| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Clinical Research Centers |
Departments of Obstetrics and Gynecology (R.A., V.B., G.A.H., L.R.B.), Medicine (R.A.), and Biostatistics (L.M.F.), University of Alabama, Birmingham, Alabama 35233
Address all correspondence and requests for reprints to: Ricardo Azziz, M.D., M.P.H., Department of Obstetrics and Gynecology, University of Alabama, 618 South 20th Street, OHB 549, Birmingham, Alabama 35233-7333.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A4/F ratio ( = net maximum change) indicated that
HI-DHS and LO-DHS had similar responses, which were greater than that
of the normal subjects, although the difference between LO-DHS patients
and normal subjects reached significance only for the AUC of the
A4 response. No difference in the sensitivity
(i.e. threshold or minimal stimulatory dose) to ACTH was
noted between the groups for any of the steroids measured. Nonetheless,
the average dose of ACTH-(1–24) required for a threshold response was
higher for DHA than for F and A4 in all groups. No
difference in mean responsivity (slope of response to incremental ACTH
stimulation) was observed for DHA and F between study groups, whereas
the responsivity of A4 was higher in HI-DHS patients than
in normal or LO-DHS women. The net maximal and the overall
(i.e. AUC) responses of DHA were greater for HI-DHS than
for normal or LO-DHS women. The response of A4 and the
A4/F ratio were greater for HI-DHS patients than for
LO-DHS patients or normal subjects. Alternatively, HI-DHS and LO-DHS
patients had similar overall responses (i.e. AUC) for
A4 or A4/F, although both were greater than
those of normal subjects. The relative differences in response to
incremental ACTH stimulation between steroids was consistent for all
subject groups studied, i.e. A4 > F or DHA.
In conclusion, our data suggest that AA excess in PCOS patients is
related to an exaggerated secretory response of the adrenal cortex for
DHA and A4, but not to an altered pituitary responsivity to
CRH or to increased sensitivity of these AAs to ACTH stimulation.
Whether the increased responsivity to ACTH for these steroids is
secondary to increased zonae reticularis mass or to differences in
P450c17
activity, particularly of the 4 pathway,
remains to be determined. |
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The AA excess of PCOS may also result from generalized adrenocortical hyperreactivity to normal levels of ACTH. Some investigators have observed an exaggerated secretion of both AAs (9, 10) and cortisol (F) (11) after ACTH administration in these patients. We have also observed that 40–50% of hyperandrogenic women demonstrate an exaggerated secretion of F, 11-deoxycortisol, and dehydroepiandrosterone (DHA) after acute ACTH-(1–24) stimulation, which correlated closely with their circulating DHS levels (12).
We have postulated that excess AAs in PCOS arises from dysfunction of the HPA axis due to 1) exaggerated pituitary secretion of ACTH in response to hypothalamic CRH, 2) excess sensitivity/responsivity of AAs to ACTH stimulation, or 3) both. We have tested our hypotheses by studying PCOS patients with and without DHS excess and age- and body mass-matched controls. In addition to improving our understanding of adrenocortical physiology, establishing the etiology of the adrenal excess may point to an abnormality common to both adrenocortical and ovarian androgen biosynthesis, i.e. an exaggerated response to their respective trophic factors.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Twelve PCOS patients with (HI-DHS) and 12 without (LO-DHS) AA excess were recruited from the University of Alabama-Birmingham reproductive endocrinology clinical population. Selection criteria for PCOS included 1) oligoovulation, defined as cycles greater than 35 days in length; 2) hirsutism, defined as a score of more than 7 using a modification of the Ferriman-Gallwey method (13) and/or increased circulating androgen levels, including either free testosterone (T) and/or androstenedione (A4) above the 95th percentile of control values, as previously reported (14); and 3) the exclusion of thyroid disorders, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia, as previously described (15). This definition is consistent with the criteria set forth at the 1990 NICHHD/NIH consensus conference (16). Subjects in the HI-DHS group had DHS levels above 8.1 µmol/L (3000 ng/mL), whereas those in the LO-DHS population had DHS levels below 7.5 µmol/L (2750 ng/mL). Women with DHS levels between 7.6–8.0 µmol/L were excluded so as to provide two distinct study groups.
