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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 48-54
Copyright © 2000 by The Endocrine Society

From The Clinical Research Centers

Effects of Aging on Adrenal Function in the Human: Responsiveness and Sensitivity of Adrenal Androgens and Cortisol to Adrenocorticotropin in Premenopausal and Postmenopausal Women1

C. Richard Parker, Jr., Scott M. Slayden, Ricardo Azziz, S. Lolita Crabbe, Gene A. Hines, Larry R. Boots and Sejong Bae

Departments of Obstetrics and Gynecology, Medicine, and Biostatistics and Biomathematics, University of Alabama, Birmingham, Alabama 35233

Address all correspondence and requests for reprints to: C. Richard Parker, Jr., Ph.D., Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35233-7333.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We sought to determine the effects of aging on several aspects of adrenal steroidogenesis in the hopes of characterizing the possible causes of adrenal androgen deficiency in elderly women. To this end, we quantified basal morning concentrations of cortisol (F), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DS), and androstenedione (A4) and then evaluated the effects of overnight dexamethasone (DEX) suppression followed by adrenal responses to graded hourly infusions of ACTH, ranging from 20–1280 ng/1.5 m2·h. Finally, we performed a standard 0.25-mg ACTH bolus stimulation test, with sampling at 1 h thereafter. Basal serum levels of DHEA, DS, and A4 were significantly reduced (~50% each) in a group of 35 healthy postmenopausal women, 55–68 yr old, compared to those in 30 healthy, regularly menstruating women, 20–25 yr old. Post-DEX levels of these C19 steroids also were significantly lower in the older women than in the younger women; the percent decrease after DEX for A4 was greater in the older women, whereas those in DHEA and DS were not age related. Basal and post-DEX levels of F were similar in both groups. Secretory responses of DS to ACTH were not informative due to its large plasma pool and slow clearance rate. The maximally stimulated levels of DHEA after ACTH bolus were significantly lower in the older women than in younger women; those of A4 were similar in both age groups, and the maximally achieved levels of F were higher in the older women than in the younger women. The sensitivity of adrenal DHEA, A4, and F to ACTH (defined as the minimal dose of ACTH required to significantly increase the steroid levels above basal post-DEX values) was similar in older and younger women. The responsiveness of the steroids of interest to ACTH (defined as the slope of the dose-response curve over the linear portion of the dose-response curve) also was similar among younger and older women. These data demonstrate that the deficiency in adrenal androgen production in women is restricted to the {Delta}5-pathway steroid products (DHEA and DS), whereas there is no reduction in the capacity of the adrenal to produce A4 or cortisol. As DHEA and DS are likely to be produced mainly in the zona reticularis of the adrenal cortex, we propose that these data point to an alteration in that cortical zone as the cause of adrenal androgen deficiency in aging. The reductions in A4 in aging are probably due to reduced ovarian secretion after menopause.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CROSS-SECTIONAL analyses revealed decreased circulating levels of several C19 steroids such as testosterone, androstenedione (A4), dehydroepiandrosterone (DHEA), and DHEA sulfate (DS) in postmenopausal women compared to those in younger women (1, 2, 3, 4, 5, 6). Deficiencies in such hormones may have an adverse impact on the health and well-being of women during aging, as is suggested by the results of several studies (6, 7, 8, 9, 10). Although it is likely that ovulatory failure and the resultant loss of ovarian follicular steroidogenesis play a direct role in the decreased production of some androgens, reductions in adrenal C19 steroid production also occurs for unknown reasons. The issue is complicated due to the fact that there appears to be no deficiency of adrenal production of corticosteroids in aging. A deficiency of pituitary ACTH secretion is not likely to be a cause of the reductions in adrenal androgen production in aging. Indeed, as there may, in fact, be a loss of sensitivity of the hypothalamic-pituitary axis to negative feedback effects of cortisol (F), the adrenal may actually be exposed to higher amounts of ACTH on a daily basis in aging (11, 12).

