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Endocrine Care: Nelly Pitteloud, Megan Hardin, Andrew A. Dwyer, Elena Valassi, Maria Yialamas, Dariush Elahi, and Frances J. Hayes Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men J Clin Endocrinol Metab 2005; 90: 2636-2641 [Abstract] [Full text] [PDF]

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Response to Letter to the Editor

Frances Hayes, Nelly Pitteloud   (20 October 2005)

Letter to the Editor

Andrea M. Isidori, Andrea Fabbri   (20 October 2005)

Response to Letter to the Editor 20 October 2005
Frances Hayes, MD Massachusetts General Hospital, Nelly Pitteloud Send letter to journal: Re: Response to Letter to the Editor FHAYES{at}PARTNERS.ORG Frances Hayes, et al.	We thank Drs. Isidori and Fabbri for their thoughtful comments on our recent manuscript demonstrating that increasing insulin resistance is associated with a decrease in Leydig cell production of testosterone (T) in men (1). While our data point to a predominantly peripheral defect as the cause of low T levels in insulin resistant men, we agree that the absence of a compensatory increase in LH levels suggests an additional more subtle hypothalamic-pituitary defect, as has been recently reported in men with type 2 diabetes (2). In light of our findings, the authors reanalyzed their previously published data (3) and demonstrated a significant correlation between the area under the curve (AUC) for hCG-stimulated T production and insulin resistance assessed by HOMA. Because this correlation was lost after adjusting for percent body fat, they questioned whether body composition might also confound the relationship between insulin sensitivity and T production in our cohort. We, therefore, reanalyzed our data to address this hypothesis focusing on body mass index (BMI) and waist-to-hip ratio (WHR) as potential confounders. Results are presented for the 18 subjects for whom complete data were available. In a multiple regression analysis with T levels at 48 hr as the dependent variable, R2 for BMI alone was 0.44, P<0.005 and addition of insulin sensitivity explained a further 13% of the variability in T levels (P<0.05). Similarly, for WHR alone R2 was 0.49, P<0.005 and the additional contribution of insulin resistance to R2 was 14% (P<0.05). While the current analysis suggests that the relationship between insulin sensitivity and T production may be independent of body composition, we are reluctant to make any definitive conclusions given our small sample size and absence of precise measurements of body fat. In previous studies, Isidori and Fabbri demonstrated that a defect in 17,20 lyase activity might underlie the reduction in Leydig cell output seen with increasing adiposity (3). Unfortunately, we have insufficient serum to measure steroid hormone precursors in our study subjects so can provide no information on whether a single enzymatic step or the entire androgen pathway is affected in insulin resistant men with low T levels. REFERENCES 1. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, Hayes FJ 2005 Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 90:2636-2641. 2. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P 2004 Frequent occurrence of hypogonadotropic hypogonadism in type diabetes. J Clin Endocrinol Metab 89:5462-5468. 3. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, Fabbri A 1999 Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 84:3673- 3680.
Letter to the Editor 20 October 2005
Andrea M. Isidori, Andrology Unit Universita “La Sapienza”, Andrea Fabbri Send letter to journal: Re: Letter to the Editor andrea.isidori{at}uniroma1.it Andrea M. Isidori, et al.	We have read with great interest the study by Frances Hayes and colleagues demonstrating that in obese and insulin resistant subjects the frequently described hypogonadism may have a peripheral origin (1). This phenomenon has been often neglected even in recent publications (2). The decline of testosterone levels occurring in obese or diabetic men (3), as well as in older males, usually is unaccompanied by a compensatory rise in gonadotrophins (4). For this reason, the hypogonadism of diabetics has been often labeled exclusively hypogonadotropic in a rather simplistic way. However, there is a number of publications showing that this phenomenon has a combined etiology, central and peripheral. Chen and Zirkin showed that aging is associated with a defective LH-signal transduction in Leydig cells (5). We demonstrated that in adult obese men, Leydig cell output is progressively reduced with increasing adiposity (3). We also provided data that a defect in 17,20 lyase activity might be responsible for this reduction and that adipocyte derived products, such as leptin, are likely to be involved (3;6). Using an elegant and rigorous approach, Hayes and colleagues demonstrated that the defect in Leydig cells testosterone production correlates with insulin resistance and excluded that it is the consequence of a chronic alteration in the hypothalamic-pituitary function (1). The importance of their paper is that for the first time, using a GnRH pretreatment protocol, they were able to exclude any confounding effect of chronic hypothalamic pituitary dysfunction. In view of their findings, we have decided to reanalyze our previously published data (3). Similarly to Hayes and colleagues, we found a positive correlation between the area under the curve (AUC) of testosterone after hCG-stimulation and insulin resistance (HOMA). However, as previously shown for leptin, this association was close to that observed for fat mass and was lost when adjusted for the total kilograms of body fat measured by DEXA scan (3). We also found that in multiple regression analysis fat mass explained most of the testosterone reduction observed in obese or insulin resistant subjects (fat mass only, R2 22%, p<0.01; additional contribution of HOMA to R2 2%, p=NS). It would be interesting to verify whether in the series by Hayes and colleagues the correlation between hCG-response and measures of insulin resistance remained significant after adjusting the hCG-induced testosterone output for BMI, WHR, or preferably kilograms of fat mass. More data on steroid hormone precursors will help to address if insulin resistance affects the whole steroidogenic pathway or a specific enzymatic step, as we found in severely obese subjects (4). In summary, we agree with Hayes that hypogonadism in obese and insulin resistant men is mostly peripheral. Whether it is due to adipokines or insulin, or the combination of both deserves further studies. REFERENCES 1. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, Hayes FJ 2005 Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab 90:2636-2641. 2. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P 2004 Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 89:5462-5468. 3. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, Fabbri A 1999 Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 84:3673- 3680. 4. Isidori AM, Strollo F, More M, Caprio M, Aversa A, Moretti C, Frajese G, Riondino G, Fabbri A 2000 Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights. J Clin Endocrinol Metab 85:1954-1962. 5. Chen H, Liu J, Luo L, Zirkin BR 2004 Dibutyryl cyclic adenosine monophosphate restores the ability of aged Leydig cells to produce testosterone at the high levels characteristic of young cells. Endocrinology 145:4441-4446. 6. Caprio M, Isidori AM, Carta AR, Moretti C, Dufau ML, Fabbri A 1999 Expression of functional leptin receptors in rodent Leydig cells. Endocrinology 140:4939-4947.