help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Buyalos, R. P.
Right arrow Articles by Azziz, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Buyalos, R. P.
Right arrow Articles by Azziz, R.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
*Genetics Home Reference
Hazardous Substances DB
*HYDROCORTISONE
*NALOXONE
Medline Plus Health Information
*Muscular Dystrophy
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3219-3224
Copyright © 1998 by The Endocrine Society

Original Studies

Androgen Response to Hypothalamic-Pituitary-Adrenal Stimulation with Naloxone in Women with Myotonic Muscular Dystrophy

R. P. Buyalos, R. V. Jackson, G. I. Grice, G. I. Hockings, D. J. Torpy1, L. M. Fox, L. R. Boots and R. Azziz

Department of Obstetrics and Gynecology, University of Kentucky (R.P.B.), Lexington, Kentucky 40536; the Department of Medicine, University of Queensland, Greenslopes Hospital (R.V.J., J.E.G., G.I.H., D.J.T.), Queensland, Australia; and the Departments of Biostatistics (L.M.F.), Obstetrics and Gynecology (L.R.B., R.A.), and Medicine (R.A.), 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, OHB-549, University of Alabama, 618 South 20th Street, Birmingham, Alabama 35233-7333.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by multisystem disease, including myotonia, muscle-wasting and weakness of all muscular tissues, and endocrine abnormalities attributed to a genetic abnormality causing a defective cAMP-dependent kinase. We have previously reported that MMD patients demonstrate ACTH hypersecretion after endogenous CRH release stimulated by naloxone administration while manifesting a normal cortisol (F) response. Additionally, others have reported a reduced adrenal androgen (AA) response to exogenous ACTH administration in MMD patients. As ACTH stimulates the secretion of both AAs and F, it is possible that the discordant relationship of these hormones in MMD patients results from a defect of adrenocortical ACTH receptor function or postreceptor signaling or subsequent biochemical events. Furthermore, the molecular abnormality seen in MMD patients may suggest that the mechanism underlying the frequently observed discordances in the secretion of glucocorticoids and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermittent glucocorticoid administration) are explainable solely via an alteration in the function of the ACTH receptor or postreceptor signaling. To ascertain whether the responses of F and AAs to endogenous ACTH diverged in this disorder, we prospectively studied the responses of these hormones to naloxone-stimulated CRH release in nine premenopausal women with MMD and seven healthy age and weight-matched control women. After naloxone infusion (125 µg/kg, iv), blood sampling was performed at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the absolute hormone level at each time, we calculated the net increment (i.e. change) at 30 and 60 min and the area under the curve (AUC) for F, ACTH, dehydroepiandrosterone (DHA), and androstenedione (A4). Consistent with our previous study, MMD patients demonstrated higher ACTH levels at all sampling times except [minud]5 min. AUC analysis revealed the ACTHAUC values were significantly higher in MMD than in control women (457 ± 346 vs. 157 ± 123 pmol/min·L; P < 0.03), whereas the FAUC response did not differ between MMD and controls (13860 ± 3473 vs. 13375 ± 3465 nmol/min·L; P > 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 ± 23 vs. 61 ± 23 µmol/L; P < 0.002). The serum concentrations of A4 at baseline, 30 min, and 60 min and DHA levels at 30 and 60 min were also significantly lower in MMD vs. control women. Additionally, the A4AUC and DHAAUC values were significantly lower in MMD patients than in controls. Furthermore, the net response of DHA at 60 min to the endogenous ACTH increase was also reduced in MMD patients compared with that in control subjects (2.3 ± 2.1 vs. 5.6 ± 2.6 nmol/L; P < 0.02).

