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Postnatal Changes of T, LH, and FSH in 46,XY Infants with Mutations in the AR Gene

Groupe hospitalier Cochin-Saint Vincent de Paul (C.B., J.-C.C., J.-L.C.), 75014 Paris, France; Centre hospitalier Charles Nicolle (C.L.), 76031 Rouen, France; Centre hospitalier Mère et Enfant (A.D.), 44000 Nantes, France; Hôpital Lapeyronie (C.S.), 34000 Montpellier, France; Centre hospitalier La Mère et l’Enfant (A.-M.B.), 25030 Besançon, France; and Hôpital Debrousse (Y.M.), 69322 Lyon, France

Address all correspondence and requests for reprints to: Dr. Claire Bouvattier, Endocrinologie Pédiatrique, Groupe hospitalier Cochin-Saint Vincent de Paul, 82 av Denfert Rochereau, 75014 Paris, France. E-mail: c.bouvattier{at}svp.ap-hop-paris.fr

	Abstract

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Androgen insensitivity syndromes (AIS) result from the incapacity for T and dihydrotestosterone to virilize male embryos and is mainly attributable to molecular defects of the AR gene. In normal males, T and LH rise during the first few months of life, and this physiological surge is commonly used to evaluate the gonadotropic axis at this age. This neonatal surge has not been evaluated in detail in newborns with AIS. We sequentially measured plasma T, LH, and FSH during the first 3 months of life in 15 neonates with AIS and AR mutation. A GnRH and an human CG stimulation test were also performed. Patients were divided in 2 groups with complete (n = 10) or partial (n = 5) AIS (CAIS or PAIS), based on the clinical phenotype. In patients with PAIS, T levels were in the high-normal range at d 30 (18.4 ± 6.9 nM) and d 60 (12.8 ± 3.8 nM). In contrast, plasma T values were below the normal range in 9 of 10 patients with CAIS at d 30 (1 ± 0.3 nM) and d 60 (1.4 ± 0.7 nM, both P < 0.004 vs. PAIS). Plasma LH values were low in CAIS at d 30 (0.7 ± 0.1U/liter) and increased normally in PAIS (8.7 ± 2.5 U/liter, P = 0.004). We conclude that the postnatal T and LH surge occurs expectedly in neonates with PAIS but is absent in those with CAIS and that the postnatal T rise requires the receptivity of the hypothalamo-pituitary axis to T.

	Introduction

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T AND ITS 5-REDUCED metabolite dihydrotestosterone are essential to virilize the urogenital tract of male embryos and act through the AR in target cells. Androgen insensitivity syndrome (AIS) is the most common cause of ambiguous genitalia (1, 2). Complete AIS (CAIS) is associated with female appearance of external genitalia, blind vagina, and presence of the testes in the inguinal areas. Partial androgen insensitivity [partial AIS (PAIS)] encompasses a spectrum of virilization defects ranging from minimal virilization in an XY individual (clitoromegaly) to perineoscrotal hypospadias. Molecular cloning and expression of the AR gene has allowed the identification of genetic lesions in the AR in most cases, although the phenotypic expression of a given mutation is quite variable (3).

In 1973, Forest et al. (4) described the evolution of plasma T concentration during the first months of life in full-term males, with a progressive rise from the first postnatal week to the second month and a gradual decrease to prepubertal levels around the age of 6 months. In parrallel, plasma LH concentrations rose until the third month of life before declining to prepubertal values slightly later than T (4, 5). This physiological T peak is commonly used by pediatric endocrinologists as a way to evaluate the male gonadotropic axis during the first 4–6 months of life.

Postpubertal patients with CAIS and intact testes have increased plasma concentrations of LH and FSH and normal or high T levels (6, 7). Studies in infants and neonates with AIS are restricted to a few case reports (8, 9, 10, 11). In the present study, we observed the hormonal profile in 15 patients with AIS during the first 3 months of life.

	Subjects and Methods

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Patients

Fifteen 46,XY newborns with androgen insensitivity were longitudinally followed during the first 90 d of life. Ten exhibited the classical features of CAIS, with female phenotypic appearance and gender assignment. Five had PAIS and were raised as males. All had a mutation of the AR gene (Table 1). There was a familial history in 7/15 cases. Patients 12 and 13 are brothers and were previously described (3).

T was measured by a direct RIA (Orion, Turku, Finland) with a detection limit of 0.17 nM and intra- and interassay coefficients of variation of 8% and 8.5%, respectively, at the level 2 nM and less than 8% at higher levels. Measurements were performed on d 2–7, 30, 60, and 90. In addition, on d 90, plasma T was measured after human CG (hCG) stimulation (3 im injections of 1500 U every other day). LH and FSH were measured 0, 15, 30, 45, 60, 90, and 120 min after iv injection of GnRH (100 µg/m²) on d 60 (12) by time-resolved immunofluorometric assay (Delfia; Wallac, Inc., Turku, Finland). Normal sex- and age-specific values for the plasma concentrations of T, LH, and FSH were used for comparison (13, 14, 15, 16, 17).

Direct sequencing of the AR gene was performed after PCR using an 373A sequencer and Taq dye terminator kit (PE Applied Biosystems, Foster City, CA).

