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Acute Stress Masking the Biochemical Phenotype of Partial Androgen Insensitivity Syndrome in a Patient with a Novel Mutation in the Androgen Receptor

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital (N.P., A.A.D., W.F.C., F.J.H.), Boston, Massachusetts 02114; and Department of Internal Medicine, University of Texas Southwestern Medical Center (J.V., M.J.M.), Dallas, Texas 75235-8857

Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: npitteloud{at}partners.org.

Hypogonadism has traditionally been classified as either hypogonadotropic or hypergonadotropic based on serum gonadotropin levels. However, when hypothalamic suppression of GnRH secretion occurs, it can mask an underlying hypergonadotropic state. In this report we document the unusual case of a 61-yr-old man with androgen insensitivity and coincidental functional hypogonadotropic hypogonadism (HH). Although functional HH is not a well-recognized entity in the male, major stress has been reported to cause transient suppression of the hypothalamic-pituitary-gonadal axis in men. The patient in question was noted to have undervirilization, minimal pubertal development, hypogonadal testosterone, and low gonadotropin levels consistent with congenital HH during a hospital admission for myocardial infarction. However, the patient had also had surgery for hypospadias, a clinical feature not typically part of the phenotypic spectrum of congenital HH. We therefore hypothesized that the combination of acute stress and chronic glucocorticoid administration for temporal arteritis induced transient HH in a patient with a disorder of sexual differentiation in whom gonadotropin levels would have otherwise been elevated. Using clinical, molecular, and genetic studies, the patient was found to have partial androgen insensitivity syndrome (PAIS) caused by a novel mutation (Ser⁷⁴⁰Cys) in the ligand-binding domain of the androgen receptor. Subsequent studies of the patient confirmed the characteristic gonadotropin and sex steroid abnormalities of PAIS. We describe for the first time a patient with PAIS presenting with a reversible hypogonadotropic biochemical profile triggered by an acute illness and corticosteroid therapy. This case highlights the necessity for caution when interpreting gonadotropin levels during acute stress.

This work was supported by NIH Grants RO1-HD-15788 and DK-03892 and a grant from the Robert A. Welch Foundation (I-1090).

M.J.M. and F.J.H. contributed equally to this work.

Abbreviations: AR, Androgen receptor; CHO, Chinese hamster ovary; CV, coefficient of variation; DHT, 5-dihydrotestosterone; HH, hypogonadotropic hypogonadism; HPG, hypothalamic-pituitary- gonadal; LBD, ligand-binding domain; MI, myocardial infarction; PAIS, partial androgen insensitivity syndrome; T, testosterone.