In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocortical response to ACTH, reflected in normal F and reduced DHA and A4 secretion. Whether this defect is inherent to the disease or simply reflects adaptive changes to chronic disease remains to be demonstrated. However, it is possible that further studies of the response of MMD patients to ACTH may reveal a mechanism that explains the frequently observed dichotomy in the secretion of glucocorticoids and AAs.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACTH STIMULATES the release of both adrenal androgen (AAs) and glucocorticoids (1), although there are many clinical situations in which the secretion of AAs and that of cortisol (F) appears to be divergent. For example, with either intermittent glucocorticoid administration (2) or acute surgical or traumatic stress (3, 4), the circulating levels of AAs are markedly reduced, whereas the circulating levels of F are either normal or markedly elevated, respectively. Alternatively, during adrenarche, the production of AAs increases without a similar change in F production (5). Although these alterations may be the result of changes in the relative activities of 17-hydroxylase and 17,20-lyase (of cytochrome P450c17), and of 3ß-hydroxysteroid dehydrogenase (6), the signal determining these changes remains unknown. Some investigators have proposed a specific adrenal androgen-secreting hormone (7, 8, 9), although its existence has yet to be confirmed (10).

Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by myotonia, wasting, and weakness of all muscular tissues, in combination with various metabolic and endocrine abnormalities that have been attributed to a defective cAMP-dependent kinase, the so-called MMD protein kinase or DMPK (11). The genetic mutation is an unstable expansion of a CTG trinucleotide sequence in the 3'-untranslated region of a gene on chromosome 19q13.3, which, based on sequence homology, encodes for a cAMP-dependent serine-threonine kinase (12, 13, 14, 15). The MMD gene undergoes alternative splicing, which is postulated to result in the encoding of multiple protein isoforms (16, 17) and may account for the phenotypic variation reported in MMD.

Many patients with MMD demonstrate ACTH hypersecretion after both endogenous CRH stimulation with naloxone and exogenous CRH administration (18, 19, 20). We initially interpreted these data as reflecting the expression of the genetic mutation (i.e. a defective cAMP-dependent kinase) in the anterior pituitary corticotroph or its receptor. Nonetheless, the F response to these stimuli generally remains normal (20), as does the 24-h urinary F level (20). Additionally, others have observed, in a mixed gender group of MMD patients, lower circulating concentrations of the AAs dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulfate (DHS) at baseline and after the exogenous administration of ACTH (21). However, the impact of gender on the circulating concentrations of AAs (22, 23), a possible confounding factor in that report needs to be considered, and the reported finding confirmed.

As ACTH stimulates the secretion of both AAs and F (1), it is possible that the discordant relationship of these hormones in MMD patients (i.e. high ACTH, normal F, and low AAs) results from a defect of adrenocortical ACTH receptor function or postreceptor signaling that affects AA synthesis and/or secretion while generally sparing F. If this were the case, then the frequently observed discordance in the secretion of glucocorticoids and AAs may be explainable solely via an alteration in the function of the ACTH receptor. Naloxone is an opioid antagonist that induces hypothalamic CRH release by blocking the endogenous opioidergic influence that tonically inhibits central noradrenergic stimulatory pathways projecting to CRH-producing neurons in the paraventricular nucleus (24, 25, 26). We have now studied women with MMD to determine whether they have discordant responses in AAs and glucocorticoids to ACTH stimulation, as these patients may be a useful model for studying the effect of abnormal postreceptor signaling on the response of the hypothalamic-pituitary-adrenal axis.

Overall, we have hypothesized that the responses of AAs and glucocorticoid to ACTH can be modified by altering its postreceptor signaling; this may occur in MDD patients as a result of their mutated and defective cAMP-dependent kinase. Therefore, to ascertain whether the responses of F and AAs to endogenous ACTH diverged in MMD patients, while controlling for the effect of gender, we prospectively studied the responses of these hormones to endogenous CRH-mediated ACTH stimulation in nine premenopausal women with MMD and seven healthy age- and weight-matched controls. We have used naloxone to induce endogenous hypothalamic CRH release (27, 28).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Seven premenopausal women with MMD and nine healthy female volunteers who served as controls were prospectively studied. The groups had similar mean ages (33.3 ± 6.7 vs. 27.3 ± 7.8 yr) and mean body mass indexes (26.1 ± 6.0 vs. 21.7 ± 1.8 kg/m2). The control subjects had no history of chronic illnesses or disorders known to affect the hypothalamic-pituitary-adrenal axis. All subjects were nonsmokers and had not taken any medications for a minimum of 4 weeks before the time of study. All subjects abstained from alcohol and caffeine for 24 h before testing. All patients and controls received a physical examination and screening tests, including a complete blood count, serum electrolyte and liver function tests, urinalysis, and electrocardiogram. The study was approved by the ethics committees of Greenslopes Hospital and the University of Queensland, where the clinical studies were performed. Informed written consents were obtained from all subjects before the study. Some of these subjects were included in a previous report (20).