In studies designed to address certain dynamics of adrenal steroidogenesis in response to ACTH, Liu et al. proposed that aging in women is associated with a defect in 17,20-lyase activity of cytochrome P450–17{alpha} (CYP450–17{alpha}) in the adrenal (13). No evidence for age-associated alterations in 17-hydroxylase activity or 3ß-hydroxysteroid dehydrogenase (3ßHSD) activity were inferred in their study. Reduced production of DHEA, but not androstenedione (A4) or F, was noted in response to bolus injections of ACTH in men and women in the study by Vermeulen and associates (14). As 17,20-lyase activity also is required for adrenal production of A4, perhaps the results from the above studies are suggestive of a zone-specific defect in the steroidogenic pathway. In the present study we sought to compare the responses of F to those of DHEA and A4 to ACTH stimulation to determine whether there were alterations in either the sensitivity or the responsiveness of the {Delta}5 C19 steroid pathway compared to those of the {Delta}4 C19 pathway and also the pathway leading to F synthesis in women during aging. Our goal was to better characterize the pattern of adrenal androgen production during aging in healthy women and to attempt to provide insights in such individuals to the likely cause for deficient adrenal androgen production that has been noted by many investigators to occur in a cross-section of aging adults.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Our protocol included careful screening of subjects to exclude those with chronic illnesses such as hypertension and diabetes and also those with any history of ovulatory disorders. To ensure as much homogeneity as possible in ovarian contribution to the steroidal milieu, we scheduled studies in the younger women (20–35 yr old) to occur during the early to midfollicular phase of their ovarian cycle. Only women with regular, spontaneous menstrual cycles and not currently or within the past 3 months being exposed to contraceptive steroids were included in the study due to the observed impact of oral contraceptive steroids on certain aspects of adrenal steroidogenesis. Among the older women (55 yr of age and older), we only included those who had undergone spontaneous menopause (still had at least one ovary) a minimum of 6 months previously, who had random FSH levels over 40 ng/mL, and who had not been exposed to any sex steroid hormone replacement for at least 3 months before the study. Basic characteristics of the women in the two age groups are shown in Table 1Go. The body mass indexes and waist/hip ratios for both groups were similar, whereas the younger women were taller and heavier than the older women. All subjects were studied at the General Clinical Research Center after giving informed written consent to participate in this protocol, which was approved by the institutional review board of the University of Alabama at Birmingham.


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  		Table 1. Characteristics of study population

 
The in vivo adrenal testing was conducted as follows. An early morning fasting blood sample was obtained to provide normal hormone values. Subsequently, the volunteers ingested 1 mg dexamethasone (DEX) at 2300 h and again on the following morning before an ACTH infusion protocol. DEX was administered to inhibit endogenous ACTH secretion and thus ensure a stable baseline of steroid levels for subsequent testing of responses to exogenous ACTH. A secondary rationale for adrenal suppression in this manner was to provide information about the relative adrenal and gonadal contributions to circulating levels of steroids; the difference between normal control levels of steroids and that after adrenal suppression was considered representative of adrenal contribution to total plasma concentrations, and the level achieved after adrenal suppression was considered to approximate gonadal contribution to plasma steroid levels. Blood was obtained in the morning after the second DEX dose to provide data for steroid levels achieved after adrenal suppression. The volunteers were then infused ACTH [ACTH-(1–24), Cortrosyn] in graded, increasing doses that included 20, 40, 80, 160, 320, 640, and 1280 ng/1.5 m2·h for 1 h at each dose level, with blood sampling at the end of each infused dose. Finally, the subjects were administered a standard bolus 0.25-mg ACTH stimulation test, with blood sampling 1 h thereafter. In this latter instance, the difference between the concentration achieved after the 0.25-mg ACTH bolus and that noted at the baseline after overnight adrenal suppression was considered to be representative of maximal adrenal steroid output. The subtle aspects of adrenal responses to graded, stepwise increases in doses of infused ACTH that we sought to determine were 1) the sensitivity of the various adrenal steroids to ACTH (i.e. the minimal dose of ACTH required to significantly increase a given steroid hormone’s concentration above its steady state, suppressed level after dexamethasone ingestion), and 2) the responsiveness of the steroids to ACTH (i.e. the slope of the dose-response curve for each steroid), which would indicate whether there was any blunting of the androgen biosynthetic pathway responses to ACTH stimulation during aging.

