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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1164-1168
Copyright © 2004 by The Endocrine Society

The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome

David D. Martin, Roland Schweizer, C. Philipp Schwarze, Martin W. Elmlinger, Michael B. Ranke and Gerhard Binder

University Children’s Hospital, D-72076 Tuebingen, Germany

Address all correspondence and requests for reprints to: Dr. Gerhard Binder, Section of Pediatric Endocrinology, University Children’s Hospital, Hoppe Seyler Strasse 1, D-72076 Tuebingen, Germany. E-mail: gerhard.binder{at}med.uni-tuebingen.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Pubarche without thelarche has been taken as clinical evidence that adrenarche is independent of gonadarche in females. This study examines whether the course of adrenarche [rise of serum dehydroepiandrosterone sulfate (DHEAS)] and pubarche (Tanner stage PH2) is independent from ovarian function. Serum DHEAS levels (n = 867) were longitudinally measured in 111 girls with Turner syndrome between 1990 and 2002. Of these, 22 had spontaneous puberty onset (Tanner stage B2), and 45 had primary ovarian failure (POF). Serum DHEAS levels were assayed by chemiluminescence and compared with those of healthy girls (n = 322; age range, 3–17 yr in both groups). Between the ages of 7 and 17 yr, girls with Turner syndrome had significantly higher age-related DHEAS levels than normal girls (P <= 0.02). Moreover, in the 9- to 15-yr-old girls, DHEAS levels were significantly higher in girls with Turner syndrome and POF than in Turner syndrome girls with spontaneous puberty onset (P <= 0.02). This discrepancy was caused by an earlier adrenarche (DHEAS levels reaching 1.1 µmol/liter) in Turner syndrome girls with POF, which occurred at a median age of 8.3 yr (80% confidence interval, 6.5–10.4 yr) vs. 10.5 yr (8.6–12.2) and 11.0 yr (8.9–12.6) in Turner syndrome girls with spontaneous puberty onset and normal girls, respectively (P = 0.003). In contrast, pubarche was delayed in Turner syndrome girls with POF [median age, 13.0 yr (80% confidence interval, 10.6–15.0) vs. 11.9 yr (10.5–13.2) in Turner syndrome girls with spontaneous puberty onset (P = 0.02) and 11.6 yr (10.6–12.5) in normal girls]. Primary gonadal failure in Turner syndrome is associated with an earlier onset of adrenarche, but delayed pubarche. These data demonstrate that normal timing of adrenarche is dependent on gonadal function and suggest that normal pubarche is the clinical manifestation of the ovarian conversion of DHEAS to active androgens.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADRENARCHE, the "adrenal puberty," is characterized by an increase in adrenal 17-ketosteroid production beginning at the age of 8 yr (1). The indicator of this process is a characteristic rise in serum dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) (2). The mechanism that initiates adrenarche is not known (3). In the absence of ACTH, adrenarche does not occur (4). In contrast to healthy children, in whom adrenarche is followed by gonadarche, the "gonadal puberty," after about 2 yr a partial or complete dissociation between adrenarche and gonadarche has been observed in several endocrine disorders affecting the gonad or the adrenal gland (1, 2, 5, 6, 7, 8, 9, 10, 11). This led to the assumption that the processes are independent of each other. The most obvious clinical consequence of adrenarche in females is the growth of sexual hair, which is the leading sign in premature adrenarche and is likely to be caused by conversion of adrenal androgens to (dihydro-)testosterone in the periphery and the ovaries (12). The rise in serum DHEAS and the onset of sexual hair growth are usually synchronized (13); however, examples of dissociation have been observed (7, 9).

Girls with Turner syndrome provided the first human model in which adrenal puberty occurs without gonadal puberty (1). Serum DHEA(S) in Turner syndrome shows a wide spectrum, ranging from normal to highly elevated (5, 7, 8, 14, 15).

In the present study, 111 girls with Turner syndrome were grouped into those with spontaneous puberty onset due to preserved function of their ovaries and those without spontaneous puberty onset because of complete loss of ovarian function. The sequence of the serum DHEAS rise and pubarche in these two groups was significantly different. The dogma of the natural dissociation between adrenarche and gonadarche is revisited on the background of the presented data.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
For this study, 111 girls with Turner syndrome (age range, 3–17 yr) were studied longitudinally in our endocrine clinic between 1990 and 2002. Breast and pubic hair stages were evaluated according to Tanner by four experienced pediatric endocrinologists.

