Endo 2012

[Michael Scally MD]

[SUN-75] Improvement in Sexual Function and Mood as a Function of Testosterone Level in Hypogonadal Men Receiving Testosterone Replacement Therapy
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-75

Xiao Ni, David Muram. Eli Lilly and Company, Indianapolis, IN; Eli Lilly and Company, Indianapolis, IN.

Based on limited available research (1-3) we undertook this post-hoc analysis to gain insights into symptomatic improvement in hypogonadal men on testosterone replacement therapy (TRT) based on whether they reached the pre-specified threshold of serum testosterone (T) 300 ng/dL.

This open-label trial (4) enrolled 155 testosterone-deficient (T<300ng/dL) men given an initial daily dose of T 60 mg in a topical solution applied to the axillae. Dose was adjusted on days 45 and 90 when necessary to maintain T within the physiological range (300-1050ng/dL). Sexual function and mood changes were assessed for 7 days preceding visits on days 1, 15, 60, and 120 by the Psychosexual Daily Questionnaire (PDQ) (5). Subjects were divided into two groups (T<300 and ?300 ng/dL) based on their T level during therapy. Analysis of covariance (ANCOVA) with adjustments for baseline PDQ scores, age, and body mass index (BMI) was used to evaluate change in PDQ scores from baseline (pre-day1) to pre-day15 and pre-day 120 (with last-observation-carried-forward for dropouts) both within and between the groups.

As early as day 15, numerical improvement was observed in all PDQ scores (sexual desire, sexual activity, percent full erection, erection maintained, and positive and negative mood) for both groups. Within-group improvement was significant (p<0.05) for all parameters except positive mood in group T<300. Improvement in PDQ scores was maintained or increased on day 120. For example, sexual desire changes on day 15 for the T<300 and ?300 ng/dL groups were 1.1 (0.2) and 0.8 (0.1) (least square means [standard error]) respectively; on day 120 values were 1.1 (0.3) and 1.5 (0.1) respectively. On day 120, changes in PDQ scores were numerically greater in the T?300 ng/dL group than in the T<300 ng/dL group, although the between-group difference was not significant (p>0.05).

These data show that symptoms in hypogonadal men receiving TRT improved by day 15 and continued until day 120. Improvements were noted even in those with T<300 after treatment. The study is limited by lack of a placebo control group and a small number of patients with serum T levels <300ng/dL after treatment and also that the analysis groupings (T groups) are based on post-baseline efficacy results. Additional research is needed to better understand the thresholds at which patients and physicians can expect symptoms of hypogonadism to improve.

(1) Kelleher S et al., J Clin Endocrinol Metab 2004;89:3813.
(2) Zitzmann M et al., J Clin Endocrinol Metab 2006;91:4335.
(3) Saad F et al., Eur J Endocrinol 2011;165:675.
(4) Wang C etal., J Clin Endocrinol Metab 1996;81:3578.
(5) Lee KK et al., J Androl 2003;24:688.

Sources of Research Support: Eli Lilly and Company.

Disclosures: XN: Researcher, Eli Lilly & Company. DM: Clinical Researcher, Eli Lilly & Company.

 

[Michael Scally MD]

[MON-53] “Late Onset Hypogonadism” Is Not an Isolated Condition — Comorbidities in Elderly Hypogonadal Men Presenting or Referred to Urological Institutions in Germany
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_MON-53

Ahmad Haider, Aksam Yassin, Louis Gooren, Farid Saad. Private Practice, Bremerhaven, Germany; Segeberger Kliniken, Norderstedt, Germany; Dresden International University, Dresden, Germany; Gulf Medical University School of Medicine, Ajman, United Arab Emirates; VUMC Amsterdam, Amsterdam, Netherlands; Bayer Pharma AG, Berlin, Germany; Gulf Medical University School, Ajman, United Arab Emirates.

Introduction: Serum testosterone declines with aging, not primarily determined by calendar age per se but rather by factors impairing the health of aging men, such as obesity, metabolic syndrome, diabetes mellitus and other diseases. We determined concurrent diseases in two cohorts of mainly elderly men with so-called late onset hypogonadism (LOH).

Methods: In two separate cumulative registry studies following identical protocols, two cohorts of 516 mainly elderly men were analyzed for concurrent diseases. Cohort A (Dr. Haider, Bremerhaven, Germany) consisted of 255 men, cohort B (Dr. Yassin, Norderstedt, Germany) of 261 men. These men had either sought urological consultation or had been referred by other disciplines because of suspected hypogonadism. All men received treatment with injections of long-acting testosterone undecanoate.

Results: The following comorbidities were encountered:

Cardiology: hypertension: A: 40%, B: 45%; coronary artery disease: A: 16%, B: 13%; condition post myocardial infarction: A 15%, B: <1%.

Internal Medicine: Diabetes mellitus: A: 31%, B: 26%; dyslipidemia: A: 18%, B: 33%.

Gastroenterology: inflammatory bowel disease: A: 16%, B: <1%.

Urology: chronic prostatitis: A: 38%, B: 11%.

Dermatology: psoriasis: A: 5%, B: <1%.

Endocrinology: Klinefelter's syndrome: A: 9%, B: 2%. In addition, there were a total of 14 patients with a history of maldescensus testis and 19 patients with a history of unilateral or bilateral orchiectomy following testicular cancer.

Orthopedics: osteoporosis: A: 14%, B: 6%.

Conclusions:
1) The majority of middle-aged to elderly patients with hypogonadism have one or more comorbidities. For adequate treatment, hypogonadal men should be examined for concurrent diseases. Testosterone administration may be a significant element in their treatment.
2) With progression of their age elderly men will suffer increasingly from ailments and hypogonadism may be an element, so far not often diagnosed. Testosterone treatment may contribute to a better quality treatment.
3) 60/516 men had conditions which cannot be categorized as “LOH”. Klinefelter's syndrome may still have been undiagnosed, and a history of maldescensus testis may be unknown.
The term “LOH” should be used with caution, and the general term “hypogonadism” may be preferable.

Sources of Research Support: Data entry was supported by Bayer Pharma AG.

