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Original Studies |
Departments of Pediatrics and Pediatric Endocrinology (N.U., D.C., R.D., F.M., K.P., S.O.), Pediatric Radiology (N.G., K.R.), and Urology (E.S.), New York University Medical Center, New York, New York 10016
Address all correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Department of Pediatric Endocrinology, New York University Medical Center, 550 First Avenue, New York, New York 10016.
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Abstract |
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We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation.
The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant’s hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy.
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Introduction |
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In the first 2 months of life, elevated estradiol values are also seen in female infants (1). An increase in ovarian follicular maturation, breast tissue enlargement, and even uterine bleeding have been observed during the early neonatal period, a time when the highest serum FSH and estradiol levels are seen (2). These findings probably represent the ovarian response to pituitary gonadotropins (3). It has been suggested that the more prolonged FSH elevation in females during infancy represents either a relative ovarian resistance to gonadotropin stimulation or a delay in the maturation of the feedback mechanism controlling gonadotropin secretion (3).
A delayed onset of genital bleeding has previously been reported in female infants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency during the neonatal period (4). It has been postulated that prolonged exposure to excessive adrenal androgens during fetal life followed by a rapid decline of these hormones postnatally with glucocorticoid treatment results in a more prolonged activation of the hypothalamic-pituitary-ovarian axis. Additionally, a greater increase in the responsiveness of internal genitalia to gonadotropins and sex hormones has been suggested to occur (4).
In this report we present a 3-month-old female infant with salt-wasting CAH due to 21-hydroxylase deficiency who had the onset of delayed menstrual bleeding with a large ovarian cyst. The possible mechanisms of this occurrence are discussed.
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Materials and Methods |
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and
Figs. 1–3)
The infant was a full-term 2860-g 46,XX product of a normal
vaginal delivery. At birth, she was noted to have clitoromegaly, a
single perineal orifice, and hyperpigmentation of the labia majora. A
pelvic sonogram during the newborn period revealed the presence of a
uterus without visualization of adnexal structures. The diagnosis of
congenital adrenal hyperplasia due to 21-hydroxylase deficiency was
made based on the 17-hydroxyprogesterone level on day 1 of life
(>14,000 ng/dL), with a serum testosterone level of 530 ng/dL and a
dehydroepiandrosterone sulfate level of 390 µg/dL. Treatment with
hydrocortisone was initiated on day 1, and due to evidence of salt
wasting (continued weight loss, serum Na of 133 mEq/L, serum K of 7.0
mEq/L, and PRA of 195 ng/mL/h), treatment with
9
-fluorohydrocortisone and sodium chloride was initiated on day 11
of life. Suppression of adrenal androgen precursors was achieved on day
17 (17-hydroxyprogesterone, 36 ng/dL; testosterone, 5 ng/dL;
androstenedione, 21 ng/dL; PRA, 1.45 ng/mL·h; Na, 140 mEq/L; K, 5.5
mEq/L; levels obtained about 6 h after the morning dose of
hydrocortisone) The infant was maintained on hydrocortisone (2.5 mg
every 8 h), 9-fluorohydrocortisone (0.15 mg once daily), and
sodium chloride (500 mg every 6 h).
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A pelvic ultrasound revealed the presence of a right ovary with a
dominant 3-cm cyst in the right lower quadrant, a stimulated uterus,
and a fluid/debris-filled vaginal cavity (Fig. 1
). A computed
tomography (CT) scan performed the following day demonstrated that the
cyst had an enhancing rim of tissue, suggesting that it most likely
represented an ovary (Fig. 2). A magnetic
resonance imaging (MR) examination performed 3 days later showed a
stimulated uterus measuring 4 cm in length (Fig. 3). In the right lower quadrant, small
cysts adjacent to the dominant cyst confirmed the presence of a
stimulated right ovary. To assess the activity of the
hypothalamic-pituitary-ovarian axis, a GnRH stimulation test was
performed. The results are presented in Table 1. At this time, the
17-hydroxyprogesterone level was 359 ng/dL, and the androstenedione
level was 26 ng/dL.
