Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

T R A N S L A T I O N A L H I G H L I G H T S F R O M J C E M A b s t r a c t s The following abstracts from The Journal of Clinical Endocrinology & Metabolism have been selected by the editors of Endocrinology as being particularly relevant to readers interested in translational science. Association between Serum Insulin-Like Growth Factor (IGF) I and IGF Binding Protein-3 and Lung Function Sven Gläser, Nele Friedrich, Ralf Ewert, Christoph Schäper, Matthias Nauck, Marcus Dörr, Henry Völzke, Stephan B. Felix, Alexander Krebs, Henri Wallaschofski, and Beate Koch (J Clin Endocrinol Metab, published April 28, 2009, 10.1210/jc.2008-2662) ABSTRACT Background: There is strong evidence that IGF-I and IGF binding protein 3 (IGFBP-3), as central mediators of endocrine and finally metabolic or anabolic effects of GH, were associated with increased lung size in acromegaly or a decrease of respiratory muscle pressures in patients with GH deficiency. The aim of the present study was to further clarify the impact of IGF-I and IGFBP-3 levels on lung volumes and respiratory pressures in a general adult population. Material and Methods: From the Study of Health in Pomerania, 1326 subjects aged 25 to 85 yr participated in standardized pulmonary function testing. IGF-I and IGFBP-3 levels were measured with the Immulite 2500 system. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity, and smoking were performed. Results: In men, positive linear associations between IGF-I and IGF-I/IGFBP-3 ratio with forced expiratory volume in 1 sec (FEV1) as well as with forced vital capacity (FVC) were detected across all ages, whereas in women this positive association was only detectable above 50 yr. Furthermore, the analyses indicated positive linear relations of IGF-I/IGFBP-3 ratio with FEV1 and FVC, respectively. No significant relations between IGF-I or IGFBP-3 and maximal inspiratory pressure was detectable in both sexes. Conclusion: In conclusion, higher IGF-I levels were associated with higher lung volumes in men, whereas in women this association was only detectable in subjects older than 50 yr. Higher IGF-I values were not associated with increased respiratory muscle strength measured as maximal inspiratory pressure. Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation Susan K. Blank, Christopher R. McCartney, Sandhya Chhabra, Kristin D. Helm, Christine A. Eagleson, R. Jeffrey Chang, and John C. Marshall (J Clin Endocrinol Metab, published April 7, 2009, 10.1210/jc.2008-2606) ABSTRACT Context: Adult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS. Objective: The aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls. Design: We conducted a controlled interventional study. Setting: The study was conducted in a general clinical research center. Participants: A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied. Intervention: Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P. Main Outcome Measure: We measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope). Results: Overall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 ⫾ 3.4 vs. 10.3 ⫾ 7.7; P ⫽ 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA 2974 endo.endojournals.org Endocrinology, June 2009, 150(6):2974 –2975 Endocrinology, June 2009, 150(6):2974 –2975 endo.endojournals.org 2975 girls (39.6 ⫾ 30.6 vs. 22.2 ⫾ 13.9 mIU/ml; P ⫽ 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P ⫽ 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 ⫾ 5.8; P ⫽ 0.04). Conclusions: Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity. Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men Bu B. Yeap, Zoë Hyde, Osvaldo P. Almeida, Paul E. Norman, S. A. Paul Chubb, Konrad Jamrozik, Leon Flicker, and Graeme J. Hankey (J Clin Endocrinol Metab, published April 7, 2009, 10.1210/jc.2008-2416) ABSTRACT Context: Lower circulating testosterone concentrations are associated with metabolic syndrome, type 2 diabetes, carotid intimamedia thickness, and aortic and lower limb arterial disease in men. However, it is unclear whether lower testosterone levels predict major cardiovascular events. Objective: We examined whether lower serum testosterone was an independently significant risk factor for symptomatic cerebrovascular events in older men. Design: This was a prospective observational study with median follow-up of 3.5 yr. Setting: Community-dwelling, stroke-free older men were studied. Participants: A total of 3443 men at least 70 yr of age participated in the study. Main Outcome Measures: Baseline serum total testosterone, SHBG, and LH were assayed. Free testosterone was calculated using mass action equations. Incident stroke or transient ischemic attack (TIA) was recorded. Results: A first stroke or TIA occurred in 119 men (3.5%). Total and free testosterone concentrations in the lowest quartiles (⬍11.7 nmol/liter and ⬍222 pmol/liter) were associated with reduced event-free survival (P ⫽ 0.014 and P ⫽ 0.01, respectively). After adjustment including age, waist-hip ratio, waist circumference, smoking, hypertension, dyslipidemia, and medical comorbidity, lower total testosterone predicted increased incidence of stroke or TIA (hazard ratio ⫽ 1.99; 95% confidence interval, 1.33–2.99). Lower free testosterone was also associated (hazard ratio ⫽ 1.69; 95% confidence interval, 1.15–2.48), whereas SHBG and LH were not independently associated with incident stroke or TIA. Conclusions: In older men, lower total testosterone levels predict increased incidence of stroke or TIA after adjusting for conventional risk factors for cardiovascular disease. Men with low-normal testosterone levels had increased risk. Further studies are warranted to determine whether interventions that raise circulating testosterone levels might prevent cerebrovascular disease in men.  (...truncated)