The girls with Turner syndrome were divided into those with spontaneous puberty onset (spontaneous puberty group) and those with complete primary ovarian failure (POF group). The definition chosen for spontaneous puberty onset was the development of breast stage B2 without estrogen replacement therapy before the age of 14 yr and no FSH level of 50 IU/liter or higher before thelarche. These two criteria were met by 22 girls with Turner syndrome. POF was defined by no spontaneous breast development and at least one FSH level of 50 IU/liter or higher before estrogen replacement therapy. These criteria were met by 45 girls with Turner syndrome. Estrogen replacement therapy was instituted in the POF group at a median age of 13.9 yr (range, 12.0–16.8 yr). The karyotypes of the two groups were generated from blood lymphocytes and are shown in Table 1Go.


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  		TABLE 1. Distribution of karyotypes in Turner syndrome girls with primary ovarian failure (POF group) and with spontaneous puberty onset (spontaneous puberty group)

 
The remaining 45 girls were still too young to be evaluated (27 cases), had serum FSH levels of 50 IU/liter or higher before spontaneous thelarche (eight cases), had no serum FSH levels of 50 IU/liter or higher before estrogen replacement therapy (five cases), or were excluded from the analysis because of anorexia nervosa, heterozygosity for congenital adrenal hyperplasia, celiac disease, or mixed gonadal dysgenesis (five cases).

Materials

Serum DHEAS, FSH, and LH were measured using an automated chemiluminescence assay system (Immulite, DPC Biermann GmbH, Germany). Inter- and intraassay coefficients ranged from 6.3–9.5% and 4.8–8.8% for DHEAS, 7.5–10.2% and 6.9–8.6% for FSH, and 6.1–8.7% and 5.5–7.7% for LH (16). For controls, serum samples from 322 healthy girls (age range, 3–17 yr) were used (16). Adrenarche was defined as the age at which DHEAS levels crossed the 1.1 µmol/liter threshold (2).

Statistics

Data are expressed as the median and 80% confidence interval unless otherwise stated. For analyses of age-related hormone level changes, eight groups were formed according to the age at which the sample was taken: 3–5, 5–7, 7–9, 9–11, 11–13, 13–15, and 15–17 yr. Statistical significance was assigned to P < 0.05 using Van der Waerden rank scores or unpaired two-tailed t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The age-related serum DHEAS levels were significantly higher in Turner syndrome girls than in controls between the ages of 7 and 17 yr (P = 0.02; 0.0001, <0.0001, <0.0001, and <0.0001 for each age group, respectively; Fig. 1Go). In addition, the POF group exhibited significantly higher age-related DHEAS levels than the spontaneous puberty group between the ages of 9–15 yr (P = 0.02; <0.0001 and <0.0001 for each age group, respectively; Fig. 1Go). This characteristic difference in DHEAS levels was caused by an earlier onset of adrenarche in the POF group (P = 0.003), with a median age of 8.3 yr compared with 10.5 yr in the spontaneous puberty group (Fig. 2Go). The normal girls had a median age of 11.0 yr at adrenarche (Fig. 2Go). The mean DHEAS levels correlated well with the mean FSH and LH levels in both Turner syndrome groups (P < 0.01; r2> 0.85) for the age groups between 5 and 17 yr (Fig. 3Go and Table 2Go).



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  		FIG. 1. Serum DHEAS levels (mean ± SD) for age in Turner syndrome girls with POF (n = 45), Turner syndrome girls with spontaneous puberty onset (n = 22), and normal girls (n = 47). {circ}, P <= 0.02 for the difference between POF group and spontaneous puberty group; *, P <= 0.02 for the difference from normal girls.

 


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  		FIG. 2. Age at adrenarche, pubarche, and thelarche in Turner syndrome girls with POF, Turner syndrome girls with spontaneous puberty onset, and normal girls (control group). Reference values for pubarche and thelarche were taken from the report by Buckler (17 ) (medians and 80% confidence intervals). The significance of differences in ages at adrenarche (*, P = 0.003) and pubarche (**, P = 0.02) between the POF group and the spontaneous puberty group are indicated.