Disclosures: AH: Principal Investigator, Bayer Schering Pharma. AY: Speaker, Bayer Schering Pharma. LG: Speaker, Bayer Schering Pharma. FS: Employee, Bayer Schering Pharma.

 

[Michael Scally MD]

[SAT-131] Waist Circumference Is Superior to Weight and BMI in Predicting Sexual Symptoms, Voiding Symptoms and Psychosomatic Symptoms in Men with Late-Onset Hypogonadism
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SAT-131

Aksam Yassin, Youssef El Douaihy, Ridwan Shabsigh, Aiman Yassin, Farid Saad. Segeberger Kliniken, Norderstedt, Germany; Dresden International University, Dresden, Germany; Gulf Medical University School of Medicine, Ajman, United Arab Emirates; Maimonides Medical Center, Brooklyn, NY; Klinikum Braunschweig, Braunschweig, Germany; Bayer Pharma AG, Berlin, Germany; Gulf Medical University School of Medicine, Ajman, United Arab Emirates.

Introduction: We investigated whether three measurements of obesity: weight, BMI, and waist circumference correlate with the International Index of Erectile Function (IIEF), the Aging Males' Symptoms questionnaire (AMS), and the International Prostate Symptom Score (IPSS).

Materials and methods: As of November 2004, 130 patients were enrolled in a prospective study on late onset hypogonadism (LOH defined as total testosterone ? 3.5 ng/mL and symptoms). All men were treated with i.m. testosterone undecanoate (TU) 1000mg. The treatment was initiated on day 1, then 6 weeks thereafter and was continued at 3 months intervals. The mean time of treatment and follow up was 4.7 years. Baseline demographic data were recorded including hormones, lipids, and glucose. Blood samples were collected at every or every other visit. In addition patients were asked to fill in three standardized questionnaires IIEF, IPSS and AMS. The Sexual Health Inventory for Men (SHIM), a short version of the IIEF was used. SPSS was used to plot weight, BMI and waist circumference versus the recorded scores on the three different questionnaires. ANOVA analysis was used to look at any possible statistical significance.

Results: The cohort's means and standard deviations for the IIEF, AMS and IPSS scores were 7.3 (±3.11), 54.63 (±7.06) and 11.65 (±4.41) respectively. The estimated curves and the ANOVA regression for continuous variables showed that waist circumference is inversely proportional to IIEF and directly proportional to AMS and IPSS with statistical significance. Weight was inversely proportional to IIEF, and directly proportional to IPSS both with statistical significance. Weight did not show enough linearity with AMS to give statistical significance. BMI and all three measurements of size had no proportionality.

Conclusion: Among weight, BMI and waist circumference, the latter is the best predictor of health related quality of life in men with LOH including sexual symptoms, voiding symptoms and other psychosomatic symptoms.

Sources of Research Support: Data entry has been supported by Bayer Pharma AG.

Disclosures: AY: Speaker, Bayer Schering Pharma. RS: Speaker, Lilly USA, LLC. FS: Employee, Bayer Schering Pharma.
Nothing to Disclose: YED, AY

 

[Michael Scally MD]

[OR28-3] Lifestyle Modification Can Reverse Hypogonadism in Men with Impaired Glucose Tolerance in the Diabetes Prevention Program
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_OR28-3

Andrew A Dwyer, Lisa M Caronia, Hang Lee, David M Nathan, Frances J Hayes. Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; St Vincent's University Hospital, Dublin, Ireland.

Background: Testosterone (T) levels tend to be lower in men with obesity and type 2 diabetes than in age-and weight matched controls. We have previously shown that increasing insulin resistance is associated with a decrease in Leydig cell T secretion (1). However, limited interventional data have addressed causality.

Aim: To examine the impact of changes in body weight and insulin sensitivity on serum T levels in men.

Subjects: 891 men with impaired glucose tolerance (IGT) from the Diabetes Prevention Program (DPP), on no medications which interfere with T levels, who were randomized to lifestyle modification (n=293), metformin (n=305), or placebo (n=293).

Methods: Anthropometric variables (BMI, waist circumference), physical activity (MET hours/week), insulin sensitivity (homeostatic model assessment (HOMA-IR) and reproductive hormone levels (T, LH) were analyzed at baseline (BL) and 12 months.

Results: BL age was 53.9 ± 0.4 y (mean ± SEM) and BMI 31.9 ± 0.2 kg/m 2. Mean T levels were not significantly different among treatment groups at BL and in the group as a whole did not change (407 ± 5 vs 417 ± 5 ng/dL, BL vs 12 months). However, men randomized to lifestyle modification had a 15% increase in T levels (417 ± 8 vs 460 ± 7 ng/dL, P<0.0001) with no change in LH (3.1 ± 0.1 vs 3.1 ± 0.1 IU/L). T levels were unchanged in the other treatment groups. The overall prevalence of hypogonadal T levels (< 300 ng/dL) at BL was 23.7%; with lifestyle modification this decreased from 20.4 to 11.1% (P<0.05), but was unchanged with metformin (24.8 vs 23.8%) and placebo (25.6 vs 24.6%).

Reduction in body weight was greater with lifestyle modification than metformin (-7.8 vs -2.8 kg, P<0.0001) as was the decrease in HOMA-IR (7.0 ± 0.3 to 5.2 ± 0.2 with lifestyle modification vs 7.2 ± 0.2 to 6.0 ± 0.3 with metformin). Change in T levels correlated with changes in body weight (r=-0.32, P<0.0001), waist circumference (r=-0.13, P=0.001) and HOMA-IR (r= -0.13, P<0.0001). There was no relationship between change in T and physical activity.

Conclusions:
(1) Almost 1 in 4 of this male DPP cohort with IGT has low T levels.
(2) Lifestyle modification increases endogenous T levels and reduces the prevalence of hypogonadism by 46%.
(3) The absence of an increase in LH suggests that enhanced Leydig cell responsiveness underlies the increase in T.
(4) Reduction in body weight appears to play an important beneficial role in improving T levels in this population.

(1) Pitteloud N et al., J Clin Endocrinol Metab 2005;90:2636.

