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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2044-2047
Copyright © 1997 by The Endocrine Society


Clinical Studies

Long-Term Testosterone Administration Increases Visceral Fat in Female to Male Transsexuals1

Jolanda M. H. Elbers, Henk Asscheman, Jacob C. Seidell, Jos A. J. Megens and Louis J. G. Gooren

Division of Endocrinology/Andrology, Hospital Vrije Universiteit (J.M.H.E., H.A., J.A.J.M., L.J.G.G.), Amsterdam; and the Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and Environmental Protection (J.C.S.), Bilthoven, The Netherlands

Address all correspondence and requests for reprints to: Dr. H. Asscheman, Division of Endocrinology/Andrology, Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.


    Abstract
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The amount of intraabdominal (visceral) fat is an important determinant of disturbances in lipid and glucose metabolism. Cross-sectional studies in women have found associations between high androgen levels and visceral fat accumulation. The causal relation between these phenomena is unknown. We, therefore, studied prospectively the effect of testosterone administration on body fat distribution in 10 young, nonobese, female to male transsexuals undergoing sex reassignment. Before, after 1 yr, and after 3 yr of testosterone administration, magnetic resonance images were obtained at the level of the abdomen, hip, and thigh to quantify both sc and visceral fat depots. After 1 yr of testosterone administration, sc fat depots at all levels showed significant reductions compared to baseline measurements. The mean visceral fat area did not change significantly, but subjects who gained weight in the first year after testosterone administration showed an increase in visceral fat. After 3 yr of testosterone administration, sc fat depots were no longer significantly lower compared to pretreatment measurements, but the mean visceral fat depot had increased significantly by 13 cm2 (95% confidence interval, 4–22 cm2), a relative increase of 47% (95% confidence interval, 8–91%) from baseline. The increase in visceral fat was most pronounced in those subjects who had gained weight.

We conclude that long term testosterone administration in young, nonobese, female subjects increases the amount of visceral fat. In addition, an increase in weight in this hyperandrogenic state leads to a preferential storage of fat in the visceral depot.


    Introduction
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
THE DISTRIBUTION of body fat appears to be predictive of the health risks of obesity. Particularly, an increased amount of intraabdominal or visceral fat is associated with insulin resistance and an atherogenic lipid profile (1, 2). Regional fat distribution differs between men and women and can, therefore, be regarded as a secondary sex characteristic. Subcutaneous fat depots on hips and thighs are considered typically female, whereas excess fat in men is predominantly stored in the abdominal regions (3). After correction for the total body fat mass, men have, on the average, more visceral fat than women (4). This sex difference suggests a potential role for sex steroid hormones in determining the site of fat deposition. In women with high levels of total testosterone and/or free testosterone, visceral fat accumulation or a high waist to hip ratio, indicative of increased abdominal fat depots, is found (5, 6). The association of high testosterone levels with insulin resistance and an abdominal fat distribution in women has led to different, opposing interpretations. According to some investigators, the underlying factor is hyperinsulinemia, which leads to an increase in ovarian testosterone production (7). Others argue that hyperandrogenicity is the primary event leading to both accumulation of visceral fat and hyperinsulinemia (8).

In the present study, we investigated prospectively the effect of long term testosterone administration on body fat distribution in young, nonobese, female to male transsexuals undergoing sex reassignment to a male status following a standardized regimen (9). This enabled us to study the effect of (exogenous) hyperandrogenicity on the distribution of body fat by quantification of both sc and visceral fat depots in female subjects.