Eleven healthy eumenorrheic women without evidence of hirsutism or endocrine disorders were recruited as controls. All study subjects had not been taking hormonal medications for at least 3 months before the study. All controls had circulating levels of total and free T, A4, and DHS within the normal limits previously described (14). Because a prior study suggested that adrenal sensitivity to ACTH-(1–24) was affected by body mass (17), and age reduces AA secretion overall (18), the three study groups were age and body mass matched. The study was approved by the institutional review board of University of Alabama, and all subjects gave written informed consent.
Acute ovine CRH (oCRH) stimulation
Studies were performed during the follicular phase of the menstrual cycle (days 3–10) or, in amenorrheic patients, the start of a withdrawal bleed induced by the administration of 100 mg progesterone in oil, im. In the event withdrawal bleeding was induced, care was taken not to begin testing (see below) earlier than 10 days after the administration of progesterone, so as to minimize any potential effect on androgen levels. The test was performed between 0700–0900 h. One microgram per kg BW oCRH (ACTHREL, Ferring Laboratories, Sufferin, NY) was administered iv over 60 s. Blood was sampled at -30, -15, and 0 min, and measurements were combined to serve as the baseline. Sampling was then performed 15, 30, 60, and 90 min after the administration of oCRH. In addition to 5 cc serum for the measurement of adrenal steroids, at each time a 1.0-cc sample of blood was collected in a prechilled siliconized ethylenediamine tetraacetate tube, immediately placed on ice, and centrifuged at 4 C, and the plasma was frozen at -70 C for the measurement of circulating ACTH. This testing was performed at the General Clinical Research Center at the University of Alabama.
Incremental ACTH-(1–24) stimulation
The adrenocortical sensitivity was determined by an incremental ACTH-(1–24) infusion similar to that previously described (17), whose precise protocol was established after preliminary investigations in a small cohort of men (19). In brief, this test was performed between days 3–10 after the beginning of the menstrual cycle or after the induction by progesterone in oil of a withdrawal bleed and 2–4 days before, or after, the oCRH test. Each woman received 1 mg dexamethasone, orally, the night before and at 0700 h on the day of testing to suppress spontaneous ACTH pulsatility and minimize the normal variability in the basal steroid levels. Breakfast was ingested at least 3 h before beginning the ACTH-(1–24) infusion. Immediately before the study, 0.25 mg ACTH-(1–24) (Cortrosyn, Organon, West Orange, NJ) was diluted in acidified normal saline with 0.1% salt-poor albumin. A continuous iv infusion of normal saline was begun at least 1 h before the ACTH-(1–24) stimulation. The dilute ACTH-(1–24) solution was then administered, beginning between 0800–0900 h, using an AutoSyringe pump (Bimeco, Largo, FL) at the following doses: 0, 20, 40, 80, 160, 320, 960, and 2880 ng/1.5 m2·h. Twenty cubic centimeters of blood were withdrawn before and at the end of every hour of infusion, and serum and plasma were separated and frozen at -70 C until assayed. At the end of the last hour of infusion, 0.25 mg ACTH-(1–24) was injected iv as a bolus, and blood was sampled for a final time 60 min later. The study lasted approximately 8 h. Subjects remained supine during the majority of this time, but were allowed to go to the bathroom and to drink fluids, including juices, to minimize the risk of hypoglycemia and/or discomfort. Testing was also performed at the General Clinical Research Center at the University of Alabama.
Hormonal assays
The levels of DHA, A4, and F were measured at each sample time during the incremental ACTH-(1–24) stimulation test and the acute oCRH stimulation. During the acute oCRH test, total and free T, sex hormone-binding globulin (SHBG), DHS, estrone (E1), estradiol (E2), and PRL were also measured in the basal samples, and circulating ACTH levels were determined at every sample time. An attempt was made to batch all samples from one study, particularly all samples from one subject. The intraassay coefficient of variance (CV) were consistently less than 10%, and the interassay variances were less than 15%.