 

[Michael Scally MD]

Phase IIb Enobosarm [SARM] Trial

[SUN-261] Prevalence and Impact of Hypogonadism in Cancer Patients with Muscle Wasting in a Phase IIb Enobosarm Trial
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-261

Adrian S Dobs, Shontelle T Dodson, Mary Ann Johnston, Michael L Hancock, Ronald A Morton, Mitchell S Steiner. Johns Hopkins University, Baltimore, MD; GTx, Inc, Memphis, TN.

Background - Hypogonadism has been associated with weight loss and poor outcomes in cancer patients. Up to 50% of males with advanced cancer are hypogonadal at presentation or during the course of treatment. Wasting in cancer patients has also been associated with a decline in physical function and performance status and has major public health significance. We conducted a Phase IIb, randomized, double blind, placebo controlled, multi-center study to evaluate the effect of enobosarm on muscle wasting and physical function in cancer patients.

Methods - Patients (n=159) were randomized to oral enobosarm (1 or 3 mg) or placebo daily for 16 wks. Patients were males >45 y and postmenopausal females, had ?2% weight loss in the 6 mths prior to randomization, BMI <35 and either NSCLC, colorectal cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukemia or breast cancer. We report on the incidence and impact of hypogonadism (T<300 ng/dL) in this population.

Results - Baseline testosterone levels were available for 93 of 103 men. 60% of male patients were hypogonadal at randomization. Distribution of hypogonadism was similar across cancers; however hypogonadal men were less likely to complete the study. Baseline T levels were positively correlated with weight loss (r=0.32, P=0.002,) with hypogonadal men demonstrating greater weight loss in the previous six months (median, -9.5%). Baseline physical function as measured by stair climb power was higher among eugonadal males compared to hypogonadal males (84.5 watts vs 70.6 watts; P=0.016). Enobosarm significantly improved physical function in this population regardless of baseline gonadal status (hypogonadal: 18.7%, P=0.0061; eugonadal: 13.2%, P=0.0032). The magnitude of improvement was greater in hypogonadal men.

Conclusions - Hypogonadism is common in male cancer patients and is correlated with weight loss and diminished physical function. In this randomized, placebo controlled trial, enobosarm improved physical function in both hypogonadal and eugonadal men despite poorer baseline physical function in hypogonadal patients. These data provide evidence that enobosarm may play an important role in the management of cancer related muscle wasting.

Disclosures: ASD: Investigator, Aeterna-Zentaris. STD: Employee, GTx, Inc. MAJ: Employee, GTx, Inc. MLH: Employee, GTx, Inc. RAM: Employee, GTx, Inc. MSS: Employee, GTx, Inc.

 

[Michael Scally MD]

[SAT-689] Effects of Growth Hormone Administration on LH Secretion and Serum Concentrations of Gonadal Steroids in Healthy Older Men and Women
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SAT-689

Shannon D Sullivan, Ranganath Muniyappa, Johannes D Veldhuis, S Mitchell Harman, Marc R Blackman. Georgetown University and Washington Hospital Center, Washington, DC; National Institutes of Health, Bethesda, MD; Mayo Clinical Research Center, Rochester, NY; National Institute on Aging, National Institutes of Health, Baltimore, MD; Kronos Longevity Research Institute, Phoenix, AZ; Phoenix VA Health Care System, Phoenix, AZ; Johns Hopkins University School of Medicine, Baltimore, MD; Veterans Affairs Medical Center, Washington, DC.

Background: Interactions between the somatotropic and hypothalamic-pituitary-gonadal (HPG) axes are well known. Pituitary gonadotrophs express IGF-I receptors; however, the effects of GH and IGF-I on LH secretion remain uncertain. In young individuals, GH contributes to regulation of both puberty and fertility via HPG axis stimulation. Aging is associated with decreased production of GH and sex steroids (SS), and increased sex hormone binding globulin (SHBG). In this study, we examined the effects of 6 months of GH administration on LH secretory dynamics and SS in healthy older men and women.

Objective: To determine effects of GH supplementation on LH secretion, SS, and SHBG in healthy older men and women.

Methods: AM concentrations of LH, IGF-I, total (TT) and free testosterone (fT), estradiol (E2), and SHBG, and nocturnal LH secretory dynamics (2000h-0800h, q20 min sampling) were measured before and after 26 weeks of administration of GH (20 ug/kg sc 3x/week, n=11M, 12W) or placebo (n=12M, 12W) in healthy, older (65-88 yr) individuals with low-normal to mildly decreased IGF-I levels. SHBG and LH were measured by immunoradiometric assay; TT, E2, and IGF-I by RIA; and fT by equilibrium dialysis. LH secretory parameters (frequency, burst mass, pulsatile production rate, and integrated LH secretion) were analyzed by multiparameter deconvolution and orderliness of secretion was assessed by use of the approximate entropy (ApEn) algorithm.

Results: At baseline, indices of LH secretion (frequency, mass per burst, pulsatile production rate) were inversely (P <0.05) related to IGF-I, but not to mean nocturnal serum GH concentrations. As expected, GH administration significantly increased serum IGF-I. In contrast, GH administration exerted no significant effects on LH secretory dynamics, including ApEn, or concentrations of SS (TT, fT, or E2) or SHBG in older women or men.

Conclusions: Thus, GH appears to exert little or no significant effect on SS, SHBG, or dynamics of LH secretion in healthy older individuals despite normalization of low-normal baseline IGF-1 levels, in contrast to its stimulatory effect on the HPG axis in younger persons. These data suggest a dissociation in the relationship between somatotropic and HPG axis function with aging that may contribute to the initiation and/or progression of menopause and andropause.

 

[sade]

Elevated Serum Testosterone and Sex Hormone Binding Globulin Associated with Sexual Dysfunction

[SUN-79] Elevated Serum Testosterone and Sex Hormone Binding Globulin Associated with Sexual Dysfunction: A Familial Disorder?
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-79

Thanh Duc Hoang, Vinh Q Mai, Patrick W Clyde, KM Mohamed Shakir. Walter Reed National Military Medical Center, Bethesda, MD.

