0021-972X/01/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Vol. 86, No. 6
Printed in U.S.A.
Adrenocortical Secretion of Dehydroepiandrosterone in
Healthy Women: Highly Variable Response to
Adrenocorticotropin*
RICARDO AZZIZ, LIESL M. FOX, HOWARD A. ZACUR, C. RICHARD PARKER, JR.,
AND LARRY R. BOOTS
Departments of Obstetrics and Gynecology (R.A., R.P., L.R.B.), Medicine (R.A.), and Biostatistics
(L.M.F.), University of Alabama, Birmingham, Alabama 35233; and Department of Gynecology and
Obstetrics, The Johns Hopkins University College of Medicine (H.A.Z.), Baltimore, Maryland 21287
ABSTRACT
Excess adrenal androgen (AA) levels are observed in 25–50% of
women with the polycystic ovary syndrome (PCOS), and AA excess in
PCOS may represent selection bias. Thus, it is possible that AA
secretion among the general population is highly variable, and that
those women who are predisposed to secreting greater amounts of AA
have a greater probability of having PCOS. We now hypothesize that
the levels of AAs are highly variable among normal nonhyperandrogenic women, and that this heterogeneity is the result of a variable
response of AAs to ACTH stimulation. To test this hypothesis we
prospectively studied the response of dehydroepiandrosterone (DHA)
and cortisol (F) to a 60-min acute stimulation with ACTH-(1–24) in
56 healthy eumenorrheic nonhirsute healthy women with a mean age
of 28.9 yr (range, 20 –37 yr.) and a mean body mass index (BMI) of 29.2
kg/m2 (18.2– 46.2 kg/m2). Baseline samples and poststimulation samples were assayed for DHA and F. The basal and ACTH-stimulated
levels of DHA, but not those of F, were negatively correlated with age,
although neither the basal nor ACTH-stimulated responses of DHA
and F varied with BMI. After controlling for age, the basal F level was
negatively correlated to its net increment (i.e. ⌬F; r ⫽ ⫺0.54; P ⬍
0.001), whereas there was no significant relationship between basal
H
YPERANDROGENISM, generally in the form of the
polycystic ovary syndrome (PCOS), affects approximately 4% of unselected reproductive-aged women (1). Although most of these patients suffer from excess ovarian
androgen secretion, excess adrenal androgen (AA) levels are
also observed in 25–50% of women with PCOS (2– 4). The
underlying etiology for the AA excess frequently observed in
PCOS remains unclear. However, AA excess in PCOS may
represent selection bias. Thus, it is possible that AA secretion
among the general population is highly variable, and that the
women who are genetically predisposed to secrete greater
amounts of AA will have a greater probability of having
PCOS. High AA secretion would then represent another of
the many factors potentially predisposing to or increasing
the risk for the development of PCOS.
Received August 23, 2000. Revision received November 15, 2000.
Accepted November 22, 2000.
Address all correspondence and requests for reprints to: Ricardo
Azziz, M.D., Department of Obstetrics and Gynecology, University of
Alabama, 618 South 20th Street, OHB 549, Birmingham, Alabama 352337333. E-mail: [email protected].
* This work was supported in part by NIH Grant RO1-HD-29364 (to
R.A.), GCRC Grant M01-RR00032, and Grant N0014-96-I-0255 from the
Office of Naval Research (to C.R.P.).
DHA and ⌬DHA. We also compared the intersubject variability (coefficient of variation) for basal and stimulated levels of DHA and F.
For basal (DHA0), 60 min (DHA60), and net increment in (⌬DHA) DHA
levels, the coefficients of variation were 67.9%, 61.4%, and 76.0%,
respectively; for F0, F60, and ⌬F, they were 40.4%, 16.9%, and 31.3%,
respectively. The variance in ⌬DHA was significantly higher, and the
variance in F60 was significantly lower than that in all other variables;
DHA0, DHA60, F0, and ⌬F had similar variances.