All steroids were quantified by RIA as indicated below. DHEA, A4, and DS were quantified by the use of commercially available RIA kits provided by Diagnostics Systems Laboratories, Inc. (Webster, TX). Cortisol was quantified by use of a direct in-house assay in methanol-treated diluted serum (1:10). The assay employs a highly specific antiserum (gift from Dr. C. E. Gomez-Sanchez, Columbia, MO), [3H]cortisol as assay tracer, and dextran-coated charcoal for separation of bound and free hormone. The assay sensitivity is 7.8 pg/tube, and the intraassay coefficients of variation for low and high values are 7.1% and 4.9%.

The methodology used for mathematical determination of the data pertaining to adrenal sensitivity and responsiveness to ACTH was adapted from that originally described by Komindr et al. (15) and is presented in great detail in our recent publication (16). Briefly described, these mathematical manipulations were performed to establish the dose of ACTH at which a given steroid’s concentration rose above baseline, which defined the sensitivity of that steroid to ACTH in both age groups, and also to establish the rate of rise during the linear portion of the dose-response curve, which defined the responsiveness to ACTH in each study group. The statistical analyses were conducted by use of SAS (Statistical Analysis Systems, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Morning serum levels of DHEA, DS, and A4 were significantly reduced in the older, postmenopausal women compared to those in the younger, ovulatory women (Table 2Go). The reduction in concentration of each of these C19 steroids was approximately 50% in the older group of women. Serum levels of F, however, were similar in both groups. The post-DEX baseline concentrations of DHEA, DS, and A4 also were significantly lower in the older women, whereas those of F were not age dependent. The extent of reduction in serum levels of DHEA and cortisol after overnight DEX suppression of the hypothalamic-pituitary axis (percentage of control levels) was similar in younger and older women (Fig. 1Go). On the other hand, the percent reduction in circulating levels of A4 after overnight DEX suppression was greater in the older women than in the younger women (P < 0.001), suggesting that more of the circulating A4 in the premenopausal women was of nonadrenal origin (presumably ovarian), than that in postmenopausal women. That the percent reduction in DHEA levels was not as great as that in F is probably due to the continuing systemic conversion of the large circulating DS pool to DHEA after adrenal secretion was suppressed.


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  		Table 2. Effects of aging on morning steroid concentrations before and after overnight dexamethasone suppression in women

 


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  		Figure 1. Effects of aging on the suppressability of adrenal steroids by dexamethasone in women. The data are presented as the mean ± SE for each of the indicated steroids (the SE for cortisol in the younger women was too small to be visible as plotted). *, P < 0.001 compared to A4 suppression in younger women.

 
The increments in DHEA and A4 above the post-DEX suppressed baseline seen after the final bolus of 0.25 mg ACTH are shown in Fig. 2Go. Whereas there was an age-related deficiency in the total response of DHEA to ACTH (P = 0.016), the maximal output of A4 in response to ACTH was similar in younger and older women. The increment in DS also was reduced (P = 0.03) in the older women (295 ± 37 ng/mL) compared to that in the younger women (451 ± 57 ng/mL). Short term changes in DS levels are, however, difficult to interpret due to its long plasma half-life (7–10 h) (6). On the other hand, the maximal F output in response to the bolus ACTH injection was slightly, albeit significantly, increased (P = 0.04) in the older women (27.6 ± 1.3 µg/dL) than in the younger women (24.4 ± 0.74 µg/dL).