    Subjects and Methods
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Subjects

Ten young, nonobese, female to male transsexuals (mean age \ SD, 24 \ 6 yr; range, 16–33 yr; mean body mass index, 23.0 \ 3.0 kg/m2; range, 18.7–26.9 kg/m2) participated in the study. They were healthy, as assessed by their medical histories, physical examinations, and laboratory measurements. They were studied before, after 1 yr, and after, on the average, 3.2 \ 0.4 yr of testosterone administration (range, 2.5–3.8 yr). They were treated with 250 mg testosterone esters (Sustanon 250, Organon, Oss, The Netherlands) every 2 weeks, im, until they were ovariectomized as part of the cross-sex treatment after, on the average, 1.9 \ 0.4 yr. After ovariectomy, they continued testosterone treatment with im injections of 250 mg testosterone esters every 3 weeks. Two subjects switched to 160 mg testosterone undecanoate (Andriol, Organon)/day, orally, during the last year. The study was approved by the ethical review board of the Hospital Vrije Universiteit, and all subjects provided informed consent.

Anthropometry and body fat distribution

Body weight was measured to the nearest 0.1 kg, and height was measured to the nearest 0.1 cm with subjects wearing only underwear. Magnetic resonance (MR) imaging was performed on a whole body scanner with a magnetic field strength of 0.6 Tesla (Teslacon II, Technicare, Solon, OH). An inversion recovery pulse sequence was used with a repetition time of 524 ms, an echo time of 24 ms, and an inversion time of 190 ms. The slice thickness was 10 mm, and the field of view was 410 or 450 mm. Transverse MR images were obtained at the level of the abdomen (lower edge of the umbilicus), the hip (upper margin of the great trochanter), and the thigh (just below the gluteal fold). Three images were taken simultaneously at each body region: one image at the level of the marker, one above, and one below this position, with a gap between the images of 0.25 cm. In all subjects, the same anatomical markers and imaging parameters were used in repeated MR acquisition.

Quantification of sc and visceral fat areas was performed using an image-analyzing computer program (developed by our Department of Biomedical Engineering) (10), based on a seed-growing procedure. After a seed point is placed in a fat depot, this fat depot can be circumscribed by selection of a pixel intensity range. The intensity range is selected for each image separately according to the pixel intensity histogram. The area of the circumscribed fat depot is quantified by converting the number of pixels to square centimeters. Muscle area was calculated from subtracting the areas of sc fat, bone, and connective tissue from the total area on the image below the marker at thigh level. To reduce variability, image analysis was performed by one observer, and the average fat area of three images per level was used in the statistical analysis. Coefficients of variation for intraobserver variability in sc fat area measurements were 2.3% (abdomen), 2.4% (hip), and 2.2% (thigh); that for visceral fat area measurements was 9.8%. Due to a technical error, the digital MR information of four subjects for one measurement occasion was lost. The original MR information on film was available and was redigitalized (Lumiscan 100, Lumisys, Sunnyvale, CA) to quantify the fat depots. To study the variability introduced by the digitalization step, MR data for all subjects were also analyzed using this procedure. No statistical difference was observed between the two measurements, and coefficients of variation appeared to be in the same range, i.e. for sc fat area measurements, between 2–3%, and for the visceral fat area, 10.7%.

Blood samples

Before and after 1 yr of testosterone administration, blood samples were obtained after an overnight fast. Standardized RIAs were used to measure serum levels of testosterone (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA) and 17ß-estradiol (Double Antibody, Sorin Biomedica, Saluggia, Italy). Sex hormone-binding globulin was measured using an immunoradiometric assay (Orion Diagnostica, Espoo, Finland).

Statistics

Variables and changes in variables during treatment did not differ statistically from a normal distribution. Baseline variables are expressed as the mean \ SD, and changes in variables during treatment are presented as the mean change from baseline and 95% confidence intervals. Because of the small study population, the paired Wilcoxon signed rank test was used to test the effect of 1 yr and 3 yr testosterone treatments vs. baseline values for the variables studied. The Spearman rank correlation test was used to study correlations between variables. Two-sided P < 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
After testosterone administration, serum testosterone increased from 1.4 \ 0.7 nmol/L before to supraphysiological levels after 1 yr of treatment (34.4 \ 32.1 nmol/L; P < 0.01), and the levels of sex hormone-binding globulin in serum decreased from 56 \ 31 nmol/L at baseline to 25 \ 10 nmol/L after 1 yr of treatment (n = 8; P < 0.05). Serum levels of 17ß-estradiol decreased from 209 \ 138 pmol/L before to 114 \ 44 pmol/L after 1 yr of treatment (P = 0.17). Mean body weight had not changed significantly after 1 yr of treatment, and the increase in weight of 2.0 \ 5.9 kg after 3 yr did not reach significance (Table 1Go). The changes in weight ranged from -10.0 to 9.6 kg after 1 yr and from -9.0 kg to 13.9 kg after 3 yr of treatment.


