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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4602-4606
Copyright © 1999 by The Endocrine Society

Original Studies

Corticotropin-Releasing Hormone: A Potent Androgen Secretagogue in Girls with Hyperandrogenism after Precocious Pubarche1

Lourdes Ibáñez, Neus Potau, Maria Victoria Marcos and Francis de Zegher

Endocrinology Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Hormonal Laboratory (N.P.), Hospital Materno-Infantil Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain; Consorci Hospitalari de Terrassa (M.V.M.), Barcelona, Spain; and Department of Pediatrics (F.d.Z.), University of Leuven, Leuven, Belgium

Address correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: lourdes.ibanez{at}deinfo.es


   Abstract
Top
 Abstract
Introduction
 Study Population and Methods
 Results
 Discussion
 References
 
CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge.

In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist.

Within a randomized cross-over design, saline or CRH (human CRH 1 µg/kg·h in saline) was infused over 3-h (1100–1400 h) into 12 adolescent girls (age 17 ± 2 yr; body mass index 21.4 ± 0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 µg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h.

ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold during CRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH.

In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.


   Introduction
Top
 Abstract
 Introduction
Study Population and Methods
 Results
 Discussion
 References
 
ORIGINALLY isolated from the ovine hypothalamus, CRH is now known to be a key regulator of the hypothalamic-pituitary-adrenal axis (1).

CRH and its binding sites are widely distributed in extrahypothalamic areas of the brain and in a series of other tissues, including the gonads and the fetal adrenal gland (2, 3, 4, 5, 6, 7, 8, 9, 10). In vitro, CRH was found to be capable of modulating gonadal steroidogenesis, including inhibition of estrogen production by rat and human granulosa cells (4, 5, 7), suggesting that this neuropeptide may also act as a paracrine or autocrine regulator of androgen biosynthesis.

CRH may be one of the factors participating in the pathogenesis of hyperandrogenism in women. The amount of CRH present in polycystic ovaries was found to be decreased (8). Furthermore, CRH was documented to exert a potent inhibitory effect on LH-stimulated dehydroepiandrosterone (DHEA) and androstenedione production by isolated human thecal cells, presumably by reducing the ovarian expression of CYP17, the gene encoding for cytochrome P450c17 (11).

Adrenarche is governed by a dual control mechanism in which an adrenal androgen secretagogue is thought to act on a zona reticularis primed by ACTH (12, 13, 14). CRH receptors are present in the human fetal adrenal, which shares many characteristics with the androgen-producing zona reticularis, and CRH is a potent direct secretagogue for adrenal androgens in men, a finding suggesting that CRH may be a key regulator of adrenarche (10, 15).

Pronounced adrenarche with precocious pubarche (PP) in girls [defined as the appearance of pubic hair before 8 yr of age (16)] has been associated with reduced fetal growth, hyperinsulinism, and low insulin-like growth factor binding-protein-1, dyslipidemia, anovulation, and ovarian hyperandrogenism (OH) (17, 18, 19, 20, 21), the latter being characterized by symptoms and signs of androgen excess and by an exaggerated ovarian 17-hydroxyprogesterone (17-OHP) response to a challenge with GnRH agonist (22).

In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist.


   Study Population and Methods
Top
 Abstract
 Introduction
 Study Population and Methods
Results
 Discussion
 References
 
Study population

Adolescent girls (n = 12; age 17.0 ± 1.9 yr; age range, 14–21 yr) with a history of PP were studied (Table 1Go). PP was attributed to exaggerated adrenarche; all girls presented with elevated androstenedione and/or DHEA-sulfate (DHEAS) levels at prepubertal PP diagnosis (16). All girls were at least 3 yr beyond menarche and presented with oligomenorrhea (irregular cycles of >45 days duration) or amenorrhea, hirsutism [indicated by a score of 8 or more in the Ferriman and Gallwey scale (23)], elevated baseline serum androstenedione, total testosterone and/or free androgen index [testosterone x 100/sex hormone-binding globulin (SHBG)], and increased mean serum insulin (MSI) levels (>84 mU/L) after a standard oral glucose tolerance test (oGTT) (19).