Background: Elevated sex hormone binding globulin (SHBG) levels have been reported to be associated with increased insulin sensitivity, hyperthyroidism, reduced risk of type 2 diabetes mellitus (1,2) and sexual dysfunction in men with chronic hepatitis C infection (3). We report a familial case of hypertestosteronemia and elevated SHBG associated with decreased libido and erectile dysfunction.

Clinical case: A 37 y/o male with a 2-year history of gradually decreased libido and erectile dysfunction was found to have repeated elevation of serum testosterone and SHBG levels. He shaves daily and denies any headaches, vision changes, breast enlargement, chest pain, shortness of breath, or weight changes. Past medical history was significant for shingles and seasonal allergy. He was taking a multivitamin daily. He never smoked and drank 2 beers weekly. He has 2 healthy children. He reports a family history of hypertension and diabetes mellitus.

Vital signs: BP 122/71, HR 60 bpm, weight 176 lbs, height 72 in, and BMI 24 kg/m2.

Physical examination: normal thyroid, no gynecomastia, no galactorrhea, normal phallus, testicles 25 cc bilaterally without palpable mass. Heart, lungs and neurological examination was normal.

Lab results: 8 A.M serum total testosterone 1186-1448 ng/dL (nl 250-1100), free testosterone 141-169 pg/mL (nl 35-155), SHBG 86-98 nmol/L (nl 10-50), LH 8.8 mIU/mL (nl 1.5-9.3), FSH 6.0 mIU/mL (nl 1.4-18.1), estradiol 58.8 pg/mL (nl 7.6-42.6), and TSH 1.09 mcIU/mL (nl 0.27-4.20).
Fasting glucose, prolactin, HCG, CBG, liver associated enzymes, hepatitis and congenital adrenal hyperplasia panels were normal. Clomiphene challenge test was normal.
Abdominal CT scan showed normal liver and adrenal glands.
Pituitary MRI, testicular ultrasound, baseline DXA scan, and EKG were all normal.

Testing of his 11 y/o daughter and 8 y/o son revealed SHBG values of 158 nmol/L (nl 24-120) and 120 nmol/L (nl 32-158) with total testosterone levels of 13 ng/dL and 5ng/dL (nl <25), respectively. Estradiol and TSH levels are normal for both children.

Conclusions: The patient most likely has familial elevated SHBG leading to hypertestosteronemia, given the fact that his daughter also has elevated SHBG and his son with high-normal SHBG. To our knowledge, hypertestosteronemia due to familial elevated SHBG has not been reported previously. Patients with hypertestosteronemia and elevated SHBG need further investigations, including possible genetic studies.

(1) Lakshman KM et al., J Gerontol A Biol Sci Med Sci 2010; 65:503-9.
(2) Perry JR et al., Human Molecular Genetics 2010; 19: 535–544.
(3) Rao J et al., J Clin Gastroenterology 2009; 43:94-95.

Very interesting. I'm going to print this article and stick it in my blood record book.

 

[Michael Scally MD]

[SUN-65] A New Combination of Testosterone and Nestorone® Transdermal Gels for Male Hormonal Contraception
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-65

Niloufar Ilani, Mara Y Roth, John K Amory, Ronald S Swerdloff, Clint Dart, Stephanie T Page, William J Bremner, Regine Sitruk-Ware, Narender Kumar, Diana Blithe, Christine Wang. Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA; University of Washington, Seattle, WA; Agile Clinical Development, Durham, NC; Population Council, New York, NY; National Institutes of Health, Bethesda, MD.

Context: Combinations of testosterone (T) and progestin transdermal gels enhance the suppression of spermatogenesis and prove effective and appealing to a majority of men for contraception. Provider-independent application of this regimen may increase acceptability and compliance among users.

Objective: To determine the effectiveness of T gel alone or combined with Nestorone (NES), a potent non-androgenic progestin, in gel formulation for suppressing spermatogenesis.

Design and Setting: Randomized, double-blind, comparator clinical trial conducted at two academic medical centers.

Participants: 99 healthy male volunteers.

Interventions: Men were randomized to one of three treatment groups applying daily transdermal gels (Group 1: T 10g + NES 0mg/placebo gel; Group 2: T 10g + NES 8mg; Group 3: T gel 10g + NES 12mg).

Outcome Variables:
1) Percentage of men who reached a sperm concentration of ?1 million/ml by 20-24 weeks of treatment.
2) The impact of each treatment on gonadotropins, sperm morphology and motility.

Results: Efficacy data analyses were performed on 56 subjects who adhered to the protocol and completed at least 20 weeks of treatment. The percentage of men with sperm concentration of ?1 million/ml was significantly higher for T+NES 8 mg (89%, P <0.0001) and T+NES 12 mg (88%, P <0.0002) than T alone group (23%). In addition, significantly more men became azoospermic in the T+NES 8 (78%, P <0.001) and T+NES 12 (69%, P <0.008) groups compared to T+NES 0 (23%). The decrease in sperm motility and normal morphology followed the decrease in sperm concentration. Median serum luteinizing hormone and follicular stimulating hormone concentrations were more suppressed in the groups receiving NES together with T. Median total and free T concentrations remained within the adult male range irrespective of treatment group. All subjects recovered to a sperm concentration of ?15 million/ml during the recovery period. Adverse effects were minimal in all groups.

Conclusion: A combination of daily NES+T gels suppressed sperm concentration to ?1 million/ml in the majority of men with minimal adverse effects. The results warrant further investigation of this combined male transdermal hormonal contraceptive regimen.

 

[Michael Scally MD]

[MON-664] Simultaneous Stimulation of Human 20 kDa Growth Hormone and 22 kDa Growth Hormone Secretion by Ghrelin
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_MON-664

Jenny Tong, David D'Alessio, Juliane Ramisch, Harold Davis, Matthias Tschoep, Martin Bidlingmaier. University of Cincinnati, Cincinnati, OH; Cincinnati VA Medical Center, Cincinnati, OH; Ludwig-Maximilians Universitat, Munich, Germany.

20 kDa human growth hormone (hGH) is produced in the pituitary by alternative splicing of the hGH-N gene. Its growth promoting ability is equal to 22 kDa hGH, the predominant form in circulation, but the effect on glucose metabolism has been debated.

Objective: To investigate the effect of ghrelin on 20 kDa and 22 kDa hGH secretion in healthy, non-obese subjects. In addition, we aimed to study the association between endogenous GH concentration and fating plasma glucose and insulin as well as the relationship between dynamic GH secretion and insulin sensitivity.

Design and Setting: Synthetic human acyl ghrelin (0.2 or 0.6 nmol/kg/hr) or saline was infused in a randomized order in 14 healthy subjects (6 M/8 F; age 27.7 ± 6.3 years; BMI 22.0 ± 2.7 kg/m2, mean ± SEM) on three separate days. Ghrelin was infused for 45 minutes to achieve steady-state levels and continued through a 3-h frequently sampled IV glucose tolerance test (FSIGT). Insulin sensitivity index (SI) was quantified using the minimal model of glucose kinetics.

Results: At baseline, the 20 kDa and 22 kDa GH concentrations were 0.35 ± 0.07 and 2.2 ± 0.4 ng/ml, respectively, with a ratio of 20 kDa:22 kDa GH of 0.13 ± 0.02. Females had significantly higher baseline GH levels than males. Ghrelin administration increased serum 20 kDa and 22 kDa GH levels in a parallel and dose dependent fashion, with no significant change in the 20kDa:22kDa GH ratio. Both baseline 20 kDa and 22 kDa GH levels were negatively correlated with fasting plasma glucose, insulin and HOMA-IR. During the FSIGT, GH secretion (AUC20 kDa GHand AUC22 kDa GH) was positively correlated with insulin sensitivity as measured by SI.

Conclusion: Our study showed that ghrelin dose dependently increased endogenous 20 kDa and 22 kDa GH secretion in healthy subjects, but did not affect the ratio of these two GH isoforms. Both circulating levels and secretion of these two GH isoforms are similarly associated with and regulated by glucose and insulin.

 

[Michael Scally MD]

[SAT-667] Glucose Modulates Gonadotropin-Releasing Hormone (GnRH) Signaling in the Pituitary Gonadotrope
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SAT-667

Charukeshi Chandrasekera, Anita Mallya, Francina Gonzalez De Los Santos, Colleen Buggs-Saxton. Wayne State University, Detroit, MI.

It is well known that women with poorly controlled diabetes have a spectrum of reproductive disorders such as delayed menarche, menstrual irregularity, and infertility. Although hyperglycemia alters hypothalamic and ovarian function, effects of hyperglycemia on the pituitary gonadotrope are presently unknown. Thus, we investigated whether hyperglycemia alters pituitary gonadotrope function.

Experiments were conducted in the mouse gonadotrope cell line (LT2). Cells were acclimated to media containing physiologic glucose concentration (100 mg/dL) and displayed no difference in viability compared to cells grown in standard media (450 mg/dL glucose). Hyperglycemia was induced by exposing LT2 cells to media containing elevated glucose concentration (600 mg/dL) for 24 hours followed by treatment with gonadotropin-releasing hormone (GnRH, 10 nM) for 2 hours. RNA was isolated and real-time PCR analysis was performed with Taqman gene expression assays for leutinizing hormone subunit (LH) and follicle stimulating hormone subunit (FSH). All data were normalized to an endogenous control gene and fold effects determined by comparison of GnRH-treated cells to control cells (glucose at 100 mg/dL with no GnRH) using the Ct method.

In LT2 cells grown in media with physiologic glucose (100 mg/dL), GnRH stimulated LH mRNA 1.65-fold and FSH mRNA 1.53-fold. When these cells were exposed to hyperglycemia (600 mg/dL glucose), the induction of FSH mRNA by GnRH was completely inhibited while LH mRNA induction by GnRH was not altered. Hyperglycemia also impaired PMA and forskolin-induced FSH activation, but did not alter activin-stimulated FSH mRNA. Metformin or insulin treatment did not reverse the inhibitory effect of hyperglycemia on GnRH-induced FSH mRNA. However, normalizing glucose concentrations back to physiologic concentration (100 mg/dL) completely reversed the inhibition of GnRH-stimulated FSH gene expression.

Taken together, our data indicate for the first time that hyperglycemia directly alters gonadotrope function by differentially modulating effects of GnRH on LH and FSH gene expression. It is well known that changes in serum levels of LH and FSH are associated with menstrual irregularity and infertility in diabetes. Thus, our observations suggest that hyperglycemia may cause dysregulation of the hypothalamic-pituitary-ovarian axis by modulating GnRH signaling pathways in the pituitary gonadotrope.

 

[Michael Scally MD]

[OR32-6] Metabolic Effects of a Growth Hormone-Releasing Factor in Obese Subjects with Reduced Growth Hormone Secretion: A Randomized, Double-Blind, Placebo-Controlled Study
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_OR32-6

Hideo Makimura, Meghan N Feldpausch, Alison M Rope, Linda C Hemphill, Martin Torriani, Hang Lee, Steven K Grinspoon. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.

Background: Obesity is associated with reduced GH secretion, and increased cardiovascular disease (CVD) risk.

Methods: To assess the effects of augmenting GH secretion on body composition and CVD risk indices, 60 obese patients (mean BMI 38±0.6 kg/m2) with reduced GH (peak GH to GHRH-arginine testing ?9 µg/L) were randomly assigned to a GHRH1-44 analogue, tesamorelin 2 mg SC QD, or placebo for 12 months. Treatment effect was determined by longitudinal linear mixed effects modeling. Dose reductions, with parallel dummy changes to placebo-treated subjects, were made by an independent physician if IGF-1 increased above normal.

Results: Body composition and demographic parameters were similar at baseline. 83% of subjects completed 6 months and 62% completed 12 months, without differences in discontinuation rates between the groups. IGF-1 increased (86±21 vs. -6±8 µg/L, tesamorelin vs. placebo; treatment effect [95% CI]: 92 [52,132] µg/L; P<0.0001). Abdominal visceral adipose tissue (VAT) (-16±9 vs.19±9 cm2; -35 [-58,-12] cm2; P=0.003) (net treatment effect of -19% relative to placebo), carotid intima-media thickness (cIMT) (-0.03±0.01 vs. 0.01±0.01 mm; -0.04 [-0.07,-0.01] mm; P= 0.02), logCRP (-0.17±0.04 vs. -0.03±0.05 mg/L; -0.15 [-0.30,-0.01] mg/L, P=0.04), and triglycerides (-26±16 vs. 12±8 mg/dL; -37 [-67,-7] mg/dL; P=0.02) improved significantly in the tesamorelin group vs. placebo. In addition, waist circumference (-2±1 vs. 1±1 cm; -3 [-5,-0.3] cm; P=0.03) and trunk fat decreased (-0.6±0.4 vs. 0.7±0.4 kg; -1.4 [-2.4,-0.3] kg; P=0.01) and lean mass increased (1.0±0.5 vs. -0.4±0.4 kg; 1.4 [0.2,2.6] kg; P=0.03). No significant effects on abdominal subcutaneous adipose tissue (SAT) (-6±6 vs. 3±11 cm2; -10 [-32,13] cm2; P=0.40) or weight were seen. No changes in fasting, 2-hr glucose or HbA1c were seen. Effects of gender were not seen in the model. There were no serious adverse events and no differences in adverse events between the groups.

Conclusion: Among obese subjects with relative reductions in GH, tesamorelin a GHRH-analogue, selectively reduces VAT, without significant effects on SAT, and improves triglycerides, CRP and cIMT, without aggravating glucose. These data suggest a functional consequence of reduced GH secretion in obesity and demonstrate an improved CVD risk profile resulting from tesamorelin. In addition, this study suggests, more broadly, that strategies to selectively reduce VAT and spare SAT may improve CVD risk in obesity.

 

[Michael Scally MD]

[MON-43] Effect of Testosterone Administration on Hepatic Fat and Insulin Resistance in Older Men in a Placebo-Controlled Randomized Trial
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_MON-43

Grace Huang, Shalender Bhasin, Elizabeth Tang, Adam Aakil, Stephan Anderson, Hernan Jara, Maithili Davda, Thomas Travison, Shehzad Basaria. Boston University School of Medicine, Boston, MA.

Background: Non-alcoholic fatty liver disease is highly prevalent and is associated with insulin resistance and proatherogenic dyslipidemia. Androgen receptor knock-out male mice display hepatic steatosis and insulin resistance, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone on hepatic fat in men are unknown.

Objective: To determine the effects of 6 months of testosterone administration on hepatic fat in older men with mobility limitation and low serum total and free testosterone levels who were participating in a placebo-controlled randomized trial (The TOM Trial).

Methods: 209 men were randomized in the parent trial to either placebo or 10 g testosterone gel daily for 6 months. Magnetic resonance imaging (MRI) scans of the liver were obtained in 73 men (36 in the placebo and 37 in the testosterone group; mean age 74 years), and hepatic fat was determined using volumetric method. Fasting glucose and insulin levels were measured and HOMAIR was calculated.

Results: Baseline liver volumes (1583 ± 363 ml vs 1522 ± 271 ml, p= 0.42), age, BMI, HOMAIR, fasting lipid profile and liver function tests were not significantly different in the testosterone and placebo arms. Serum testosterone concentrations increased from 250 ± 72 ng/dl and 229 ± 58 ng/dl to 632 ± 363 ng/dl and 272 ± 153 ng/dl in the testosterone and placebo groups, respectively. After 6 months of testosterone administration, the changes in liver volume were not different between the two groups (p-value = 0.5). Similarly, the change in HOMAIR was not significantly different between the groups. Multiple regression analysis did not show any relationship between the change in testosterone concentrations and change in liver volume.

Conclusion: Testosterone administration in older men with mobility limitation and low testosterone was not associated with a reduction in hepatic fat. Larger clinical trials are needed to determine whether testosterone reduces liver fat and outcomes in men with nonalcoholic hepatic steatosis.

 

[Michael Scally MD]

[SUN-178] The Relationship between Sex Hormones, SHBG, and Endothelial Function in Older Men: Data from the PIVUS Study
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-178

Chiara Cattabiani, Gian Paolo Ceda, Fulvio Lauretani, Andrea Artoni, Rosalia Aloe, Giulia Schiavi, Marco Mantovani, Riccardo Volpi, Graziano Ceresini, Giuseppe Lippi, Tommy Cederholm, Lars Lind, Marcello Maggio. University Hospital of Parma, Parma, Italy; University Hospital of Parma, Parma, Italy; University Hospital of Parma, Parma, Italy; Uppsala University Hospital, Uppsala, Sweden; Uppsala University Hospital, Uppsala, Sweden.

Background. Epidemiological studies have shown that low sex hormone binding globulin (SHBG) and testosterone (T) and high estradiol (E2) are independent predictors of metabolic syndrome and its components including hypertension in adult-older men (1).Preliminary data support a potential role of low SHBG in the risk of PAD in older men (2). However, despite the emerging link between SHBG, sex hormones and cardiovascular disease, the direct relationship with endothelium function has never been addressed. This is of importance since endothelium-dependent vasodilation assessed by the invasive forearm technique with acetylcholine given in the brachial artery (EDV) has been recently shown to be an independent risk factor of cardiovascular events in the older population (3).

Aim of the study. To test the association between SHBG, sex hormones and endothelial function in older men.

Methods and Results. Participants 70 years of age of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), with complete data on EDV, and the brachial artery ultrasound technique with flow-mediated dilatation (FMD) were evaluated. From the entire sample of 1016 subjects, we used data of 430 men having information on SHBG, estradiol, T and endothelial function. SHBG, E2 and T were assessed by chemiluminescence (Beckman Coulter). The MDC for E2, T and SHBG were 73 pmol/L, 0.35 nmol/L and 2 nmol/L. The interassay coefficients of variation (CV) was <20% for E2, the intra and inter CVs <4 and <7% for T, the interassay CV 5.3% for SHBG. Generalized linear models adjusted for multiple confounders including BMI, C Reactive Protein, fasting insulin, were used to test the relationship between sex hormones, SHBG and endothelial function. In a crude analysis we found a positive significant relationship between SHBG and EDV (?± SE 4235.2 ± 908.5,p <.0001) but not with FMD. The relationship was maintained after adjustment for T (?± SE 3734.6± 1364.7, p=0.0065) and further adjustment for additional confounders including E2(?± SE 2898.9± 1413. 1,p=0.04). No significant relationship was found between T, E2 and EDV or FMD.

Conclusions. In older men SHBG, but not testosterone and estradiol, is positively and independently associated with endothelium-dependent vasodilation.

1. Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011;40(1):189-207.

2. Haring R, Travison TG, Bashin S, Vasan RS, Wallaschofski H, Davda MN, Coviello A, Murabito JM. Relationship between sex hormone concentrations, peripheral arterial disease, and change in ankle-brachial index: findings from the Framingham Heart Study. J Clin Endocrinol Metab 2011Dec;96(12):3724-32.

3. Lind L, Berglund L, Larsson A, Sundström J.Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease.Circulation. 2011 Apr 12;123(14):1545-51.

 

[Michael Scally MD]

[MON-85] Meal Timing and Composition Influence Ghrelin Levels, Appetite Scores and Weight Loss Maintenance in Overweight and Obese Adults
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_MON-85

Daniela Jakubowicz, Oren Froy, Julio Wainstein, Mona Boaz. Wolfson Medical Center, Tel Aviv University, Holon, Israel; The Hebrew University of Jerusalem, Rehovot, Israel; Wolfson Medical Center, Tel Aviv University, Holon, Israel; Wolfson Medical Center, Tel Aviv University, Holon, Israel.

Background: Although dietary restriction often results in initial weight loss, the majority of obese dieters fail to maintain their reduced weight. Diet-induced weight loss results in compensatory increase of hunger, craving and decreased ghrelin suppression that encourage weight regain. A high protein and carbohydrate breakfast may overcome these compensatory changes and prevent obesity relapse.

Methods: In this study 193 obese (BMI 32.2±1.0 kg/m2), sedentary non diabetic adult men and women (47±7 years) were randomized to a low carbohydrate breakfast (LCb) or an isocaloric diet with high carbohydrate and protein breakfast (HCPb). Anthropometric measures were assessed every 4 weeks. Fasting glucose, insulin, ghrelin, lipids, craving scores and breakfast meal challenge assessing hunger, satiety, insulin and ghrelin responses, were performed at baseline, after a diet Intervention period (week 16) and after a follow-up period (week 32).

Results: At week 16, groups exhibited similar weight loss:-15.1±1.9 kg in LCb group vs. 13.5±2.3 kg in HCPb group, p=0.11. From week 16 to week 32, LCb group regained 11.6 ±2.6 kg, while the HCPb group lost additional 6.9±1.7 kg. Ghrelin levels were reduced after breakfast by 45.2% and 29.5% following the HCPb and LCb, respectively. Satiety was significantly improved and hunger and craving scores significantly reduced in the HCPb group vs. the LCb group.

Conclusion: A high carbohydrate and protein breakfast may prevent weight regain by reducing diet-induced compensatory changes in hunger, cravings and ghrelin suppression.

To achieve long-term weight loss, meal timing and macronutrient composition must counteract these compensatory mechanisms which encourage weight regain after weight loss.

 

[Michael Scally MD]

[SUN-LB3] Comparison of the Effect of High Calorie Breakfast Diet vs High Calorie Dinner Diet on Weight Loss, Ghrelin, Lipids and Appetite Scores in Obese Non Diabetic Women
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_SUN-LB3

Daniela Jakubowicz, Mona Boaz, Yosepha Bar-Dayan, Julio Wainstein. Tel Aviv University, Holon, Israel; Tel Aviv University, Holon, Israel.

Background: Recently we have shown that compared to low carbohydrate (CH) diet, an isocaloric diet with addition of high calorie breakfast (B) that also included dessert, promoted sustained weight(W) loss(WL) and prevented W regain by reducing diet-induced compensatory changes in hunger, cravings and ghrelin suppression. Direct effects of meal timing (morning vs. evening increased calories) were not tested.

Objective: To search whether a change in meal timing by increasing calories in the morning vs in the evening has a differential impact on WL, ghrelin suppression, lipids and appetite scores. Our hypothesis is that comparing with high calorie dinner (D) + reduced B (HCDd), the high calorie B + reduced D (HCBd), would enhance WL, ghrelin suppression and appetite scores.

Methods: 73 obese women (BMI 32.3±2.0 kg/m2), aged 46±6 years, were randomized to two isocaloric (1400 kcal) weight loss diets during 12 weeks (Wk). Both diets had the same composition but differ in the meal timing distribution

1)HCBd consisted in large B with 700 Kcal(Kc)with % of CH; protein; fat: 50:30:20%; lunch (500 Kc, 20:45:25%), and small D (200 Kc, 13:40:47%).

2)HCDd consisted in low calorie B (200 Kc, 13:40:47%),lunch(500 Kc, 20:45:25%), and large D (700 Kc, 50:30:20%).

Anthropometric measures were assessed every 4Wk. Fasting glucose, insulin, ghrelin, lipids, OGTT, craving scores as well as B and D challenge were performed at baseline and at Wk12

Results: After Wk12 intervention, the HCBd group (g) lost 8.7±1.4 kg vs 3.48±2.3 kg the HCDd g. In comparison to the HCDd g, the HCBd g showed 61% greater WL, P<0.05,a 35% greater reduction in waist circumference (P<0.06) and a 17% greater reduction in percent body fat (P=NS). Ghrelin levels were reduced after B by 46.2% in the HCBd group and 18.5% after D in the HCDd g(P>0.005). Satiety was significantly improved and hunger and craving scores significantly reduced in the HCBd vs HCDd g (P>0.005). Mean serum triglyceride levels decrease by 44% (from 184.2±16.6 to 102.2±7.7 mg/dl) in the HCBd g while increase 6.3% (from 180.5±20.6 to 192.4±17.5 mg/dl) in the HCDd g(P>0.005). Total cholesterol (C), HDL-C and LDL-C, did not differ between the groups.

Conclusion: Isocaloric WL diets with different meal timing, differently influence WL rate, ghrelin, appetite and lipid levels. HCBd with reduced intake at D result in enhanced WL, increased ghrelin suppression and might be useful alternative for management of obesity.