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Table 1. Baseline and changes in body weight, fat area, and muscle area measurements during testosterone administration in 10 young nonobese female subjects

 
After 1 yr of testosterone administration, sc fat area measurements had decreased significantly at all levels measured, whereas the mean visceral fat area had not changed (Table 1Go). Compared to baseline, the area measurements after 3 yr of treatment showed small nonsignificant reductions in sc fat. In contrast, an absolute increase of 13 cm2 (95% confidence interval, 4–22 cm2) was observed in the visceral fat area (P = 0.013). The mean relative percent change in the visceral fat area, calculated from the individual changes from baseline, was 47% (95% confidence interval, 8–91%). A graphic presentation of the relative changes, expressed as percentage from baseline, after 1 yr, and after 3 yr of testosterone administration, is given in Fig. 1Go. Relative changes in body weight were strongly correlated with relative changes in visceral fat and sc fat at the abdominal level (Fig. 2Go). After both 1 and 3 yr of testosterone administration, the relative changes in visceral fat were greater than those in sc abdominal fat.



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Figure 1. Relative changes, expressed as percent change from baseline, in visceral and sc fat depots after 1 and 3 yr of testosterone administration in 10 female subjects. visc, Visceral fat; sc abd, sc abdominal fat; hip, sc hip fat; thigh, sc thigh fat. *, P < 0.05. Data are the mean ± SD.

 


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Figure 2. Relation between relative percent changes in body weight (x-axis) and relative percent changes in visceral fat areas (solid circles) and sc abdominal fat areas (sc abd fat; open squares; y-axis) after 1 yr (left graphic) and after 3 yr (right graphic) of testosterone administration in 10 female subjects. *, P < 0.05 (Spearman rank correlations).

 
The anabolic effect of testosterone on muscle mass was reflected by an increase of 12.6 \ 7.6% in muscle area at the thigh level after 1 yr. Muscle area remained at this level after 3 yr of treatment, with an increase of 11.0 \ 9.8% compared to baseline (Table 1Go).


    Discussion
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The present study shows that long term testosterone administration to young, nonobese female subjects induced a redistribution of fat depots, with a preferential accumulation of visceral fat if weight gain occurred. A shift from a typical female fat distribution to a more male type of body fat distribution was observed. After 1 yr, a relative redistribution of body fat had begun; at that time the visceral fat area had not yet increased significantly, but significant reductions were seen in the sc fat depots. Fat area measurements on MR images obtained after 3 yr of testosterone administration showed an absolute increase in visceral fat, whereas sc fat depots were reduced, but were no longer significantly different from baseline. In a study by Lovejoy et al. (11), the effect of exogenous androgens on regional fat distribution was investigated in obese, postmenopausal women undergoing weight loss through caloric restriction. In this study, an absolute increase in visceral abdominal fat and a loss of sc fat at the levels of abdomen and thigh were observed after 9 months of administration of nandrolone decanoate, an anabolic steroid with weak androgenic activity. The visceral fat depot had increased despite a weight reduction. In the present study, we did not observe an absolute increase in mean visceral fat after 1 yr of testosterone administration. However, a strong positive correlation was present between changes in body weight and changes in the visceral fat area. Also, for the sc fat depots, there was a positive correlation with changes in body weight after 1 yr, but all subjects lost sc fat regardless of increases in body weight. Thus, weight gain resulted in a preferential accumulation of fat in the visceral depot in hyperandrogenic female subjects. After 3 yr of treatment, an absolute increase in mean visceral fat was observed, and relative changes in this fat depot were larger than those in the sc abdominal fat depot. It seems that long term exposure to high levels of testosterone is required to increase the visceral fat depot in young, nonobese female subjects.