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  		Table 1. Clinical characteristics of the study population (n = 12)

 
None of the girls presented evidence suggestive of thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia, diabetes mellitus or glucose intolerance (24), or nonclassic adrenal hyperplasia (25, 26); none had a body mass index more than 26 Kg/m2 or had received steroid medication during the preceding 6 months. Clinical characteristics, baseline androgen, and MSI levels after oGTT are summarized in Table 1Go. Girls were studied either during the follicular phase of the menstrual cycle or at random after at least 3 months of amenorrhea (without evidence of pregnancy).

The study protocol was approved by the Institutional Review Board of the Barcelona Hospital. Written informed consent was obtained prior to study start.

Methods

As summarized in Fig. 1Go, the study was performed according to a randomized, cross-over design, there being 4–8 weeks between study sessions for each subject. Baseline blood samples (time 0) were obtained at 0800 h after dexamethasone pretreatment (1 mg at midnight) and before administration of a GnRH agonist (500 µg leuprolide acetate sc; Procrin, Abbott, Madrid, Spain). Three hours after baseline, either saline or human CRH in saline was infused (CRH 1 µg/kg·h iv) for 3 h.



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  		Figure 1. Study design. Either saline or human CRH in saline was infused (1 µg/Kg·h iv for 3 h) starting 3 h after GnRH agonist administration (leuprolide acetate, 500 µg sc at time 0). All girls were pretreated with dexamethasone (1 mg po) about 8 h before time 0.

 
Serum LH, FSH, cortisol, androstenedione, DHEA and DHEAS were measured at 0, 3, 6, and 24 h; serum ACTH and 17-OHP were determined at 0, 6, and 24 h, and testosterone and estradiol were measured before and 24 h after GnRH agonist administration. Previous studies have provided evidence that maximal pituitary and gonadal responses to GnRH agonist occur respectively, around 3 and 24 h after administration; a 17-OHP increment more than 160 ng/dL has been defined as a hyperresponse (18, 27).

Hormone assays and statistics

Before ACTH measurement, blood samples were placed into prechilled tubes containing ethylenediaminetetraacetate, processed on ice, immediately centrifuged at cold temperature, and frozen. ACTH and DHEAS were determined by a solid-phase, two-site chemiluminiscent enzyme immunometric assay using an Immulite Automated analyzer; the intra- and interassay coefficients of variation (CV) were 6.1% and 8.3% and 8.1% and 13%, respectively. The sensitivity of the ACTH assay was 10 pg/mL. DHEA was assayed using a tritiated kit (ICN Biomedical Inc., Carson, CA). The intra- and interassay CV were 7% and 14%, respectively. Cortisol was measured by RIA (Immunotech, France). The intra- and interassay CV were 6.5% and 6.9%, respectively. LH and FSH were measured using a commercially available microparticle enzyme immunoassay (IMX System, Abbott, Chicago, IL). The intra- and interassay CV were 3.0% and 5.4%, respectively, for LH and 4.1% and 6.9%, respectively, for FSH. Serum 17-OHP, androstenedione, testosterone, estradiol, and SHBG levels were measured by RIA, as described (19).

Results are expressed as mean ± SEM, unless stated otherwise. The Mann-Whitney test was used for statistical comparisons (significance at P < 0.05).


   Results
Top
 Abstract
 Introduction
 Study Population and Methods
 Results
Discussion
 References
 
ACTH concentrations after saline or CRH were all below 45 pg/mL (10 pmol/L); median ACTH concentrations (interquartile ranges) were, respectively, less than or equal to 10 (<=10–12.4) and 24.4 (15.0–32.8) pg/mL. Neither saline nor human CRH infusion evoked significant increases in 17-OHP levels. Median values and interquartile ranges for cortisol were all below 1 µg/dL (<27.6 mmol/L) at baseline and after saline infusion and were no more than 22.8 µg/dL [range, 17.7–26.1 µg/dL (488–720 nmol/L)] after 3 h of CRH infusion.

Table 2Go summarizes the LH and FSH responses to GnRH agonist. The responses were not detectably affected by CRH infusion (data not shown); accordingly, individual results obtained in the two study sessions were averaged.


