Effect of adrenocorticotropin on production rates and metabolic clearance rates of testosterone and estradiol.

002 l-972X/78/4702-0307$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society

Vol. 47, No. 2 Printed in U.S.A.

Effect of Adrenocorticotropin on Production Rates and Metabolic Clearance Rates of Testosterone and Estradiol* J. HOWARD PRATTf AND C. LONGCOPE Boston University School of Medicine, Boston; and the Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545 level (30 ± 2 to 26 ± 2 pg/ml) or the P B (53 ± 4 to 54 ± 6 jug/day). The fractional conversion of testosterone to estradiol, [p]l&, did not change (0.0032 ± 0.0006 to 0.0032 ± 0.0004). In both women, the MCR for estradiol rose, but the changes in levels and estradiol PB were divergent. In both men, although the MCRs for androstenedione and estrone did not change appreciably, the circulating levels and PBS rose. The mean level of LH in six men did not change under these conditions (51 ± 11 before and 57 ± 11 ng/ml after ACTH). We conclude that in men, ACTH increases the metabolism of testosterone and decreases its circulating level, synthesis, and production rate. During the course of the study, LH levels did not rise in response to the fall in testosterone. The circulating level and PB of estradiol remain unchanged because ACTH results in increased production of androstenedione and estrone, both of which are converted to estradiol. In women, the PB of testosterone does not fall after ACTH, presumably because of the increased PB of androstenedione. (JClinEndocrinolMetab 47': 307,1978)

ABSTRACT. Using the constant infusion technique, [7-3H]testosterone and [4-l4C]estradiol were infused into six men and two women and [7-3H]androstenedione and [4-14C]estrone were infused into two men before and after the administration of 60 U ACTH every 12 h for four doses. Measurements of the MCRs, plasma levels of endogenous hormones, and blood production rates (PBs) were performed before and after ACTH. The fraction of infused androgen converted to and measured as estrogen ([P]BB DEST ) was also determined before and after ACTH. In all six men, ACTH caused a significant rise in the mean value for the MCR of testosterone from 900 ± 80 to 1250 ± 80 (SE) liters/day, a significant decrease in the mean value for levels of testosterone from 5.2 ± 0.9 to 2.0 ± 0.6 ng/ml, and a significant decrease in the PB of testosterone from 4.5 ± 0.5 to 2.3 ± 0.6 mg/day. In both women, MCR of testosterone rose, the plasma levels remained essentially unchanged, and the PBS increased. In the men, ACTH administration resulted in a nonsignificant rise in the MCR of estradiol from 1760 ± 50 to 2010 ± 120 liters/day, and no change in the circulating

T

ESTOSTERONE blood levels fall in men after ACTH administration (1-6). Similarly, in situations where ACTH secretion is increased, circulating testosterone levels may be low as in Cushing's disease (7), in Cushing's syndrome due to ectopic tumor secretion of ACTH (8), with surgical and psychological stress (9-15), and with physical strain such as Received August 31, 1977. Address reprint requests to: Dr. C. Longcope, Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545. * This work was supported in part by Grants HD-08034 from the NICHHD, NIH; AM-08657; and HD-03034. These studies were carried out in the Clinical Research Center of Boston City Hospital, Boston University Division, which is supported by Grant RR-533 from the General Clinical Research Center's Program of the Division of Research Resources (NIH). This work was presented in part at the 57th Annual Meeting of the Endocrine Society, San Francisco, CA, 1976. t Present address: Indiana University School of Medicine, Department of Medicine, 1100 West Michigan Street, Indianapolis, Indiana 46202.

running a marathon (16). Rivarola, et al. (2) showed in two male subjects that ACTH reduced the testosterone production rate; however, few data are available about the dynamic events involving the MCRs and production rates of testosterone that would result from an effect of ACTH to lower peripheral levels of testosterone. The following study was done to look at the effect of ACTH on the testosterone MCR and production rate. In addition, as in men estrodiol arises primarily through peripheral conversion from testosterone, measurement of the MCR and production rates of estradiol were made before and after ACTH administration. Materials and Methods Subjects were healthy volunteers (eight men and two women) between the ages of 21-27 yr old who had given informed consent for the studies and were on no medication. All infusions were done

