Decreased Adrenal Androgen Sensitivity to ACTH During Aging

Lawrence Parker, Thomas Gral, Vicki Perrigo, and Ronald Skowsky

During the human aging process, basal plasma levels of cortisol and aldosterone demonstrate little change, while concentrations of adrenal androgens (AA) such as dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and androstenedione (A) decrease dramatically in men and women. There is no age-related change in ACTH concentrations to explain this observation. In this study, ACTH (cosyntropin, al -24 corticotropin) stimulation tests were performed on elderly subjects and controls to test the hypothesis that analogous to the aging testicular Leydig cell, AA-producing cells of the aging adrenal gland may become less sensitive to physiological levels of ACTH, but still retain their sensitivity to elevated ACTH levels.

Results showed that in the elderly subjects, basal levels and ACTH-stimulatability of cortisol and aldosterone were unchanged. In agreement with earlier studies, basal levels of AA were found to be decreased in the elderly. However, ACTH stimulation demonstrated impaired reserve of DHA and A, and a total lack of stimulatability of DHAS. These findings could be explained by an age-related loss of adrenal enzymes or cell populations which produce AA, a loss or decrease in a subpopulation of ACTH receptors specific for AA production, or loss of a pituitary factor necessary for AA secretion.

B ASAL PLASMA LEVELS of cortisol’.’ and

aldosterone314 remain relatively constant during

the human aging process. However, concentrations of adrenal androgens (AA) such as dehydroepiandroste-

rone (DHA), and dehydroepiandrosterone sulfate

(DHAS) decrease markedly with age’-’ in both sexes.

The observed age-related declines in DHA and DHAS concentrations do not reflect increased metabolic

clearance rates,’ but rather markedly decreased

production rates at a time when production rates of

aidosterone,” deoxycorticosterone,” and cortiso123’2.‘3 are only mildly diminished.

Since ACTH and cortisol production rates are closely linked, the explanation for the age-related

dissociation between cortisol and AA production rules

out declines in AA production secondary to declines in ACTH concentration. Other hypotheses to explain

these changes include a primary change in intra-

adrenal physiology of unknown causation, or the exis- tence of a pituitary hormone which stimulates AA production either by itself or in conjunction with

ACTH (adrenal androgen stimulating hormone

[AASH], Grumbach and Kaplan;‘43’s or cortical androgen stimulating hormone [CASH], Parker and Ode11’6~‘7).

In this study we have attempted to test the hypothe- sis that the adrenal undergoes aging changes which

make AA production less sensitive to normal levels of circulating ACTH. The analogous situation occurs in

the Leydig cells of the testis in aging men. Recent studies show that normal testosterone levels are main-

tained by healthy elderly men, but at the expense of elevated gonadotrophin levels.‘8.‘9 In this study, to test

sensitivity of AA production to elevated ACTH levels, peripheral cortisol, aldosterone, androstenedione (A), DHA and DHAS concentrations were measured in control and elderly subjects before and during a 4-hr

cosyntropin (al-24 ACTH) infusion.

MATERIALS AND METHODS

Subjects

Subjects had no evidence of hepatic disease, as measured by

serum bilirubin, SCOT and SGPT; and no renal disease as deter-

mined by BUN, serum creatinine and/or creatinine clearance. No

subjects were taking glucocorticoid or androgenic medications, and

all signed consent forms after the project was explained to them.

Subjects of all ages were ambulatory. Control subjects were volun-

teers from VA Hospital wards, while elderly volunteers were resi-

dents of the VA Medical Center Nursing Home. Control subjects

were 7 men and 2 women 35562-yr-old with an average age of 51 yr.

Elderly subjects were 9 men and I woman age 733102-yr-old with

an average age of 85 yr.

Methods

On the morning of testing, each subject underwent a 4 hr infusion

of 25 units of cosyntropin ((~I-24 corticotropin; Cortrosyr?; Orga-

non Pharm., Inc., New Jersey) in 500 ml of 5% dextrose/water.

Blood was drawn for steroid hormone analysis by radioimmunoas-

say2’ at time 0, 2, and 4 hr via an indwelling catheter with a 3-way

stopcock. Steroid hormone concentrations were compared (A)

between groups at the same time point, and (B) between stimulated

and control values within the same group by Student’s t test.

RESULTS

Results of the 4 hr cosyntropin infusion stimulation tests are shown in Fig. 1. Asterisks in Fig. 1 denote

statistically significant differences between groups at

the same time point (A). For reasons of clarity,

From the Department of Medicine. Divisions of Endocrinology

and Gerontology, VA Medical Center, 5901 East Seventh Street,

Long Beach, California.

This work was supported in part by Veterans Administration

Merit Review Grant 10234673I-001 awarded to Dr. Parker.

Received for publication November 20. 1980.

Address reprint requests to D. Lawrence Parker, M.D., Depari-

ment of Medicine. Division of Endocrinology, VA Medical Center,

10 South, 5901 East Seventh Street, Long Beach, Calif 90822.

B I981 by Grune & Stratton, Inc.