In conclusion, in our population of healthy reproductive-aged
women we observed that both basal and ACTH-stimulated levels of
DHA after ACTH-(1–24) stimulation had significantly greater intersubject variance (⬃60 –70%) compared with the basal and poststimulation levels of F (⬃15– 40%). These data support the hypothesis that
among normal women, AA (i.e. DHA) levels are highly variable compared to those of F. In addition, the intersubject variability in DHA
levels is at least in part due to a variable response of AAs to ACTH
stimulation. Whether the AA excess frequently observed in PCOS is
due to the greater risk of those women with higher AA levels, basally
and after ACTH stimulation, remains to be confirmed. (J Clin Endocrinol Metab 86: 2513–2517, 2001)
In support of this hypothesis, various investigators have
reported that circulating levels of the adrenal androgens
dehydroepiandrosterone (DHA) and DHA sulfate (DHS) appear to be under significant genetic control (5, 6). In fact,
some investigators have noted that the genetic influence on
AA levels may be greater in women than in men (7). Other
data also support the suggestion that the circulating AA
levels in women are predetermined to a significant degree.
For example, the relative circulating level of DHS in postmenopausal women appears to vary little over time. Thus,
individuals who had higher levels of DHS early in menopause tended to always have higher levels relative to other
menopausal women and vice versa independent of the agerelated decline in AA levels normally observed (8). Overall,
it appears that AA levels are highly individualized, and that
this variability may be under significant genetic influence.
ACTH stimulates the release of both AAs and glucocorticoids in vivo (9) and in vitro (10). Hence, it is possible that
the elevated AA levels found in PCOS patients with AA
excess reflect an exaggerated response of these steroids to
ACTH, and that this adrenal response to ACTH is under
genetic control. In fact, we previously reported that AA excess in PCOS patients is related to an exaggerated secretory
2513
2514
JCE & M • 2001
Vol. 86 • No. 6
AZZIZ ET AL.
response of the adrenal cortex to ACTH for both DHA and
androstenedione, but not to altered pituitary responsivity to
CRH or to increased sensitivity of the adrenal cortex to
ACTH (11).
Overall, it is then possible that AA excess among PCOS
patients represents selection bias, such that women who are
genetically predisposed to secrete greater amounts of AA
will be at greater risk of developing PCOS. This suggestion
would require that AA secretion among the general population be highly variable. We now hypothesize that compared with cortisol (F), the levels of AAs are highly variable
among normal nonhyperandrogenic women. We further hypothesize that this heterogeneity in AA secretion is the result
of a variable response of AAs to ACTH stimulation. To test
these hypotheses we prospectively studied the responses of
DHA and F to acute stimulation with ACTH-(1–24) in
healthy eumenorrheic nonhirsute women.
Subjects and Methods
Subjects
We recruited 56 eumenorrheic women with regular menstrual cycles
every 26 –32 days, without evidence of hirsutism, with a negative family
history for endocrine disorders, and taking no medications, including
oral contraceptives. All underwent acute adrenal stimulation testing, as
outlined below, after appropriate written and informed consent was
obtained according to the guidelines of the joint committee on clinical
investigation of The Johns Hopkins Hospital and the institutional review
board of University of Alabama (Birmingham, AL).
Study protocol
Acute adrenal stimulation was performed as previously described (9).
In brief, all studies were performed between 0800 –1030 h in the fasting
state during the follicular phase (days 3– 8) of the menstrual cycle.
Dexamethasone was not administered before the study so that resting
basal steroid levels could be assessed. Three baseline samples were
obtained 15 min apart and mixed to form the 0 min (basal) sample.
Immediately thereafter 1 mg ACTH-(1–24) (Cortrosyn, Organon, West
Orange, NJ) was administered iv over 60 s, and blood was sampled 60
min later. Serum was separated and stored at ⫺20 C until assayed.
We previously reported that 1 mg ACTH-(1–24), iv, elicits a maximum response of adrenocortical steroids regardless of body weight (9).
Furthermore, we noted that the steroid response to this dose of ACTH(1–24) is highly reproducible over time (9).
Hormonal measures
Baseline samples were assayed for DHS, DHA, and F, and DHA and
F were also measured in the 60 min samples. Serum samples from all
patients were batched for analysis, and hormonal assays were performed at one time.