Study design

All patients underwent naloxone stimulation, which was performed in the midafternoon after a 3-h fast. An iv cannula was inserted in the forearm with a stop-cock to facilitate blood sampling and naloxone administration. Forty-five minutes after cannula insertion and 5 min before naloxone administration, basal blood samples were taken. Intravenous naloxone (0.4 mg/mL; Narcan, The Boots Co., North Rocks, Australia; 125 µg/kg) was administered over 60–90 s. Additional blood samples were drawn at 30 and 60 min, and plasma was frozen at -70 C until assayed. In addition to the 5 mL blood obtained for the measurement of adrenal steroids, at each time point an additional 1.0-mL blood sample 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 until assayed for circulating ACTH.

Hormonal determinations

At all sample times, unextracted plasma was assayed for ACTH, and extracted plasma was used to assay F, DHA, and androstenedione (A4). DHS was assayed in the basal (-5 min) samples only, as the levels of this steroid change little, if at all, during short term stimulation (29). To minimize the potential confounding variable of interassay variation, all samples from one individual were assayed together.

ACTH levels were measured in unextracted plasma by RIA, as previously described (30), using [125]ACTH (IM.183, Amersham Australia, North Ryde, Australia) and the anticorticotropin serum Ig, IgG-ACTH-1 (IgG Corp., Nashville, TN), which is directed at the 5–18 sequence of ACTH. DHA was measured by RIA after plasma extraction column separation (Sephadex LH-20) using MECI2:isopropyl alcohol (97:3) as the column solvent, and dextran-coated charcoal to separate bound from free steroid, as previously described (31). The antibody used is generated in-house and cross-reacts less than 1% with all androgens tested, as previously reported (32). The intraassay coefficients of variation were 9.8%, 4.7%, and 4.3% for low, medium, and high values, respectively. A4 was measured using a solid phase RIA kit (Diagnostic Systems Laboratories, Webster, TX), with intraassay variances of 8.4%, 9.9%, and 9.2% for low, medium, and high values, respectively. DHS was measured by direct solid phase RIA kits (Diagnostic Products Corp., Los Angeles, CA), with intraassay variances of 4.1% and 6.7% for high and low values, respectively. Plasma F levels were determined at the University of Queensland, Greenslopes Hospital, using extracted plasma by modifications of a previously published high performance liquid chromatography method (33), with prednisolone as an internal standard, and extraction with ether-dichloromethane (60:40). Chromatography was performed on a 3-µm silica column (Dynamax Short-One, Rainin Instrument Co., Woburn, MA), with a mobile phase consisting of hexane-dicholoromethane-ethanol-glacial acetic acid (652.5:300:45:2.5) at a flow rate of 2 mL/min, and UV detection at 254 nm. Recovery was 95–100% for F and prednisolone, and the routine detectable concentration was 25 nmol/L. The inter- and intraassay variances at 165 nmol/L were 6.2% and 4.5%, respectively.