Specifically, DHA was assayed by RIA using an antibody developed in-house (cross-reaction of <1% with any steroid tested) and dextran-charcoal separation of free and bound hormone, after serum extraction and column separation [Sephadex LH-20 and MeCl2-isopropyl alcohol (97:3) as eluate] (20). The intraassay CVs were 9.8% and 11.5% for high and low values, respectively. DHS, the primary indicator of AA excess, was measured by RIA using a double antibody method (Diagnostic Systems Laboratory, Webster, TX). Because of the importance of this steroid for the above studies, we proceeded to further characterize the assay method. The antibody cross-reacts 6% with A4 and 11% with DHA. Nonetheless, this alters the results in a negligible manner, because the circulating concentrations of these cross-reactants are 1000-fold less than that of DHS. The intraassay CVs were 3.2% and 1.6%, and the interassay CVs were 2.6% and 6.0%, for low and high values, respectively. A4 was measured by a direct solid phase RIA (Diagnostic Systems Laboratories). For the total T assay, the antiserum was produced in-house (21). The 3H tracer was obtained from DuPont (Wilmington, DE), and the standards were obtained from Steraloids (Wilton, NH). Extraction with 5 mL ether was performed on 0.5 mL serum (female) or 0.2 mL serum (male). The dried extract was then resuspended in buffer and assayed by RIA, using activated charcoal to separate free from bound steroid. SHBG activity was measured by diffusion equilibrium dialysis using Sephadex G-25 and [3H]T as the ligand. Free T was calculated as described by Pearlman (22). ACTH levels were measured by direct RIA using materials supplied by Nichols Institute Diagnostics (San Juan Capistrano, CA), with a sensitivity of 3 pg/sample. E2 levels were determined using a double antibody RIA (Pantex, Santa Monica, CA). E1 was measured by RIA, using charcoal-dextran to separate free from bound hormone (Radioassay Systems Laboratory, Carson, CA). The intraassay CV were 2.0% and 4.6% for low and high E2 levels, respectively, and 3.7% and 1% for low and high E1 values, respectively. PRL was assayed using a double antibody RIA (Clinetics, Tustin, CA) with intraassay variances of 12% and 9.8% for low and high values, respectively.
Statistical analysis
Repeated measures (for changes over time within the same group) or one-way (for comparison between groups at one specific time) ANOVA was used to compare the variables, followed by the Fisher’s protected least significant difference test if significant differences were present. Correlation analysis was performed using the Pearson coefficient of correlation. Statistical significance was determined as P < 0.05.
The variables under study were as follows.
Response to oCRH. For ACTH and individual steroid levels,
and the DHA/F and A4/F ratios, we calculated 1)
the net maximal response (i.e. change from baseline to peak;
), 2) the ratio of the net maximal response of each steroid to that
of ACTH (i.e. steroid/ACTH), and 3) the overall
response, determined as the area under the curve (AUC) for each
response.
Sensitivity to ACTH stimulation. The average dose of ACTH-(1–24) necessary for the detection of a significant change (response) in the steroid level from the baseline (threshold dose) was defined as previously reported (17): threshold = t0.975 [rad]2S2/n, where t0.975 was the t distribution at the 0.975 percentile and the appropriate degrees of freedom, S2 was the variance based on the ANOVA data, and n was the number of subjects.
Responsivity to ACTH. Linear regression models were developed for each steroid response, using the linear portion of the curves (i.e. from 320 ng/1.5 m2·h to 2880 ng/1.5 m2·h) and the resulting slope used to define the responsivity of the steroid to ACTH.
Response to ACTH stimulation. For A4,
DHA, F, A4/F, and DHA/F, we calculated 1) the net
maximal response (
), determined as the difference from baseline to
maximum (peak) hormonal value; and 2) the overall response, determined
by the AUC for the response to ACTH for each of parameters noted
above.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
As expected, all three groups differed with regard to mean DHS
level, whereas age, body mass index (BMI), and PRL, E1, and
E2 levels were similar (Table 1
). Total T and SHBG levels were higher
in PCOS patients than in controls, although they were not different in
HI-DHS and LO-DHS PCOS patients. Nonetheless, the levels of free T were
greater in HI-DHS than in LO-DHS patients; in turn, the LO-DHS women
had lower SHBG levels than normal subjects. To determine the cause of
this difference, we noted that considering all PCOS patients combined
(n = 24), the circulating level of DHS was negatively correlated
to BMI (r = -0.44; P < 0.03). This negative
association appeared primarily to be present in HI-DHS (r =
-0.50; P = 0.0974), not LO-DHS (r = -0.08;
P = 0.80), subjects.
|
The net maximal responses [i.e. for ACTH,
A4, DHA, and F (Figs. 1 and 2);
for the DHA/ACTH, A4/ACTH, and
F/ACTH ratios; and for the DHA/F ratio] were similar in
all groups (Table 2). Nonetheless, the
AUC for DHA or DHA/F indicated a greater response for HI-DHS than for
LO-DHS or normal subjects, with LO-DHS patients having a similar
response as normal subjects (Table 3).
