0021-972X/97/$03.00/0 Vol. 82, No.

10
Journal of Clinical Endocrinology and Metabolism Printed in U.S.A.
Copyright © 1997 by The Endocrine Society

Menstrual Bleeding in a Female Infant with Congenital

Adrenal Hyperplasia: Altered Maturation of the
Hypothalamic-Pituitary-Ovarian Axis
NAVEEN ULI, DAISY CHIN, RAPHAEL DAVID, NANCY GENEISER,
KEVIN ROCHE, FLAVIA MARINO, ELLEN SHAPIRO, KRIS PRASAD,

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AND SHARON OBERFIELD

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

ABSTRACT ultrasound demonstrated a marked decrease in the size of the right

Vaginal bleeding during the neonatal period is commonly related ovary, and the dominant cyst was no longer seen. The patient had a
to the withdrawal of maternal estrogens. Vaginal bleeding has also heightened FSH response to GnRH and elevated levels of estradiol for
been reported in female infants with congenital adrenal hyperplasia age. At 5 months of age, no further episodes of sustained vaginal
and has been proposed to be due to a treatment-induced activation of bleeding were observed. Repeat hormonal levels were prepubertal,
the hypothalamic-pituitary-ovarian axis. and pelvic sonogram demonstrated no evidence of stimulation.
We report a female infant with the salt-losing form of congenital The findings in our patient suggest that a decline in adrenal an-
adrenal hyperplasia due to 21-hydroxylase deficiency, who had the drogens after glucocorticoid treatment resulted in an increase in go-
onset of vaginal bleeding at 3 months of life. Adrenal steroid sup- nadotropin levels, which then triggered a transient and augmented
pression had been achieved by 2.5 weeks of age. At the time of bleed- end-organ response (menses). Further, we suggest that our infant’s
ing, imaging studies revealed an enlarged right ovary with a domi- hormonal findings may reflect a delay in the timely development of
nant 3-cm cyst and additional small cysts that had not been seen on the negative restraint by sex steroids on gonadotropins that is nor-
the newborn sonogram. The uterus was enlarged and stimulated. mally observed in infancy. (J Clin Endocrinol Metab 82: 3298 –3302,
Three weeks later (1 week after the cessation of bleeding), repeat 1997)

G ONADOTROPIN secretion patterns differ in males and

females during early infancy. In females, FSH rises
earlier and LH rises later than in males. The rise in FSH is
plasia (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
considerably greater in females than in males. Normally followed by a rapid decline of these hormones postnatally
thereafter, as the hypothalamic-pituitary unit matures, in- with glucocorticoid treatment results in a more prolonged
creasing sensitivity to the negative feedback of gonadal ste- activation of the hypothalamic-pituitary-ovarian axis. Addi-
roids is associated with a decline in gonadotropin levels. This tionally, a greater increase in the responsiveness of internal
state is usually maintained until the onset of puberty. genitalia to gonadotropins and sex hormones has been sug-
In the first 2 months of life, elevated estradiol values are gested to occur (4).
also seen in female infants (1). An increase in ovarian fol- In this report we present a 3-month-old female infant with
licular maturation, breast tissue enlargement, and even uter- salt-wasting CAH due to 21-hydroxylase deficiency who had
ine bleeding have been observed during the early neonatal the onset of delayed menstrual bleeding with a large ovarian
period, a time when the highest serum FSH and estradiol cyst. The possible mechanisms of this occurrence are
levels are seen (2). These findings probably represent the discussed.
ovarian response to pituitary gonadotropins (3). It has been
suggested that the more prolonged FSH elevation in females Materials and Methods
during infancy represents either a relative ovarian resistance Case report (Table 1 and Figs. 1–3)
to gonadotropin stimulation or a delay in the maturation of
The infant was a full-term 2860-g 46,XX product of a normal vaginal
the feedback mechanism controlling gonadotropin secretion delivery. At birth, she was noted to have clitoromegaly, a single perineal
(3). orifice, and hyperpigmentation of the labia majora. A pelvic sonogram
A delayed onset of genital bleeding has previously been during the newborn period revealed the presence of a uterus without
reported in female infants with congenital adrenal hyper- 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
Received September 20, 1996. Revision received February 24, 1997. serum testosterone level of 530 ng/dL and a dehydroepiandrosterone
Rerevision received June 6, 1997. Accepted June 11, 1997. sulfate level of 390 mg/dL. Treatment with hydrocortisone was initiated
Address all correspondence and requests for reprints to: Sharon E. on day 1, and due to evidence of salt wasting (continued weight loss,
Oberfield, M.D., Department of Pediatric Endocrinology, New York serum Na of 133 mEq/L, serum K of 7.0 mEq/L, and PRA of 195
University Medical Center, 550 First Avenue, New York, New York ng/mL/h), treatment with 9a-fluorohydrocortisone and sodium chlo-
10016. ride was initiated on day 11 of life. Suppression of adrenal androgen

