Minipuberty hormone arousal, a clue for differential diagnosis of 46,XY DSD

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 631-640-Pediatric Endocrinology Case Reports: Disorders of Sexual Differentiation
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-633
Alfonso Galderisi*, Sara Azzolini, Ilaria Tosetto, Elena Marcon, Giuliano Cuccarolo and Nella Augusta Greggio
University of Padova, Padova, Italy
Background: Postnatal gonadotropins and sex steroids undergo a temporary surge from the 2nd week of life up to the 12th- month in males and the 24th month in females respectively. The hormonal pattern observed is sex specific, with prevalence of FSH on LH in females with respect to males (1). Specific features of minipuberty have been described in complete (CAIS) and partial androgen insensitivity syndrome (PAIS), despite that, a comparative analysis with other DSDs  has never been provided. We compared the mean basal values of gonadotropins and testosterone measured every 6th month from the 2nd week of life up to the 2nd year in 2 cases of 46,XY Complete Gonadal Dysgenesis (CGD), 1 testicular regression syndrome (TRS), 2 PAIS, 2 CAIS.

CGD (Female phenotype, female gonadal remnant, no defects in the sequence of SRY, NR5A1 or SOX): FSH25.56±25.75UI/L; LH6.94±4.26UI/L; FSH/LH ratio 8.69±5.27; testosterone 0.19±0.18nmol/L.

TRS (Male phenotype, no detectable testes with ultrasound and laparoscopic exams, no testosterone increases after the GnRH test) We followed the patient up to 3.4 years, observing a persistence of high basal FSH and LH levels, with undetectable testosterone. Mean FSH96.93±16.58UI/L; LH6,97±3.04UI/L; FSH/LH15,49±5.46, testosterone<0.1nmol/L.

CAIS (Female phenotype, inguinal testes, nonsense mutations in the AR gene). The average hormonal values were FSH0,6 ±0.56nmol/L; LH0.55±0.64nmol/L; testosterone 0.49±0.13 nmol/L

PAIS (Male phenotype with ambiguous genitalia, defect present in the AR gene associated with partial AIS): FSH3.95±2,47UI/L; LH7.65±5.59UI/L; FSH/LH0.54±0.07; testosterone 700±834.9nmol/L.

Discussion: CGD and CAIS may represent a tough differential diagnosis, both of them have female phenotype and a 46,XY karyotype, but the presence of a functional androgen receptor in 46,XY CGD determines a female-like (1) post-natal hormonal rise (FSH/LH ratio>1). In CAIS no increase in FSH and LH is observed up to the 2nd year, probably due to lack of an androginal prenatal “priming” effect. Such, is confirmed from animal models (2).

TRS should be differentiated by PAIS with cryptorchidism and male phenotype: they have 46,XY karyotype, but while PAIS shows a male-like minipuberty with FSH/LH<1, TRS demonstrates a female-like ratio (FSH/LH>1) and a persistent increase of gonadotropins, due to the absence of inhibin B and testosterone negative feedback.

Conclusion: The analysis of FSH, LH and testosterone, from the 2nd week of life to the 2nd year, provides a substantial clue for the diagnosis of 46,XY DSDs. In presence of a suspect DSD, once the karyotype has been obtained, the infant should be evaluated for FSH, LH, testosterone in order to address the specific genetic analysis. The opportunity of targeting the genetic analysis according to the hormonal milieu, may allow us to save resources and provide patients with precocious management information.

1) Quigley CA. Editorial: The postnatal gonadotropin and sex steroid surge-insights from the androgen insensitivity syndrome. J Clin Endocrinol Metab. 2002 Jan;87(1):24-8.   2) Recabarren SE, Recabarren M, Rojas-Garcia PP, Cordero M, Reyes C, Sir-Petermann T. Prenatal exposure to androgen excess increases LH pulse amplitude during postnatal life in male sheep. Horm Metab Res. 2012 Sep;44(9):688-93. 3) Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, Morel Y, Chaussain JL. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab. 2002 Jan;87(1):29-32

Nothing to Disclose: AG, SA, IT, EM, GC, NAG

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