DHS was measured by direct RIA (Diagnostic Products, Los Angeles,
CA), and DHA was measured by RIA using a single antibody, separating
free from bound steroid with dextran-coated charcoal (Radioassay Systems Laboratories, Inc., Carson, CA). The intraassay coefficients of variation (CVs) were 4.1%, 6%, and 7% for DHS, and 9.8%, 4.7%, and 4.3%
for DHA for low, medium, and high values, respectively. F levels were
determined by RIA as previously described (12), except that tritiated,
rather than iodinated, F was used, and dextran-coated charcoal was used
to separate antibody-bound and free steroid. The intraassay CVs were
4.3% and 6.7% for high and low values, respectively.
Statistical analysis
In addition to determining the steroid levels at 0 min (basal level or
steroid0) and 60 min (maximal response or steroid60) after ACTH-(1–24)
administration, the net change (net increment) in hormone levels was
calculated (⌬steroid). Correlations were established using the Pearson
correlation coefficient analysis. The CVs were compared by the Duncan’s multiple range test (␣ ⫽ 0.05) and Fischer’s least significant difference test.
Results
The mean age of our main study group consisting of 56
study subjects was 28.9 yr (range, 20 –37 yr) with a mean
body mass index (BMI) of 29.2 kg/m2 (range, 18.2– 46.2 kg/
m2). Their mean basal and stimulated values (and ranges)
before and after ACTH-(1–24) stimulation are depicted in
Table 1 and Fig. 1. The ACTH-stimulated F levels in our
subjects fell within the range previously reported for normal
individuals (13, 14).
Relationship between the basal DHA and F levels and their
responses to ACTH-(1–24)
The basal levels of DHA (i.e. DHA0) and its response to
ACTH (i.e. DHA60 and ⌬DHA) were negatively correlated
(decreased) with age (r ⫽ ⫺0.46, ⫺0.58, and ⫺0.52; P ⬍
0.0001– 0.0009, respectively). Alternatively, neither F0, F60,
nor ⌬F varied with subject age. Furthermore, neither basal
nor ACTH-stimulated responses of DHA and F varied with
BMI. The circulating level of DHS was positively correlated
with the DHA0 and DHA60 values (r ⫽ 0.47 and 0.35; P ⬍
0.008 and 0.02, respectively), but not with ⌬DHA. Alternatively, DHS levels were not correlated to either the basal level
of F or its response to ACTH.
The basal levels of both DHA and F (i.e. DHA0 and F0,
respectively) were positively correlated to their maximal
poststimulation values (i.e. DHA60 and F60; r ⫽ 0.71; P ⬍
0.0001 and r ⫽ 0.46; P ⬍ 0.0004, respectively). In contrast, the
basal F level was negatively correlated to its net increment
or change (i.e. ⌬F; r ⫽ ⫺0.53; P ⬍ 0.001), although DHA0 was
positively correlated to the ⌬DHA value (r ⫽ 0.39; P ⬍ 0.006).
The relationship between the basal levels of DHA and F
and their respective responses to ACTH-(1–24) were then
reanalyzed, controlling for subject age. The basal levels of F
and ⌬F remained negatively correlated (r ⫽ ⫺0.54; P ⬍
0.0001), whereas the positive relationship between DHA0
and ⌬DHA was no longer significant (r ⫽ 0.20; P ⫽ 0.17).
Figure 2 depicts the relationship between the basal levels of
DHA and F and their respective increments, controlling for
subject age.
TABLE 1. Mean basal and ACTH-(1–24)-stimulated hormone
levels in 56 healthy eumenorrheic nonhirsute women
Hormonea
DHS (␮mol/L)
DHA0 (nmol/L)
DHA60 (nmol/L)
⌬DHA (nmol/L)
F0 (nmol/L)
F60 (nmol/L)
⌬F (nmol/L)
Mean ⫾
SD
4.7 ⫾ 2.2
8.46 ⫾ 5.72
22.29 ⫾ 13.69
14.25 ⫾ 10.82
183.7 ⫾ 74.2
428.2 ⫾ 72.6
244.4 ⫾ 76.4
Range
1.2–10.3
0.35–32.31
0.52– 65.32
0.02–51.87
44.6– 400.0
300.7– 670.4
49.6– 402.8
DHS, Dehydroepiandrosterone sulfate; DHA, dehydroepiandrosterone; F, cortisol.
a
The steroid levels at 0 min and 60 min after ACTH-(1–24) administration, and the net change in circulating levels is Steroid0,
Steroid60, and ⌬Steroid.
