyclic variations in lipoprotein levels may need to be considered in the design and interpretation of studies in reproductive-age women and in the clinical management of women’s cholesterol.

  
  
  
• The Relationship between Peroxisome Proliferator-Activated Receptor-{gamma} and Renin: A Human Genetics Study
  

  Context: Peroxisome proliferator-activated receptor (PPAR) agonists often cause volume retention and edema. A relationship between PPAR and renin may play a role in this process.

  Objective: The aim was to examine the relationship between the PPAR gene and plasma renin activity (PRA) levels in human hypertension.

  Design, Participants, and Measures: A candidate gene association study was conducted with two distinct groups of human participants: Caucasian hypertensives (n = 395) and African-American hypertensives (n = 55). Single nucleotide polymorphisms of the PPAR gene were analyzed. Phenotype studies were conducted after participants consumed a low-salt diet (10 mmol/d) for 7 d and included PRA and aldosterone measurements before and after a 60-min angiotensin II infusion (3 ng/kg · min).

  Results: Participants homozygous for the minor allele of rs2959272 (CC) had significantly higher PRA levels at baseline (P = 0.016) than major allele carriers (AA, AC) in Caucasian-hypertensive participants. The association of the C allele carrier status with increased PRA levels was replicated in the group of African-American hypertensive participants (P = 0.027). The Fisher’s combined P value for both observations was significant (P = 0.002).

  Conclusions: These results demonstrate the first known association between a PPAR single nucleotide polymorphism and alterations in PRA levels in humans with hypertension. This link between PPAR and renin raises the possibility of a genetically based mechanism for the increased volume retention and edema in some users of PPAR agonists.

  
  
  
• Skeletal Muscle Phosphocreatine Recovery after Submaximal Exercise in Children and Young and Middle-Aged Adults
  

  Context: Elderly subjects have reduced mitochondrial function. However, it remains unclear whether the decline in mitochondrial function begins earlier in the life span.

  Objective: The objective of the study was to determine skeletal muscle mitochondrial oxidative phosphorylation by ³¹phosphorous-magnetic resonance spectroscopy (MRS) across a variety of age groups.

  Design: This was a cross-sectional study of 121 healthy normal-weight and overweight individuals from age 8 to 55 yr.

  Setting: The study was conducted at a single university medical center in Boston, MA.

  Participants: Participants included 68 children and 53 adults from the Boston community.

  Interventions and Main Outcome Measures: Phosphocreatine (PCr) recovery was evaluated by ³¹phosphorous-MRS after submaximal exercise. Subjects were also evaluated with anthropometric measurements, metabolic profiles, and measures of physical activity.

  Results: PCr recovery determined by ³¹phosphorous-MRS is positively associated with age in univariate analysis in a cohort of individuals aged 8–55 yr (r = +0.55, P < 0.0001). Stratification of subjects into four age groups (prepubertal and early pubertal children, pubertal and postpubertal children < 18 yr, young adults aged 18–39 yr, and middle aged adults aged 40–55 yr) demonstrates prolongation of PCr recovery with increasing age across the four groups (P < 0.0001 by ANOVA). The relationship between PCr recovery and age remains strong when controlling for gender; race; ethnicity; body mass index; measures of physical activity and inactivity; and anthropometric, nutritional, and metabolic parameters (P < 0.004).

  Conclusions: Skeletal muscle PCr recovery measured by ³¹phosphorous-MRS is prolonged with age, even in children and young adults.

  
  
  
• Exercise and Fasting Activate Growth Hormone-Dependent Myocellular Signal Transducer and Activator of Transcription-5b Phosphorylation and Insulin-Like Growth Factor-I Messenger Ribonucleic Acid Expression in Humans
  

  Context: GH secretion is increased by stress, such as fasting and exercise.