3298
 MENSTRUAL BLEEDING IN AN INFANT WITH CAH 3299

TABLE 1. Sequential serum estradiol, FSH/LH, and FSH/LH response to GnRH stimulation

Day of life: 70 90 95 102 109 151 528

Postbleed 2 Postbleed, Postbleed, Postbleed
Clinical findings: Prebleed Day 3 of bleed Day 8 of bleed
days 1 week 2 months 14 months
Time (min): Random 0/30/60/90 Random Random 0/30/60 Random Random
Estradiol (ng/dL) 1.0 5.6 6.5 8.2 4.9 1.7 ,0.5
FSH (mIU/mL) 6.8/20/26/23 10 10/62/69 17
LH (mIU/mL) 0.68/6.7/5.3/4.4 0.64 0.66/21/14 0.5
DFSH 19.2 59
DLH 6.02 20.3
DFSH/DLH 3.19 2.9

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FIG. 1. Midline longitudinal (A) and
transverse (B) ultrasound images show
prominence of the lower uterine seg-
ment/cervix, with fluid in the vagina.
An endometrial echo is identified on the
longitudinal image (arrow). A trans-
verse image through the vagina dem-
onstrates a large amount of debris and
fluid in the vaginal canal.
3300 ULI ET AL. JCE & M • 1997
Vol 82 • No 10

precursors was achieved on day 17 (17-hydroxyprogesterone, 36 ng/dL; an enhancing rim of tissue, suggesting that it most likely represented an
testosterone, 5 ng/dL; androstenedione, 21 ng/dL; PRA, 1.45 ng/mLzh; ovary (Fig. 2). A magnetic resonance imaging (MR) examination per-
Na, 140 mEq/L; K, 5.5 mEq/L; levels obtained about 6 h after the formed 3 days later showed a stimulated uterus measuring 4 cm in
morning dose of hydrocortisone) The infant was maintained on hydro- length (Fig. 3). In the right lower quadrant, small cysts adjacent to the
cortisone (2.5 mg every 8 h), 9a-fluorohydrocortisone (0.15 mg once dominant cyst confirmed the presence of a stimulated right ovary. To
daily), and sodium chloride (500 mg every 6 h). assess the activity of the hypothalamic-pituitary-ovarian axis, a GnRH
On day 88 of life, the infant had the onset of vaginal bleeding ac- stimulation test was performed. The results are presented in Table 1. At
companied by transient fever. Physical examination revealed ambigu- this time, the 17-hydroxyprogesterone level was 359 ng/dL, and the
ous genitalia as before, with no palpable breast buds and absent pubic androstenedione level was 26 ng/dL.
hair. Catheterization of the vagina yielded a minimal amount of blood. On the fifth hospitalization day, the infant was noted to have bilateral
Urine, blood, and cerebrospinal fluid cultures were negative for bacteria. breast buds, with glandular tissue measuring 0.75 cm on the right side
A pelvic ultrasound revealed the presence of a right ovary with a and 0.5 cm on the left side. She continued to have scant vaginal bleeding
dominant 3-cm cyst in the right lower quadrant, a stimulated uterus, and for a total of 12 days. During a follow-up visit on day 102 of life, she had
a fluid/debris-filled vaginal cavity (Fig. 1). A computed tomography smaller breast buds, measuring less than 0.5 cm bilaterally, and the

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(CT) scan performed the following day demonstrated that the cyst had vaginal bleeding had resolved. Serum hormone measurements at that

FIG. 2. CT with oral and iv contrast

demonstrates a 3-cm cystic structure in
the right lower quadrant with an en-
hancing rim of tissue (arrow).