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PRATT AND LONGCOPE

with the subject supine and fasting. Diethyl ether was redistilled and passed through an alumina column before use. All other reagents used were prepared as described (17, 18). [7-3H]Testosterone (SA, 25 Ci/mmol), [4-14C]testosterone (SA, 57.5 mCi/mmol), [4-14C]androstenedione (SA, 57.5 mCi/mmol), [4-14C]estradiol (SA, 54 mCi/ mmol), and [4-14C]estrone (SA, 54 mCi/mmol) were all obtained from New England Nuclear Corp. [73 H]Androstenedione (SA, 4.2 Ci/mmol) was obtained from Amersham-Searle Corp. 3H- and l4Clabeled androgens and estrogens were purified and the purity was checked as described (19, 20). Nonradioactive estrone and estradiol were obtained from Steraloids Co. and crystallized from methanol before use. Alumina HF-254 basic type E and Silica gel HF-254 were obtained from Brinkman Co., Westbury, NY. Whatman no. 2 paper was used for paper chromatography. Control blood samples for RIA of endogenous steroid levels and LH were obtained between 0800-0900 h on the 2 days before the first infusion. After the collection of the second control blood sample, subjects received a priming dose of 10 ml 8% ethanol in normal saline containing either 40 fxCi [7-3H]testosterone and 2 juCi [4-l4C]estradiol (six men and two women) or 40 juCi [7-3H]androstenedione and 2 juCi [4-14C]estrone (two men) followed immediately by a constant infusion of the same pair of radiolabeled steroids in 15 ml 8% ethanol in normal saline. The infusions lasted 3.5 h, during which the subjects received 60 juCI [3H]androgen and 3 /xCi [14C]estrogen. Over the last hour of the infusion, three blood samples were drawn and the plasma was stored frozen until analyzed for radioactivity as the free steroids. The subjects then received 60 U ACTH gel (Acthar) at the end of the infusion, at 0800 and 2000 h on the following day, and 0800 h on the 3rd day. After the fourth injection of ACTH, a blood sample was obtained for RIA of endogenous steriod levels and LH, and the subjects then received a priming dose and a constant infusion of the same pair of steroids they had previously received. Blood samples were drawn three times over the last hour of the 3.5-h infusion and were analyzed for radioactivity as the free steriods. All samples were analyzed for radioactivity as previously described (17, 18). Briefly, the method entails the addition of indicators to correct for losses, solvent extraction, and phenolic partition to separate the androgens from the estrogens. The androgens were further purified with multiple chromatographical procedures. The estrogens were separated and further purified as free steroids and as

JCE&M Vol47

1978 No 2

derivatives using multiple chromatographical procedures. The radioactivity of androstenedione, testosterone, estrone, and estradiol was then determined in a Nuclear-Chicago spectrophotometer and the final amounts of radioactivity were calculated after correction for procedural losses. Counting errors were determined (21) and were P > 0.05), and the PB remained unchanged (53 ± 4 to 54 ± 6 ju,g/day). In the two women who received ACTH, the MCR2 increased in both, but the effects on the plasma concentration and production rates were divergent. Effect of ACTH on androstenedione and estrone dynamics As shown in Table 2, the administration of ACTH resulted in small increases of 2 and 3% for the MCR of androstenedione (MCRA) and 5 and 8% for MCR1 (\ estrone). The increases in iA and i1 were greater (9 and 40%) and thus, the PBS increased for both steroids in both men studied. Effect of ACTH on LH In subjects 1-6, administration of ACTH had no consistent or significant (P > 0.1) effect on LH; the mean values were 51 ± 11 ng/ml before and 57 ± 11 ng/ml after ACTH.

TABLE 1. MCR, plasma concentrations (i), PB, and [p]?^ values for testosterone and estradiol before and after ACTH for men (subjects 1-6) and women (subjects 11 and 12). Testosterone >

-A-

Subject no.

1 2 3 4 5 6

T

gex

M M M M M M

Mean ± SE

11 12

F F

Estradiol

MCR (liters/day)

iT (ng/ml)

PB' (mg/day)

Before After

Before After

Before After

2

MCR (liters/day)

i* (pg/ml)

P,," (fig/day)

Before After

Before After

Before After

Before

After

1360 1240 1610 1080 1080 1110

4.8 4.3 3.6 3.6 5.8 9.4

1.1 1.4 0.6 1.7 2.1 4.9

4.2 3.9 4.5 2.8 5.2 6.4

1.5 1.8 1.0 1.8 2.3 5.4

0.0044 0.0008 0.0029 0.0054 0.0031 0.0025

0.0038 0.0027 0.0042 0.0043 0.0022 0.0022

1840 1820 1760 1710 1920 1530

2120 2010 2320 1530 1850 2260

35 34 32 30

900 80

1250

5.2

4.5 0.5

2.3 0.6

0.0032 0.0006

0.0032 0.0004

2010

0.9

2.0 0.6

1760

80

50

510 660

680 860

0.25 0.20

0.26 0.30

0.13 0.13

0.18 0.26

0.0017 0.0023

0.0021 0.0018

1620 1570

800 910 1250

770 900 680

30

37 26 25 26 18 27

64 62 56 51 38 46

78 52 58 40 33 61

120

30 2

26 2

53 4

54 6

1830 1710

173 105

193 67

178 165

224 114

20


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JCE&M • 1978 Vol47 • No 2

PRATT AND LONGCOPE

TABLE 2. MCR, plasma concentrations (i), PB, and [P]BB' values for androstenedione (A) and estrone (1) before and after ACTH in men Androstenedione Subject no.