 

[Michael Scally MD]

[MON-135] Transient Glucocorticoid Excess Causes Persisting Changes in Lean Body Mass and Fat Mass in Mice Fed a High-Fat Diet
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_MON-135

Hanna E Auvinen, Johannes A Romijn, Nienke R Biermasz, Mariette R Boon, Louis M Havekes, Johannes WA Smit, Patrick CN Rensen, Alberto M Pereira. Leiden University Medical Center, Leiden, Netherlands.

Introduction In humans, Cushing's syndrome (CS) is associated with an increased incidence of the metabolic syndrome, increased cardiovascular morbidity and mortality, even after long-term correction of glucocorticoid (GC) excess.

Aim To evaluate the effects of transient overexposure to GC on the metabolic changes in the long-term in mice.

Methods Single housed male C57Bl/6J mice were fed either a low fat (LFD) or high fat diet (HFD) and given corticosterone (CORT) (50 microg/ml) or vehicle in the drinking water for 4 wks, followed by a washout period for 4 or 8 wks thereafter. Plasma circadian corticosterone levels were assessed at baseline and at wks 4, 8, and 12 after the start of exposure. Lipids, insulin, and glucose levels were measured after an overnight fast. Insulin sensitivity was assessed by hyperinsulenemic-euglycemic clamp at week 8 and 12 for the low fat diet fed mice and week 12 for the high fat diet fed mice. Lean and body- and fat mass were analyzed by DEXA.

Results CORT-treatment transiently increased plasma corticosterone by 37-, 13-, 3- and 13-fold (LFD), and 25-, 5-, 2-, and 9-fold (HFD) at 07.00h, 12.00h, 18.00h and 22.00h, respectively. At week 8, peak CORT levels at 18.00h were suppressed in both diet groups, returning to baseline levels at week 12. CORT-treatment increased food intake and plasma levels of insulin, trigycerides, free fatty acids and cholesterol in both diet groups. Abrogation of CORT normalized food intake, whereas body weight was increased in HFD fed mice but remained unchanged in LFD fed mice. At week 12, insulin was still significantly higher in CORT treated mice in both diet groups. There were no differences in the lean body or fat mass at week 8 and 12 weeks in LFD fed mice but HFD fed CORT mice had persistently lower lean body mass and higher fat mass. Hyperinsulinemic-euglycemic clamp at week 8 or 12 in CORT-treated mice vs controls indicated no changes in either diet group.

Conclusion In mice, transient CORT excess induces long-lasting changes in body composition only in the presence of HFD. These diet dependent effects of CORT might contribute to the persistent adverse cardiovascular risk profile as observed in patients treated for Cushing's syndrome.

 

[Michael Scally MD]

[OR34-1] BclI Glucocorticoid Receptor Polymorphism Is Associated with Greater Body Fatness and Higher Insulin Resistance: The Hoorn and CODAM Studies
http://www.abstracts2view.com/endo/view.php?nu=ENDO12L_OR34-1

CCM Geelen, MMJ van Greevenbroek, NC Schaper, G Nijpels, LM 't Hart, CG Schalkwijk, I Ferreira, CJH van der Kallen, EFC van Rossum, HP Sauerwein, JM Dekker, CDA Stehouwer, B Havekes. Maastricht University Medical Center, Maastricht, Netherlands; Maastricht University Medical Center, Maastricht, Netherlands; VU University Medical Center, Amsterdam, Netherlands; Leiden University Medical Center, Leiden, Netherlands; Leiden University Medical Center, Leiden, Netherlands; Maastricht University Medical Center, Maastricht, Netherlands; Erasmus Medical Center, Rotterdam, Netherlands; Maastricht University Medical Center, Maastricht, Netherlands.

Background: Glucocorticoid receptor (GR) polymorphisms play an important role in the downstream effects of glucocorticoids (GCs). The BclI polymorphism has been shown to be associated with an enhanced GC sensitivity, which may result in greater abdominal obesity and its metabolic consequences. We have investigated the association of the BclI polymorphism with body fatness/fat distribution and insulin resistance in a large sample combining data from 2 cohort studies, which were both enriched with participants with a disturbed glucose metabolism and type 2 diabetes (DM2).

Patients and methods: The present study included 1228 participants (aged 64.7 ± 8.5 years, 22.6% had impaired glucose metabolism and 32.6% had DM2) from the Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM, n=543) and the Hoorn Study (n=685), who were genotyped for the BclI polymorphism using Taqman SNP genotyping assays; 519 (42%) were non-carriers (CC), 540 (44%) were heterozygous (CG) and 169 (14%) were homozygous (GG) carriers of the G-allele. Linear regression analyses adjusted for cohort, sex, age, glucose metabolism, smoking and use of medication were used to compare carriers of one or two G-alleles to non-carriers (dominant model; CG+GG vs. CC) and homozygous carriers to carriers of one or no G-allele (recessive model; GG vs. CC+CG). BMI (kg/m2), waist and hip circumferences (cm), and waist-hip-ratio (WHR) were used as measures of total fat and fat distribution. Insulin resistance was estimated using the standardized homeostatic model assessment of insulin resistance index (HOMA2-IR).

Results: In the fully adjusted recessive model, individuals with the GG genotype had a higher BMI (regression coefficient ?=1.05 (95% confidence interval: 0.41-1.70), p=0.001), waist (?=2.66 (0.90-4.41), p=0.003) and hip circumference (?=2.25 (0.86-3.64), p=0.002), and a higher HOMA2-IR (?=0.08 (0.01-0.16), p=0.034) when compared to the CC+CG genotype. There was no difference in WHR. In the dominant model, waist and hip circumferences tended to be higher in CG+GG carriers than in non-carriers of the G-allele (?=1.07 (-0.16-2.30), p=0.087 and ?=0.79 (-0.18-1.77), p=0.110 resp.). Genotypes were consistent with Hardy-Weinberg equilibrium (p>0.05) and the observed effects were largely comparable in both cohorts.

Conclusion: This study demonstrates that homozygous G-allele carriers of the BclI polymorphism have a significantly greater total body fatness and higher insulin resistance.