Statistical analysis

In addition to the absolute hormone concentration at each sample time, the net increment (i.e. change) at 30 and 60 min, and the areas under the curve (hormoneAUC) after naloxone administration were calculated for ACTH, F, DHA, and A4. Each parameter was compared between groups using the unpaired t test. ANOVA followed by Fisher’s least exact test for comparison of multiple means was used for comparing hormonal values between sample times. Correlations were assessed using the Pearson correlation coefficient. P < 0.05 was considered to represent statistical significance. Results are expressed as the mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal hormone levels

Basal hormone levels for MMD and control patients are shown in Table 1Go. MMD patients had lower mean basal A4 and DHS levels compared with controls. Additionally, there were no significant differences in the baseline plasma concentrations of ACTH, DHA, or F between MMD and healthy age-, weight-, and sex-matched control subjects. The basal DHS to DHA ratio was significantly lower for MDD patients than controls (2063 ± 1025 vs. 6187 ± 1952, respectively; P < 0.0001).


View this table:
[in this window]
[in a new window]
  		Table 1. Baseline ACTH, F, DHA, DHS, and A4 levels in women with MMD and age-, weight-, and sex-matched healthy control subjects

 
ACTH and F responses after iv naloxone

The responses of ACTH and F to naloxone administration are shown in Fig. 1Go. The mean ACTH levels 30 and 60 min after naloxone administration were significantly higher in MMD patients than in control women (Fig. 1Go). Likewise, the net change in ACTH from baseline at both 30 min (data not shown) and 60 min (Table 2Go) as well as the ACTHAUC (Fig. 2Go) were significantly greater in MMD patients than in healthy controls.



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. The mean ± SD levels of ACTH, F, A4, and DHA 5 min before and 30 and 60 min after endogenous CRH stimulation with naloxone (125 µg/kg, iv) in female patients with MMD and healthy control women. *, P < 0.05 compared with controls.

 

View this table:
[in this window]
[in a new window]
  		Table 2. Net increment (change or {Delta}) from baseline to 60 min after naloxone administration in ACTH, F, DHA, and A4 levels in women with MMD and age-, weight-, and sex-matched healthy control subjects

 


View larger version (35K):
[in this window]
[in a new window]
  		Figure 2. The mean ± SD for the AUCs for A4, DHA, F, and ACTH after endogenous CRH stimulation with naloxone (125 µg/kg, iv) in female patients with MMD and healthy control women. *, P < 0.05 compared with controls.

 
Despite the greater endogenous ACTH secretion, the mean basal and stimulated F levels (Fig. 1Go) and the net change (Table 2Go) did not differ between MMD and control subjects. In addition, the FAUC was similar between groups (Fig. 2Go).

Adrenal androgen response after iv naloxone

The mean circulating levels of A4 and DHA at 30 and 60 min after naloxone infusion were significantly lower in MMD women than in control patients (Fig. 1Go). The incremental change in DHA from baseline to 30 min (data not shown) and 60 min (Table 2Go) was also lower among MMD patients compared with control women; although the differences in the changes in A4 from baseline to either 30 min (data not shown) or 60 min (Table 2Go) did not reach statistical significance. Likewise, A4AUC and DHAAUC were significantly lower among MMD patients compared with controls (Fig. 2Go). No significant correlation was found between the basal, stimulated, or net increment ({Delta}) ACTH values and the respective basal, stimulated, or net increment values of DHS, DHA, or A4. Nonetheless, a trend toward a positive association was observed between the basal ACTH and the basal A4 level (r = 0.60; P = 0.066) among MMD patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The purpose of this investigation was to explore the divergent androgen and F responses in women with MMD. Previously, Carter and Steinbeck studied a group of 12 male and 7 female MMD patients and observed lower basal serum concentrations of DHA and DHS compared with those in healthy control subjects (21). In this mixed gender cohort, a similar rise in DHA, DHS, and F was observed during the 4-h interval after a 25-µg corticotropin infusion. Subsequently, we reported ACTH hyperresponsiveness to naloxone-induced CRH secretion in a group of 39 patients (18 females and 21 males) with MMD with a normal F response, although AA activity was not examined (20). We have now confirmed the dichotomous response of glucocorticoids and AAs to endogenous ACTH stimulation in same sex (i.e. female) MMD patients. Our data revealed reduced basal DHS and A4 and normal F levels in MMD patients compared with those in healthy control women despite similar basal and higher stimulated ACTH levels. In fact, although the ACTH secretion in response to endogenous CRH stimulation was markedly higher, blunted A4 and DHA responses and a normal F response were observed. In addition to this dichotomous response to ACTH, MMD patients had a lower DHS/DHA ratio compared with controls, suggesting a reduction in DHA sulfation, i.e. sulfotransferase activity. Hence, it is possible that these abnormalities reflect the defective cAMP-dependent kinase reported in MMD patients, and that the study of these individuals may yield clues to the molecular mechanism underlying the dichotomous role of ACTH in the production and secretion of AAs and glucocorticoids.