 


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  		FIG. 3. Serum FSH (A) and LH (B) levels (mean ± SD) for age in Turner syndrome girls with POF (n = 45), Turner syndrome girls with spontaneous puberty onset (n = 22), and normal girls (n = 47). {circ}, P <= 0.02 for the difference between POF group and spontaneous puberty group; *, P <= 0.02 for the difference from normal girls.

 

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  		TABLE 2. DHEAS, FSH, and LH levels at Tanner stage PH2 (pubarche) in Turner syndrome girls with primary ovarian failure (POF group) and with spontaneous puberty onset (spontaneous puberty group)

 
Despite high DHEAS levels, pubarche was delayed in the POF group compared with the Turner syndrome girls with spontaneous puberty onset. Pubarche occurred more than 4.5 yr after adrenarche at a median age of 13.0 yr (P = 0.02; Fig. 2Go). In contrast, the spontaneous puberty group exhibited pubarche 1.4 yr after adrenarche at a median age of 11.9 yr. This was not significantly different from the published reference data on healthy girls reported by Buckler et al. (17) (Fig. 2Go). In addition, the timing of thelarche in the spontaneous puberty group did not differ significantly from the reference data (Fig. 2Go).

The discrepancy between adrenarche and pubarche was apparently based on the necessity for higher DHEAS levels for pubarche to occur in the POF group. For further analysis, we selected all hormone measurements performed at first presentation with PH2 (pubarche): serum DHEAS and FSH levels were available from 35 girls of the POF group and 16 girls of the spontaneous puberty group. At PH2, DHEAS levels in the girls of the POF group were, on the average, 1.8 times higher than those in the girls of the spontaneous puberty group (P < 0.0001; Table 2Go). Furthermore, between 6 and 8 yr of age, DHEAS levels were already more than 1.1 µmol/liter in eight of 10 POF girls for whom both DHEAS and FSH were available (26 samples), whereas FSH levels were only increased above 12 IU/liter in three of 10 girls (Fig. 4Go).



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  		FIG. 4. Between the ages of 6 and 8 yr, DHEAS levels were precociously elevated above 1.1 µmol/liter (adrenarche) in eight of the 10 Turner syndrome girls with POF for whom both DHEAS and FSH were available (26 samples). FSH levels above 12 IU/liter were present in only three of these 10 girls with Turner syndrome.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study examines the relationship among adrenarche, pubarche, and ovarian function in 111 Turner syndrome girls whose gonadal and adrenal maturation has been studied longitudinally. In the Turner syndrome girls with POF, a dramatic chronological dissociation with a very early serum DHEAS rise, the adrenarche, and a very late pubarche was observed. In contrast, Turner syndrome girls with remaining ovarian function had no early serum DHEAS rise and a normal age at pubarche. Serum DHEAS levels for age were elevated in the majority of Turner syndrome girls between ages of 7 and 17 yr, but this elevation was significantly milder or absent in girls with remaining ovarian function. Previous studies found a normal positive correlation between DHEA and DHEAS serum levels in Turner syndrome (5, 7, 18). Contradictory data were reported on the levels of these prohormones. Some investigators found normal levels (serum DHEA and DHEAS) (5, 7), and some observed elevated levels [total urinary DHEA (8) and serum DHEA (14, 15)], but the detailed data from all of these studies showed a wide spectrum of DHEA(S) levels, ranging from normal to high. The present data suggest that the discrepant results of these previous studies concerning DHEA(S) levels in Turner syndrome could be eluded if ovarian function is taken into account.

Pubarche has often been taken as the clinical sign of adrenarche, and therefore, the terms adrenarche and pubarche are frequently used synonymously (2, 8, 19, 20). However, a dissociation between pubarche and biochemically determined adrenarche can occur in girls with precocious puberty, who have pubarche long before adrenarche (7, 9). The opposite situation was reported in some girls with Turner syndrome (7). A late onset of pubarche with a slow progression of pubic hair growth can be extracted from the data of the only existing, cross-sectional, study on adrenarche and pubic hair stage in 22 Turner syndrome girls (8). Albright et al. (1) also reported late and sparse pubic hair in an observational study of 11 Turner syndrome girls. The present study of the relationship and timing of pubarche and adrenarche in Turner syndrome comprises by far the largest group of individuals longitudinally studied. Our data clearly indicate that adrenarche and pubarche are dissociated in girls with Turner syndrome who have POF. This phenomenon raises two questions. 1) What is the cause of the delay of pubarche after adrenarche in Turner syndrome girls with POF? 2) Why is the serum DHEAS rise of adrenarche so early in Turner syndrome girls with POF?

