RESPONSE OF THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS TO SURGERY*

Transcription

1 FERTILITY AND STERILITY Copyright ' 1978 The American Fertility Society Voi.'30, No.5, November 1978 Printed in U.S A. RESPONSE OF THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS TO SURGERY* ALLAN R. GLASS, M.D.t CHARLES E. SMITH, M.D. GERALD S. KIDD, M.D. ROBERT A. VIGERSKY; M.D. Kyle Metabolic Unit, Walter Reed Army Medical Center, Washington, D. C To evaluate the response of the hypothalamic-pituitary-testicular axis to surgery, serum levels of gonadotropins and steroid hormones were measured prior to and after elective surgery in men under age 50. Twelve men having surgery under general anesthesia had significant decreases in serum testosterone levels after surgery (P < 0.02). Six men having surgery under spinal or local anesthesia did not show a significant reduction in serum testosterone. By the 2nd postoperative day, the magnitude of the decreases in serum testosterone and serum free testosterone were similar (23% and 25%, respectively) in men having surgery under general anesthesia, and the changes in serum testosterone and serum free testosterone were significantly correlated (r = 0.69, P < 0.02). In subjects having general anesthesia, serum levels of estradiol, androstenedione, and 17-hydroxyprogesterone tended to fall, although not significantly, while serum follicle-stimulating hormone and the testosterone to estradiol ratio did not change. Serum luteinizing hormone (LH) levels increased by a mean of 19% after surgery under general anesthesia, although this increase was not statistically significant. The concomitant fall of serum testosterone and serum free testosterone after surgery under general anesthesia suggested that this fall is due to a decrease in testosterone secretion rather than a primary change in testosterone clearance or serum binding of testosterone. This decrease in testosterone secretion was not due to a specific block in the distal. steps of testosterone biosynthesis nor to hypothalamic-pituitary suppression by elevated estradiol levels. The nonsignificant increase in serum LH is consistent with either a primary testicular defect or hypothalamic-pituitary dysfunction as the cause of the fall in serum testosterone after surgery under general anesthesia. Fertil Steril 30:560, 1978 Since it was first observed in 1968 that serum testosterone levels in men fell after surgery, 1 this phenomenon has been studied extensively as a model for the response of the hypothalamicpituitary-testicular axis to acute stress. However, the mechanism of this decrease in serum testosterone has not been clarified. Therefore, we measured serum levels of gonadotropins and steroid Received May 23, 1978; accepted June 23, *The opinions contained herein are not to be construed as official views of the Department of Defense. tto whom requests should be addressed. hormones before and after surgery in 18 men under age 50. We attempted to determine whether the fall in serum testosterone after surgery reflected (1) a change in testosterone binding or clearance, (2) suppression ofthe hypothalamicpituitary unit by elevated estradiol levels, or (3) a specific block in testosterone biosynthesis. MATERIALS AND METHODS All men under age 50 having elective general surgery were invited to participate in the study. Five men having herniorraphy under spinal anesthesia were studied, as was one man having 560