Our previous data suggested that the ACTH hyperresponsiveness in MMD is either a function of an abnormality of hypothalamic CRH release or of the pituitary corticotroph receptor or postreceptor signaling (20). The present data suggest that MMD patients may also have a defect in their adrenocortical response to ACTH, which may be due an alteration in the ACTH receptor or postreceptor action. The action of ACTH is believed to be mediated through specific cell membrane receptors, associated via the secondary messengers calcium and G proteins positively coupled to cAMP (34). In support of abnormal ACTH receptor function in MMD, we have previously reported that nifedipine, a calcium channel blockers, delays, but does not reduce, the ACTH and F responses in MMD (35). In contrast, in healthy control subjects nifedipine reduced their ACTH response, although it did not alter its timing. The different effects on ACTH release of MMD and controls by calcium channel blockers implies abnormal calcium transport in the corticotrophs of MMD patients and suggests a potential cellular basis for the widespread clinical manifestations of this disorder, particularly as abnormal calcium channel function has been implicated in the pathogenesis of other human neuromuscular disorders (36, 37).

Another potential explanation of abnormal ACTH receptor functioning arises from data recently reported that implicate abnormal intranuclear messenger ribonucleic acid (mRNA) processing as the cause of the defective protein kinase activity observed in MMD (38, 39). In brief, a dominant negative effect at the RNA level is caused by the abnormal nascent RNA that affects the processing of the normal DMPK RNA and potentially other RNAs. Is has been proposed that the intranuclear mRNA-binding proteins, which bind to the CUG repeat, get trapped in the nucleus in MMD as a result of the absence of a polyadenylase tail in the mutant mRNA. This could affect nuclear-cytoplasmic transfer of other mRNAs dependent on these mRNA-binding proteins. This would then lead to defective protein synthesis for a large number of enzymes and/or structural proteins, possibly including those involved in ACTH receptor function.

The alterations in the response to ACTH seen in MMD may also result from a decrease in the zona reticularis mass, similar to the change associated with the age-related decrease in AA secretion (40). The decrease in zona reticularis volume may relate to the chronic disease state of MMD patients. For example, acutely ill and burn patients demonstrate a progressive reduction in androgen levels, whereas F levels remain elevated or continue to rise (41, 42). However, our MMD patients were not acutely ill, were ambulatory, and, although affected by their disease, were in no acute distress. Furthermore, a negative effect of their chronic disease state on AA levels is unlikely to occur in MMD patients, as suppression of AA levels is not seen in patients with facioscapulohumeral dystrophy with a similar degree of disability (19).

Another possible explanation for the abnormal adrenocortical response to the exaggerated ACTH secretion observed in MMD that does not involve defective ACTH receptor function is a selective decrease in 17,20-lyase activity. Adrenal androgens are the result of the action of the P450c17 enzyme, which has both 17-hydroxylase and 17,20-lyase functions. Miller and colleagues recently reported that altering the serine autophosphorylation of human P450c17 modulated the 17,20-lyase function of the enzyme (43). MMD appears to be associated with abnormal protein kinase activity, and sequence analysis has revealed homology between the DMPK and members of a subfamily of serine-threonine protein kinases that is closely related to cAMP-dependent protein kinases (11). Hence, it is possible that the disorder is associated with abnormal autophosphorylation of P450c17 and reduced AA production. As P450c17 is present in both the gonads and the adrenals, it would seem likely that MMD patients would also have gonadal abnormalities. In fact, hypergonadotropic hypogonadism occurs in approximately 50% of males with MMD (44, 45).