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  		Table 2. Serum LH and FSH concentrations (medians and interquartiles) before (time 0) and after GnRH agonist administration (3, 6, and 24 hr). At each point in time, individual values (n=12) are averages of concentrations measured in two study sessions (one with saline and one with human CRH infusion).

 
Figs. 2Go and 3Go depict the increments in the serum concentrations of DHEAS, androstenedione, and DHEA elicited by the infusion of CRH vs. saline (all P < 0.0001). Relative increments during CRH vs. saline infusion averaged, respectively, 46% vs. -3% for DHEAS, 176% vs. 10% for androstenedione, and 560% vs. 40% for DHEA.



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  		Figure 2. Average changes in serum concentrations of DHEAS, androstenedione, and DHEA after administration of a GnRH agonist at time 0 and during infusion of either saline (CRH-) or hCRH (CRH+) into 12 hyperandrogenic adolescent girls with a history of PP.

 


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  		Figure 3. Relative changes (medians and interquartiles) in serum concentrations of DHEAS, androstenedione, and DHEA between start and end of a 3-h infusion with either saline (CRH-) or human CRH in saline (CRH+) into hyperandrogenic adolescent girls with a history of PP.

 
As shown in Table 3Go, the infusion of CRH failed to exert a detectable effect on the steroid responses to GnRH agonist. Five of the 12 adolescents displayed a 17-OHP hyperresponse to GnRH agonist, suggestive of OH.


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  		Table 3. Median and interquartile serum steroid concentrations before and 24 h after sc GnRH agonist administration in girls infused with saline (CRH-) or human CRH (CRH+) between 3 and 6 h after GnRH agonist injection. CRH had no significant effect

 

   Discussion
Top
 Abstract
 Introduction
 Study Population and Methods
 Results
 Discussion
References
 
CRH infusion into hyperandrogenic girls, who had been pretreated with dexamethasone, was found to produce a modest rise in serum ACTH, followed by a consistent increment of cortisol (with no significant changes in 17-OHP) and a striking increase in DHEA, DHEAS, and androstenedione. These marked adrenal steroid responses are unlikely to be solely attributable to the observed ACTH rises (28, 29, 30). The present results extend the immediate CRH effects on adrenal androgen release that have recently been documented in healthy, young men (15) and they corroborate CRH as candidate for the endogenous role of adjuvant adrenal androgen secretagogue.

The origin of the endogenous CRH, hypothesized to be physiologically involved, is currently unknown, as is the mechanism whereby CRH seems to stimulate adrenal androgen release. The presence of CRH receptors in the zona reticularis has, up to this time, not been explored. The zona reticularis develops at the interface of adrenal cortex and medulla (12). Adrenomedullary chromaffin cells are present in all zones of the adult adrenal cortex and have recently been shown to secrete CRH and ACTH, among other neuropeptides (31). Recent in vitro studies have provided direct evidence for paracrine and juxtacrine interactions between the two cell types [i.e. secretory products from chromaffin cells are potent stimulators of adrenocortical steroidogenesis (32)]. It is conceivable that the principal source of CRH at the time of adrenarche is the adrenal medulla. Whereas CRH and ACTH are coupled in sequence at the hypothalamic-pituitary level, they may be coupled in parallel within the zona reticularis.

In the present study paradigm, CRH failed to detectably affect the gonadotropin and ovarian steroid responses to GnRH agonist. Previous studies indicated that ovine or human CRH infusions were capable of attenuating LH secretion in women, monkeys and rats through modulation of GnRH release into the pituitary circulation (33, 34, 35). Besides the anterior pituitary, the adrenal zona reticularis, rather than the ovary, seems to be the primary target for circulating CRH.

In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to stimulation with gonadotropins.


   Acknowledgments
 
We thank Dr. Eric Mehuys (Ferring, Belgium) for the gift of CRH and Ms. Karin Vanweser, R.N., for editorial assistance. F.d.Z. is a Clinical Research Investigator, Fund for Scientific Research (Flanders, Belgium).


   Footnotes
 
1 Supported by a scholarship from the European Society for Paediatric Endocrinology. Back

Received August 12, 1999.

Revised October 4, 1999.

Accepted October 4, 1999.


   References
Top
 Abstract
 Introduction
 Study Population and Methods
 Results
 Discussion
 References
 

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