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Early Assessment of Hypothalamic-Pituitary-Gonadal Function in Patients with Congenital Hypothyroidism of Central Origin

Department of Pediatric Endocrinology (D.A.v.T., J.J.M.d.V., T.V.), Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands; and Department of Pediatrics (E.J.S., H.A.D.v.d.W.), Subdivision Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: David A. van Tijn, M.D., Department of Pediatric Endocrinology, Emma Children’s Hospital, G8-205, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: tijn1{at}planet.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Early recognition of gonadotropic dysfunction could enable well-timed growth and maturation and prevent damage to gonads and external genitalia. The adaptation of the Dutch neonatal screening program for congenital hypothyroidism in the mid 1990s resulted in enhanced detection of congenital hypothyroidism of central origin (CH-C), with high likelihood of multiple pituitary hormone deficiency, including gonadotropin (Gn) deficiency.

Objective: We analyzed GnRH test results and baseline Gn and sex hormone measurements in 15 infants with CH-C to examine these diagnostic tools for assessment of the integrity of the hypothalamus-pituitary-gonad axis in young infants.

Design: In a nationwide prospective study (1994–1996), patients were referred to our department if neonatal CH screening results were indicative of CH-C. When CH-C was confirmed, GnRH tests and baseline Gn and sex hormone measurements took place at the age of 3 months, when euthyroid status had been accomplished by T₄ supplementation, and if necessary, cortisol supplementation was installed.

Setting: The study took place at the Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam (referral center).

Patients: The study included 15 neonates (five girls and 10 boys) with CH-C, detected by neonatal screening, in whom investigation of the hypothalamus-pituitary-gonad axis could be performed at 3 months of age.

Main Outcome Measures: Results of GnRH tests and baseline Gn and sex hormone measurements were assessed.

Results: GnRH tests at 3 months of age showed a pattern indicative of endogenous GnRH stimulation in nine infants and a blunted response in six. Baseline Gn and sex hormone concentrations except estradiol (P = 0.053) were significantly different between responders and nonresponders.

Conclusions: The GnRH test and baseline measurements of Gn and sex hormone serum concentrations at 3 months of age are promising options in the assessment of hypothalamic-pituitary-gonadal function in infants with CH-C of both sexes.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE POSTNATAL SURGE of gonadotropins (Gn) and sex hormones, as a consequence of the continued action of the fetal GnRH pulse generator and the transient activation of the hypothalamus-pituitary-gonad (HPG) axis during the first postnatal months (1, 2, 3, 4, 5), provides an opportunity to evaluate the gonadal axis long before puberty (6). Although the postnatal surge has been known since the early 1970s, insight in its mechanisms and significance at the endocrine, anatomical, and behavioral level is still largely speculative (7). Nevertheless, there is accumulating evidence that early initiation of treatment of Gn deficiency may positively affect growth of the external genitalia (6), ovarian follicular maturation (8), and spermatogenesis (9, 10). Furthermore, because delayed or failing pubertal development not only causes delayed progression of secondary sexual characteristics but also of physical and psychological growth and maturation, early recognition of gonadal axis dysfunction would enable timely therapeutic intervention and thus well-timed growth and maturation (11, 12). Several categories of patients could benefit from early diagnosis of gonadal axis dysfunction: infants with multiple pituitary hormone deficiency (MPHD), children born to families with hereditary hypogonadism, and those born with underdeveloped or ambiguous genitalia and/or cryptorchidism. In many cases, early treatment with testosterone (T) has proven to be effective regarding phallic and scrotal development (13), whereas treatment with Gn may be a promising option, especially regarding Sertoli cell function and fertility (14, 15).