Finally, chronic ACTH hypersecretion alone due to the stress of the disorder or as a consequence of their hypothalamic-pituitary dysfunction may result in a blunting of the adrenocortical response to ACTH via either a relative reduction in the reticularis zone mass and/or down-regulation of ACTH receptors. Nonetheless, in other clinical conditions, chronic ACTH overstimulation results in an exaggerated AA secretion, with hypertrophy or enlargement of the adrenal cortex (e.g. adrenal hyperplasia).

In conclusion, the secretion of AAs and F in response to endogenous ACTH secretion is divergent in MMD. Abnormal postreceptor signaling of the ACTH receptor is suggested by the fact that although the secretion of ACTH is exaggerated, the secretion of F is normal, and that of AAs is reduced. However, abnormal P450c17 function may also account for the divergence in adrenocortical response. It is possible that the putative defect in cAMP-dependent kinase function, or nuclear trapping of CUG directed mRNA-binding proteins, is responsible for this alteration. Nonetheless, these mechanisms remain to be confirmed by molecular analysis of adrenocortical tissue obtained from MMD patients. Finally, our data suggest that the discordant secretion of AAs and glucocorticoids observed in many clinical conditions, notably adrenarche, may be secondary to alterations in ACTH postreceptor signaling and not to the existence of specific AA-stimulating factors.


   Footnotes
 
1 Current address: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. Back

Received March 19, 1998.

Revised May 19, 1998.