0026&0495/81/3006&0014$01.00/0

Metabolism, Vol. 30. No. 6 (June), 198 1 601

602

o( l-24 CORTICOTROPIN INFUSION

CORTISOL ALDOSTERONE

2

I 1 1 I 1 1

0 2 4 0 2 4

25U

ANDROSTENEDIONE

25U

DHA DHAS

6 h 4 w

25U

- ColjTlxx

--- ELDERLY

t- I I

0 2 4 0 1 4 *

25U 25U

HOURS

ELDERLY DIFFERENT FROM CONTROL: * p < 0.05 * + P~O.005

symbols denoting differences between the stimulated

and 0 time points within a single group (B) are not included in Fig. 1, but these differences are described

below.

Cortisol

A. There were no significant differences between the control and elderly groups in basal or stimulated

concentrations. B. Within each group, all 2 and 4 hr points were

significantly greater than the 0 time point (p < 0.001).

Aldosterone

A. There was a tendency towards higher basal and stimulated aldosterone concentrations in the elderly group, but it was not statistically significant.

B. Within each group, all 2 and 4 hr points were significantly greater than the 0 time point (p < 0.001).

Androstendione

A. Basal and 2 hr A concentrations were lower in the elderly group (p < 0.05). A trend towards lower

PARKER ET AL.

Fig. 1. Serum concentrations of cor- tisol, aldosterone, androstenedione, DHA and DHAS before and during an infusion of 25 units of coayntropin in elderly and control subjects. Asterisks signify diier- ences between steroid concentrations in elderly and control subjects at the same time point.

values at 4 hr in the elderly group was not statistically

significant.

B. The 2 and 4 hr stimulated A concentrations were significantly different from the 0 value in both groups

at p < 0.01, except for the 2 hr value in the elderly

group which was significant at a lower level (p <

0.05).

DHA

A. Basal and stimulated DHA concentrations in the elderly group were significantly less than those of

the control group (p < 0.05 and p c 0.005, respec-

tively). B. Stimulated DHA concentrations in the control

group were significantly higher than those at 0 time (p < 0.001). Within the elderly group, stimulated DHA values at 2 and 4 hr were not significantly elevated (p -C 0.05).

DHAS

A. DHAS concentrations in the elderly group never rose above basal levels and were significantly less than those of the control group at 2 and 4 hr (p < 0.005).

B. Stimulated DHAS levels in the control group

DECREASED ADRENAL ANDROGEN SENSITIVITY

were significantly higher than those at 0 time (p <

0.05). Within the elderly group, the flat DHAS response indicates no stimulation during the cosyntro-

pin infusion.

DISCUSSION

The present study demonstrates unchanged basal and ACTH-stimulated concentrations of cortisol and

aldosterone with age. Previous studies have demon-

strated unchanged basal levels of both steroids and

normal levels of cortisol following ACTH stimulation

with increasing age.‘,* With respect to stimulated aldosterone concentrations, the renin-angiotensin re- sponse diminishes with age.33432’ However, an evalua- tion of aldosterone stimulatability following ACTH in

the elderly has not been previously reported.

In contrast to the above evidence of normal adrenal glucocorticoid and mineralocorticoid basal levels and

reserve during the aging process, the present results verify previous data on decreased basal AA concentra-

tions with age.5-8 In addition, the present data demon- strate a total lack of ACTH-responsive adrenocortical reserve with respect to DHAS, as well as a decreased

reserve for A and DHA.

There are several possible explanations for the above findings. At the adrenal level, there could be an age-related loss of cell populations which produce AA.

Alternatively, such aging cells could theoretically lose ACTH receptors which would have to be relatively

specific for AA production, or lose enzymes critical for

AA production such as 17-20 desmolase, either partially or completely.

603

Such aging changes have previously been described

in other systems. There are many instances of a decrease in hormone receptor concentration with age, with retention of normal binding affinity.** The loss of

adrenal ACTH receptors during aging which are specific for AA, as contrasted with those for cortisol

and aldosterone, may be a reflection of the observation

that there are multiple functional and distinct adrenal

stimulatory receptors, such as those for ACTH and choleratoxin. The selective loss of adrenal cell

enzymes with age may be analogous to the observed

loss of the enzyme 11 /3-hydroxylase in aging bovine

adrenal cell cultures.‘4 At the hypothalamic and pituitary level, the

decreased AA levels and reserve could reflect age-

related primary loss of a pituitary factor such as

AASH or CASH, or a secondary loss due to decreas- ing levels of a hypothalamic releasing factor, analo-

gous to CRF and ACTH. This hypothesis must remain

tentative, however, since such substances presently are

only detectable by bioassay,‘6,‘7 which makes analysis

of large numbers of clinical samples a cumbersome process. The possibility also exists that the observed

changes in AA stimulatability with age are related to

changes in other potential AA modulating factors such as prostaglandins or lipotrophin-related peptides.”

ACKNOWLEDGMENT

The authors gratefully acknowledge the expert technical and

secretarial assistance of Leo Moons. MS.. and colleagues, and

Linda Burkhardt, respectively.

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