Since the introduction of highly sensitive Gn and sex hormone immunoassays in the late 1980s (16), a number of series of sequential determinations of baseline serum concentrations of Gn and sex hormones in young infants have been published (17, 18, 19, 20). However, none have been linked to simultaneous GnRH test results. The adaptation of the Dutch neonatal screening program for congenital hypothyroidism in the mid 1990s resulted in enhanced detection of congenital hypothyroidism of central origin (CH-C) (21, 22, 23) and provided an opportunity to investigate HPG function in a cohort of infants at risk for Gn deficiency. It is, therefore, the first cohort reported with such high a priori likelihood of disturbance of gonadotropic function, investigated at such an early age. Results of GnRH tests in 15 CH-C patients, performed at the age of 3 months, were analyzed together with baseline measurements of Gn and sex hormone serum concentrations. The objective of this study was to examine these diagnostic tools for assessment of the integrity of the HPG axis in young infants.

	Subjects and Methods

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Subjects

The subjects were 15 neonates (five girls and 10 boys) with CH-C, detected by neonatal screening in 1994–1996 and participating in a nationwide prospective study (22). For 13 of the 15 patients (87%), the abnormal screening result was the first sign of pituitary hormone deficiency. The most frequently encountered perinatal problems were pathological neonatal jaundice or elevated plasma concentrations of the transaminases (n = 6; 40%), hypoglycemia (n = 6; 40%), and persistent vomiting (n = 2; 13%). Agenesis of the corpus callosum was seen in three of the patients (20%); none of the 15 patients had optic nerve hypoplasia and none had cleft lip or palate. In three of the 15 patients (20%), there was a positive family history of pituitary hormone deficiency; in five patients (33%), there were dysmorphic features. Tables 1 and 2 summarize perinatal characteristics and pituitary function evaluation of these patients. In addition to TSH deficiency (100%), eight of the 15 patients (53%) had ACTH deficiency and nine of the 15 patients (60%) had GH deficiency. Of those nine patients, two had normal arginine test results at the age of 3 months but showed growth retardation around the age of 2.5 yr. Both had repeated GH stimulation tests that yielded severely impaired GH release after stimulation with arginine, GHRH, and clonidine, respectively. In seven of 14 patients (50%) assessed by magnetic resonance imaging (MRI), a major pituitary malformation was detected (22).

Hormone assays

All Gn and sex hormone assays were performed in the laboratory of the VU University Medical Center, Amsterdam. Serum LH and FSH were measured by immunoluminometric assay (Amerlite; Amersham, Little Chalfont, UK) with detection limits of 0.3 and 0.5 mIU/ml (0.3 and 0.5 IU/liter), respectively. Intra- and interassay coefficients of variation (CVs) were maximal 6 and 10%, respectively. Serum E2 was measured by RIA (Sorin Biomedica, Saluggia, Italy) with a detection limit of 5 pg/ml (18 pmol/liter). Intra- and interassay CV were maximal 4 and 11%, respectively. Serum T was measured by RIA (Coat-a-Count; Diagnostic Products Corp., Los Angeles, CA) with a detection limit of 0.1 ng/ml (0.25 nmol/liter). Intra- and interassay CV were maximal 6 and 12%, respectively.

GnRH tests

After iv bolus administration of 1–11 GnRH (LHRH Relefact; Hoechst Pharma, Frankfurt am Main, Germany) in a dose of 10 µg/kg body mass, samples were drawn via an indwelling catheter before and 15, 30, 45, 60, and 120 min after GnRH infusion. All blood samples were centrifuged immediately after collection, and serum was stored at –20 or –70 C until hormone measurements were performed.

MRI of the brain

To examine hypothalamic and pituitary morphology, MRI studies were performed using a 1.5 Tesla Siemens Magnetom. Transversal (5 mm), sagittal (3 mm), and coronal (3 mm) T1-weighted spin-echo images were obtained. In the transversal plane, also proton density as well as T2-weighted turbo-spin-echo sequences were used. In addition, a T1-weighted three-dimensional series (MPRage) was taken.