Accepted May 29, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Azziz R, Bradley Jr E, Huth J, 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.[Abstract]
  2. Avgerinos PC, Butler Jr, GB, Tsokos GC, et al. 1987 Dissociation between cortisol and adrenal androgen secretion in patients receiving alternate day prednisone therapy. J Clin Endocrinol Metab. 65:24–29.[Abstract]
  3. Parker Jr CR, Baxter CR. 1985 Divergence in adrenal steroid secretory pattern after thermal injury in adult patients. J Trauma. 25:508–510.[Medline]
  4. Lephart ED, Baxter CR, Parker Jr CR. 1987 Effect of burn trauma on adrenal and testicular steroid hormone production. J Clin Endocrinol Metab. 64:842–848.[Abstract]
  5. Azziz R. 1992 Hirsutism. In: Carpenter SE, Rock JA, eds. Pediatric and adolescent gynecology, New York: Raven Press; 239–266.
  6. Schiebinger RJ, Albertson BD, Cassorla FG, Bowyer DW, Geelhoed GW, Cutler Jr GB. 1981 The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase. J Clin Invest. 67:1177–1182.
  7. Grumbach MM, Richards GE, Conte FA, Kaplan SL. 1978 Clinical disorders of adrenal function and puberty: an assessment of the role of the adrenal cortex in normal and abnormal puberty in man and evidence for an ACTH-like pituitary adrenal androgen stimulating hormone. In: James VHT, Giusti Ms, Giusti G, Martini L, eds. The endocrine function of the human adrenal cortex, Proceedings of the Serono Symposia. New York: Academic Press; vol 18:583–612.
  8. Parker LN, Odell WD. 1980 Control of adrenal androgen secretion. Endocr Rev. 1:392–410.[Medline]
  9. Parker L, Lifrak E, Shively, et al. Human adrenal gland cortical androgen-stimulating hormone (CASH) is identical with a portion of the joining peptide of pituitary pro-opiomelanocortin (POMC) [Abstract 299]. Proc of the 71st Annual Meet of The Endocrine Soc. 1989.
  10. O’Connell Y, McKenna TJ, Cunningham SK. 1993 Effects of pro-opiomelanocortin-derived peptides on adrenal steroidogenesis in guinea-pig adrenal cells in vitro. J Steroid Biochem Mol Biol. 44:77–83.[CrossRef][Medline]
  11. Harris S, Moncrieff C, Johnson K. 1996 Myotonic dystrophy: will the real gene please step forward. Hum Mol Genet. 5:1417–1423.[Abstract]
  12. Fu Y-H, Pizzuti A, Fenwick RG, et al. 1992 An unstable triple repeat in a gene related to myotonic muscular dystrophy. Science. 255:1256–1258.[Abstract/Free Full Text]
  13. Brook JD, McCurragh ME, Harley HG, et. al. 1992 Molecular basis of myotonic dystrophy: expansion of trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 68:799–808.[CrossRef][Medline]
  14. Madadevan M, Tsilfidis C, Sabourin L, et al. 1992 Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science. 255:1253–1255.[Abstract/Free Full Text]
  15. Lavedan C, Hofmann-Radvnyi H, Shelbourne P, et al. 1993 Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am J Hum Genet. 52:875–883.[Medline]
  16. Jansen G, Mahadevan M, Amemiya C, et al. 1992 Characterization of the myotonic dystrophy region predicts multiple protein isoforms encoding mRNAs. Nat Genet. 1:261–266.[CrossRef][Medline]
  17. Takahashi S, Miyamoto A, Oki J, Okuno A. 1996 CTG trinucleotide repeat length and clinical expression in a family with myotonic dystrophy. Brain Dev. 18:127–130.[CrossRef][Medline]
  18. Jackson RV, Fleming GA, Sussman CR, et al. 1988 Increased pro-opiomelanocrtin-derived peptide release in myotonic dystrophy. Aust Pediatr J. [Suppl 1] 24:70–73.
  19. Grice JE, Jackson J, Hewett M, Penfold PJ, Jackson RV. 1991 Adrenocortico-tropin hyperresponsiveness in myotonic dystrophy following oral fenfluramine administration. J Neuroendocrinol. 3:69–73.
  20. Grice JE, Jackson RV, Hockings GI, Torpy DJ, Walters MM, Crosbie GV . 1995. Adrenocorticotropin hyperresponse to the corticotropin-releasing hormone-mediated stimulus of naloxone in patients with myotonic dystrophy. J Clin Endocrinol Metab. 80:179–184.
  21. Carter JN, Steinbeck KS . 1985. Reduced adrenal androgens in patients with myotonic dystrophy. J Clin Endocrinol Metab. 60:611–614.
  22. Zumoff B, Rosenfeld RS, Strain GW, Levin J, Fukushima DK. 1980 Sex differences in the twenty-four-hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults. J Clin Endocrinol Metab. 51:330–333.[Abstract]
  23. 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]
  24. Jackson RV, Grice JE, Jackson AJ, Hockings GI. 1990 Naloxone-induced ACTH release in man is inhibited by clonidine. Clin Exp Pharmicol Physiol. 17:179–184.
  25. Al-Damluji S. 1991 Measuring the activity of brain adrenergic receptors in man. J Endocrinol Invest. 14:245–254.[Medline]
