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From the Clinical Research Centers |
Developmental Endocrinology Branch, Warren Grant Magnuson Clinical Cener, National Institutes of Health, Bethesda, Maryland 20892
Address correspondence and requests for reprints to: Penelope P. Feuillan, M.D., Developmental Endocrinology Branch, Warren Grant Magnuson Clinical Cener, National Institutes of Health, Bethesda, Maryland 20892.
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Abstract |
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1-fetoprotein were normal. By 4 yr after
therapy, all patients had pubertal stage V pubic hair; their body mass
index was not different from that of the normal boys at any time point.
The dimensions of the patients’ hamartomas did not change during or
after therapy, and no patient reported new neurological symptoms or
signs suggestive of an enlarging lesion at any time during or after
discontinuation of treatment. Two families did report episodes of
emotional lability and truancy as the patients reentered puberty after
discontinuation of treatment. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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HH is also an important cause of PP in boys (2), and the GnRH analogs are known to be effective therapy. To determine whether the recovery of the pituitary-gonadal unit in boys with PP due to HH is comparable with that observed in girls, we studied 11 boys with HH for 2–5 yr after discontinuation of GnRH analog therapy.
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Subjects and Methods |
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Therapy was discontinued at the age when normal puberty would be expected (11–13 yr), and in-hospital follow-up evaluations were performed every 1–2 yr at the Clinical Center of the NIH. Immunoreactive LH and FSH were measured (3) from 0–120 min after the iv administration of 100 µg GnRH at 0900 h. Serum testosterone (T) was measured (4) at 0 min. A single observer (J.V.J.) estimated pubertal stage and measured testis volume with a Prader orchidometer. Testicular structure was assessed using ultrasonography.
The BMI was calculated from weight (kg)/height (m)2 , and the SD score was calculated from the BMI of normal boys using published standards (5).
Over the initial 4–6 yr of GnRH analog therapy, the dimensions of the patient’s hamartomas were estimated using CT performed serially every 12–24 months. In 10 boys, one or more MRI studies were also performed in parallel with CT. Thereafter, MRI (10 boys) or CT (1 boy) was used as medically indicated during and after discontinuation of treatment.
For comparative purposes, we measured LH and FSH after 100 µg GnRH, T, testis volume, and BMI in six normal boys aged 13.5–17 yr and in pubertal stage IV–V.
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Results |
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, top)Whereas LH and FSH were suppressed at the end of GnRH analog treatment (yr 0), peak GnRH-stimulated levels had risen to the normal range by 1 yr and were not significantly different from normal at 2, 3, and 4–5 yr after treatment. The mean peak LH/FSH ratio was significantly lower than normal at 0 yr and at 1 yr after therapy [2.4 ± 0.8 and 2.7 ± 1.1 (P < 0.01 and P < 0.04, respectively, compared with normal: 4.9 ± 1.3)], but had risen to the normal range at the 2-, 3-, and 4- to 5-yr time points.
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, bottom)Serum T rose to the normal range by 1 yr after therapy and was normal at all subsequent time points. However, although the corresponding testis volume had increased significantly (compared with yr 0) at 1 yr, the mean ± SD testis volume remained smaller than that of the normal boys until posttherapy yr 2, 3, and 4–5.
Testicular ultrasonography revealed that two boys had developed
diffuse, punctate, echogenic foci, suggestive of calcifications, in the
parenchyma of the testes. Both boys’ testes had had normal
echogenicity before and during their early years of treatment. In both
boys the punctate foci were observed during GnRH analog therapy and
persisted unchanged during and after discontinuation of treatment. One
boy had begun GnRH analog therapy at 1.3 yr. His mean testis volume at
that time was estimated at 5.3 mL and it remained between 4.0 and 5.5
mL throughout therapy. Echogenic foci, distributed uniformly throughout
the parenchyma of both testes, were first observed at age 6 yr, after 4
yr of therapy. By 4 yr after discontinuation of GnRH analog, his testis
volume had increased to 20 mL. The other boy began GnRH analog therapy
at 2.6 yr. At that time, his testis volume was 8 mL; it decreased to
5.5–6. mL during therapy. Punctate, echogenic foci were first observed
in the right testis at age 10 yr, after 8 yr of treatment. By 5 yr
after discontinuation of GnRH analog, his testis volume had increased
to 21 mL. No mass or surface irregularity was detected, and there was
no tenderness elicited on manual examination in either boy at any time.
Serum levels of the tumor markers ß-hCG and 1-fetoprotein were in
the normal range in both boys. The second boy also had a small,
unilateral hydrocele, as did five other boys whose testis structure was
otherwise unremarkable. An isolated, unilateral, hypoechoic,
2.5–5.6-mm cyst-like area was observed in the epidydimis of three boys
(two with hydrocele, see above) 2–4 yr after discontinuation of
treatment.