The AUCs for A4 and A4/F
(Table 3) and the A4/F ratio (Table 2)
indicated that HI-DHS and LO-DHS women had similar responses, which
were greater than that of normal subjects, although the difference
between LO-DHS patients and normal subjects reached significance only
for the AUC of the A4 response.
|
|
|
|
Sensitivity to ACTH-(1–24). A repeated measures ANOVA was
performed within each group to determine the time point at which the
DHA, A4, and F values first became significantly
different from the initial baseline values. Furthermore, the doses of
ACTH-(1–24) required for a threshold response per steroid/group were
calculated. No difference in either of these measures of sensitivity to
ACTH was noted between the groups for any of the steroids measured
(Fig. 3). Nonetheless, the average dose
of ACTH-(1–24) for a threshold response was higher for DHA than for F
or A4 in all groups.
|
.
Significant results from the analyses are indicated. For DHA, the
levels at 20, 40, and 960 ng/1.5 m2·h were significantly
different between the HI-DHS and LO-DHS PCOS patients. For
A4, the mean levels at all doses were
significantly lower for normal subjects than for PCOS patients, with no
difference between HI-DHS and LO-DHS women. For F, the only difference
noted was a higher mean value for normal women at the 160 ng/1.5
m2·h dose. Reviewing the calculated responsivity values
(Table 4), we noted that the only
difference between groups was a higher mean A4
response for HI-DHS patients compared to normal subjects and LO-DHS
patients. Although the responsivity of DHA appeared higher for HI-DHS
than for either LO-DHS or normal subjects, the differences were not
significant (P = 0.1467 and 0.6102, respectively).
Alternatively, the difference between steroids was consistent for all
subject groups studied, namely that the overall slope of the response
of A4 was greater than that of either F or
DHA.
|
|
) for DHA was higher in HI-DHS patients than in
LO-DHS patients or normal subjects, although the difference between the
groups did reach significance (8.9 ± 4.0 vs. 5.5
± 2.7 and 7.2 ± 3.8 nmol/L, respectively; P =
0.075). In fact, it would require 86 subjects in each group to show
such a difference with a power of 0.80 and an = 0.05. Nonetheless,
the net maximal DHA/F was higher for HI-DHS than for either
LO-DHS or normal subjects (3.5 ± 1.6, 2.1 ± 1.3, and
2.3 ± 1.0 x 10-5, respectively;
P < 0.01–0.04). Furthermore, the overall response
(i.e. AUC) of DHA or DHA/F was higher for HI-DHS patients
than for either LO-DHS or normal women (Table 5).
|
A4/F ratio was greater for HI-DHS patients
than for LO-DHS patients or normal subjects (1.2 ± 0.4, 0.8
± 0.3, and 0.6 ± 0.2 x 10-5, respectively;
P < 0.0002–0.008), with no significant difference
between LO-DHS and normal subjects. Nonetheless, when calculating the
AUC (i.e. overall response) of A4 and
A4/F, HI-DHS and LO-DHS patients had similar
responses, and both were greater than those of the normal individuals
(Table 5
). |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our data do not demonstrate a difference in the ACTH response to acute CRH stimulation between PCOS patients and weight/age-matched controls regardless of the presence of AA excess, consistent with findings of others (23). Other investigators have also not found gross differences in the HPA axis of patients with PCOS. For example, there does not appear to be a higher morning plasma level or an altered circadian or diurnal variation in ACTH between PCOS or hirsute patients and control women (7, 8, 24, 25, 26). Furthermore, the response of endogenous ACTH to metyrapone administration (which results in increases in endogenous CRH and ACTH) was reported to be similar in hirsute and/or PCOS patients and control women (7, 25). Although Lanzone and colleagues noted that women with PCOS had a significantly greater ACTH response to CRH stimulation than controls, their PCOS patients were also significantly more overweight than the controls (58% vs. 13% prevalence of obesity; P < 0.05), a possible confounding factor (24). In fact, Pasquali et al. noted that women with android obesity (i.e. increased waist/hip ratio) had a greater response of ACTH to CRH stimulation than women with gynecoid obesity (27). Nonetheless, in the study by Lanzone and colleagues, PCOS and control women had similar waist/hip ratios (24), and the reason(s) for the discrepancy in CRH stimulation results between our study and theirs is unclear.