It is not likely that a state of hypoestrogenism after ovariectomy might (partially) explain our findings. Part of the administered testosterone is peripherally aromatized to estradiol. In a study in which we investigated ovariectomized female to male transsexuals receiving similar testosterone dosages, serum estradiol levels were not different from levels in eugonadal women in their early follicular phase (12) and were similar to those in eugonadal men. Thus, after ovariectomy, testosterone administration to our subjects still generated serum estradiol levels in a range comparable to levels in eugonadal women in the follicular phase. Further, the association between weight gain and visceral fat accumulation points in the same direction after 1 yr of testosterone administration as after 3 yr of testosterone administration, indicating that ovariectomy did not lead to a change in this relationship.

A limitation of the present study is the fact that it was not possible to compose a control group of young women with the same degree of variation in weight over 3 yr of follow-up. To our knowledge no detailed long term studies have been performed investigating prospectively the changes in the visceral fat depot in young women. However, cross-sectional studies in young women have shown that fat tissue is mainly located in the sc fat depots and that excess fat is preferentially stored sc, with a rather constant visceral fat depot (3, 4, 13). We, therefore, compared our data with those obtained for quantification of sc and visceral fat areas in 34 Dutch women with a wide range in age and body mass index (13). It appeared in our subjects that the increase in visceral fat area was larger and the change in sc fat area was smaller than expected on the basis of findings in the comparison group, although such a comparison with our study population should be performed with caution.

In an earlier study we found that 4-month administration of similar doses of testosterone to female to male transsexuals (of comparable age) did not increase fasting insulin levels significantly, but did lead to decreased insulin sensitivity (14). This observation, combined with our present results, shows similarities with the findings in women with high endogenous testosterone levels. The latter show both increased abdominal fat depots and insulin resistance. In the subjects of our study, nonobese, endocrine unremarkable, female subjects between the ages of 16–33 yr, the primary event leading to abdominal fat accumulation and insulin insensitivity was exogenous hyperandrogenism. This observation might be relevant for determination of the primary event in women with a combination of hyperandrogenism, insulin resistance, and abdominal fat accumulation. Some researchers believe that hyperinsulinemia is the primary event (7). Of note, however, is the fact that in our experiment testosterone levels were far above levels encountered in most spontaneous hyperandrogenic states in women.

These findings in women are dissimilar with some observations in men. Cross-sectional studies in men suggest an inverse association between testosterone levels and abdominal fat distribution (15). Oral testosterone treatment of middle-aged obese men with low normal testosterone levels seemed to reduce visceral fat (16). The oral administration might have been significant for the effects of the testosterone preparation, as in a study comparing the effects of oral anabolic steroids with those of parenteral testosterone treatment (as used in our study), only the oral preparation had this effect, not the parenteral testosterone preparation (17). Further, factors such as age or duration of testosterone exposure may determine the effect of testosterone on visceral fat. The men in the above studies (16, 17) were at least 40 yr of age or older, with a presumed exposure to their endogenous testosterone of some 25 yr.

This study resolves some of the uncertainties with regard to the association between testosterone and visceral fat in women by demonstrating that long term testosterone exposure increases visceral fat in young, nonobese female subjects.


    Acknowledgments
 
We thank T. Schweigmann from the Department of Diagnostic Radiology of the Hospital Vrije Universiteit for MR acquisition, and F. Hoogenraad and H. van de Mortel from the Department of Biomedical Engineering of the Hospital Vrije Universiteit for their technical assistance with the image analysis. We also thank J. Welleweerd from the Department of Radiotherapy of the University Hospital Utrecht for the opportunity to redigitalize MR information.