  26. Grossman AE, Besser GM. 1982 Opiates control ACTH through a noradrenergic mechanism. Clin Endocrinol (Oxf). 17:287–290.[Medline]
  27. Torpy DJ, Grice JE, Hockings GI, Crosbie GV, Walters MM, Jackson RV. 1995 The effect of desipramine on basal and naloxone-stimulated cortisol secretion in humans: interaction of two drugs acting on noradrenergic control of adrenocorticotropin secretion. J Clin Endocrinol Metab. 80:802–806.[Abstract]
  28. Hockings GI, Grice JE, Walters MM, Crosbie GV, Torpy DJ, Jackson RV. 1995 A synergistic adrenocorticotropin response to naloxone and vasopressin in normal humans: evidence that naloxone stimulates endogenous corticotropin-releasing hormone. Neuroendocrinology. 61:198–206.[Medline]
  29. Parker LN, Odell WM. 1980 Control of adrenal androgen secretion. Endocr Rev. 1:392–410.
  30. Nicholson WE, Davis DR, Sherell BJ, Orth DN. 1984 Rapid radioimmunoassay for corticotropin in unextracted plasma. Clin Chem. 30:259–265.[Abstract]
  31. Murphy BEP. 1970 Methodological problems in competitive protein-binding techniques: the use of Sephadex column chromatography to separate steroids. Acta Endocrinol (Copenh). [Suppl] 147:37–60.
  32. Azziz R, Rittmaster RS, Fox LM, Bradley EL, Potter HD, Boots LR. 1998 The role of the ovary in the adrenal androgen excess of hyperandrogenic women. Fertil Steril. 69:851–859.[CrossRef][Medline]
  33. Scott NR, Chakraborty J, Marks V. 1988 Determination of prednisolone, prednisone, and cortisol in human plasma by high-performance liquid chromatography. Anal Biochem. 108:266–268.
  34. Tatro JB. 1996 Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. Neuroimmunomodulation. 3:259–284.[Medline]
  35. Hockings GI, Grice JE, Crosbie GV, Walters MM, Jackson RV. 1993 Altered hypothalamic-pituitary responsiveness in myotonic dystrophy: in vitro evidence for abnormal dihydropyridine insensitive calcium transport. J Clin Endocrinol Metab. 76:1433–1438.[Abstract]
  36. Kim YI, Neher E. 1988 IgG from patients with Lambert-Eaton syndrome blocks voltage-dependent calcium channels. Science. 239:405–408.[Abstract/Free Full Text]
  37. Fong P, Turner PR, Denetclaw WF, Steinhardt RA. 1990 Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin. Science. 250:673–676.[Abstract/Free Full Text]
  38. Morrone A, Pegoraro E, Angelini C, Zammarchi E, Marconi G, Hoffman EP. 1997 RNA metabolism in myotonic dystrophy. J Clin Invest. 99:1691–1698.[Medline]
  39. Wang J, Pegoraro E, Menegazzo E, et al. 1995. Myotonic dystrophy: evidence for a possible dominant negative RNA mutation. Hum Mol Genet. 4:599–606.
  40. Parker CR Jr, Mixon RL, Brissie RM, Grizzle WE. 1997 Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab. 82:3898–3901.[Abstract/Free Full Text]
  41. Lephart ED, Baxter CR, Parker Jr CR. 1987 Effect of burn trauma on adrenal and testicular steroid hormone production. J Clin Endocrinol Metab. 64:842–848.
  42. Wade CE, Lindberg JS, Cockrell JL, et al. 1988 Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients. J Clin Endocrinol Metab. 67:223–227.[Abstract]
  43. Zhang L, Rodriguez H, Ohino S, Miller W. 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.[Abstract/Free Full Text]
  44. Harper P, Penny R, Foley TP, et al. 1972 Gonadal function in males with myotonic dystrophy. J Clin Endocrinol Metab. 35:852–856.[Medline]
  45. Sagel J, Distiller LA, Morley JE, Isaacs H. 1975 Myotonia dystrophica: studies on gonadal function using luteinizing hormone-releasing hormone. J Clin Endocrinol Mtab. 40:1110–1113.[Abstract]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
A. Johansson, R. Andrew, H. Forsberg, K. Cederquist, B. R. Walker, and T. Olsson
Glucocorticoid Metabolism and Adrenocortical Reactivity to ACTH in Myotonic Dystrophy
J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4276 - 4283.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Johansson, K. Carlström, B. Ahrén, K. Cederquist, E. Krylborg, H. Forsberg, and T. Olsson
Abnormal Cytokine and Adrenocortical Hormone Regulation in Myotonic Dystrophy
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3169 - 3176.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Buyalos, R. P.
Right arrow Articles by Azziz, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Buyalos, R. P.
Right arrow Articles by Azziz, R.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
*Genetics Home Reference
Hazardous Substances DB
*HYDROCORTISONE
*NALOXONE
Medline Plus Health Information
*Muscular Dystrophy

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals