Latest Endocrine news from JCEM

oral contraceptives & progestin are bad news.
Metformin needs to be started pre teens in overweight kids.
50% of Diabetic men have testosterone deficiency

Selected Abstracts

Evidence for Insulin Suppression of Baseline Luteinizing Hormone in Women with Polycystic Ovarian Syndrome and Normal Women Mark A. Lawson*, Sonia Jain, R. Jeffrey Chang ea University of California, San Diego,

Context: In PCOS women the relationship of insulin to LH secretion and responses to GnRH remains unresolved. A rigorous analytical examination of this relationship has not been performed.

Objective: To determine the relationship of basal LH secretion and responses to GnRH, insulin and other endocrine variables in normal and PCOS women.

Design: In PCOS and normal women, mean composite 12 h LH secretion was analyzed for correlating factors. LH responses to varying doses of GnRH during a fixed rate of insulin infusion and LH responses to a fixed dose of GnRH during varying doses of insulin infusion were analyzed for contributing factors.

Setting: General Clinical Research Center, University of California, San Diego

Patients: 18 PCOS and 21 normal women underwent studies of frequent blood sampling and GnRH stimulation before and during insulin infusion.

Main outcome measures: Group mean composite 12h LH levels were assessed with respect to other endocrine variables. In addition, LH responses to GnRH with or without insulin infusion were assessed.

Results: In normal women, insulin negatively predicted mean LH. In PCOS, the combined effect of BMI (negative) and testosterone (positive) predicted LH. The best predictor of LH was BMI and insulin combined. Basal LH and LH responses to GnRH were unaltered by insulin infusion in normal women. These measures were reduced during insulin infusion in PCOS women.

Conclusions: In PCOS, insulin infusion suppresses pituitary response to GnRH. In normal women, insulin negatively correlates with mean LH and suppresses GnRH response at a high infusion rate.

Accuracy of Diagnostic Tests for Cushing’s Syndrome. A Systematic Review and Meta-analyses
Mohamed B. Elamin Victor M. Montori ea Mayo Clinic,

Context: The diagnosis of Cushing’s syndrome (CS) requires the use of tests of unregulated hypercortisolism that have unclear accuracy.
Objective: To summarize evidence on the accuracy of common tests for diagnosing CS.

Data synthesis: We found 27 eligible studies, with a high prevalence (794 (9.2%) of 8631 patients had CS) and severity of CS. The tests had similar accuracy: UFC (n=14 studies, LR+ 10.6, CI 5.5, 20.5; LR- 0.16, CI 0.08, 0.33), salivary MC (n=4, LR+ 8.8, CI 3.5, 21.8; LR- 0.07, CI 0, 1.2), and the 1-mg overnight DST (n=14, LR+ 16.4, CI 9.3, 28.8; LR- 0.06, CI 0.03, 0.14). Combined testing strategies (e.g., a positive result in both UFC and 1-mg overnight DST) had similar diagnostic accuracy (n=3, LR+ 15.4, CI 0.7, 358; LR- 0.11, CI 0.007, 1.57).

Conclusions: Commonly used tests to diagnose CS appear highly accurate in referral practices with samples enriched with patients with CS. Their performance in usual clinical practice remains unclear.

Effect of Low Dose Oral Contraceptives on Metabolic Risk Factors in African-American Women
Barbara A. Frempong, Anne E. Sumner* ea National Institutes of Health, Bethesda,

Context: Effect of OCP-use on cardiovascular risk in African-American women is unknown.

Objective: To examine in African-American women, the effect of OCP-use on insulin resistance, glucose intolerance and triglycerides (TG). Design: Cross-sectional study

Setting: Study was conducted at the National Institutes of Health Clinical Research Center

Participants: One-hundred-four healthy non-diabetic African-American women (21 OCP-users, 83 controls, age mean±SD, 34.7±7.6years, BMI 31±8.4kg/m2)

Interventions: Subjects had oral glucose tolerance tests (OGTT), insulin modified-frequently sampled intravenous glucose tolerance tests and fasting lipid profiles. Insulin resistance was determined by the insulin sensitivity index (SI).

Main Outcome Measures: Insulin resistance, glucose tolerance status and TG levels.

Results: Fasting glucose did not differ between OCP-users and controls (P=0.27). In contrast, compared to controls, 2-hour glucose (135±23 vs.120±25 mg/dL, P=0.01) and fasting TG (73 ±31 vs.57 ±27 mg/dL, P=0.02) were higher in OCP-users. OCP-users tended to be more insulin resistant than controls (SI: 2.51±2.01 vs. 3.46±2.09, P=0.09). Multiple regression analysis revealed that BMI, age and OCP-use were significant determinants of 2-hour glucose (adjR2=0.37; P<0.001) and TG levels (adjR2=0.21; P<0.001). As BMI was a determinant of both 2-hour glucose and TG, participants were divided into non-obese and obese groups and the analyses repeated. Among the non-obese women, the OCP-users were more insulin resistant (SI: 2.91±1.58 vs. 4.35±1.88, P=0.03) and had higher prevalence of glucose intolerance than controls (OR 5.7; 95% CI 1.4–24, P=0.01).

Conclusion: In African-American women OCP-use is associated with increase in markers of cardiovascular risk manifested by increased insulin resistance, glucose intolerance and elevated triglycerides.

Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women
Jennifer S. Lee*, ea Steven R. Cummings University of California, Washington; Ohio, Harvard, Alabama-Birmingham School of Medicine;

Context: Endogenous estradiol, testosterone, and sex hormone-binding globulin (SHBG) may influence the risk of hip fracture.

Design and Methods: From the Women’s Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time non-pathological hip fracture (median follow up=7 years) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum.

Results: Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk (odds ratio, OR = 0.62; 95% CI: 0.44, 0.88); those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI: 0.29, 0.66); and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI: 1.31, 2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI: 1.12, 2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI: 0.40, 1.00), but estradiol no longer was associated (OR = 0.72; 95% CI: 0.42, 1.23).

Conclusions: High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.

Changes over 14 Years in Androgenicity and Body Mass Index in a Bi-racial Cohort of Reproductive Age Women
Barbara Sternfeld* David S. Siscovick ea
Kaiser Permanente; & Unoversities of Northwestern Texas, Alabama,Minnesota, Washington,

Background: Body mass index is directly related to testosterone (total T and free T) and inversely to sex hormone binding globulin (SHBG) cross-sectionally, but little is known about how changes in body fat and androgen markers affect each other over time.

Methods: Participants included 969 white and black women from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, who were ages 18–30 at entry into the study and were pre- or peri-menopausal 16 years later at the time of the CARDIA Women’s Study (CWS). Total T and SHBG, were assayed from specimens drawn at the CWS examination and stored serum from the Years 2 and 10 CARDIA exams. Free T was calculated based on total T and SHBG. Body mass index (BMI) and waist circumference were measured at Years 2, 10 and 16.

Results: Despite clinically significant increases in BMI and waist circumference, total T and free T tended to decline while SHBG remained relatively constant. BMI and waist circumference were directly correlated with free T and inversely correlated with SHBG in cross-sectional analyses. In longitudinal, multivariable analyses, an annualized increase in BMI was inversely related to a concurrent annualized decrease in SHBG (beta = -0.79 ng/dl, s.e. = 0.22 in blacks; beta = -1.07 ng/dl, s.e. = 0.31 in whites). However, early increases in BMI were not related to later decreases in SHBG.

Conclusion: Increases in adiposity are closely tied to decreases in SHBG, but changes in body mass index and SHBG may occur concurrently rather than sequentially.

Low Testosterone Levels are Common and Associated with Insulin Resistance in Men with Diabetes

Mathis Grossmann George Jerums ea University of Melbourne,

Context: Low testosterone levels are common in men with type 2 diabetes and may be associated with insulin resistance.

Objective: We investigated prevalence of testosterone deficiency and the relationship between testosterone and insulin resistance in a large cohort of men with type 2 and type 1 diabetes.

Design: Cross-sectional survey of 580 men with type 2 diabetes and 69 men with type 1 diabetes. A subgroup of 262 men with type 2 diabetes was then reassessed after a median of six months.

Results: Forty-three percent of men with type 2 diabetes had a reduced total testosterone (TT), and 57% had a reduced calculated free testosterone (cFT). Only 7% of men with type 1 diabetes had low TT. By contrast, 20.3% of men with type 1 diabetes had low cFT, similar to that observed in type 2 diabetes (age-BMI adjusted odds ratio 1.4, 95% CI 0.7–2.9). Low testosterone levels were independently associated with insulin resistance in men with type 1 diabetes, as well as type 2 diabetes. Serial measurements also revealed an inverse relationship between changes in testosterone levels and insulin resistance.

Conclusions: Testosterone deficiency is common in men with diabetes, regardless of the type. Testosterone levels are partly influenced by insulin resistance, which may represent an important avenue for intervention, while the utility of testosterone replacement remains to be established in prospective trials.

Metformin Treatment for 4 yr to Reduce Total and Visceral Fat in Low-Birthweight Girls with Precocious Pubarche

Lourdes Ibáñez* ea University of Barcelona, University of Leuven,

Context and Objective: A low birthweight (LBW) tends to be followed by overweight, due to an excess of fat, including visceral fat. LBW girls with precocious pubarche (PP; pubic hair <8 yr) are at high risk for developing an adipose state of hyperinsulinemic androgen excess that leads towards early menarche. We explored the effects of insulin sensitization with metformin in LBW-PP girls.

Setting, Design, Patients, Intervention: Prepubertal LBW girls with PP [mean BW 2.4 Kg; age 7.9 yr; body mass index (BMI) 18.4 Kg/m2]; girls were randomly assigned to remain untreated (n=19) or to receive metformin for 4 yr (n=19; 425 mg/d for 2 yr, then 850 mg/d for 2 yr).

Main outcomes: at start and after 4 yr: height, weight; fasting insulin, glucose, IGF-I, testosterone, lipids, leptin, high-molecular weight (HMW)-adiponectin; body composition by absorptiometry; abdominal fat partitioning (only 4 yr) by magnetic resonance imaging; menarcheal status.

Results: Metformin-treated girls gained on average 5.5 Kg (or 50%) less fat, were after 4 yr less insulin resistant and less hyperandrogenic, had lower IGF-I levels and a less atherogenic lipid profile, and were less likely to be post-menarcheal than untreated girls, while their gains in height, lean mass and bone mineral density were similar. After 4 yr, untreated girls had more visceral fat, a higher ratio of visceral-to-subcutaneous fat, and a higher leptin-to-HMW adiponectin ratio (all 50% higher) than metformin-treated girls.

Conclusion: Long-term metformin treatment appears to reduce total and visceral fat in LBW-PP girls, and to delay menarche without attenuating linear growth, thereby opening the perspective that adult height may be increased.

24-h Serum Levels of Growth Hormone, Prolactin and Cortisol in Pre- and Postmenopausal Women. The effect of combined estrogen and progestin treatment
Nea Kalleinen , Olli Polo ea Universities of Turku & Tampere. Finland

Objective: To study the 24-h profiles of growth hormone (GH), prolactin (PRL) and cortisol concentrations in older postmenopausal and in middle-aged premenopausal women, before and after estrogen-progestin treatment (EPT).

Design: A randomized, placebo-controlled trial. GH, PRL and cortisol were sampled every 20 min for 24 hours in 18 postmenopausal (aged 58–70 years) and 17 premenopausal (aged 45–51 years) women before and after six months of EPT.

Results: The mean 24-h GH (1.0 vs 1.8 mU/L, p = 0.033) and PRL (6.8 vs 10.0 ng/mL, p = 0.009) concentrations were lower in postmenopausal than in premenopausal women. After EPT the postmenopausal GH and PRL did not differ from premenopausal baseline levels. Postmenopausal mean 24-h GH (p < 0.001) and PRL (p = 0.002), daytime GH (p < 0.001) and nighttime PRL (p = 0.004) were higher during EPT compared to placebo. Cortisol levels did not differ. Premenopausal mean nighttime PRL (p = 0.026) and cortisol (p = 0.018) were higher during EPT compared to placebo. Postmenopausal PRL and premenopausal GH and PRL concentrations were higher at night than during the day. EPT did not alter this pattern.

Conclusions: Menopause was associated with decreased 24-h levels of GH and PRL, which were reversible with EPT. In contrast, cortisol levels were not affected by menopause or EPT. In middle-aged premenopausal women the studied effects of EPT were limited to nighttime increases of PRL and cortisol.

EFFECTS IN POSTMENOPAUSAL WOMEN OF ESTRADIOL AND MEDROXYPROGESTERONE ALONE AND COMBINED ON RESISTANCE ARTERY FUNCTION AND ENDOTHELIAL MORPHOLOGY AND MOVEMENT
Karolina Kublickiene Andrea R. Genazzani Tommaso Simoncini ea
Universities of Karolinska & Pisa,

Context: Endothelial dysfunction in resistance arteries after menopause is imortant for the development of high blood pressure and cardiovascular disease.

Objective: To study the effects of different hormone replacement therapies (HRT) on the function and morphology of isolated resistance arteries, and to look for their mechanistic basis.

Design and setting: A randomized, placebo-controlled double-blind study in a University hospital, along with laboratory-based studies.

Patients and interventions: We isolated resistance arteries in subcutaneous biopsies from 55 postmenopausal women before and after 3 months of therapy with estradiol (E2), medroxyprogesterone acetate (MPA), E2 + MPA or placebo. In addition, we studied isolated human endothelial cells.

Main Outcome Measures and Results: Artery flow-mediated dilatation was augmented after treatment with E2 or E2+MPA, whereas MPA or placebo had no effect. Pressure-induced myogenic tone was reduced by E2 + MPA, while it was unchanged in the other groups. Scanning microscopy showed that E2 improved endothelial cell morphology and decreased signs of endothelial apoptosis, but the addition of MPA impaired these events. E2, MPA or the combination all increased the expression and phosphorylation of the actin-binding protein, moesin and of the focal adhesion complex controller, focal adhesion kinase and induced the rearrangement of cytoskeletal actin and vinculin fibers. All treatments promoted endothelial cell horizontal migration, with E2 inducing the strongest effect.

Conclusions: This study suggests that HRT with estrogens or in combination with MPA may benefit the function of resistance arteries and may preserve the morphological integrity of endothelial cells by regulatory actions on the cytoskeleton.

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