    Footnotes
 
1 This work was supported by The Netherlands Organization for Scientific Research (Grant 904–62-124). Presented in part at the Sixth European Congress on Obesity, May 31 through June 3, 1995, Copenhagen, Denmark. Back

Received December 18, 1996.

Revised March 24, 1997.

Accepted March 31, 1997.


    References
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Björntorp P. 1991 Metabolic implications of body fat distribution. Diabetes Care. 14:1132–1143.[Abstract]
  2. Kissebah AH, Krakower GR. 1994 Regional adiposity and morbidity. Physiol Rev. 74:761–811.[Free Full Text]
  3. Enzi G, Gasparo M, Biondetti PR, Fiore D, Semisa M, Zurlo F. 1986 Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography. Am J Clin Nutr. 44:739–746.[Abstract/Free Full Text]
  4. Lemieux S, Prud’homme D, Bouchard C, Tremblay A, Després J-P. 1993 Sex differences in the relation of visceral adipose tissue accumulation to total body fatness. Am J Clin Nutr. 58:463–467.[Abstract/Free Full Text]
  5. Evans DJ, Barth JH, Burke CW. 1988 Body fat topography in women with androgen excess. Int J Obesity. 12:157–162.[Medline]
  6. Wild RA. 1995 Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med. 98(Suppl 1A):27S–32S.
  7. Poretsky L. 1991 On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 12:3–13.[Abstract/Free Full Text]
  8. Björntorp P. 1993 Hyperandrogenicity in women–a prediabetic condition? J Intern Med. 234:579–583.[Medline]
  9. Walker PA, Berger JC, Green R, Laub DR, Reynolds CL, Wollman L. 1985 Standards of care. The hormonal and surgical sex reassignment of gender dysphoric patients. Arch Sex Behav. 14:79–90.[CrossRef][Medline]
  10. Elbers JMH, Haumann G, Asscheman H, Seidell JC, Gooren LJG. 1995 Reproducibility of fat area measurements in young non-obese subjects by computerized analysis of magnetic resonance images [Abstract]. Int J Obesity. 19(Suppl 2):51.
  11. Lovejoy JC, Bray GA, Bourgeois MO, et al. 1996 Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women–a clinical research center study. J Clin Endocrinol Metab. 81:2198–2203.[Abstract]
  12. Spinder T, Spijkstra JJ, Gooren LJG, Hompes PGA, van Kessel H. 1989 Effects of long-term testosterone administration on gonadotropin secretion in agonadal female to male transsexuals compared with hypogonadal and normal women. J Clin Endocrinol Metab. 68:200–207.[Abstract/Free Full Text]
  13. Seidell JC, Oosterlee A, Deurenberg P, Hautvast JGAJ, Ruijs JHJ. 1988 Abdominal fat depots measured with computed tomography: effects of degree of obesity, sex, and age. Eur J Clin Nutr. 42:805–815.[Medline]
  14. Polderman KH, Gooren LJG, Asscheman H, Bakker A, Heine RJ. 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab. 79:265–271.[Abstract]
  15. Seidell JC, Björntorp P, Sjöström L, Kvist H, Sannerstedt R. 1990 Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism. 39:897–901.[CrossRef][Medline]
  16. Mårin P, Holmång S, Jönsson L, et al. 1992 The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obesity. 16:991–997.
  17. Lovejoy JC, Bray GA, Greeson CS, et al. 1995 Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men. Int J Obesity. 19:614–624.



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J. M. H. Elbers, H. Asscheman, J. C. Seidell, M. Frolich, A. E. Meinders, and L. J. G. Gooren
Reversal of the Sex Difference in Serum Leptin Levels upon Cross-Sex Hormone Administration in Transsexuals
J. Clin. Endocrinol. Metab., October 1, 1997; 82(10): 3267 - 3270.
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