2 Vol. 30, No.5 SERUM TESTOSTERONE AFI'ER SURGERY 561 lymph node biopsy under local anesthesia. The types of anesthesia used in the 12 men having surgery under general anesthesia were as follows: fentanyl (5 men), enflurane (3 men), halothane (1 man), methoxyflurane (1 man), fentanyl plus halothane (1 man), and fentanyl plus enflurane (1 man). In addition, all but one of the patients having general anesthesia also received nitrous oxide. Operations performed included cholecystectomy (two men), herniorraphy (two men), exploratory laparotomy (two men), partial hepatectomy (one man), nephrectomy (one man), partial gastrectomy (one man), appendectomy (one man), thyroidectomy (one man), and fistula excision (one man). Preoperative history and physical examination revealed that three of the men having surgery under general anesthesia had abnormalities of the hypothalamic~pituitary-testicular axis: unilateral orchiectomy for torsion of the testis (one man), oligospermia and testicular atrophy after mumps orchitis (one man), and unilateral orchiectomy after bilateral undescended testes until age 11 (one man). The hormonal changes after surgery in these men were similar to those of the rest of the group and they were not excluded from analysis. All patients provided written informed consent. Blood was obtained daily for 5 days on each subject, beginning the day prior to surgery (blood was not obtained from one spinal anesthesia subject on the 3rd postoperative day). All samples were drawn between 3 P.M. and 6 P.M., and three samples obtained at 15-minute intervals were pooled for each daily specimen. Blood was allowed to clot at room temperature and the serum was frozen until assayed. Serum testosterone was measured by radioimmunoassay on all samples. 2 Serum free testosterone was measured by equilibrium dialysis 3 on samples obtained preoperatively and on the 2nd postoperative day in subjects having surgery under general anesthesia. These samples were also assayed for luteinizing hormone (LH), 4 follicle-stimulating hormone (FSH), 4 estradiol, 5 androstenedione (10 patients), and 17-hydroxyprogesterone (11 patients) by radioimmunoassay. 17-Hydroxyprogesterone and androstenedione were measured after ether extraction and column chromatography on Sephadex LH-20, using cyclohexane-benzene-methanol as eluant (60:40:10 for 17-hydroxyprogesterone, 80: 15:5 for androstenedione). Antisera were generated in rabbits against 17 -hydroxyprogesterone- 3 -carboxymethy loxime( C MO )-bovine serum albumin (BSA) and androstenedione-6-cmo BSA. The 17 -hydroxyprogesterone antiserum cross-reacted 10% with progesterone and 2% with androstene-3,20-diol (5a or 5{3), but these steroids had been removed by the prior chromatography. Dextran-charcoal was used to separate bound from free hormone, and recoveries were calculated for each sample (average 80% ). Limits of detectability for 17~hydroxyprogesterone and androstenedione were 12 and 20 pg, respectively, and the interassay variations were 9% and 13%, respectively. Each patient's samples were measured in the same run of each hormone assay. Statistical analysis was done by Student's t-test for either paired or unpaired data as appropriate. RESULTS Surgery under general anesthesia resulted in a significant decrease in serum testosterone levels, as assessed either by the integrated percentage change in serum testosterone over 4 days (P < 0.02; Fig. 1) or by the absolute fall in serum testosterone by the 2nd postoperative day (P < 0.01; Table 1). The subjects having surgery under spinal or local anesthesia did not show a significant.fall in serum testosterone when evaluated by the same techniques (Fig. 1). The mean percentage decrease in serum free testosterone by the 2nd postoperative day (25 ± 5% [standard error]) was similar in magnitude to the fall in total serum testosterone (23 ± 4% ), and the changes in total and free testosterone were significantly correlated (r = FIG. 1. Changes in serum testosterone after surgery, expressed as percentage change from preoperative baseline value, in 12 men having general anesthesia (e-e) and 6 men having spinal or local anesthesia (0-- -0). Error flags indicate 1 SE.

3 562 GLASSET AL. TABLE 1. Serum Hormone Levels before and after Surgery under General Anesthesia Hormone Testosterone (ng/dl) Free testosterone (ng/dl) Estradiol (pg/ml) LH (miu/ml) FSH (miu/ml) Androstenedione (ng/dl) 17-Hydroxyprogesterone (ng/dl) Preoperative' 623 ± ± ± ± ± ± ± 12 2nd postoperative day' 463 ± 49b 11.9 ± 2.0b 30.2 ± ± ± ± 12 48± 12 "Values are means ±standard error. bp < 0.01 versus preoperative value (paired t-test). 0.69; P < 0.02). By the 2nd postoperative day, serum free testosterone levels fell in all 12 subjects, while total serum testosterone fell in 11 subjects and was unchanged in 1. Serum estradiol levels fell slightly (14%) but not significantly after surgery, while the ratio of testosterone to estradiol did not change. Serum FSH levels did not change after surgery under general anesthesia, while serum LH levels showed a 19% mean increase that was not statistically significant. Serum levels of androstenedione and 17 -hydroxyprogesterone tended to fall after surgery, although these changes did not attain statistical significance. However, since adrenocorticotropic hormone can increase the serum levels of both androstenedione and 17- hydroxyprogesterone, 6 7 a reduction in the testicular contribution to the serum levels of these steroids might be obscured by an increased adrenal contribution due to adrenal hyperactivity resulting from surgical stress. After excluding four subjects with afternoon cortisol levels greater than 10 J.Lg/dl on the 2nd postoperative day, however, we were still unable to show a significant fall in serum levels of androstenedione and 17- hydroxyprogesterone. DISCUSSION Our study confirms several previous reports showing that serum testosterone levels in men fall significantly after surgery under general anesthesia. 1 8 " 20 Patients having surgery under spinal or local anesthesia did not show a significant fall in serum testosterone, although the patterns of their changes in serum testosterone were similar to those of the group receiving general anesthesia (Fig. 1). The difference between the two groups might be due to the type of anesthesia or to the relatively minor nature of the surgery performed under spinal or local anesthesia. Serum testosterone is known to fall after bron- November 1978 choscopy under general anesthesia but not after bronchoscopy under local anesthesia. 18 On the other hand, serum testosterone has been reported to fall significantly in some men having surgery under spinal anesthesia, 15 and Matsumoto et al,9 reported that the decrease in serum testosterone levels was greater in men having more extensive surgery. Thus, both the type of anesthesia and the extent of the surgery seem to be important factors in determining the magnitude of the fall in serum testosterone after operation. The decrease in serum levels of testosterone in our study was somewhat smaller than that noted in previous studies, and several factors may account for this difference. First, all of our blood samples were obtained in the late afternoon, whereas in the previous studies, sampling was done in the morning. Serum testosterone is known to peak in the early morning hours and fall during the dayy Second, the anesthetic agents used most commonly in our subjects (enflurane, fentanyl) have not been used in the previous studies. Finally, most of our patients underwent less extensive surgery than the patients in most of the previous studies, and, as pointed out above, it has been reported that the fall in serum testosterone is greater after more extensive surgery. In fact, most of our patients underwent surgery that would be classified as "moderate" rather than "major" by the criteria of Matsumoto et al., 9 and the fall in serum testosterone in our study is similar to that reported by them for patients having "moderate" surgery. We found that the magnitude of the fall in serum free testosterone (25%) was very similar to the magnitude of the fall in total serum testosterone (23%), and the changes in total serum testosterone and serum free testosterone were significantly correlated. This finding suggests that the fall in serum testosterone is due to decreased testosterone secretion rather than decreased serum binding of testosterone. Moreover, a primary change in clearance of testosterone alone would not produce any changes in free testosterone, since an intact hypothalamic-pituitary-testicular axis should be able to overcome any tendency of testosterone to fall as a result of increased clearance. Monden et al.u reached a similar conclusion based on the fall in urinary testosterone metabolites after surgery. Serum estradiol levels fell slightly, but not significantly, after surgery, and the testosterone to estradiol ratio was unchanged. Thus, the fall in serum testosterone after surgery is not due to suppression of the hypothalamic-pituitary unit by