On the fifth hospitalization day, the infant was noted to have bilateral breast buds, with glandular tissue measuring 0.75 cm on the right side and 0.5 cm on the left side. She continued to have scant vaginal bleeding for a total of 12 days. During a follow-up visit on day 102 of life, she had smaller breast buds, measuring less than 0.5 cm bilaterally, and the vaginal bleeding had resolved. Serum hormone measurements at that time revealed a persistently elevated estradiol level of 8.2 ng/dL, with a FSH level of 10.0 mIU/mL and a LH level of 0.64 mIU/mL.
On day 109 of life, the infant still had palpable breast buds,
measuring less than 0.5 cm bilaterally, and was thriving. The GnRH
stimulation test was repeated (see Table 1). Serum
17-hydroxyprogesterone was 62 ng/dL, and testosterone was less than 3
ng/dL. Pelvic sonogram performed on the same day revealed the uterus to
measure 3.8 cm in length, with an identifiable endometrial echo. The
right ovary was smaller and now measured 2.2 x 1.4 x 1.5 cm
and contained multiple cysts. However, the dominant cyst was no longer
seen. The left ovary was not definitively identified. Apart from
minimal spotting on one diaper on day 114 of life, she had no more
episodes of vaginal bleeding.
Three weeks after cessation of the vaginal bleeding, on day 127 of life, a follow-up pelvic sonogram was performed, and the uterus was noted to have decreased in size and now measured 2.4 cm in length, with the fundus being smaller than the cervix. An endometrial echo was again visible, but the ovaries were not definitively visualized, consistent with nonstimulated pelvic organs.
Two months after the initial bleeding, the infant had barely palpable
breast buds. Examination was otherwise unremarkable. Endocrine
evaluation revealed estradiol of 1.7 ng/dL, FSH of 17 mIU/mL, and LH of
0.5 mIU/mL. At 7 months of age, or 4 months after her bleeding, breast
tissue was no longer present, and her examination was completely
prepubertal. Fourteen months after her initial bleeding episode, she
remains prepubertal on physical examination. A random serum estradiol
measurement was less than 0.5 ng/dL. She continues to receive treatment
with hydrocortisone (2.5 mg every 8 h), 9-fluorohydrocortisone
(0.15 mg daily), and sodium chloride (2 g daily).
17-Hydroxyprogesterone and testosterone were measured by minor modification of previously described standard RIA methods after column extraction with Celite by the Pediatric Endocrine Laboratory of New York University-Bellevue Hospital Center or Endocrine Sciences (Calabasas Hills, CA).
Androstenedione, estradiol, and PRA were measured by RIA, and FSH and LH were determined by immunochemiluminometric assay (ICMA) at Endocrine Sciences Laboratories.
Sequential pelvic ultrasonography was performed and interpreted by the same pediatric radiologists (N.G. and K.R.).
The GnRH stimulation test was performed using Factrel (gonadorelin hydrochloride, Ayerst Laboratories, Philadelphia, PA; 100 µg/m2 given as an iv bolus over 2 min). FSH and LH levels were determined before and 30, 60, and on one occasion 90 min after the administration of Factrel.
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Results |
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As stated, at the time of the initial bleeding (day 88 of life), our patient demonstrated hormone levels consistent with reasonable control of her 21-hydroxylase deficiency. She did not have a significant maternal estrogen effect at birth, as evidenced by the lack of breast buds during the neonatal period. On day 70 a random estradiol measurement was 1.0 ng/dL. However, on day 90, 2 days after the onset of vaginal bleeding, her estradiol had risen to 5.6 ng/dL, with further increases to 6.5 and 8.2 ng/dL on days 95 and 102, respectively, when breast buds were conspicuous. On day 109, 1 week after vaginal bleeding had resolved, estradiol was declining, and by day 151 it reached a level of 1.7 ng/dL, or only slightly higher than expected for age.
A GnRH stimulation test on day 90 at the onset of bleeding demonstrated
a maximal FSH response to 26 mIU/mL (
FSH, 19.2) and of LH to 6.7
mIU/mL ( LH, 6.02), with a ratio of FSH to LH of 3.19. A
second GnRH stimulation test on day 109, 1 week after bleeding had
stopped, demonstrated more pronounced FSH and LH responses. The maximal
FSH response was 69 mIU/mL ( FSH, 59), and the maximal LH response
was 21 mIU/mL (, LH 20.3), but the FSH to LH ratio remained
essentially the same at 2.9.