VARIABILITY OF DHA SECRETION AMONG WOMEN
FIG. 1. Levels of F and DHA before (0 min) and after the administration of 1 mg ACTH-(1–24), iv (60 min). Note the wide intersubject
variation in the 60 min DHA levels compared with those of F.
Intersubject variability in DHA and F
In the main study group of 56 subjects we first calculated
the intersubject CVs for each of the six variables under study.
For DHA0, DHA60, and ⌬DHA, the CVs were 67.9%, 61.4%,
and 76.0%, respectively; for F0, F60, and ⌬F, they were 40.4%,
16.9%, and 31.3%, respectively. We then compared the CVs
of these variables by Duncan’s multiple range test (with an
␣ ⫽ 0.05). The CV of ⌬DHA was significantly higher than
those of all other variables, the CV of F60 was significantly
lower than those of all other variables, and DHA0, DHA60, F0,
and ⌬F had similar CVs. Similar findings were obtained
when the CVs of DHA0, DHA60, ⌬DHA, F0, F60, and ⌬F were
compared by Fischer’s least significant difference test (i.e.
least squares means method).
The fractional difference from the mean of the group for
each subject was also calculated (i.e. the observed subject
value minus the group mean, with the difference divided by
the group mean). As before, comparison of these differences
by fischer’s least significant difference test indicated that the
maximal F response (i.e. F60) had significantly less intersubject variability than all other variables (P ⬍ 0.04 – 0.0001),
except ⌬F. In contrast, the CV of ⌬DHA was significantly
greater than that of all other variables (P ⬍ 0.02– 0.0001),
except DHA0.
2515
FIG. 2. Depicted are the scattergrams of the relationship between the
basal F (F0) and DHA (DHA0) levels and their respective net increments or change (⌬F0 – 60 and ⌬DHA0 – 60) after the administration of
1 mg ACTH-(1–24), iv (60 min) After controlling for age, the basal level
of F and its net increment were negatively correlated (r ⫽ ⫺0.54; P ⬍
0.0001), whereas the basal level of DHA was not correlated to its net
increment (r ⫽ 0.20; P ⫽ 0.17). The dark lines depict these correlations.
Discussion
Overall, in our population of healthy reproductive-aged
women, both basal and maximal levels of DHA after ACTH(1–24) stimulation had significantly greater intersubject variance (i.e. 60 –70%) compared to the basal level and the response of total F (i.e. 15– 40%). These data support the
hypothesis that among normal women, AA (i.e. DHA) levels
are highly variable, at least compared to those of F. Hence,
it is possible that the presence of AA excess in 25–30% of
PCOS patients simply reflects selection bias, such that
women who are genetically predisposed to secrete greater
amounts of AAs will have a greater probability of having the
hyperandrogenic disorder PCOS.
It is unlikely that the difference in intersubject variability
between DHA and F is due to a greater intrinsic variability
of the response to ACTH within subjects over time. In fact,
we previously reported that the intersubject variability of the
response to ACTH-(1–24) stimulation was equally stable for
DHA and F (i.e. area under the response curve studied for up
to 6 months), with CVs of 16% and 7%, respectively (9). It is
also possible that the lesser variability of F after ACTH stimulation, compared with that of DHA, is due to the greater
2516
JCE & M • 2001
Vol. 86 • No. 6
AZZIZ ET AL.
degree of binding of F by corticosteroid-binding globulin
compared with the lesser binding of DHA by sex hormonebinding globulin (15). However, studying a separate cohort
of 18 healthy women, we observed that the intersubject variability of unbound F after ACTH-(1–24) stimulation remained low at 26% (Azziz, R., unpublished data).
The intersubject uniformity in the maximal response of
total F to stimulation was reflected by the fact that the higher
the basal level of F, the lesser its net increment (i.e. change)
in response to stimulation. Alternatively, after controlling for
the effect of age, there was no relationship between the basal
DHA level and its net increment after ACTH-(1–24) stimulation. Hence, the intersubject variability in DHA levels is at
least in part due to a variable response of AAs to ACTH
stimulation.