The growth of sexual hair in humans is prompted by activation of the testosterone receptor by ligands, of which testosterone and dihydrotestosterone are by far the most potent (21). Previous efforts to isolate a receptor for DHEA have failed (22). Therefore, the connection between the serum DHEAS rise and pubarche in females is thought to be indirect; the steroid sulfatase catalyzes the step from DHEAS to DHEA, which is metabolized further by the 3ß-hydroxysteroid dehydrogenase to androstenedione and by the 17ß-hydroxysteroid dehydrogenase to testosterone. These steps of DHEAS metabolism occur in peripheral tissues such as skin, fat, and muscle cells (12) as well as in the ovary (23). Our results suggest that the ovary plays a major role in the metabolism of adrenal DHEA to potent androgens during pubarche; the Turner syndrome girls with POF needed DHEAS levels 1.8 times higher than those of girls with functioning ovaries to develop pubarche. At this substrate level, the peripheral nonovarian conversion of DHEAS into testosterone may have reached the efficacy required for induction of pubarche. Interestingly, the early rise of DHEAS levels during childhood, which results in high DHEAS levels at puberty and adolescence, is transient and does not cause DHEAS excess in adult women with Turner syndrome. These women were reported to have normal serum levels of DHEAS, but had 25–40% reduced levels of testosterone and androstenedione in comparison with healthy controls (24). Therefore, in adult women with Turner syndrome the downstream conversion of DHEA to androgens in peripheral tissues may not fully compensate for the lack of ovarian enzymatic activity, but may enable a continuous normalization of DHEAS levels.

It is known that the development of adrenarche is related morphologically to the growth and differentiation of the zona reticularis and functionally to a high 17,20-lyase activity in the presence of a low 3ß-hydroxysteroid dehydrogenase activity, permitting 17-ketosteroid secretion to increase independently from cortisol secretion (2). A putative specific pituitary peptide that initiates adrenarche has not yet been identified. ACTH itself plays a permissive role, but it does not trigger adrenarche (4, 25). The hypothesis that gonadotropins are the principal promoters of adrenarche (1) has been challenged by several findings of dissociation between gonadotropins and DHEAS (5, 9, 19, 26, 27).

In this study, FSH and LH oversecretion correlated well with the elevated DHEAS levels in the girls with Turner syndrome. However, several girls exhibited the DHEAS rise earlier than the FSH or LH rise. Similarly, a recent study of very young girls with precocious puberty showed that chemical ablation of the ovaries by continuous administration of a LH-releasing hormone agonist was accompanied by early adrenarche, although gonadotropins were completely suppressed (28).

Our finding of the early DHEAS rise of adrenarche in Turner syndrome girls with POF is very likely to be caused by a missing ovarian factor that has a direct or indirect suppressive effect on adrenarche. We hypothesize that the ovary, which metabolizes DHEA to testosterone, provides some negative feedback mechanism to the adrenal gland regarding its up-regulation of DHEA production, which is more likely a gradual maturational process than an acute event (28). In the absence of ovarian function (POF), DHEA is converted into its active metabolites only in the periphery. This conversion is not as effective as in the ovary, which is illustrated by the weak effect of high DHEAS levels on pubarche. In practice, DHEAS measurement in girls with Turner syndrome between the ages of 6–8 yr may provide a sensitive tool for determining POF. In combination with FSH determination, the efficiency of this hormonal test may further increase.

In conclusion, primary gonadal failure in Turner syndrome is associated with an earlier onset of adrenarche, but delayed pubarche. This suggests a dependency of adrenarche on ovarian function; the regulation of adrenarche and the timing of pubarche require normal ovarian activity. Therefore, premature adrenarche (and pubarche) in otherwise healthy girls may be the first manifestation of a functional defect of the ovary rather than the adrenal gland.


   Footnotes
 
This study was supported by the Growth Research Center Tübingen (Pharmacia, Pfizer).

Abbreviations: DHEA, Dehydroepiandrosterone; DHEAS, DHEA sulfate; POF, primary ovarian failure.

Received September 30, 2003.

Accepted December 8, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Albright F, Smith P, Fraser R 1942 A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair. Am J Med Sci 204:625–648[CrossRef]
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