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  		Figure 2. Effects of aging on maximal output of DHEA and A4 in women in response to ACTH after overnight DEX suppression. The data are presented as the mean ± SE and represent the increment in hormone concentration between the post-DEX baseline concentration and that achieved 1 h after a 0.25-mg bolus of ACTH. *, P < 0.02 compared to DHEA output in younger women.

 
The dose-response curves for DHEA, A4, and F to the graded infusions of ACTH are presented in Figs. 3Go-5. The responses of DS to these relatively low doses of ACTH were small (<50% increase over DEX-suppressed levels) in younger and older women as a consequence of its large plasma pool size and low MCR and are therefore not presented. There were no obvious differences in the characteristics of the dose-response curves for any of these steroids according to age. The sensitivity of each steroid to ACTH, defined as the minimal dose of ACTH required to elicit a significant rise in each steroid’s level above the baseline, did not change significantly with age (Fig. 6Go). In each group, F secretion was approximately 2 times more sensitive to ACTH than was DHEA. The sensitivity of A4 to ACTH was enhanced, but not significantly, among the older women compared to that in younger women. The responsiveness of F to ACTH was considerably greater than that of either DHEA or A4 in both age groups (Table 3Go). However, there was no change in the responsiveness of any steroid to ACTH (defined as the slope of the linear portion of the dose-response curve) as a function of aging (Table 3Go). Nevertheless, as pointed out earlier, there was a significant reduction in overall output of DHEA in response to ACTH in the postmenopausal women compared to the younger women.



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  		Figure 3. Dose-response plot of DHEA in younger and older women during graded 1-h infusions of increasing doses of ACTH. ACTH doses are in nanograms per 1.5 m2/h.

 


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  		Figure 6. Effects of aging on the sensitivity of cortisol, DHEA, and A4 to ACTH in women. The data, which are plotted as the mean, represent the dose of infused ACTH (nanograms per 1.5 m2/h) required to significantly increase serum levels of each steroid above the post-DEX suppressed baseline values. The reduction in the sensitivity of A4 secretion to ACTH in the older women was not statistically significant.

 

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  		Table 3. Effects of aging on adrenal responsiveness to ACTH in women

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although many investigators have noted dramatically lower levels of DHEA and DS in elderly humans compared to young adults (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14), a satisfactory explanation for the cause of this adrenal androgen-deficient state has not been forthcoming. The current study demonstrates that although the total adrenal output of DHEA and DS is reduced in response to ACTH in postmenopausal women, the adrenal output of A4 seems to be stable as a function of age. Our data also suggest that the strikingly reduced levels of A4 in the postmenopausal women compared to those in the younger women are probably a consequence of reductions in ovarian production in aging and also partially due to reductions in circulating levels of DHEA that could be converted to A4 in peripheral tissues. In premenopausal women, the ovary contributes significantly to the plasma A4 pool (17, 18, 19). Consequently, our data are consistent with the view that most of the A4 in plasma of postmenopausal women is ultimately of adrenal origin, which supports the findings of Whorl et al., who reported that A4 levels were reduced over 90% after adrenalectomy in postmenopausal women (19). A similarly high contribution of the adrenal to plasma DHEA was apparent among women in that study (19). We found that F secretion by the adrenal in response to ACTH infusion followed by a bolus of ACTH was increased somewhat in the older women compared to that in younger ovulatory women. Clearly, then, there would seem to be no evidence for a deficiency in the {Delta}4 3-ketosteroid pathway in the adrenal leading to either glucocorticosteroid production (F) or to that of the C19 steroid, A4. In two other studies, there also appeared to be no reductions in the ability of the adrenal to secrete A4 in response to ACTH in postmenopausal women (13, 14).