1 2

A

MCR (liters/day)

iA (ng/ml)

Estrone A.I

PB A (mg/day)

M HB

1

MCR (liters/day)

i1 (pg/ml)

PB1

Oig

Before

After

Before

After

Before

After

Before

After

Before

After

Before

After

Before

After

3020 1820

3110 1860

0.5 1.3

0.7 3.6

1.5 2.4

2.2 6.7

0.022 0.029

0.016 0.019

3300 2340

3460 2540

23 30

25 53

76 70

85 135

Discussion Our findings with respect to the effect of ACTH on the MCRT confirm those of Rivarola et al. (2) in showing that there is a marked increase in the MCRT after the administration of ACTH to both men and women. The mechanism whereby ACTH causes an increase in the MCRT is not apparent from our studies. It is possible that the action of ACTH is indirectly mediated through the stimulation of glucocorticoid production by the adrenal and that it is the glucocorticoids themselves which are the direct cause for the increase in the MCR. In studies in two men and one woman (Pratt, J. H., and C. Longcope, unpublished data), we found that the MCRT was increased slightly (14 to 22%) by the administration of hydrocortisone (50 mg) on the same time schedule as ACTH treatment. This led us to suspect that at least a part of the effect of ACTH is secondary to glucocorticoid stimulation. However, Irvine et al. (5) have reported that ACTH administration to an Addisonian resulted in a decrease in plasma testosterone, although these authors did not measure the MCR. Pratt et al. (28) have reported that the MCR for aldosterone is increased by ACTH administration. However, Zipser et al. (29) have suggested that this increase is spurious and is secondary to a redistribution of aldosterone from plasma to red blood cells, as they found no change in the whole blood MCR for aldosterone after ACTH but did find an increase in the plasma MCR. Such a redistribution is unlikely to be the explanation for our findings with respect to testosterone because in two subjects we also noted an increase in the whole blood MCR for testosterone. Testosterone is bound primarily to a ^-globulin and only a small fraction is bound to corticosteroid-binding globulin (CBG) (30).

An increase in circulating cortisol after ACTH administration would displace testosterone from CBG; however, Burke and Anderson (31) have shown that even large increases of cortisol do not increase the free testosterone level. Therefore, it is likely that other mechanisms, such as an increase in hepatic or other tissue blood flow or a direct action of ACTH and/or cortisol on tissue enzyme systems, are responsible for the increase in MCR. An increase in its MCR would initially lower the circulating concentration of testosterone in the blood. However, provided that the hypothalamic-pituitary-gonadal axis is intact, there should eventually be an increase in the production rate of testosterone in order to maintain a constant plasma concentration (32). Therefore, it would be expected that the increase in the MCR would be followed by a compensatory rise in the plasma concentration, but we did not find this to be the case over the short time interval studied. Along with others (1-6), we have shown a decrease in plasma testosterone after administration of ACTH to men. In these studies, testosterone fell after the administration of ACTH by im or iv routes and as a purified corticotropin gel or as a synthetic /S1"24-corticotropin. The decrease in testosterone was noted as soon as 4 h and as long as 24 h after the im administration of ACTH. In our studies, bloods were always drawn at 0800-0900 h to avoid problems of diurnal variation (33). We used samples drawn on 2 different days to blunt the effect of secretory episodes (34) but drew only one sample on the final day. As our six men all show a consistent decrease in testosterone and are similar to those reported by others, we feel that these findings cannot be explained by variation in sampling with respect to secretory episodes.


ACTH, TESTOSTERONE, AND ESTRADIOL On a relative basis, the decrease (65 ± 5%) in the plasma concentration was also greater than the increase (36 ± 6%) in the MCR, so that the calculated P B T fell (52 ± 5%) in all subjects studied. This is similar to the data reported by Rivarola (2) who measured the PB T in two men after they received ACTH. Because in men the PB T can be accounted for on the basis of testicular secretion of testosterone (26), a decrease in the production rate of testosterone is secondary to a decrease in the testicular secretion of testosterone. The decrease in the secretion of testosterone could be due to a primary alteration in testicular function, due secondarily to a lack of gonadotropins, or to both a primary and secondary defect. Tcholakin and Eik-Nes (35) reported that the stress of anesthesia in dogs caused a block in testicular steroidogenesis between 3/?-hydroxypregn-5-en-20-one (A5pregnenolone) and testosterone. This is consistent with a primary testicular defect associated with ACTH. A decrease in both testosterone secretion and circulating levels would be expected to cause a rise in LH, but in our studies as well as others (4, 5), the LH levels showed no significant change after ACTH. This failure to find any change in LH may be due in part to the relatively acute nature of the experiments, as Luton et al. (36) reported that both testosterone and LH levels were low in male Cushing's disease. In addition, it is possible that the magnitude of any change in LH caused by the fall in testosterone would have been too small to have been measured under these conditions. The administration of ACTH does not seem to have the same effect on estradiol dynamics as it does on testosterone dynamics. While four of the six male subjects showed an increase in the estradiol MCR with ACTH, the other two subjects showed a decrease, so that the mean change is not significant. We have no explanation for the difference in the dynamics of estradiol in these two subjects after ACTH except to say that perhaps in the two subjects that showed a fall in the estradiol MCR, there was a shift of estradiol to the binding globulin as the testosterone levels fell. As estradiol arises in part from the peripheral