FIG. 3. Sagittal (A) and coronal (B) T2-weighted MR images (TR 6500 ms, TE 130 ms). The sagittal image demonstrates a debris/fluid-filled
vagina (straight arrow) and uterus with a prominent endometrium (curved arrow). On the coronal image, multiple small cysts (straight arrow)
and a large dominant cyst are indicative of an ovary in the right lower quadrant. A prominent lower uterine segment is also noted (curved arrow).
 MENSTRUAL BLEEDING IN AN INFANT WITH CAH 3301

time revealed a persistently elevated estradiol level of 8.2 ng/dL, with Pelvic imaging studies
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 Pelvic ultrasound was performed on day 88 (Fig. 1), CT on
less than 0.5 cm bilaterally, and was thriving. The GnRH stimulation test day 89 (Fig. 2), and MR on day 92 (Fig. 3). They demonstrated
was repeated (see Table 1). Serum 17-hydroxyprogesterone was 62 ng/ a stimulated uterus with a prominent endometrial echo, mea-
dL, and testosterone was less than 3 ng/dL. Pelvic sonogram performed suring approximately 2.5 mm in the antero-posterior direc-
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 tion, a fluid- and debris-filled vagina, and a stimulated right
measured 2.2 3 1.4 3 1.5 cm and contained multiple cysts. However, the ovary with a dominant 3-cm cyst. (MR was helpful, in that
dominant cyst was no longer seen. The left ovary was not definitively the small cysts confirming the presence of ovarian tissue
identified. Apart from minimal spotting on one diaper on day 114 of life, were not appreciated on either the ultrasound or the CT.) A
she had no more episodes of vaginal bleeding.
Three weeks after cessation of the vaginal bleeding, on day 127 of life,
follow-up ultrasound on day 109 (not shown) demonstrated
a follow-up pelvic sonogram was performed, and the uterus was noted the uterus and ovary to be less prominent, and the dominant