We did not demonstrate a gross abnormality in the ACTH response to CRH stimulation between patients with PCOS with and without excess DHS when the test was performed in the morning. Nonetheless, the net responses (i.e. change) in cortisol and ACTH after CRH administration are greater if the test is performed in the evening, secondary to the circadian decrease in the basal levels of these hormones (28). Hence, it could be argued that CRH testing should have been performed in the evening to detect subtle differences in pituitary sensitivity/response. However, Nieman and colleagues did not find that CRH testing in the evening was more sensitive for the diagnosis of Cushing’s syndrome than were tests performed in the morning (29). Nonetheless, if the HPA axis were subtly, but chronically, overactive, it could result in subclinical hypertrophy and/or hyperplasia of the zonae reticularis/fasciculata, with a consequent overresponse to ACTH stimulation. In support of this hypothesis, Stewart et al. reported that the ACTH pulse frequency was lower in seven women with PCOS than in nine controls (3.6 ± 0.4 vs. 5.9 ± 0.6 pulses/12 h; P < 0.05), with no change in mean pulse amplitude or level, suggesting some blunting of the HPA axis (8). Nonetheless, changes in the HPA axis may actually reflect primary alterations in adrenocortical biosynthesis, e.g. a gland that intrinsically overresponds to ACTH may result in the compensatory reduction or blunting of the hypothalamic-pituitary response. Hence, although very subtle and minimal defects in hypothalamic-pituitary function may be present in PCOS patients with DHS excess (8, 20), it is unlikely that we have missed a significant defect.
If the ACTH response to CRH is not altered in PCOS patients with AA excess compared to that in control women or PCOS patients without AA excess, then perhaps the sensitivity or responsiveness of AAs to ACTH stimulation is abnormal. In support of this hypothesis, Laue et al. studied the adrenocortical sensitivity and responsivity of F and DHA using a series of five 1-h ACTH tests with ACTH-(1–24) doses ranging from 0–1 µg/kg in patients with postadolescent acne (30). These investigators noted that although the response curves of F were similar in patients and controls, the ratio of DHA/F was greater among acneic women. Alternatively, Lachelin and colleagues administered two pulses of 200 ng/1.5 m2 ACTH-(1–24), separated by 2 h, to nine controls and the same number of PCOS patients (9). These investigators did not detect a difference between PCOS and control women in the response of adrenal steroids to this minimal stimulation, suggesting the absence of an alteration in adrenocortical sensitivity to ACTH. Our data, obtained using a more sophisticated method of assessing adrenocortical sensitivity, support the concept that the AA excess found in approximately half of PCOS patients is not related to an altered sensitivity to ACTH stimulation. The sensitivity of DHA to ACTH stimulation was lower than those of F and A4 for all of our study groups. This is consistent with the findings of Komindr and colleagues in normal eumenorrheic obese women, although in that study the threshold dose of ACTH-(1–24) was similar for DHA and A4 (17).
We assessed responsivity, or the slope of steroid secretion, to
determine whether PCOS patients with DHS excess had a more rapid output
of AAs in response to ACTH stimulation. The only difference between
groups was a higher mean A4 responsivity for PCOS
patients with AA excess compared with that of normal women or PCOS
patients without elevated DHS levels. However, most clearly the net
maximal and overall responses of DHA and A4, but
not F, to direct and indirect (via CRH) ACTH stimulation were greatest
in HI-DHS patients. In fact, LO-DHS patients had a DHA output in
response to ACTH similar to that of normal subjects, although they may
have had a marginally higher secretion of A4. In
conclusion, our data suggest that AA excess in PCOS patients is related
to an exaggerated response (i.e. increased capacity) of the
adrenal cortex to A4 and DHA, but not to altered
pituitary responsivity to CRH or increased sensitivity of the adrenal
cortex to ACTH stimulation. Whether the increased response of the
adrenal to ACTH is secondary to increased zonae reticularis mass or to
differences in P450c17 activity remains to be determined.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received October 29, 1997.
Revised February 24, 1998.