  Objective: Our study was designed to test the hypothesis that fasting and exercise increase GH levels, GH-dependent signal transducer and activator of transcription (STAT)-5b phosphorylation, and IGF-I mRNA levels in human skeletal muscle.

  Design and Participants: Eight healthy men (25.5 ± 4.3 yr) were studied for 6 h (a 4 h basal and a 2 h clamp period) in the basal state and after 72 h fasting and a 1-h ergometer cycling at 65% maximal oxygen uptake. Muscle biopsies were taken at t = 30 and 270 min.

  Setting: The study was conducted at a university clinical research unit.

  Results: During exercise, GH concentrations rapidly increased to greater than 10 ng/ml (P < 0.001). Thirty minutes after exercise, we observed a 4-fold increase in signal transducer and activator of transcription (STAT)-5 phosphorylation (P < 0.001) followed by an increase in IGF-I mRNA after 270 min (P = 0.026). During fasting, more sporadic GH bursts occurred, leading to an overall 3-fold increase in GH area under the curve_t=0–270 (P < 0.001). Similarly, STAT5 patterns were less consistent, with a tendency toward increased phosphorylation (P = 0.067, area under the curve_t=0–270), whereas IGF-I mRNAs were persistently increased (P < 0.01).

  Conclusions: Our data show that myocellular GH signaling is stimulated after exercise and fasting in terms of increased STAT5 phosphorylation and/or IGF-I gene expression. This suggests that exercise with brief, well-defined GH peaks leads to distinct STAT5 phosphorylation and subsequent IGF-I gene expression, whereas fasting induces more sporadic GH bursts and less distinct but more persistent activation of the GH signal.

  
  
  
• An Autosomal Recessive Syndrome of Joint Contractures, Muscular Atrophy, Microcytic Anemia, and Panniculitis-Associated Lipodystrophy
  

  Context: Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome.

  Objective: The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome.

  Results: We report the detailed phenotype of two males and one female patient, 26–34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well.

  Conclusions: We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.

  
  
  
• High Efficacy of Concomitant Treatment of Undifferentiated (Anaplastic) Thyroid Cancer with Radiation and Docetaxel
  

  Context: Anaplastic thyroid carcinoma (ATC) is a rare but aggressive solid tumor with a very short survival time even with multimodality treatment. In view of in vitro data and the high rate of p53 mutations in ATC, we have used combined treatment with external beam radiation and docetaxel.

  Objective: The objective was to analyze the activity using radiation plus docetaxel.

  Design: The design was a retrospective analysis.

  Setting: The study was performed in a referral center of a university hospital.

  Patients: A total of six patients with ATC were treated at our institution.

  Intervention: Treatment consisted of standard external beam radiation of 60.0 Gy in 30 fractions along with docetaxel at a flat dose of 100 mg absolute every 3 wk for a total of six cycles starting within the first week of radiation.

  Outcome Measure: The outcome measure included clinical response and survival.

  Results: Five patients completed radiochemotherapy. One patient has completed radiation but is still on treatment with docetaxel. Four patients achieved complete remission and two partial response. During radiation therapy, four patients developed severe mucositis/stomatitis and two dermatitis, necessitating hospitalization. Two patients developed pneumonia and one urinary tract infection. All patients were hospitalized for a median of 17 d (range, 4–40 d) because of toxicites. After a median follow up of 21.5 months (range, 2–40 months), five patients are alive.

  Conclusion: The preliminary data suggest that the combination of radiation and concomitant docetaxel is highly effective in patients with ATC. However, a formal phase II study is needed to assess the therapeutic potential of this combination.

  
  
  
• Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women with TSH Levels between 2.5 and 5.0 in the First Trimester of Pregnancy
  

  Context: The definition of what constitutes a normal TSH during pregnancy is in flux. Recent studies suggested that the first trimester upper limit of normal for TSH should be 2.5 mIU/liter.

