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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2720
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 93-97
Copyright © 2007 by The Endocrine Society

Parturition Itself Is the Basis for Fetal Adrenal Involution

Shlomit Ben-David1, Nehama Zuckerman-Levin1, Monica Epelman, Zila Shen-Orr, Moshe Levin, Polo Sujov and Ze’ev Hochberg

Department of Neonatology (S.B.-D., P.S.), Meyer Children’s Hospital, Haifa 31096, Israel; Division of Endocrinology (N.Z.-L., M.L., Z.H.), Meyer Children’s Hospital, Haifa 31096, Israel; Department of Radiology (M.E.), Rambam Medical Center, Haifa 31096, Israel; Endocrine Laboratory (Z.S.-O.), Rambam Medical Center, Haifa 31096, Israel; and Faculty of Medicine (P.S., Z.H.), Technion-Israel Institute of Technology, Haifa 31096, Israel

Address all correspondence and requests for reprints to: Nehama Zuckerman-Levin, M.D., Pediatric Endocrinology, Meyer Children’s Hospital, POB 9602, Haifa 31096, Israel. E-mail: zuckerln{at}netvision.net.il.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Newborn infants show a postnatal decline in androgen levels as the fetal adrenal glands involute.

Hypothesis: Placental factors up-regulate dehydroepiandrosterone sulfate (DHEA-S) generation. Hence, regardless of age, parturition will result in fetal adrenal involution and decline in DHEA-S levels.

Subjects and Methods: Premature neonates (n = 30) with gestational age 26–35 wk were studied. Adrenal volume by ultrasonography and serum DHEA-S, cortisol, and androstendione levels were followed weekly between d 1 and 28 of life.

Results: Serum DHEA-S was high on d 1 of life, declining rapidly regardless of gestational age during the first week of life (P < 0.001), and serum androstenedione and cortisol levels followed a similar pattern. Androstenedione levels showed a rise as of d 21 of life in boys but not in girls. The adrenals decreased in ultrasonographic volume from d 1 to 14 of life (P < 0.001), regardless of gestational age.

Conclusions: Involution of the adrenal is faster than previously reported and, regardless of gestational age, occurs within the first week of life in terms of hormone secretion and within 2 wk in adrenal size. Involution involves a decline in DHEA-S but also in androstenedione and cortisol secretion, with a change in enzymatic activity. Males and females differ in their androstenedione levels and enzymatic activity. Parturition itself is the basis for fetal adrenal involution, supporting a key role for placental factors in maintaining the fetal adrenal and generating adrenal androgens.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HUMAN FETAL adrenal is unique in its structure, anatomy, and function. Its cortex is composed of two morphologically distinct zones, the fetal zone and the definitive zone. The latter occupies 10–20% of the cortex, and its main secretory product is cortisol. The fetal zone, nearly 80–90% of adrenal cortex at term, secretes mainly androgens (1, 2). The synthesis and secretion of the fetal adrenal steroids is special for its massive production of {Delta}5 3ß-hydroxysteroids due to low 3ß-hydroxysteroid dehydrogenase (3ß-HSD) expression in the fetal zone (3, 4, 5, 6). In utero the generation of dehydroepiandrosterone (DHEA) parallels the increase in fetal size during the second and third trimester of pregnancy (7). At the end of a full pregnancy, DHEA/DHEA sulfate (DHEA-S) levels are high and are greater than adult blood levels. After birth, the fetal adrenals undergo involution, losing in a month 50% of their mass (1). Adrenal involution is followed by rapid decline in androgen secretion (8, 9, 10, 11).

The working hypotheses of the study were that if placental factors up-regulate adrenal androgens’ production, then parturition, regardless of age, would result in a rapid decline in neonatal DHEA-S levels. On the other hand, if fetal factors are the drive for fetal DHEA/DHEA-S generation, premature parturition would result in a delayed adrenal involution. Toward these hypotheses, the adrenal involution of 30 premature neonates was studied by means of hormone secretion and adrenal ultrasonography.