Statistical analysis

Descriptive statistics were computed for all variables. The Mann-Whitney U test was used to compare median values, and Pearson correlation tests were used to estimate interrelations between different determinants of HPG function. For all analyses, a two-tailed P value of <0.05 was considered statistically significant. SPSS 10.1 (SPSS Inc., Chicago, IL) was used for statistical computations.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
At 6 wk of age, all five girls had very low LH and FSH serum concentrations (<0.1–1.2 mIU/ml), and none had detectable E2. Five of the eight boys, in whom data were available at 6 wk of age, had substantial serum concentrations of both Gn [LH, 0.4–14 mIU/ml (0.4–14 IU/liter); FSH, 1.5–4.6 mIU/ml (1.5–4.6 IU/liter)] and T [0.3–1.8 ng/ml (1.0–6.1 nmol/liter)], whereas the remaining three had undetectable or very low Gn serum concentrations [LH, all <0.3 mIU/ml (<0.3 IU/liter); FSH, <0.5–0.7 mIU/ml (<0.5–0.7 IU/liter)] and T [all <0.1 ng/ml (<0.25 nmol/liter)] (Table 2). For two of the boys, data at 6 wk of age were not available.

At 3 months of age, none of the girls had detectable baseline LH, whereas only two showed a substantial increase of LH [>3 mIU/ml (>3 IU/liter)] in response to GnRH administration. All five girls had baseline FSH serum concentrations above the detection limit [0.8–5.2 mIU/ml (0.8–5.2 IU/liter)], but only two showed substantial increase [>6 mIU/ml (>6 IU/liter)] in response to GnRH. The two girls with substantial LH and FSH response to GnRH had detectable E2, whereas the three girls with deficient Gn response to GnRH had undetectable E2. At this age, seven of the 10 boys had substantial LH and FSH response to GnRH [>3 mIU/ml (> 3 IU/liter)] and baseline T serum concentrations [0.4–2.2 ng/ml (1.5–7.8 nmol/liter)] in the reference range as established by Andersson et al. (17). The remaining three boys had undetectable baseline T and very low Gn peak values in response to GnRH (Table 2). Thus, at this age, nine of the 15 infants had baseline Gn and T/E2 concentrations and GnRH test results indicative of endogenous GnRH stimulation. The remaining three boys had baseline morning serum concentrations of T less than 0.6 ng/ml (<2 nmol/liter), and the remaining three girls had baseline morning serum concentrations of E2 less than 11 pg/ml (<40 pmol/liter), in combination with blunted response to GnRH, i.e. LH peak less than 3 mIU/ml (<3 IU/liter) and FSH peak less than 3 mIU/ml (<3IU/liter) in boys or less than 6 mIU/ml (<6 IU/liter) in girls.

Mann-Whitney U tests showed significant differences between the GnRH-responsive vs. GnRH-unresponsive infants in both GnRH-stimulated LH (P = 0.002) and FSH (P = 0.003) serum concentrations as well as baseline serum concentrations of T (P = 0.020) but not E2 (P = 0.053) (Table 3). Pearson correlation tests showed significant correlations between the GnRH-stimulated LH peak and baseline T and E2 serum concentrations (P < 0.05 and P < 0.001, respectively). Also, a significant correlation between the FSH peak concentration and baseline E2 (P < 0.05), but not T (P = 0.26), was observed. GnRH-stimulated LH and FSH peaks were significantly correlated as well (P < 0.05).

Patients 2 and 3 had a (stretched) penis length more than 2 SD below the mean: 19 and 23 mm (diameter, 9 mm), respectively. Both had normally descended testes, estimated at 0.8–1.0 ml each. Patient 4 had the smallest phallus (length, 6 mm; diameter, 5 mm). In addition, he had (coronal) hypospadia. His testes were of normal size and were palpable in the inguinal space.