  Objective: The objective of the study was to evaluate the pregnancy loss and preterm delivery rate in first-trimester thyroid peroxidase antibody-negative women with TSH values between 2.5 and 5.0 mIU/liter.

  Design: The present study is a component of a recently published large-scale prospective trial that evaluated the impact of levothyroxine treatment on maternal and neonatal complications in thyroid peroxidase-positive women with TSH levels above 2.5 mIU/liter. The present study evaluated 4123 thyroid peroxidase antibody-negative women with TSH levels at or below 5.0 mIU/liter. Women were divided into two groups based on their initial TSH: group A, TSH level below 2.5 mIU/liter, excluding hyperthyroid women defined as an undetectable TSH with an elevated free T₄, and group B, TSH level between 2.5 and 5.0 mIU/liter.

  Setting: The study was conducted at two ambulatory clinics of community hospitals in southern Italy.

  Patients: A total of 4123 women were evaluated.

  Intervention: There was no intervention.

  Main Outcome Measures: The incidence of pregnancy loss and preterm delivery in group A as compared with group B was measured.

  Results: The rate of pregnancy loss was significantly higher in group B as compared with group A (6.1 vs. 3.6% respectively, P = 0.006). There was no difference in the rate of preterm delivery between the two groups.

  Conclusions: The increased incidence of pregnancy loss in pregnant women with TSH levels between 2.5 and 5.0 mIU/liter provides strong physiological evidence to support redefining the TSH upper limit of normal in the first trimester to 2.5 mIU/liter.

  
  
  
• Higher High-Density Lipoprotein Cholesterol in African-American Women with Polycystic Ovary Syndrome Compared with Caucasian Counterparts
  

  Context: Studies have demonstrated lipid differences among African-Americans and Caucasians and between women with polycystic ovary syndrome (PCOS) and normally ovulating women. However, few studies have examined racial differences in lipoprotein levels in women with PCOS.

  Objective: This study compared lipoprotein levels in African-American and Caucasian women with PCOS.

  Design and Setting: We performed a retrospective chart review of 398 subjects seen as new patients for PCOS at the Duke University Medical Center Endocrinology Clinic in Durham, NC.

  Patients: We identified 126 charts appropriate for review, based on a diagnosis of PCOS (using the 1990 National Institutes of Health criteria), a self-reported race of either Caucasian or African-American, and a body mass index (BMI) higher than 25. We excluded patients taking glucophage, oral contraceptives, or lipid-lowering medications.

  Main Outcome Measure: Age, BMI, total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, random triglycerides (TG), and oral glucose tolerance test measurements were collected and included in the analysis.

  Results: African-American women with PCOS had higher HDL cholesterol levels (52.6 vs. 47.5 mg/dl, P = 0.019), lower non-HDL cholesterol (134.1 vs. 154.6 mg/dl, P = 0.046), and lower TG levels (97.5 vs. 168.2 mg/dl, P < 0.001) than Caucasian women. These differences could not be attributed to age, BMI, or differences in insulin resistance as determined by homeostasis model assessment of insulin resistance.

  Conclusion: African-American women with PCOS appear to have a more favorable lipid profile than Caucasian women with PCOS having higher HDL cholesterol, lower non-HDL cholesterol, and lower TG when BMI and insulin resistance are equal.

  
  
  
• Familial Nephrogenic Syndrome of Inappropriate Antidiuresis: Dissociation between Aquaporin-2 and Vasopressin Excretion
  

  Context: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), the X-linked disease resulting from activating mutation of the vasopressin V2 receptor gene (AVPR2), is a recently described condition causative of episodes of hyponatremia in boys and male and female adults.

  Objective: The objective of the study was the pathophysiological characterization of NSIAD.

  Design: A family with NSIAD was identified and investigated for hyponatremic episodes and degrees of urine dilution defects. For the first time, the impact of the mutated V2R on aquaporin 2 (AQP2) excretion is reported.

  Setting: The study was conducted at a referral center.