Both F and A4 are dependant upon the combined actions of 3ßHSD and of CYP450–17{alpha}. These components of the steroidogenic pathway are coexistent in the zona fasciculata (20, 21, 22). One could therefore speculate that if there is any adrenal deficiency of 17,20-lyase activity of CYP450–17{alpha}, as suggested by Liu et al. (13), such a deficiency probably is not manifested in the zona fasciculata. Formation of DHEA and DS is dependant upon the absence of 3ßHSD but the presence of CYP450–17{alpha} and, at least in the case of DS, the added availability of DHEA-sulfotransferase. The zona reticularis of the adrenal cortex clearly has the appropriate set of enzymes to serve as the site of formation of DS and is likely to be a major site of DHEA formation as well (20, 21, 22, 23, 24, 25). Therefore, our current data coupled with the functional zonation of the steroidogenic pathway suggest that adrenal androgen deficiency in aging is probably due to a defect in the zona reticularis, specifically the {Delta}5 C19 steroidogenic pathway.

In support of such a view, we recently found that there are morphological alterations in the adrenal in men during aging, such that the zona reticularis is reduced in size compared to the rest of the cortex (26). Subsequently, we also noted that the distribution of DHEA sulfotransferase in the adrenals of aging men and women is reduced compared to that in young adults (25). As there is no evidence for reductions in the {Delta}4 3-ketosteroid steroidogenic pathway for C21 or C19 steroids from the results of our current study [or from those of others (13, 14)], we propose that most if not all of the age-associated deficiency in adrenal androgen production is due to changes in the maintenance of the functional and morphological integrity of the zona reticularis. The nature of the problem could involve a deleterious shift in the relative rates of formation of reticularis cells compared to the rates of cell death in that zone. Another possibility might be that there is morphological and functional conversion of some reticularis cells into a population of cells that no longer have the capability of forming DHEA/DS. Unfortunately, very little is currently known about the origin or maintenance of cells of the human zona reticularis.

Insofar as the steroidogenic pathway of the zona reticularis is concerned, it seems to be strikingly similar to that of the fetal zone of the human fetal adrenal gland, which also has a paucity of 3ßHSD (27, 28), but has abundant DHEA sulfotransferase (29, 30) and CYP450–17{alpha} (28). DHEA sulfotransferase in cultured human adrenal cells is modulated by the protein kinase A and C pathways (31, 32, 33). Transforming growth factor-ß inhibits basal and ACTH-stimulated DS production in human adrenal cells (34, 35), and we have found that this cytokine inhibits basal and ACTH-stimulated levels of DHEA sulfotransferase messenger ribonucleic acid and enzyme in such cells (33, 36). Beyond these observations, knowledge of the regulation of DHEA sulfotransferase in the human adrenal is very incomplete. Studies to address the maintenance of this enzymatic activity and other characteristics of the zona reticularis functional phenotype may provide clues to the mechanisms for the age-associated deficiency in secretion of DHEA/DS.



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  		Figure 4. Dose-response plot of A4 in younger and older women during graded 1-h infusions of increasing doses of ACTH. ACTH doses are in nanograms per 1.5 m2/h.

 


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  		Figure 5. Dose-response plot of cortisol in younger and older women during graded 1-h infusions of increasing doses of ACTH. ACTH doses are in nanograms per 1.5 m2/h.

 

   Acknowledgments
 
We thank Vanessa Black, B.S., for assistance with patient recruitment, H. Downing Potter for technical assistance, and the staff of the General Clinical Research Center for their invaluable help with this project.


   Footnotes
 
1 This work was supported by Grant AG-12142 (to C.R.P.) and NIH/National Center for Research Resources Grant MO1-RR-00032, which supported the General Clinical Research Center at the University of Alabama-Birmingham. Back

Received October 28, 1998.

Revised September 15, 1999.