All 11 boys had Tanner stage V pubic hair by 4 yr after stopping treatment. Severe, cystic acne, requiring treatment with Retin-A, was observed in one boy at age 17 yr, 4 yr after stopping therapy. Other boys reported mild to moderate facial acne after discontinuation of therapy.
BMI
The mean BMI SD score was not significantly different from that of the normal boys at any time point after discontinuation of therapy, however, two patients and one normal boy were frankly obese (BMI SD: + 2.5, + 2.4, and + 2.2, respectively). As anticipated, the patients’ mean ± SD BMI rose as they reentered puberty after discontinuation of therapy and was significantly greater by the 3- and 4- to 5-yr time points (24.9 ± 3.0 and 27.9 ± 3.3, P > 0.002 compared with 0 yr: 22.4 ± 2.2).
Neurological and behavioral findings
The CT and MRI studies indicated that the antero-posterior dimension of the hamartomas (mean ± SD, 1.3 ± 0.3 cm; range, 0.8–1.6 cm) did not change during or after therapy in any of the nine boys who had not had surgical excision of their hamartoma. In addition, none of the 11 boys had progressive, worsening visual or neurological symptoms suggestive of an enlarging lesion over the years of follow-up.
One boy who had initially presented with a 1.6-cm hamartoma, gelastic seizures, developmental delay, and PP at the age of 3 yr continued to require treatment with anticonvulsant medications during and after discontinuation of GnRH agonist treatment. No other boy is known to have developed seizure, persistent headache, visual changes, or other severe neurological abnormality during or after GnRH analog therapy, although two families reported episodes of severe emotional lability and truancy as boys entered puberty after discontinuation of treatment.
All 11 boys themselves reported nighttime erections at 2–4 yr after discontinuation of therapy, and 4 (at ages 17–19 yr) asserted that they had had sexual relations with female partners. There were no reports that pregnancies had resulted from these relations.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In boys, who are the subjects of this report, IPP is a very rare condition. For this reason, it was not possible to do a comparative study (boys with HH vs. IPP) such as we previously published in girls. We did find, however, that the overall tempo of recovery of the hormonal components of puberty was comparable in boys and girls and that the pituitary-gonadal unit in both sexes had returned to normal by 2 yr after therapy. However, in contrast to our previous observations in girls, our current findings in boys with HH indicate that patients had normal GnRH-stimulated peak LH and normal LH/FSH ratios by 2 yr after stopping treatment. Although the mean testis volumes of these patients did not achieve those of the normal pubertal stage V males until 2 yr after therapy had been discontinued, this interval is comparable with the time span of testicular growth in normal, pubertal boys. There also seemed to be a normal incidence of obesity (1 of 11 patients) in boys, and no apparent increased risk of seizure onset during or after discontinuation of therapy.
We are not able to explain the ultrasound finding in two boys of
punctate echogenic foci suggestive of testicular calcifications. In
both cases, these foci were not observed before or during the early
years of GnRH analog treatment. Foci were first noted after 4 and 8 yr
of treatment and did not resolve after GnRH analog was stopped. In
neither case were there physical findings suggestive of a mass or
tumor, and serum levels of ß-hCG and 1-fetoprotein were normal.
Nonetheless, testicular calcifications have a known association with
germ cell tumors and have also been observed in children with
cryptorchidism and dysgenetic testes (6, 7).
Calcifications have also been detected in autopsy specimens from adult
men with no known testicular pathology (6). The prevalence
of echogenic foci in normal boys and men is uncertain, and there is
little or no information on this particular finding, or on testicular
morphology in general, during and/or after discontinuation of long-term
GnRH agonists. Early primate studies indicated complete reversibility
of the changes in testicular morphology induced by treatment with GnRH
agonists, however, the subjects of this trial were adult rhesus
monkeys, treatment was for a period of only 20 months, and the duration
of follow-up was only 8 months after stopping treatment
(8).
Although our findings are reassuring, all young adults, male and female, who underwent prolonged suppression of the pituitary-gonadal axis during childhood deserve continued, careful medical follow-up to confirm the safety of GnRH analog treatment and to assess its effects, if any, on subsequent sexual functioning and fertility.
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Footnotes |
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2 Present address: Lilly Research Laboratories, Eli Lilly & Company,
Indianapolis, Indiana 46285.
Received April 27, 2000.
Revised June 22, 2000.
Accepted July 17, 2000.
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References |
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This article has been cited by other articles:
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  J.-C. Carel, E. A. Eugster, A. Rogol, L. Ghizzoni, M. R. Palmert, and on behalf of the members of the ESPE-LWPES GnRH An Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children Pediatrics, April 1, 2009; 123(4): e752 - e762. [Abstract] [Full Text] [PDF]
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