4 Vol. 30, No.5 SERUM TESTOSTERONE AFTER SURGERY 563 elevated estradiol levels. Furthermore, since at least 50% of estradiol in men is derived from testosterone,22 the tendency of serum estradiol to fall after surgery, with an unchanged testosterone to estradiol ratio, is consistent with reduced testosterone secretion. A surgically induced block in testosterone biosynthesis was suggested by Tcholakian and Eik-Nes,23 who found that testicular venous testosterone in dogs declined after surgery, while testicular venous pregnenolone rose. Supporting the concept of a block in testosterone biosynthesis after surgery in humans is the finding of unchanged urinary pregnanetriol after operation despite a fall in urinary testosterone metabolites. 18 If surgery caused a block in one of the last two enzymes in testosterone biosynthesis (17-20 lyase or 17-hydroxysteroid dehydrogenase), one might anticipate that the serum level of the substrate for the blocked enzyme (17-hydroxyprogesterone or androstenedione, respectively) would rise, as it does in congenital defects of these enzymes. In fact, we found that serum levels of 17- hydroxyprogesterone and androstenedione tended to fall, although not significantly, after surgery. This finding is consistent with decreased activity of the entire testosterone biosynthetic pathway. If a specific block in testosterone biosynthesis is responsible for the fall in serum testosterone after surgery, it must be at or before 17-hydroxylase. Our data do not permit a definite conclusion as to whether the fall in serum testosterone after surgery is due to a primary testicular defect, a primary hypothalamic-pituitary defect, or both. If the fall in serum testosterone is due to a primary testicular defect, serum LH should rise as a feedback response. If the fall in serum testosterone is due to hypothalamic-pituitary dysfunction, serum LH should fall as serum testosterone falls. If defects are present at both sites, the response of serum LH is indeterminate. Previous studies have shown an increase, a decrease, or no change in LH accompanying the fall in serum testosterone after surgery. The ability of human chorionic gonadotropin to stimulate significant increases in serum testosterone postoperatively would support a hypothalamic or pituitary defect.18 Using a multiple sampling technique shown to increase the accuracy of estimating mean serum LH levels,25 we found that LH tended to increase, although not significantly, after surgery, a finding consistent with either a primary testicular defect, a hypothalamicpituitary defect, or both. The identity of the factor associated with surgery which leads to the fall in serum testosterone remains obscure. Glucocorticoids, which can be elevated for several days after surgery, are known to suppress serum testosterone. 26 However, the fall in serum testosterone after surgery has been seen in men whose adrenals were suppressed by exogenous glucocorticoid throughout the pre- and postoperative periods. 18 Further studies will be necessary to identify the location of the specific defect(s) in the hypothalamicpituitary-testicular axis which cause the fall in serum testosterone after surgery as well as the nature of the factor associated with surgery that leads to such defects. Acknowledgments. We would like to thank Ethelbert Dawson for expert technical assistance and Ms. Denise Legere for invaluable secretarial help. We also express our appreciation to Col. Robert Muir, MC, and the members of the surgical service, Walter Reed Army Medical Center, for allowing us to study their patients, and to Mr. Norman Beaudry for his helpful advice. REFERENCES 1. 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