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

Thirty consecutive premature newborns (26–35 wk gestational age; 18 males and 12 females) were included in this prospective study (Table 1Go). The Helsinki Committees of the Rambam Medical Center and the Israel Ministry of Health approved the protocol, and parents signed informed consents. Eight infants were delivered by cesarean section, the others by spontaneous delivery. Subjects were excluded from the study if they had any of the following: massive intracranial bleeding, chromosomal or genetic aberrations, ambiguous genitalia, or abnormal thyroid function tests. Subjects were divided into three subgroups according to the following gestational ages: group A, 26–28 wk; B, 29–32 wk; C, 33–35 wk. Blood samples were taken in small volumes as part of routine blood tests in these patients.


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  		TABLE 1. Weight, height, and head circumference of the three study groups at birth

 
For each infant, we measured serum levels of adrenal hormones DHEA-S (micromoles per liter), cortisol and androstenedione (nanomoles per liter) at d 1, 7, 14, 21, and 28. To minimize the stress effect of parturition, samples were taken at least 12 h after birth.

Adrenal gland volume (cubic centimeters) by ultrasonography was measured in groups A and B at d 1, 7, 14, 21, and 28.

For a rough indirect estimation of 3ß-HSD, DHEA-S sulfotransferase, and sulfatase activity, we calculated the androstenedione/DHEA-S ratio, and for 17 hydroxylase activity, we calculated the androstenedione/cortisol ratio.

Methods

The volume of the adrenal gland was calculated according to the two-limb model as previously suggested (12), whereby each limb is assumed to be cylindrical, using the sagittal, axial, and coronal dimensions, and the calculated ultrasonographic volume is presented in cubic centimeters. The ultrasound scanner used a 5 MHz transducer (model SSD-1400; Aloka Co., Tokyo, Japan). Serum levels of cortisol and DHEA-S were measured by competitive immunoassays with the Immulite Analyzer (Diagnostic Products Corp., Los Angeles, CA). Androstenedione levels were measured by a double antibody RIA kit (Diagnostic Systems Laboratories, Webster, TX). Cross-reactivity of DHEA-S was 0.1% with androstenedione and less than 0.01% with cortisol. Cross-reactivity of cortisol with androstenedione and DHEA-S was less than 0.01%, and cross-reactivity of androstenedione was 0.04% with cortisol and less than 0.01% with DHEA-S.

Statistical methods

Statistical analysis used separate variance t-test. Differences were regarded significant with P values of less than 0.05.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go demonstrates the ultrasonographic volume of the adrenals (in cubic centimeters) for groups A and B. The adrenal volume decreased within the first 14 d of life by 50 and 75% in groups A and B, respectively, regardless of gestational age (P < 0.001).


Figure 1
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  		FIG. 1. Mean ultrasonographic adrenal volume in cubic centimeters for groups A (n = 7; 26–28 wk gestation) ({blacksquare}) and B (n = 8; 29–32 wk gestation) ({blacktriangleup}). SEM < 22% for each time point.

 
Figures 2Go, 3Go, and 4AGo present DHEA-S, cortisol, and androstenedione levels for each gestational age group from d 1–28. Serum DHEA-S was high on d 1 of life in all premature subjects and was falling sharply during the first week of life, regardless of gestational age. DHEA-S levels decreased by 88, 75, and 74% in groups A, B, and C, respectively (P < 0.001).


Figure 2
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  		FIG. 2. Mean DHEA-S levels (micromoles per liter) for groups A (n = 11; 26–28 wk), B (n = 11; 29–32 wk), and C (n = 8; 33–35 wk gestation). SEM < 28% for each time point. Shaded area, Normal adult reference values.

 

Figure 3
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  		FIG. 3. Mean cortisol levels (nanomoles per liter) for groups A (n = 11; 26–28 wk), B (n = 11; 29–32 wk), and C (n = 8; 33–35 wk gestation). SEM < 31% for each time point. Shaded area, Normal adult reference values.