Pelvic imaging studies
Pelvic ultrasound was performed on day 88 (Fig. 1), CT on day 89
(Fig. 2), and MR on day 92 (Fig. 3). They demonstrated a stimulated
uterus with a prominent endometrial echo, measuring approximately 2.5
mm in the antero-posterior direction, a fluid- and debris-filled
vagina, and a stimulated right ovary with a dominant 3-cm cyst. (MR was
helpful, in that the small cysts confirming the presence of ovarian
tissue were not appreciated on either the ultrasound or the CT.) A
follow-up ultrasound on day 109 (not shown) demonstrated the uterus and
ovary to be less prominent, and the dominant cyst was no longer
identified. A follow-up study on day 127 (not shown) failed to
visualize either ovary, consistent with pelvic organs in a
nonstimulated state.
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Discussion |
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As at the time of the initial vaginal bleeding on day 88 of life, our patient demonstrated a hormonal profile consistent with good metabolic control of her 21-hydroxylase deficiency, the source of her estrogens was probably not due to peripheral conversion of adrenal androgens. On the third day of the bleeding, serum estradiol was elevated, and the GnRH stimulation test demonstrated a brisk response to both FSH and LH, while maintaining the early infantile, albeit exaggerated, pattern of FSH predominance. We acknowledge that no data are currently available for GnRH-induced FSH and LH levels by ICMA in this age group. However, we suggest that the response indeed mimicked the pattern observed in prepubertal infants (Reiter, E., personal communication).
When related temporally to the initial sonographic findings of multiple small cysts and a single large dominant cyst in the right ovary, the clinical course indicates an ovarian response to exaggerated pituitary gonadotropin activity. At the time that breast development was noted, serum estradiol was continuing to rise; it reached a maximum level 2 weeks after the onset of uterine bleeding and declined thereafter. A reduction in the size of the ovary with nonvisualization of the dominant cyst and a regression of breast size followed the decline in estradiol levels. Indeed, 14 months after the bleeding episode, she remains prepubertal with estradiol levels below 0.5 ng/dL. A repeat GnRH test demonstrated the preservation of FSH predominance while maintaining brisk responses to both FSH and LH. This is in keeping with the previous observation of the maintenance of the sex dichotomy of FSH secretion in response to GnRH in patients with CAH despite exposure of the females to excessive androgens during the intrauterine and neonatal periods (10).
In contrast to the findings of our report, elevated basal serum LH levels were recently reported in female infants with 21-hydroxylase deficiency during the first 3 months of life after treatment with hydrocortisone; the LH levels were similar to those observed in control infant males. The researchers suggested that the elevated basal LH levels in their treated female infants represented a reversal of the normal sex dichotomy. We are unable to adequately compare these reported findings (11) to those in our infant inasmuch as the assays used were different (immunoenzymoassay vs. ICMA), and the FSH and LH responses to GnRH were not assessed.
Additionally, the roles of FSH and LH in fetal ovarian maturation are currently under investigation (12, 13). In fetal pigs, lower levels of FSH and LH receptor concentrations have been demonstrated in the ovaries compared to those in the fetal testes (13). It has been suggested that this dichotomous finding is responsible for the relative lack of fetal ovarian growth compared to fetal testicular growth. Further, for both sexes an inverse correlation has been observed between fetal gonadotropin levels and fetal gonadal receptors, i.e. elevated gonadotropin levels appear to down-regulate gonadal gonadotropin receptors. We suggest that these gonadotropin receptor-mediated events may account for the previously reported phenomenon of the relative resistance of infant ovaries to gonadotropin stimulation.
We extrapolate from the animal model that in our patient, the suppression of pituitary gonadotropin by elevated androgens during fetal life prevented the occurrence of down-regulation of the ovarian gonadotropin receptors. We suggest further that the glucocorticoid treatment-mediated androgen suppression led to a marked rise in gonadotropin levels, resulting in significant stimulation of the existing ovarian gonadotropin receptors. Growth of the ovarian follicles and estrogen secretion subsequently occurred and manifested clinically as thelarche and endometrial bleeding. Further studies of the ontogeny of fetal gonadal development in humans are needed to allow better understanding of our patient’s findings.
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Acknowledgments |
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Received September 20, 1996.
Revised February 24, 1997.
Revised June 6, 1997.
Accepted June 11, 1997.
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References |
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