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to have decreased in size and now measured 2.4 cm in length, with the cyst was no longer identified. A follow-up study on day 127
fundus being smaller than the cervix. An endometrial echo was again (not shown) failed to visualize either ovary, consistent with
visible, but the ovaries were not definitively visualized, consistent with pelvic organs in a nonstimulated state.
nonstimulated pelvic organs.
Two months after the initial bleeding, the infant had barely palpable
breast buds. Examination was otherwise unremarkable. Endocrine eval- Discussion
uation 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 Technical advances in ultrasonography, including meth-
tissue was no longer present, and her examination was completely ods of enhanced anatomical resolution, have revealed that
prepubertal. Fourteen months after her initial bleeding episode, she microcysts of the ovary can be a normal finding in females
remains prepubertal on physical examination. A random serum estra-
diol measurement was less than 0.5 ng/dL. She continues to receive during the later part of infancy and early childhood (5, 6).
treatment with hydrocortisone (2.5 mg every 8 h), 9a-fluorohydrocor- Maturation of the ovaries begins in early childhood, with the
tisone (0.15 mg daily), and sodium chloride (2 g daily). ovarian volumes correlated with age. The uterus, however,
17-Hydroxyprogesterone and testosterone were measured by minor does not begin to mature until about 7 yr of age, after which
modification of previously described standard RIA methods after col-
increases in uterine volume and corpus to cervix ratio be-
umn extraction with Celite by the Pediatric Endocrine Laboratory of
New York University-Bellevue Hospital Center or Endocrine Sciences come apparent (6). Females with premature thelarche, a de-
(Calabasas Hills, CA). velopmental variant of normal puberty, have been shown to
Androstenedione, estradiol, and PRA were measured by RIA, and have an increased frequency of follicular cysts of the ovary,
FSH and LH were determined by immunochemiluminometric assay measuring up to 10 mm in diameter (5, 7), with ovarian and
(ICMA) at Endocrine Sciences Laboratories.
Sequential pelvic ultrasonography was performed and interpreted by uterine volumes being maintained in the normal range (7).
the same pediatric radiologists (N.G. and K.R.). Girls with idiopathic precocious puberty, on the other hand,
The GnRH stimulation test was performed using Factrel (gonadorelin have increases in both uterine and ovarian volumes, with the
hydrochloride, Ayerst Laboratories, Philadelphia, PA; 100 mg/m2 given additional finding of larger and more numerous ovarian
as an iv bolus over 2 min). FSH and LH levels were determined before
cysts (8). Females with congenital adrenal hyperplasia due to
and 30, 60, and on one occasion 90 min after the administration of Factrel.
21-hydroxylase deficiency have been reported to have a
Results greater frequency of nonhomogeneous ovarian structure.
During early childhood, although the presence of a few small
Clinical and hormonal findings
cysts has been noted, no increases in total ovarian volume or
As stated, at the time of the initial bleeding (day 88 of life), uterine size have been reported (9). In the only other study
our patient demonstrated hormone levels consistent with of infants with CAH in whom vaginal bleeding was reported,
reasonable control of her 21-hydroxylase deficiency. She did sonographic evaluation was not performed (4). The presence
not have a significant maternal estrogen effect at birth, as of a dominant ovarian cyst measuring more than 10 mm, as
evidenced by the lack of breast buds during the neonatal noted in our patient, has not been reported to date in an
period. On day 70 a random estradiol measurement was 1.0 infant with CAH.
ng/dL. However, on day 90, 2 days after the onset of vaginal As at the time of the initial vaginal bleeding on day 88 of
bleeding, her estradiol had risen to 5.6 ng/dL, with further life, our patient demonstrated a hormonal profile consistent
increases to 6.5 and 8.2 ng/dL on days 95 and 102, respec- with good metabolic control of her 21-hydroxylase defi-
tively, when breast buds were conspicuous. On day 109, 1 ciency, the source of her estrogens was probably not due to
week after vaginal bleeding had resolved, estradiol was de- peripheral conversion of adrenal androgens. On the third
clining, and by day 151 it reached a level of 1.7 ng/dL, or only day of the bleeding, serum estradiol was elevated, and the
slightly higher than expected for age. GnRH stimulation test demonstrated a brisk response to both
A GnRH stimulation test on day 90 at the onset of bleeding FSH and LH, while maintaining the early infantile, albeit
demonstrated a maximal FSH response to 26 mIU/mL (D exaggerated, pattern of FSH predominance. We acknowl-
FSH, 19.2) and of LH to 6.7 mIU/mL (D LH, 6.02), with a ratio edge that no data are currently available for GnRH-induced
of D FSH to D LH of 3.19. A second GnRH stimulation test FSH and LH levels by ICMA in this age group. However, we
on day 109, 1 week after bleeding had stopped, demonstrated suggest that the response indeed mimicked the pattern
more pronounced FSH and LH responses. The maximal FSH observed in prepubertal infants (Reiter, E., personal
response was 69 mIU/mL (D FSH, 59), and the maximal LH communication).
response was 21 mIU/mL (D, LH 20.3), but the D FSH to D When related temporally to the initial sonographic find-
LH ratio remained essentially the same at 2.9. ings of multiple small cysts and a single large dominant cyst
3302 ULI ET AL. JCE & M • 1997
Vol 82 • No 10

in the right ovary, the clinical course indicates an ovarian androgen suppression led to a marked rise in gonadotropin
response to exaggerated pituitary gonadotropin activity. At levels, resulting in significant stimulation of the existing
the time that breast development was noted, serum estradiol ovarian gonadotropin receptors. Growth of the ovarian fol-
was continuing to rise; it reached a maximum level 2 weeks licles and estrogen secretion subsequently occurred and
after the onset of uterine bleeding and declined thereafter. A manifested clinically as thelarche and endometrial bleeding.
reduction in the size of the ovary with nonvisualization of the Further studies of the ontogeny of fetal gonadal development
dominant cyst and a regression of breast size followed the in humans are needed to allow better understanding of our
decline in estradiol levels. Indeed, 14 months after the bleed- patient’s findings.
ing episode, she remains prepubertal with estradiol levels
below 0.5 ng/dL. A repeat GnRH test demonstrated the Acknowledgments
preservation of FSH predominance while maintaining brisk
responses to both FSH and LH. This is in keeping with the We thank Dr. Natalie Geary for her help with the evaluation of this

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patient. We also thank Ms. Vi Catena for her secretarial help with the
previous observation of the maintenance of the sex dichot- preparation of this manuscript.
omy 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). References
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