 

Figure 4
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  		FIG. 4. A, Mean androstenedione levels (nanomoles per liter) for groups A (n = 11; 26–28 wk), B (n = 11; 29–32 wk), and C (n = 8; 33–35 wk gestation). SEM < 10% for each time point. Shaded area, Normal adult reference values. B, Androstenedione levels in boys (open bars) and girls (hatched bars) for all gestational ages (mean ± SEM). a, Significant difference between boys and girls (P < 0.014); b, significant difference between d 1 and 7 in boys (P < 0.0001); c, significant difference between d 14 and 28 in boys (P < 0.0012).

 
Serum cortisol declined in the same time period by 72, 75, and 82% in groups A, B, and C, respectively (P < 0.001).

Serum androstenedione levels followed a similar pattern, declining by 53, 68, and 80% in groups A, B, and C, respectively (P < 0.001), from d 1 to 7.

Androstenedione level showed a rise, as of d 21 of life, with a different pattern in male and female newborns (Fig. 4BGo). After a decrease in androstenedione levels on d 7 in both boys and girls (P < 0.0001), boys demonstrated a significant rise in androstenedione levels as of d 21 of life (P < 0.0012). Androstenedione levels in boys were higher than in girls in all postpartum days (P < 0.014).

Absolute levels and percent decrease of all three hormones did not correlate with gestational age.

When estimating enzyme activity, one has to consider the three orders of magnitude higher serum levels of DHEA-S compared with androstenedione and cortisol.

Figure 5Go shows that the androstenedione/DHEA-S ratio in boys increases from d 1 to 7 (P < 0.01), decreases from d 7 to 14 (P < 0.03), and increases from d 14 to 28 (P < 0.0004), whereas in girls this ratio decreases (P < 0.04). Ratios were higher in boys than in girls on d 21 and 28 postpartum (P < 0.01).


Figure 5
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  		FIG. 5. Mean androstenedione/DHEA-S ratio ({per thousand}) in boys (open bars) and girls (hatched bars) as a measure of 3ß-HSD, DHEA-S sulfotransferase, and sulfatase activity for all gestational ages (mean ± SEM). a, Significant difference between boys and girls (P < 0.01); b, significant difference between d 1 and 7 in boys (P < 0.01); c, significant difference between d 14 and 28 in boys (P < 0.0004); d, significant difference between d 7 and 14 in boys (P < 0.03); e, significant difference between d 14 and 28 in girls (P < 0.04).

 
Figure 6Go presents the androstenedione/cortisol ratio in boys, which was low until d 14 and rose until d 28 postpartum (P < 0.0001), whereas in girls the ratio was low and did not change. The ratio was higher in boys than in girls on d 28 postpartum (P < 0.001).


Figure 6
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  		FIG. 6. Mean androstenedione/cortisol ratio (%) in boys (open bars) and girls (hatched bars) as a measure of 17-hydroxylase activity for all gestational ages (mean ± SEM). a, Significant difference between boys and girls (P < 0.001); c, significant difference between d 14 and 28 in boys (P < 0.0001).

 

   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The fetal adrenal glands reach a weight of 4–5 g each at full term, and in relation to body weight they are about 20 times heavier than the adult glands (1). It was previously reported that on d 4 of life the adrenal looses 25% of its mass; at 1 month of age, it has lost 50%, and at 1 yr it has lost 75% of its birth mass (1). A decline in steroid secretion at birth is also well documented (1, 8, 9, 10, 11). It was suggested that in full-term infants the adrenal gland involutes more rapidly (13, 14). Results of this study show that within the first 2 wk of life, the large fetal adrenal shrinks to its normal infantile size. In terms of hormone secretion, steroid hormone levels drop even faster and within the first week of life.

