Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome

To the Editor:

We would like to thank Dr. Brennan et al for their fine article (1). In this study, they found that dehydroepiandrosterone (DHEAS) was negatively correlated to insulin resistance in patients with polycystic ovary syndrome (PCOS) and the independent variables that affect the insulin resistance, in decreasing importance, were body mass index (BMI), waist-to-hip ratio (WHR), age, DHEAS, free testosterone (T), sex hormone binding globulin (SHBG) and 17-hydroxyprogesterone (17-OHP).

It has been reported that there is a close relationship adipose tissue and adrenal gland physiology (2). The adrenal glands are embedded in adipose tissue. On the other hand, adipocytes have frequently been observed in proximity to adrenal vessels or as clusters in zona glomerulosa and fasciculata, where they are in direct contact with steroid-producing cells (2).  Oxidized fatty acid stimulates basal and ACTH-induced DHEAS production (2). Another study showed that postmenopausal women with high levels of DHEAS had high WHR (3). DHEAS levels have also been shown to be influenced by age, mood, depression, and smoking status (4, 5). Therefore, the study would be better if the demographic characteristics of the study population such as age, BMI, WHR, and lifestyle factors like mood, depression, and smoking status of the participants were defined in the text.

The correlation analysis between DHEAS and insulin resistance may be affected by these variables. The number of insulin-resistant patients that were assessed by homeostatic model of insulin resistance of this population was also important. The results might be different statistically in multiple regression analysis if the percentage of insulin-resistant group was higher or lower; that was not defined in the text. Other parameters like Ferriman – Gallwey score, fasting insulin and glucose levels, total and free T, SHBG, 17-OHP should also be added in order to show the characteristics of the study group to the readers.

Hyperinsulinemia increases ovarian theca androgen production and decreases production of SHBG by the liver (6).It has been reported that free T was strongly associated with insulin resistance (6). Another study found that SHBG can be used as a single predictor to define the patients with an increased risk of insulin resistance in nonobese women with PCOS (7). In this study, the relationship between insulin resistance DHEAS was stronger than free T and SHBG levels. I think this issue must also be discussed in the text.

Fatma Ferda Verit, MD
Department of Obstetrics and Gynecology
Harran University, Faculty of Medicine
Sanliurfa, Turkey

References
1. Brennan K, Huang A, Azziz R. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome, Fertil Steril 2008 Apr 24 [Epub ahead of print].

2. Roberge C, Carpentier AC, Langlois MF, Baillargeon JP, Ardilouze JL, Maheux P,et al. Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Am J Physiol Endocrinol Metab 2007; 293(6):E1465-78.

3. Barrett-Connor E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab 1996 ;81(1):59-64.

4. Orentreich N, Brind HL, Rixer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551–5.

5. Rasmusson AM, Wu R, Paliwal P, Anderson GM, Krishnan-Sarin S. A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study. Psychopharmacology (Berl). 2006 ;186(3):473-80.

6. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. (Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society). The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2008 Oct 22.
[In press].

7. Cibula D, Skrha J, Hill M, Fanta M, Haaková L, VrbIková J, et al. Prediction of insulin sensitivity in nonobese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002 ;87(12):5821-5.

Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.01.162

The Authors Respond:

We would like to thank Dr. Verit for her comments regarding our paper on DHEAS and insulin resistance in PCOS patients.  We have included the baseline characteristics of our study population in Table 1.  Mood, including depression, and smoking status were not characteristics for which we collected data.  These may be important variables to include in future studies.

Table 1: Characteristics of study population of 352 Polycystic Ovary Syndrome Patients
Variable	Min	Median	Mean	Max	Standard Deviation
Age (y)	13.3	26.56	27.2	49.02	7.51
HT (inches)	52	64.75	64.6	72.25	2.56
WT (lbs)	89	210.5	211.4	366	57.94
BMI (kg/m2)	16.5	35.12	35.6	65.5	9.49
WHR	0.57	0.83	0.80	1.25	0.08
Total T (ng/dL)	14	80.0	88.5	635	55.42
Free T (ng/dL)	0.12	0.85	0.9	4.09	0.44
SHBG (nmol/L)	60	160	170.3	670	63.0
DHEAS (ng/mL)	213	1892	2073.7	6692	1112.0
17-OHP (ng/mL)	0.16	1.33	1.60	8.66	1.22
FG Score	0	8	8.4	31	4.94
Fasting Insulin (μU/mL)	1	18	22.1	94	16.42
Fasting Glucose (mg/dL)	4	87	89.8	242	17.59
HOMA-IR (mol x µU/L2)	3.47	68.62	91	614.8	77.3

The HOMA-IR estimates insulin resistance using the fasting glucose and insulin levels.  We calculated the HOMA-IR on all PCOS patients in our population, as we felt it was important to study the relationship between the potential predictors of insulin resistance and the HOMA-IR whether or not the patient actually carries a diagnosis of insulin resistance.  However, the percentage of patients with insulin resistance in our population does not materially affect the regression and correlation between DHEAS and HOMA-IR in this population.  The regression and correlation represent a relationship between these two variables.  If the correct scale is chosen, which is the log scale in this case, the correlation will hold true for both low and high values of HOMA-IR, as these values are simply different points on the same continuum.  Having a population with more low values of HOMA-IR (less insulin resistance) or high values of HOMA-IR (more insulin resistance) will not change the relationship between HOMA-IR and DHEAS.

In the multivariate regression analysis, we controlled for other possible confounding variables when evaluating the relationship between DHEAS and HOMA-IR.  We agree with Dr. Verit that FT and SHBG are associated with insulin resistance in PCOS, as indicated by our multivariate analysis in the published study.  We did find that the relationship between DHEAS and insulin resistance was stronger than that of FT or SHBG in the multivariate analysis, and consequently concluded that that this indicates that DHEAS is one of several important factors when examining predictors of insulin resistance in PCOS.

Kathleen Brennan, MD
Andy Huang, MD, MBA
Ricardo Azziz, MD, MBA, MPH
Cedars-Sinai Medical Center
David Geffen UCLA School of Medicine
Los Angeles, California

Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.01.163