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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1053-1058
Copyright © 2004 by The Endocrine Society

CLINICAL CASE SEMINAR

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

Nelly Pitteloud, Jacob Villegas, Andrew A. Dwyer, William F. Crowley, Jr., Michael J. McPhaul and Frances J. Hayes

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOGONADISM IS DEFINED as a defect in either or both of the two major functions of the testis, i.e. the production of testosterone (T) and/or spermatogenesis. Primary or hypergonadotropic hypogonadism results from a defect occurring at the level of the testis, whereas secondary or hypogonadotropic hypogonadism (HH) results from a defect at the hypothalamus and/or pituitary. Although serum gonadotropin levels distinguish primary from secondary hypogonadism in most instances, there are occasions where they may be misleading. Gonadotropin levels cannot be relied upon to detect concomitant central and testicular defects in the hypothalamic-pituitary-gonadal (HPG) axis. Severe illnesses, such as surgical trauma (1, 2), starvation (3), acute and chronic opioid use (4), burns (5), and myocardial infarction (MI) (6), are all clinical circumstances accompanied by a disruption of the HPG axis in men. During major stress, a biphasic response in gonadotropin secretion has been observed. Such stresses directly suppress Leydig cell production of T immediately after their onset. When the stress becomes prolonged, hypogonadotropism supervenes, further decreasing serum T levels (7). Thus, HH induced by chronic stress may mask an underlying primary gonadal defect.

In this report we describe a 61-yr-old man who presented with an unusual phenotype and suppressed gonadotropin levels in the setting of an acute MI and chronic corticosteroid therapy. Clinical, molecular, and genetic studies ultimately revealed partial androgen insensitivity syndrome (PAIS) caused by a novel partially inactivating mutation (Ser740Cys) in the ligand-binding domain (LBD) of the androgen receptor (AR). This unique case highlights the critical role of stress and/or corticosteroid therapy in inducing HH and thereby masking the typical biochemical profile of PAIS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case presentation

A 61-yr-old man was admitted to the Massachusetts General Hospital for acute MI. His hospital course was complicated by ventricular tachycardia, necessitating the placement of a defibrillator. An endocrine consultation was sought when physical examination demonstrated severe undervirilization. On questioning, it was revealed that the proband was born with anomalies of his genitalia, including microphallus, right cryptorchidism, and perineoscrotal hypospadias. He underwent several unsuccessful operations for correction of his hypospadias. The remaining fenestrations on the ventral side of his phallus resulted in his inability to urinate while standing.

In his midteens, he reported an increase in libido and erections without ejaculation. However, he failed to develop any secondary sexual characteristics, had no growth of his phallus or testes, and developed significant breast enlargement. He never sought medical attention for his undervirilization, but had reduction mammoplasty for his prominent bilateral gynecomastia. He had never been married or had sexual intercourse. His past medical history included type I diabetes mellitus since the age of 9 yr complicated by coronary artery disease and mild peripheral neuropathy (hemoglobin A1c at presentation, 10.6%). He was also diagnosed with temporal arteritis 3 months before his MI. His medications included prednisone (60 mg daily), insulin therapy, furosemide, captopril, calcium, and vitamin D. On physical examination, he appeared feminized, with no facial hair and scant axillary and pubic hair. He had a female escutcheon and bilateral scars from mammoplasty. Genital examination revealed microphallus (stretched penile length, 2 cm) with fenestrations on the ventral side. Testicular size as measured by Prader orchidometer was prepubertal (1 ml on the right and 4 ml on the left), with no palpable masses.

Hormonal analysis d 5 post-MI

Hormonal assessment revealed serum T of 28 ng/dl (0.9 nmol/liter), 5{alpha}-dihydrotestosterone (DHT) of 3.4 ng/dl (0.12 nmol/liter), estradiol of less than 50 pg/ml (<180 pmol/liter), LH less than 1.6 IU/liter, FSH of 3.1 IU/liter, and a low inhibin B level of 55 pg/ml (normal range, 150–400). His thyroid function tests were consistent with euthyroid sick syndrome [TSH, 1.55 µU/ml (normal range, 0.5–5); T4, 4.2 µg/dl (normal range, 4.5–10.9); T3, 55 ng/dl (normal range, 60–181)]. His serum prolactin and ferritin concentrations were normal. Due to his high dose steroid therapy, the pituitary-adrenal axis was not evaluated. Semen analysis could not be performed, as the patient was unable to produce an ejaculate.