Accepted September 22, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Migeon CJ, Keller AR, Lawrence B, Shepart II TH. 1957 Dehydroepandrosterone and androsterone levels in human plasma. Effect of age and sex: day-to-day and diurnal variations. J Clin Endocrinol Metab. 17:1051–1062.
  2. Roger M, Nahoul K, Scholler R, Bagrel D. 1980 Evolution with ageing of four plasma androgens in postmenopausal women. Maturitas. 2:171–177.[CrossRef][Medline]
  3. Orentreich N, Brind JL, Rizer RL, Vogelman JH. 1984 Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 59:551–555.[Abstract/Free Full Text]
  4. Carlstrom K, Brody S, Lunell, N-O, et al. 1988 Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: differences related to age and sex. Maturitas. 10:297–306.[CrossRef][Medline]
  5. Labrie F, Belanger A, Cusan L, Gomez J-L, Candas B. 1997 Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 82:2396–2402.[Abstract/Free Full Text]
  6. Baulieu E-E. 1996 Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab. 81:3147–3151.[CrossRef][Medline]
  7. Nordin BEC, Robertson A, Seamark, RF, et al. 1985 The relation between calcium adsorption, seum dehydroepiandrosterone, and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metab. 60:651–657.[Abstract/Free Full Text]
  8. Yanase T, Fukahori M, Taniguchi S, et al. 1996 Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in Alzheimer’s disease and in cerebrovascular dementia. Endocr J. 43:119–123.[Medline]
  9. Rabaglia G, Forti P, Maioli F, et al. 1996 The relationship of dehydroepiandrosterone sulfate (DHEAS) to endocrine-metabolic parameters and functional status in the oldest-old. Results from an Italian study on healthy free-living over-ninety-year-olds. J Clin Endocrinol Metab. 81:1173–1178.[Abstract]
  10. Kalmijn S, Laurer LJ, Stolk RP, et al. 1998 A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab. 83:3487–3492.[Abstract/Free Full Text]
  11. Wilkinson CW, Peskind ER, Raskind MA. 1997 Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology. 65:79–90.[Medline]
  12. Boscara M, Paoletta A, Scarpa E, et al. 1998 Age-related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man. J Clin Endocrinol Metab. 83:1380–1383.[Abstract/Free Full Text]
  13. Liu CH, Laughlin GA, Fischer UG, Yen SSC. 1990 Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity. J Clin Endocrinol Metab. 71:900–906.[Abstract/Free Full Text]
  14. Vermeulen A, Deslypere JP, Schelfhout W, Verdonck L, Rubens R. 1982 Adrenocortical function in old age: response to acute adrenocorticotropin stimulation. J Clin Endocrinol Metab. 54:187–191.[Abstract/Free Full Text]
  15. Komindr S, Kurta BR, Stevens MD, Karas JG, Bittle JB, Givens JR. 1986 Relative sensitivity and responsivity of serum cortisol and two adrenal androgens to {alpha}-adrenocorticotropin-(1–24) in normal and obese, nonhirsute, eumenorrheic women. J Clin Endocrinol Metab. 63:860–864.[Abstract/Free Full Text]
  16. Slayden SM, Crabbe L, Bae S, Potter HD, Azziz R, Parker Jr CR. 1998 The effect of 17ß-estradiol on adrenocortical sensitivity, reponsiveness and steroidogenesis in postmenopausal women. J Clin Endocrinol Metab. 83:519–552.[Abstract/Free Full Text]
  17. Abraham GE. 1974 Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab. 39:340–346.[Abstract/Free Full Text]
  18. Judd HL, Lucas WE, Yen SSC. 1974 Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol. 118:793–798.[Medline]
  19. Worgul TJ, Santen RJ, Samojlik E, Wells SA. 1982 How effective is surgical adrenalectomy in lowering steroid hormone concentrations. J Clin Endocrinol Metab. 54:22–26.[Abstract/Free Full Text]
  20. Sasano H, Mason JI, Sasano N. 1989 Immunohistochemical study of cytochrome P-45017{alpha} in human adrenocortical disorders. Hum Pathol. 20:113–117.[CrossRef][Medline]