311

conversion of testosterone, it might have been expected that circulating levels and the production rate of estradiol would fall as did testosterone's. However, we found that the circulating level and production rate of estradiol remained essentially unchanged, which suggests that something other than testosterone became a prominent source for estradiol after ACTH administration, as the fractional conversion of testosterone to estradiol did not change. Doerr and Pirke (6) noted a significant decline (from 22 to 17 pg/ml) in estradiol levels in 13 subjects given 2 mg /^"^-corticotropin im for 3 days, but could not demonstrate a decrease after only 1 day of treatment. Therefore, it is possible that the fall in estradiol levels is not so rapid as the fall in testosterone levels and the difference between our findings and those of Doerr and Pirke with respect to estradiol is due to the longer term of administration of ACTH in their studies. It is unlikely that the testis which normally secretes estradiol (37, 38) increased this secretion after ACTH because the LH levels remained constant. Estradiol is not a secretory product of the adrenal either before or after ACTH (39). A more likely explanation is that the amount of estradiol arising from androstenedione and estrone increased after ACTH, as the production rate of both androstenedione and estrone rose appreciably after ACTH administration in our two subjects. Baird et al. also noted in men and women a marked increase in the adrenal secretion of both of these steroids after ACTH (39). In the two subjects in whom it could be measured, the contributions of androstenedione and estrone to circulating estradiol increased 20-50% and this would have approximated the decrease in the contribution of testosterone to estradiol. Therefore, androstenedione and estrone have become important sources for estradiol under the conditions of our experiments. The increased production of androstenedione and estrone might also have played a role in maintaining LH levels unchanged despite the drop in testosterone, as both of these steroids can effect LH secretion (40, 41). In the two women studied, the MCR and the production rate of testosterone both in-


PRATT AND LONGCOPE

312

creased after ACTH. As in women the major source of testosterone is from androstenedione (42), the presumed increased production of androstenedione as a result of ACTH stimulation would result in more androstenedione being converted to testosterone and, hence, an increase in the latter's production rate. The MCR for estradiol increased in both women, but the effects on the plasma levels and production rates were not marked. Although the groups are small, it would nevertheless seem that the effect of ACTH on testosterone and estradiol dynamics is different in men and women.

Acknowledgments The authors wish to thank Mrs. Charlene Frantz and

Mr. Charles Flood for their excellent technical assistance.

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International Council of Sports and Physical Education (at UNESCO) Research Group on Biochemistry of Exercise Fourth International Symposium on Biochemistry of Exercise "Exercise and Hormone Regulation" Date: June 19-22, 1979 Location: University of Brussels Language: English

r Aim: The symposium will be focused on the regulatory mechanisms which permit the maintenance of muscular exercise in human and animal organisms. The influence of short term and long term exercise, training, and sex inheritance on normal subjects, as well as the adaptation to exercise of patients with metabolic disturbances, such as diabetes, obesity, and cardiovascular diseases will be taken into consideration. The use and abuse of anabolic steroids will also be considered. Free communications will be accepted. Correspondence: Prof. J. Poortmans Chimie Physiologique—ISEPK Universite Libre de Bruxelles 28, avenue P. Heger B-1050 Brussells (Belgium)


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Effect of cooling and rewarming rates on glycerolated human erythrocytes.

3,3',5'-Triiodothyronine (reverse T3) and 3,3',5-triiodothyronine (T3) in fetal and adult sheep: studies of metabolic clearance rates, production rates, serum binding, and thyroidal content relative to thyroxine.

Production and metabolic clearance of 1,25-dihydroxyvitamin D in men: effect of advancing age.

On correlation between SIDS rates and general infant mortality rates.

Effect of quality of bowel preparation on quality indicators of adenoma detection rates and colonoscopy completion rates.

Decline and depletion rates of oil production: a comprehensive investigation.