  Patients: Five patients of seven carriers (two young brothers and their mother and her two sisters) were investigated together with age-matched controls.

  Interventions: There were no interventions.

  Results: In NSIAD patients, urinary AQP2 excretion occurred independently of concomitant vasopressin excretion and strongly correlated with urine osmolality, confirming direct AQP2 involvement in urine concentration. Water loading was followed by a very slow and incomplete elimination in the asymptomatic hemizygous boy with no suppression of AQP2 excretion and a delayed elimination in the heterozygous women because of an incomplete suppression of AQP2, and it induced hyponatremia in all NSIAD patients. Two hemizygous carriers presented with severe hyponatremia-induced seizures, and the repetition in one of them led to mental retardation.

  Conclusions: Hyponatremia was a constant and characteristic aspect of the abnormal response to even mild water-loading tests in an asymptomatic hemizygous child as well as heterozygous adults. We confirm the phenotypic variability of NSIAD, a disease that should be regarded in pediatric intensive care units in presence of severe and/or recurrent hyponatremia, and also in adults, because carriers are prone to hyponatremia.

  
  
  
• A Decrease of Calcitonin Serum Concentrations Less Than 50 Percent 30 Minutes after Thyroid Surgery Suggests Incomplete C-Cell Tumor Tissue Removal
  

  Context and Objectives: The prognosis of medullary thyroid carcinoma (MTC) depends on the completeness of the first surgical treatment. To date, it is not possible to predict whether the tumor has been completely removed after surgery. The aim of this study was to evaluate the reliability of an intraoperative calcitonin monitoring as a predictor of the final outcome after surgery in patients with MTC.

  Patients and Methods: Twenty patients underwent total thyroidectomy and central lymph node dissection on the basis of a positive pentagastrin test. In six cases a preoperative diagnosis of MTC was achieved at the cytological examination. During the surgical intervention, calcitonin was measured at the time of anesthesia, at the time of manipulation, and 10 and 30 min after surgical excision. At the histological examination, 10 patients had MTC and 10 had C cell hyperplasia.

  Results: As compared with calcitonin levels before thyroidectomy, a decrease of calcitonin greater than 50% 30 min after surgery was able to significantly distinguish patients who were cured from those who experienced persistence of disease. It was not possible to find a similar result when the decrease of calcitonin 10 min after surgery was considered.

  Conclusions: A rate of calcitonin decrease less than 50% 30 min after thyroidectomy plus central neck lymph node dissection suggests the persistence of tumor tissue in patients operated for MTC. These results indicate that intraoperative calcitonin monitoring may be a useful tool to predict the completeness of surgery in patients with MTC.

  
  
  
• Plasma Procalcitonin Is Associated with Obesity, Insulin Resistance, and the Metabolic Syndrome
  

  Context: Procalcitonin, a well-known biomarker of sepsis and bacterial infections, is produced by adipose tissue and has potential as a marker for chronic low-grade inflammation.

  Objectives: The objective of this study was to investigate whether plasma procalcitonin levels in the normal range are associated with obesity, insulin resistance, and metabolic syndrome (MS) in the general population.

  Methods: Plasma procalcitonin (0.006–0.1 ng/ml) was measured in 3197 men and 3638 women (aged 28–75 yr) of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study using an ultrasensitive immunoluminometric assay. MS was defined according to Adult Treatment Panel III criteria.

  Results: Median (interquartile range) plasma procalcitonin was 0.018 (0.015–0.022) ng/ml in men and 0.014 (0.012–0.017) ng/ml in women (P < 0.001). Plasma procalcitonin was positively associated with body mass index and waist circumference. In both sexes, cross-sectional associations of plasma procalcitonin with insulin resistance and components of the MS remained significant after adjustment for age, body mass index, waist circumference, and other covariates. The age-adjusted odds ratio (OR) for MS was 3.2 [95% confidence interval (CI) = 2.5–4.2) in men and 4.1 (95% CI = 3.0–5.5) in women, when comparing the highest with the lowest quartile of plasma procalcitonin. The multivariate-adjusted OR for MS was 1.9 (95% CI = 1.4–2.6) in men and 2.3 (95% CI = 1.6–3.3) in women. The multivariate-adjusted OR for insulin resistance was 3.3 (95% CI = 2.4–4.3) in men and 2.5 (95% CI = 1.9–3.4) in women.