The high degree of variation in the AA response to ACTH(1–24) compared to that of F indicates that although ACTH
is an important determining factor of F secretion, this hormone appears to be only partially responsible for AA secretion. In fact, other as yet unknown factors seem to play an
important, and possibly determinant, role in the regulation
of AA biosynthesis. Various clinical examples illustrate the
dichotomous secretion of AAs and glucocorticoids. For example, in patients with myotonic dystrophy the circulating
level of AAs and their response to ACTH are markedly
reduced, although the level and response of F are either
normal or markedly elevated (16). In addition, with little
change in glucocorticoid secretion, the levels of AAs increase
during adrenarche and progressively decline with age (17).
Finally, in our present study a greater individual DHA response (i.e. net increment) to ACTH stimulation did not
directly predict higher basal levels of either DHA or DHS.
Hence, it appears that control of F and AA secretion frequently diverges, and that factors other than ACTH are important determinants of AA biosynthesis.
The mechanism(s) underlying the variability of the DHA
response to ACTH remains unknown. Variations in extraadrenal factors, such as degree of insulinemia or amount of the
putative cortical androgen-secreting hormone (18), may play
a role in determining the variability in AA secretion. However, it is more likely that the intersubject variability in AA
secretion reflects an intraadrenal process. For example, differences in the responsivity of AAs and F to acute ACTH
stimulation may reflect differences in the relative cell mass
of the zonae fasciculata and reticularis of the adrenal cortex.
Another promising mechanism accounting for the intersubject variability in AA secretion is variation in the function of
P450c17. This enzyme possesses both 17␣-hydroxylase and
17,20-lyase activities; the latter activity is critical for androgen biosynthesis. Importantly, the 17␣-hydroxylase and
17,20-lyase activities of P450c17 are differentially regulated.
For example, 17,20-lyase activity can be modified by variations in the amounts of the cofactors P450-oxidoreductase
(19, 20) and cytochrome b5 (21–23), by changes in the structural elements that allow P450c17 to interact with P450oxidoreductase (24), and by the degree of P450c17 phosphorylation (25). Hence, genetic or environmental factors that
modulate 17,20-lyase activity are likely to play a key role in
controlling AA secretion.
Our results suggest that there is significant populational
heterogeneity in the adrenal secretion of DHA in response to
ACTH, whereas there is little intersubject variability for maximum F secretion in response to ACTH. Teleologically this
steroidogenic arrangement makes sense, because an insufficient or excessive F response to ACTH can be life-threatening, whereas variations in the secretion of AAs are not.
Thus, evolutionary pressures may favor tight control of F
production, but much more lax production of AAs. In conclusion, our study in a population of healthy nonhyperandrogenic women indicates that the levels of AAs are highly
variable between subjects and that this heterogeneity may be
the result in part of a variable response of AAs to ACTH
stimulation. Hence, it is possible that the presence of AA
excess in 25–30% of PCOS patients simply reflects selection
bias, such that women who are genetically predisposed to
secrete greater amounts of AAs will have a greater probability of having this hyperandrogenic disorder PCOS. Nonetheless, this hypothesis remains to be confirmed.
References
1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz
R. 1998 Prevalence of the polycystic ovary syndrome in unselected black and
white women of the Southeastern United States: a prospective study. J Clin
Endocrinol Metab. 83:3078 –3082.
2. Wild RA, Umstot ES, Andersen RN, Ranney GB, Givens JR. 1983 Androgen
parameters and their correlation with body weight in one hundred thirty-eight
women thought to have hyperandrogenism. Am J Obstet Gynecol.
146:602– 606.
3. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. 1992 Does ethnicity
influence the prevalence of adrenal hyperandrogenism and insulin resistance
in polycystic ovary syndrome? Am J Obstet Gynecol. 167:1807–1812.
4. Morán C, Knochenhauer ES, Boots LR, Azziz R. 1999 Adrenal androgen
excess in hyperandrogenism: relation to age and body mass. Fertil Steril.
71:671– 674.
5. Rotter JI, Wong FL, Lifrak ET, Parker LN. 1985 A genetic component to the
variation of dehydroepiandrosterone sulfate. Metabolism. 34:731–736.
6. Meikle AW, Stringham JD, Woodward MG, Bishop DT. 1988 Heritability of
variation of plasma cortisol levels. Metabolism. 37:514 –517.