The family pedigree includes three affected individuals: the proband (III-1), a maternal aunt (II-3), and a grandniece (V-II). The aunt was married, but she did not have children. In her eighties, she confided to the proband that as an infant she had abnormal genitalia, which required surgery. The grandniece is now 4 yr old and was born with female external genitalia. However, soon after birth, she underwent surgery to remove inguinal testes and is being raised as a female. There was no evidence of consanguinity in the family.

Although most clinical features (undervirilization, minimal pubertal development, hypogonadal T, and low gonadotropin levels) were consistent with HH, severe hypospadias is not typically part of the phenotypic spectrum of congenital HH. Furthermore, the patient exhibited an X-linked disorder of ambiguous genitalia. We therefore hypothesized that the combination of acute stress and chronic glucocorticoid administration induced transient HH in a patient with PAIS in whom gonadotropin levels would have otherwise been elevated. To prove this hypothesis, we conducted the following clinical, genetic, and molecular studies.

Clinical studies

Hormonal assessment 6 months post-MI. The patient agreed to return for a follow-up visit 6 months after his admission for acute MI, at which time his serum gonadotropin and T levels were repeated.

Hormonal assessment 12 yr previously. At our request, the proband gave his consent to retrieve the results of a clinical blood sample drawn at another institution 12 yr previously, which included gonadotropin and T measurements.

Determination of the AR coding sequence

After obtaining written informed consent, blood samples were obtained to prepare DNA and to establish a continuous lymphoblastoid cell line. DNA was extracted both from whole blood samples and from this lymphoblastoid cell strain and was purified using routine methods. PCR amplifications of exons 1–8 were performed following published procedures (8). Each segment of the AR open reading frame was sequenced, with the exception of the GGC repeat encoding the glycine homopolymeric segment. Alterations in sequence that were identified were confirmed by sequence analysis of fragments that were derived from two separate amplifications.

Functional characterization of the mutant AR

A cDNA encoding the mutant AR was prepared by PCR mutagenesis and cloned into a mammalian expression vector for use in functional studies. Receptor function was assessed by transfection of CV1 cells with an expression vector encoding the mutant or normal AR and the mouse mammary tumor virus luciferase reporter plasmid. Twenty-four hours after transfection, the medium was changed to include 5% charcoal-stripped serum containing no hormone or varying concentrations of T, DHT, or mibolerone (7,17-dimethyl, 19-nortestosterone) (9). After an additional 48 h of incubation, the cells were harvested, and luciferase activity was measured. Luciferase activity reflects the transcriptional activity of the different ARs.

Ligand binding properties of the mutant AR

The mutant AR predicted from the analysis of the patient DNA sample was stably expressed in Chinese hamster ovary (CHO) cells to examine the binding characteristics of the mutant receptor protein (9). Cultures of CHO cells were transfected with expression plasmids encoding the normal or mutant AR and the selectable marker, G418. Pools of approximately 200 G418-resistant colonies were propagated as pools. These populations were used to compare the kinetics of ligand binding by normal and mutant ARs. Immunoblots were performed to permit the results of the ligand binding and functional assays to be interpreted in light of the levels of receptor protein expressed (10).