  Conclusions: Elevated plasma procalcitonin levels in the normal range are associated with measures of obesity, insulin resistance, and MS in the general population.

  
  
  
• Expression of Adrenomedullin in Human Oviduct, Its Regulation by the Hormonal Cycle and Contact with Spermatozoa, and Its Effect on Ciliary Beat Frequency of the Oviductal Epithelium
  

  Context: Adrenomedullin (ADM) has been found expressed in the mouse oviduct and might play a role in reproduction.

  Objective: The objective of the study was to demonstrate the expression of ADM in the human oviduct, investigate its regulation by steroidal hormones and spermatozoa contact, and study its effect on ciliary beat frequency (CBF) in the human oviduct.

  Design, Setting, Patients, and Interventions: Oviducts from women undergoing hysterectomy for benign diseases in a university hospital were collected. The oviducts were treated with estradiol and/or progesterone to simulate different phases of the ovarian cycle. ADM expression was studied at the peptide and mRNA levels by immunohistochemistry and RT-PCR, respectively. CBF was measured after treatment with graded concentrations of ADM and its antagonists. Cells from OE-E6/E7, an immortalized oviductal cell line, as well as oviductal tissue were cocultured with and without direct contact with capacitated human spermatozoa to compare oviductal cell ADM expression levels. CBF was also analyzed in oviductal tissue after spermatozoa-oviduct coincubation.

  Results: ADM expression was the highest in the isthmic region and in a hormonal environment simulating the early luteal phase. CBF was increased by ADM in a dose-dependent manner, which was blocked by ADM and calcitonin-gene-related peptide receptor antagonists. Direct contact with spermatozoa in coculture resulted in higher ADM expression in OE-E6/E7 cell line and oviductal tissue and higher CBF in oviductal epithelium.

  Conclusions: ADM expression in the human oviduct is hormone dependent and is up-regulated by sperm contact. ADM stimulates ciliary motility of the human oviduct.

  
  
  
• A Large Study of Androgen Receptor Germline Variants and Their Relation to Sex Hormone Levels and Prostate Cancer Risk. Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
  

  Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.

  Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.

  Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 x 10^–5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).

  Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

  
  
  
• Analysis of Recently Identified Osteoporosis Susceptibility Genes in Han Chinese Women
  

  Background: In Europeans and populations of European origin, several osteoporosis susceptibility genes, including ZBTB40, RANK, RANKL, OPG, MHC, and ESR1, were recently identified. However, none of these has been fully investigated in Han Chinese populations.

  Objective and Design: In this relatively large cross-sectional sample of 1012 Han Chinese women, 21 single-nucleotide polymorphisms (SNPs) within 11 candidate genes that were newly identified in Europeans were tested, and their associations with bone mineral densities (BMDs) and osteoporotic fracture were investigated.

  Results: A total of 21 SNPs were genotyped. Five SNPs in four genes [ZBTB40 (rs7524102, rs6696981), ESR1 (rs9479055), OPG (rs6469804), and RANK (rs3018362)] were found to be associated with lumbar spine BMD. Seven SNPs in five genes [ZBTB40 (rs7524102, rs6696981), OPG (rs6993813, rs6469804), RANK (rs3018362), LRP5 (rs3736228), and SOST (rs1513670)] were found to be associated with total hip BMD. SPTBN1 (rs11898505) and SOST (rs1107748) were associated with osteoporotic fracture. A significant gene–gene interaction for osteoporotic fracture involving rs1107748 in SOST and rs6469804 in OPG gene was identified from generalized multifactor dimensionality reduction analysis.