Patient 4, born at 32 wk gestation, needs a separate description. He was one of the two patients with hypogenitalism (penis hypoplasia, penoscrotal hypospadia, cryptorchidism with underdeveloped, and bifid scrotum). The appearance of his genitalia resembled that of the patient with pan-hypopituitarism described by Burgner et al. (25). Also, he proved to be TSH, ACTH, and GH deficient and had PPE (22). However, unexpectedly, he had normal baseline serum concentrations of both Gn and T at the age of 18 d and also at the age of 94 d, when his GnRH test showed early pubertal responses [LH peak, 5.2 mIU/ml (5.2 IU/liter); FSH peak, 3.1 mIU/ml (3.1 IU/liter)]. From the age of 6.5 months, serum T remained undetectable. Treatment with a long-acting T preparation (4 doses of 25 mg im at 3-wk intervals) resulted in satisfactory catch-up growth of the penis into the normal size range. An orchidopexia, performed at the age of 3 yr, revealed testes of normal size and with vital appearance. Besides hypogenitalism, he was found to have mental retardation, microcephaly, large ears, and sparse hair, resembling Oliver-McFarlane syndrome. To date, we cannot conclude whether this patient’s hypogenitalism/cryptorchidism is due to prematurity, Gn deficiency, or Oliver-McFarlane syndrome (in which occasionally Gn deficiency has been described) (26). Therefore, he was excluded from the aforementioned statistical analysis.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The adaptation of the Dutch neonatal screening program for congenital hypothyroidism in the mid 1990s resulted in enhanced detection of CH-C (21, 23). Consequently, we are since confronted with a considerable number of neonates with pituitary hormone deficiency, mostly multiple (22). The early detection of TSH, ACTH, and GH deficiencies enables early correction of the deficient hormonal states, and significant damage to the central nervous system can thus be prevented. As evidence accumulates that delay of treatment of Gn deficiency might cause damage to growth of the external genitalia (6), ovarian follicular maturation (8), and spermatogenesis (9, 10), early diagnosis of Gn deficiency is desirable, especially because these problems may be countered by early treatment with T (13) or Gn (14, 15). We therefore evaluated the possibilities for analysis of the integrity of the HPG axis in young infants.

When the inhibitory action of the placenta-derived steroids on the neonatal GnRH pulse generator and pituitary gonadotrophs disappears after birth (5), serum Gn concentrations increase substantially at 1–2 wk of age (27). In boys, serum LH levels peak at 1–3 months of age, concomitant with an increase in T levels (mini-puberty) (20, 28, 29, 30). After 4 months, LH levels decline into the low prepubertal range. In girls, a similar pattern is shown, except that their LH peak is lower. Levels of FSH increase to peak 1 wk to 3 months after birth in boys and decline to prepubertal values thereafter. In girls, a more marked FSH peak is found 2–3 months after birth (3), whereas E2 levels can be increased (compared with the prepubertal state) during the first 6 months of life (4).

We first measured and analyzed baseline Gn and sex hormone serum concentrations at referral (median, 41 d). At this age, the Gn and sex hormone secretion have not reached their respective mini-pubertal peak values yet (1, 2, 3, 4, 5). Furthermore, because all subjects still had untreated CH-C and the majority had additional untreated pituitary hormone deficiencies at this age, the results may have been (negatively) influenced in this phase. Still, at this age, there was a clear dichotomy among the male CH-C patients: five boys had serum T and Gn concentrations in the early pubertal range, whereas three boys had undetectable or very low T and Gn concentrations. In contrast, all female CH-C patients had undetectable or very low E2 and Gn concentrations. Thus, baseline Gn and sex hormone determinations at 6 wk of age may be informative in boys but not (yet) in girls.