  21. Sasano H, Mason JI, Sasano N, Nagura H. 1990 Immunolocalization of 3ß-hydroxysteroid dehydrogenase in human adrenal cortex and in its disorders. Endocr Pathol. 1:94–101.[CrossRef]
  22. Endoh A, Kristiansen SB, Casson PR, Buster JE, Hornsby PJ. 1996 The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3ß-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. 81:3558–3565.[Abstract]
  23. Cameron EHD, Jones T, Cones D, Anderson ABM, Griffiths K. 1969 Further studies on the relationship between C19- and C21-steroid synthesis in the human adrenal gland. J Endocrinol. 45:215–230.[Abstract/Free Full Text]
  24. Kennerson AR, McDonald DA, Adams JB. 1983 Dehydroepiandrosterone sulfotransferase localization in human adrenal glands: a light and electron microscopic study. J Clin Endocrinol Metab. 56:786–790.[Abstract/Free Full Text]
  25. Connell M, Mixon RL, Brissie RL, Parker Jr CR. 1999 Age effects on immunohistochemical localization of DHEA sulfotransferase in the adrenal cortex of women. Proc 46th Meeting of The Society for Gynecologic Investigation, Atlanta, GA, 1999, P92A.
  26. Parker Jr CR, Mixon RL, Brissie RM, Grizzle WE. 1997 Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab. 82:3898–3900.[Abstract/Free Full Text]
  27. Parker Jr CR, Faye-Petersen O, Stankovic AK, Mason JI, Grizzle WE. 1995 Immunohistochemical evaluation of the cellular localization and ontogeny of 3ß-hydroxysteroid dehydrogenase/{Delta}5–4 isomerase in the human fetal adrenal gland. Endocr Res. 21:69–80.[Medline]
  28. Mesiano S, Coulter C, Jaffe RB. 1993 Localization of cytochrome P450 cholesterol side-chain cleavage, cytodhrome P450 17{alpha}-hydroxylase/17,20-lyase, and 3ß-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation. J Clin Endocrinol Metab. 77:1184–1189.[Abstract]
  29. Parker Jr CR, Falany CN, Stankovic AK, Stockard CR. Stankovic AK, Grizzle WE. 1994 Immunohistochemical localization of dehydroepiandrosterone sulfotransferase in human fetal tissues. J Clin Endocrinol Metab. 78:234–236.[Abstract]
  30. Barker EV, Hume R, Hallas A, Coughtrie MWH. 1994 Dehydroepiandrosterone sulfotransferase in the developing human fetus: quantitative biochemical and immunological characterization of the hepatic, renal, and adrenal enzymes. Endocrinology. 134:982–989.[Abstract/Free Full Text]
  31. McAllister JM, Hornsby PJ. 1988 Dual regulation of 3ß-hydroxysteroid dehydrogenase, 17{alpha}-hydroxylase, and dehydroepiandrosterone sulfotransferase by adenosine 3'5'-monophosphate and activators of protein kinase C in cultured human adrenocortical cells. Endocrinology. 122:2012–2018.[Abstract/Free Full Text]
  32. Parker Jr CR, Stankovic AK, Falany CN, Faye-Petersen O, Grizzle WE. 1995 Immunocytochemical analyses of dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. J Clin Endocrinol Metab. 80:1027–1031.[Abstract]
  33. Parker Jr CR, Stankovic AK, Faye-Petersen O, Falany CN, Li H, Jian M. 1998 Effects of ACTH, and cytokines on dehydroepiandrosterone sulfotransferase messenger RNA in human adrenal cells. Endocr Res. 24:669–673.[Medline]
  34. Stankovic AK, Parker Jr CR. 1994 Effects of transforming growth factor-ß on human fetal adrenal steroid production. Mol Cell Endocrinol. 99:145–151.[CrossRef][Medline]
  35. Lebrethon MC, Jaillard C, Naville B, Begeot M, Saez JM. 1994 Effects of transforming growth factor ß-1 on human adrenocortical fasciculata-reticularis cell differentiated functions. J Clin Endocrinol Metab. 79:1033–1039.[Abstract]
  36. Parker Jr CR, Stankovic AK, Falany CN, Grizzle WE. 1996 Effect of TGF-ß on dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells. Proc NY Acad Sci. 774:326–328.



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