Accepted April 3, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-adrenocorticotropin-(1–24)
in normal and obese, nonhirsute, eumenorrheic women. J Clin
Endocrinol Metab. 63:860–864.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  S. E Kasim-Karakas, W. M Cunningham, and A. Tsodikov Relation of nutrients and hormones in polycystic ovary syndrome Am. J. Clinical Nutrition, March 1, 2007; 85(3): 688 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. CARMINA Ovarian and Adrenal Hyperandrogenism Ann. N.Y. Acad. Sci., December 1, 2006; 1092(1): 130 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhou, I. M. Bird, D. A. Dumesic, and D. H. Abbott Adrenal Hyperandrogenism Is Induced by Fetal Androgen Excess in a Rhesus Monkey Model of Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6630 - 6637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Diamanti-Kandarakis and C. Piperi Genetics of polycystic ovary syndrome: searching for the way out of the labyrinth Hum. Reprod. Update, November 1, 2005; 11(6): 631 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.H. Abbott, D.K. Barnett, C.M. Bruns, and D.A. Dumesic Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update, July 1, 2005; 11(4): 357 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Ehrmann Polycystic Ovary Syndrome N. Engl. J. Med., March 24, 2005; 352(12): 1223 - 1236. [Full Text] [PDF]
|
|
|
|
|
|
D. Glintborg, A. P. Hermann, K. Brusgaard, J. Hangaard, C. Hagen, and M. Andersen Significantly Higher Adrenocorticotropin-Stimulated Cortisol and 17-Hydroxyprogesterone Levels in 337 Consecutive, Premenopausal, Caucasian, Hirsute Patients Compared with Healthy Controls J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1347 - 1353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. O. Yildiz, K. S. Woods, F. Stanczyk, A. Bartolucci, and R. Azziz Stability of Adrenocortical Steroidogenesis over Time in Healthy Women and Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5558 - 5562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Piltonen, R. Koivunen, A. Perheentupa, L. Morin-Papunen, A. Ruokonen, and J. S. Tapanainen Ovarian Age-Related Responsiveness to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3769 - 3775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guido, D. Romualdi, R. Suriano, M. Giuliani, B. Costantini, R. Apa, and A. Lanzone Effect of pioglitazone treatment on the adrenal androgen response to corticotrophin in obese patients with polycystic ovary syndrome Hum. Reprod., March 1, 2004; 19(3): 534 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fassnacht, N. Schlenz, S. B. Schneider, S. A. Wudy, B. Allolio, and W. Arlt Beyond Adrenal and Ovarian Androgen Generation: Increased Peripheral 5{alpha}-Reductase Activity in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2760 - 2766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cermik, B. Selam, and H. S. Taylor Regulation of HOXA-10 Expression by Testosterone in Vitro and in the Endometrium of Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 238 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Cheung, S. M. Pride, B. H. Yuen, and L. Sy In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome Hum. Reprod., October 1, 2002; 17(10): 2540 - 2547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Arslanian, V. Lewy, K. Danadian, and R. Saad Metformin Therapy in Obese Adolescents with Polycystic Ovary Syndrome and Impaired Glucose Tolerance: Amelioration of Exaggerated Adrenal Response to Adrenocorticotropin with Reduction of Insulinemia/Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1555 - 1559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Guercio, M. A. Rivarola, E. Chaler, M. Maceiras, and A. Belgorosky Relationship between the GH/IGF-I Axis, Insulin Sensitivity, and Adrenal Androgens in Normal Prepubertal and Pubertal Boys J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1162 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Azziz, L. M. Fox, H. A. Zacur, C. R. Parker Jr., and L. R. Boots Adrenocortical Secretion of Dehydroepiandrosterone in Healthy Women: Highly Variable Response to Adrenocorticotropin J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2513 - 2517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Barbier, C. Girard, L. Berger, M. El Alfy, A. Belanger, and D. W. Hum The Androgen-Conjugating Uridine Diphosphoglucuronosyltransferase-2B Enzymes Are Differentially Expressed Temporally and Spatially in the Monkey Follicle throughout the Menstrual Cycle Endocrinology, June 1, 2001; 142(6): 2499 - 2507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. M. Martens, D. H. Geller, W. Arlt, R. J. Auchus, V. S. Ossovskaya, H. Rodriguez, A. Dunaif, and W. L. Miller Enzymatic Activities of P450c17 Stably Expressed in Fibroblasts from Patients with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4338 - 4346. [Abstract] [Full Text]
|
|
|
|
|
|
R. Azziz, V. Y. Black, E. S. Knochenhauer, G. A. Hines, and L. R. Boots Ovulation After Glucocorticoid Suppression of Adrenal Androgens in the Polycystic Ovary Syndrome Is Not Predicted by the Basal Dehydroepiandrosterone Sulfate Level J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 946 - 950. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||