For aforementioned reasons, our main focus was on baseline Gn and sex hormone serum concentrations and GnRH test results at the age of 3 months, well within the phase of peak Gn secretion in both sexes. Moreover, by this age, euthyroid status had been accomplished by T₄ supplementation, and in case of glucocorticoid deficiency, cortisol supplementation had been established in physiological dosages. A dichotomy in baseline Gn and sex hormone concentrations was seen in both sexes. The GnRH test results were even more discriminative. Altogether, nine of the 15 infants (60%) had test results comparable with those of midpubertal children, i.e. Tanner stages 2–4 (31). The apparent activity of their HPG axis implies endogenous GnRH stimulation. Six infants (40%) had weak Gn responses to GnRH and baseline morning serum concentrations of T less than 0.6 ng/ml (<2 nmol/liter) in boys and E2 less than 11 pg/ml (<40 pmol/liter) in girls.

Obviously, the integrity of the HPG axis cannot be definitively validated at this age, but circumstantial evidence for Gn deficiency was acquired from the fact that all patients unresponsive to GnRH had MPHD (all except one were deficient in TSH, ACTH, and GH), and all except one had PPE on MRI. All determinants of HPG function except E2 (P = 0.053) were significantly higher in the patients responsive to GnRH than in those unresponsive to GnRH, as calculated by Mann-Whitney U tests (Table 3).

Pearson correlation tests showed significant correlations between the GnRH-stimulated LH peak and baseline T and E2 serum concentrations at the age of 3 months. Can we, therefore, conclude that single random (morning) determinations of Gn and sex hormones enable establishment of HPG axis integrity at a young age, provided that the appropriate moment is chosen? First of all, definite proof (i.e. well-timed vs. delayed or failing pubertal development and subsequent fertility) of the test results presented here can only come from follow-up of at least two decades. Furthermore, the severity of Gn deficiency covers a wide spectrum. Therefore, at this stage, the possibility of a subgroup of patients with partial deficiency, who might exhibit timely pubertal onset but incomplete progression of sexual maturation (11, 12), cannot be excluded. Moreover, considering the sex differences in the timing of the postnatal surge of Gn and sex hormones, in females, testing at the age of 6 months instead of 3 months could be more sensitive (4). Finally, because both Gn are secreted in a pulsatile fashion, a single determination might not reliably reflect the baseline concentration. In contrast, GnRH-stimulated peak LH and FSH serum concentrations show excellent correlation with maximal spontaneous nocturnal LH and FSH serum concentrations (r = 0.83 for LH, and r = 0.91 for FSH; P < 0.00001) (32).

We conclude that a GnRH test, performed at the age of 3 months (or potentially some months later in girls), in combination with baseline Gn and sex hormone serum concentrations at the same age, may be a promising way to assess the integrity of the HPG axis in both sexes. This timing enables diagnosis and supplementation of accompanying pituitary hormone deficiencies before the investigation of gonadal function takes place.

	Acknowledgments

 
We are indebted to the patients and their parents; to the referring pediatricians and pediatric endocrinologists; to Brenda Wiedijk, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, for her indispensable assistance in collection of the data; to Jeanne Huijser-Geenen and Marie Lomecky from the endocrinological laboratory, VU University Medical Center, Amsterdam, for their expertise; and Heather Houlihan for review of the English syntax.

	Footnotes

 
Current address for E.J.S.: Department of Pediatrics, Isala Clinics, Zwolle, The Netherlands.

This work was supported by Grant 28-1060-2 (to J.J.M.d.V. and T.V.) from The Netherlands Organization for Health Research and Development (ZON-MW), The Hague, The Netherlands.

Author Disclosure Summary: D.A.v.T., E.J.S., H.A.D.v.d.W., J.J.M.d.V., and T.V. have nothing to declare.

First Published Online October 17, 2006

Abbreviations: CH-C, Congenital hypothyroidism of central origin; CV, coefficient of variation; E2, estradiol; Gn, gonadotropin; HPG, hypothalamus-pituitary-gonad; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; PPE, posterior pituitary ectopia; T, testosterone.

Received March 29, 2006.

Accepted October 10, 2006.

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