Statistical analysis

Data are reported as mean ± 1 SD. For comparisons, parametric methods were used: t test (2-way test) and Pearson correlation test, to examine relationships between variables. For all statistical tests, significance was defined as P < 0.05.

	Results

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Patients with CAIS came to attention after the identification of inguinal testes at birth in 9 of 10 cases. In one case, discordance between chromosomal sex and external genitalia lead to the diagnosis. All PAIS patients had ambiguous genitalia.

Hormonal values are presented in Figs. 1, 2, and 3 and Tables 1 and 2. In CAIS, basal plasma T values were below the normal range from d 2–7 to d 90 in 9 of 10 patients. Only 1 patient with CAIS (patient no. 2) had T values within the normal range for males at d 30 and d 60 (5.5 and 9.3 nM, respectively). In infants with PAIS, T was significantly higher than in those with CAIS at d 30 (P = 0.005) and d 60 (P = 0.004), with median values between 4.8 and 18 nM during the 3 first months of life. The highest T value was measured at d 30 in all 5 cases.

View larger version (14K): [in this window] [in a new window]   Figure 1. Longitudinal evolution of plasma T during the first 3 months of life in patients with PAIS (n = 5) or CAIS (n = 10), in comparison with normal values established by Forest et al. (13 ).

View larger version (18K): [in this window] [in a new window]   Figure 2. Basal and post-hCG plasma T in CAIS and PAIS.

View larger version (17K): [in this window] [in a new window]   Figure 3. Basal and post-GnRH LH concentrations in CAIS and PAIS.

In 9 of 10 patients with CAIS, the median basal plasma LH levels, during the 3 first months of life, were lower than 0.9 U/liter. In contrast, patients with PAIS had significantly higher median values of 8.7 U/liter (P = 0.004) at d 30 and 2.8 U/liter (P = 0.02) at d 60. Peak plasma LH, after stimulation with GnRH, was also different between the 2 groups: the median value was 19.9 U/liter in PAIS (range, 15.5–24 U/liter) and 5.2 U/liter in CAIS (P = 0.0004, Tables 1 and 2, Fig. 3). Basal FSH levels were similar in the 2 groups. Peak plasma FSH, after stimulation with GnRH, was higher in PAIS than in CAIS (10.9 vs. 2 U/liter, P = 0.04).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this report, we have analyzed the postnatal surge of plasma LH and T in newborns with CAIS or PAIS. This surge is normal, or even increased, in PAIS; whereas it is absent in most patients with CAIS.

The hypothalamo-pituitary-gonadal axis is transiently activated during the first months of human postnatal life. After birth, high levels of maternal E2 drop rapidly, and plasma T falls, due to the clearance of hCG. These events contribute to the rise of circulating gonadotropins, responsible for the subsequent rise of T. In primates, the postnatal T surge can be abolished by a GnRH agonist, confirming its gonadotropin dependency (4, 13, 16, 18).

Published studies of hormonal investigations in patients with AIS have concentrated on older children and adults (6, 7, 10, 11, 19, 20). Postpubertal patients with complete forms of androgen resistance (CAIS) have markedly elevated serum LH levels and normal-to-high T concentrations, suggesting that the hypothalamic-pituitary unit is relatively unresponsive to the inhibitory feedback effects of circulating T. FSH levels are more variable, indicating normal control by other gonadal products, such as inhibin. Postpubertal patients with PAIS also have elevated LH values.

Studies in neonates with AIS are restricted to a few case reports (1, 9, 18, 21, 22, 23). Our five PAIS patients follow the expected pattern of exaggerated T and LH surge, similar to the findings in pubertal patients. Their plasma T and LH values were often above the range of normal controls. This increase of LH secretion reflects the postnatal sensitivity of the gonadotropic axis to negative feedback by androgens, altered by the AR mutation. Surprisingly, all but one CAIS newborn had no activation of the gonadotropic axis, with no LH and T surge, and a significantly decreased response of LH to GnRH at 3 months of life. This remarkable difference between CAIS and PAIS suggests that the normal transient LH rise in male infants requires prior, intrauterine, androgen action on the gonadotropic axis. In addition, our results rule out a major role for postnatal E2 decrease as a primary mechanism driving the neonatal LH surge, as previously suggested (24). We have no explanation for the different pattern observed in one of our patients with CAIS, who had a normal, or even strong, increase of T and LH. T biosynthesis assessed by Leydig cell response to hCG was normal or high in all cases. Plasma T increased more than five times in all neonates with CAIS, whereas a 2- to 3-fold increase is generally considered normal (25).

In conclusion, our study provides data about the regulation of the gonadotropic axis during the first months of life in individuals with androgen insensitivity. The postnatal rise of T and LH is normal or elevated in PAIS but absent in almost all infants with CAIS. We conclude that the postnatal T rise requires the receptivity of the hypothalamo-pituitary axis to T, as described in male rats (26).

	Acknowledgments

 

	Footnotes

 
Abbreviations: AIS, Androgen insensitivity syndrome(s); CAIS, complete AIS; hCG, human CG; PAIS, partial AIS.

Received June 30, 2000.

Accepted July 2, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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