  Conclusions: Our study provides an independent replication of the associations between several SNPs in ZBTB40, ESR1, OPG, RANK, LRP5, and SOST with lumbar spine and/or total hip BMDs in a large sample of Han Chinese women. The results of this study further support the significant associations found between osteoporotic fracture and SNPs in SPTBN1 and SOST. Our results suggest that these variants represent osteoporosis susceptibility genes in both Han Chinese and European populations.

  
  
  
• Seven Novel DAX1 Mutations with Loss of Function Identified in Chinese Patients with Congenital Adrenal Hypoplasia
  

  Context: DAX1 (for dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1; also called NROB1) mutations are responsible for adrenal failure and hypogonadotropic hypogonadism in patients with adrenal hypoplasia congenita (AHC), through a loss of trans-repression of SF-1 (for steroidogenic factor-1)-mediated StAR (for steroidogenic acute regulatory protein) and LHβ transcriptional activities and a reduction of GnRH expression. The correlation of clinical features with genetic and functional alterations of the gene was investigated in detail in AHC patients.

  Objective: The present study aimed at identifying DAX1 mutations in Chinese AHC patients and investigating the functional defects of detected novel mutations.

  Patients and Methods: Nine patients with AHC were recruited from eight families. DAX1 mutations were screened, and the transcriptional activities of the identified mutations were assessed in vitro.

  Results: DAX1 mutations were detected in all nine patients enrolled in the study, with eight different mutations. Among the latter, seven are novel mutations, including two missense (L262P and C368F), one nonsense (Q222X), and four frame-shift (637delC, 652_653delAC, 973delC, and 774_775insCC) mutations. The functional studies showed that the mutant DAX1 was impaired by nuclear localization, loss of trans-repression of StAR and LHβ transcriptional activities, and reduction of GnRH expression.

  Conclusion: These findings provide insight into the molecular events by which DAX1 mutations influence the hypothalamus-pituitary-gonadal and hypothalamus-pituitary-adrenal axis and lead to AHC and hypogonadotropic hypogonadism.

  
  
  
• An Antiinflammatory and Reactive Oxygen Species Suppressive Effects of an Extract of Polygonum Cuspidatum Containing Resveratrol
  

  Background: Resveratrol have been shown to exert an antiinflammatory and antiaging effects in vitro and in animal models.

  Objective: The objective of the study was to investigate the effect of a Polygonum cuspidatum extract (PCE) containing resveratrol on oxidative and inflammatory stress in normal subjects.

  Research Design and Methods: Two groups (10 each) of normal-weight healthy subjects were randomized to placebo or PCE containing 40 mg resveratrol daily for 6 wk. Fasting blood samples were obtained prior to and after treatment at 1, 3, and 6 wk. Mononuclear cells were prepared for reactive oxygen species generation, RNA isolation, nuclear extract, and total cell homogenate preparation. Indices of oxidative and inflammatory stress, suppressor of cytokine signaling-3, phosphotyrosine phosphatase-1B, jun-N-terminal kinase-1, and inhibitor of B-kinase-β were measured by RT-PCR and Western blotting.

  Results: The extract induced a significant reduction in reactive oxygen species generation, the expression of p47^phox, intranuclear nuclear factor-B binding, and the expression of jun-N-terminal kinase-1, inhibitor of B-kinase-β, phosphotyrosine phosphatase-1B, and suppressor of cytokine signaling-3 in mononuclear cells when compared with the baseline and the placebo. PCE intake also suppressed plasma concentrations of TNF-, IL-6, and C-reactive protein. There was no change in these indices in the control group given placebo.

  Conclusions: The PCE-containing resveratrol has a comprehensive suppressive effect on oxidative and inflammatory stress.

  
  
  
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