7. Rice T, Sprecher DL, Borecki IB, Mitchell LE, Laskarzewski PM, Rao DC.
1993 The Cincinnati Myocardial Infarction and Hormone Family Study: family
resemblance for dehydroepiandrosterone sulfate in control and myocardial
infarction families. Metabolism. 42:1284 –1290.
8. Thomas G, Frenoy N, Legrain S, Sebag-Lanoe R, Baulieu E, Debuire B. 1994
Serum dehydroepiandrosterone sulfate levels as an individual marker. J Clin
Endocrinol Metab. 79:1273–1276.
9. Azziz R, Bradley Jr E, Huth J, Boots LR, Parker Jr CR, Zacur HA. 1990 Acute
adrenocorticotropin-(1–24) (ACTH) adrenal stimulation in eumenorrheic
women: reproducibility and effect of ACTH dose, subject weight and sampling
time. J Clin Endocrinol Metab. 70:1273–1279.
10. Hines GA, Azziz R. 1999 Impact of architectural disruption on adrenocortical
steroidogenesis. J Clin Endocrinol Metab. 84:1017–1021.
11. Azziz R, Black V, Hines GA, Fox LM, Bradley Jr E, Boots LR. 1998 Adrenal
androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab.
83:2317–2323.
12. Gomez-Sanchez C, Milewich L, Holland OB. 1977 Radioiodinated derivatives
for steroid radioimmunoassay. Application to the radioimmunoassay of cortisol. J Lab Clin Med. 80:902–909.
13. May ME, Carey RM. 1985 Rapid adrenocorticotropic hormone test in practice.
Retrospective review. Am J Med. 79:679 – 684.
14. Arvat E, Di Vito L, Lanfranco F, et al. 2000 Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in
normal humans: dose-response study. J Clin Endocrinol Metab. 85:3141–3146.
15. Dunn JF, Nisula BC, Rodbard D. 1981 Transport of steroid hormones: binding
of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 53:58 – 68.
16. Buyalos RP, Grice JE, Jackson RV, et al. 1998 Androgen response to hypothalamic-pituitary-adrenal stimulation with naloxone in women with myotonic muscular dystrophy. J Clin Endocrinol Metab. 83:3219 –3224.
17. Azziz R, Koulianos G. 1991 Adrenal androgens and reproductive aging in
females. Semin Reprod Endocrinol. 9:249 –260.
VARIABILITY OF DHA SECRETION AMONG WOMEN
18. Parker LN, Odell WD. 1980 Control of adrenal androgen secretion. Endocr
Rev. 1:392– 410.
19. Lin D, Black SM, Nagahama Y, Miller WL. 1993 Steroid 17␣-hydroxylase and
17,20 lyase activities of P450c17: Contributions of serine106 and P450 reductase.
Endocrinology. 132:2498 –2506.
20. Yanagibashi K, Hall PF. 1986 Role of electron transport in the regulation of
the lyase activity of C-21 side-chain cleavage P450 from porcine adrenal and
testicular microsomes. J Biol Chem. 261:8429 – 8433.
21. Auchus RJ, Lee TC, Miller WL. 1998 Cytochrome b5 augments the 17,20 lyase
activity of human P450c17 without direct electron transfer. J Biol Chem.
273:3158 –3165.
22. Katagiri M, Kagawa N, Waterman MR. 1995 The role of cytochrome b5 in the
2517
biosynthesis of androgens by human P450c17. Arch Biochem Biophys.
317:343–347.
23. Lee-Robichaud P, Wright JN, Akhtar ME, Akhtar M. 1995 Modulation of the
activity of human 17␣-hydroxylase-17,20-lyase (CYP17) by cytochrome b5:
endocrinological and mechanistic implications. Biochem J. 308:901–908.
24. Geller DH, Auchus RJ, Miller WL. 1999 P450c17 mutations R347H and R358Q
selectively disrupt 17,20-lyase activity by disrupting interactions with P450
oxidoreductase and cytochrome b5. Mol Endocrinol. 13:167–175.
25. Zhang L-H, Rodriguez H, Ohno S, Miller WL. 1995 Serine phosphorylation of human P450c17 increases 17,20 lyase activity: Implications for
adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA.
92:10619 –10623.