This pattern of rapid involution was demonstrated in all neonates, regardless of their gestational age. The present findings disagree with previous reports that involution of the adrenal is related to gestational age rather than birth (15, 16). That study used urinary levels of 3ß-OH-5ene steroids as a measure of urinary fetal zone steroids and suggested that the fetal adrenals maintain high androgen levels for 3–4 wk after term. The urinary metabolites were inversely correlated to ACTH levels (16).

Measuring adrenal volume by ultrasonography bares a methodological difficulty, because the shape of the gland is multipart. We used a model based on a two-limb shape of the adrenal gland (12) and assumed each limb to be cylindrical. The width and length are in the same order as other reports of ultrasonographic adrenal size (12, 17), although it is hard to evaluate the precise anatomical size of the glands, and the ultrasonographic volumes given are meant for between-group and over-time comparison only.

Serum cortisol levels were within normal adult reference for 0800 h cortisol on d 1 and declined within 7 d, regardless of gestational age, confirming previous reports (18, 19). These documented cortisol levels are in accordance with a reference level of this age group and have to be considered in the context of infants under stress because involution of the fetal zone precedes the full development of the definitive zone (20, 21, 22).

Serum androstenedione levels paralleled the pattern of a rapid decrease of DHEA-S and cortisol but were followed in males only by an increase in androstenedione levels as of d 21 of life. This pattern of rise in male neonates is similar to that reported for testosterone (23), and it seems to be due to gonadal secretion. Gonads may also be responsible for the higher androstenedione levels in boys vs. girls after parturition. The data show an increase in the androstenedione/DHEA-S ratio, reflecting an increase in the combined activity of 3ß-HSD, DHEA-S sulfotransferase, and sulfatase. The latter is highly expressed in the placenta, and parturition eliminates this activity.

Indeed, low 3ß-HSD activity is characteristic of the fetal zone compared with the definitive zone cells (1). Lower activity of the enzymes on the first day of life reflects the disappearance of the placenta, and the later rise in boys demonstrates gonadal activity, seen in boys but not in girls.

We also show a rise in 17-hydroxylase activity during the same time period, which is noted more in boys. Fetal adrenal produces androgens due to increased 17-hydroxylase activity, enhanced by cytochrome b5 (24, 25). Parturition followed by adrenal involution involves a low 17-hydroxylase activity, which was demonstrated in our subjects. Rise in enzyme activity in boys is also connected to gonadal contribution.

Previous studies investigated the possible placental factors that maintain the fetal adrenal and might disappear at parturition. Coculture of placental tissue with ACTH-stimulated fetal adrenal cells demonstrated inhibition of cortisol production in the fetal adrenal (26). In vitro studies in human fetal adrenal cells (27, 28, 29) and in human adrenal microsomes (30) showed that estrogens inhibit adrenal 3ß-HSD activity. Indeed, fetal unconjugated levels of total estrogen (estrone, estradiol, and estriol) from the placenta dramatically rise from 17–20 wk gestation to term (31), and estrogen levels increase in direct correlation with the adrenal weight and the DHEA-S pool (32). A recent study in baboons questioned the role of estrogens in fetal adrenal zone development and suggested that estrogens act as a feedback system to control physiological secretion of estrogen precursors (33). Studies in vivo demonstrated that IGF-II of placental or adrenal origin is another possible regulator of fetal adrenal development and a mediator of ACTH action (34, 35). Increased placental CRH production at the end of gestation, together with various growth factors, may exert direct stimulation of fetal adrenal steroidogenesis (35, 36) and elevation of estrogen levels.

We conclude that parturition itself is the basis for fetal adrenal involution and for neonatal recovery of the definitive adrenal enzyme activity after birth.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online October 31, 2006

1 S.B.-D. and N.Z.-L. contributed equally to this work, and both are to be considered first authors. Back

Abbreviations: DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; 3ß-HSD, 3ß-hydroxysteroid dehydrogenase.

Received December 15, 2005.

Accepted October 23, 2006.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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