Hormone assays

Serum LH and FSH concentrations were determined by microparticle enzyme immunoassay using the automated AxSYM system (Abbott Laboratories, Chicago, IL). The Second International Reference Preparation was used as the reference standard. The assay sensitivity for both LH and FSH was 1.6 IU/liter. The intraassay coefficients of variation (CVs) for LH and FSH were less than 7% and less than 6%, respectively, with interassay CVs for both hormones of less than 7.4%. Serum T concentrations were measured using the Coat-A-Count RIA kit (Diagnostic Products Corp., Los Angeles, CA), which had intra- and interassay CVs of less than 10%. Inhibin B was measured using a commercially available (Serotec, Oxford, UK), double-antibody ELISA. In our use, the clinical detection limit of this assay is 50 pg/ml, with a CV of 4–6% within plate and 15–18% between plates. Estradiol was measured by the Abbott AxSYM system, which had an analytical sensitivity of 10 pg/ml and a functional sensitivity of 20 pg/ml. The intraassay CV is 6.4%, and the interassay CV is 10.6%. DHT was measured in serum or plasma after oxidation and extraction of samples using a commercial solid phase immunoassay (Diagnostic Systems Laboratories, Inc., Webster, TX). The limit of detection is 5.0 pg/ml, and the reportable range of the method is 5–2000 pg/ml. Specimens containing levels higher than 2000 pg/ml must be diluted and retested. The within-assay precision is less than 7%, and the between-assay CV is less than 10%. The reference range (95% confidence interval) for reproductively healthy men is 240–850 pg/ml.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical studies

Hormonal assessment 6 months post-MI. The patient returned 6 months after his admission for acute MI, after his cardiac condition had stabilized. At this time, the prednisone dose for his temporal arteritis had been titrated to the lowest controlling dose (20 mg). His hormonal profile now demonstrated elevated gonadotropin levels and a T level in the mid-normal range (Table 1Go). His thyroid function tests had normalized.


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  		TABLE 1. Biochemical profile of a patient with PAIS at different points in his care

 
Hormonal assessment 12 yr previously. The blood sample drawn 12 yr previously demonstrated markedly elevated T and gonadotropin levels (Table 1Go).

DNA sequencing

Direct sequencing analysis of PCR products revealed the presence of a previously unreported missense mutation on codon 740 in the fifth exon, changing TCC (serine) to TGC (cysteine). Serine 740 is located in the LBD of the AR protein. The mutation was confirmed on both strands using DNA from two separate amplifications. Neither the maternal aunt nor the grandniece was tested for the mutation.

The S740C mutant AR is defective in functional assays

The clinical phenotype suggested a partial defect of AR function. In keeping with this expectation, functional studies demonstrated reduced activity of the mutant AR compared with the normal AR. This defect was most pronounced in response to stimulation with physiological ligands, such as DHT and T. Although the level of reporter gene activation effected by the normal AR increased as the concentration of DHT was increased, only low levels of activation were observed for the mutant AR assayed in parallel. Activation was even more profoundly abnormal in response to stimulation with T (data not shown). In contrast, the activity of the mutant AR was similar to that of the normal AR after stimulation with saturating concentrations of mibolerone (Fig. 1Go).



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  		FIG. 1. The S740C mutant AR is impaired in functional assays. CV1 cells were transfected with the mouse mammary tumor virus-luciferase reporter plasmid and expression vectors encoding either normal or mutant AR. Twenty-four hours later, the medium was changed to medium containing 5% charcoal-stripped serum with no hormone, mibolerone, or 5{alpha}-DHT at the indicated concentrations. After an additional 48 h of incubation, the cells were harvested, and luciferase activity was measured. The data from one representative experiment are presented and are normalized to the luciferase values measured compared with the activity measured after stimulation of the normal AR with 2 nM mibolerone (shown as the numbers above the individual bars). In this figure, this value is set at 100% and corresponds to an activity of 1.1 x 107 relative light units.

 
The S740C mutant AR displays altered ligand-binding kinetics

To examine the basis for the differences in activity observed in functional assays, we established cell strains that stably express the normal and mutant ARs. These cell strains were then assayed to measure the specific activity of androgen binding in a whole cell binding assay using tritiated mibolerone and DHT. These findings demonstrate that although the S740C mutant AR is able to bind mibolerone with high affinity, it does so with approximately 2-fold lower affinity compared with binding by the normal AR (data not shown). This abnormality of ligand binding is even more pronounced when binding assays are conducted using tritiated DHT (Fig. 2Go), with specific binding by the mutant AR detected only at the highest ligand concentrations. These differences cannot be accounted for by the levels of immunoreactive AR detected in the cell strains (Fig. 2Go, inset).



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  		FIG. 2. The S740C mutant human AR (hAR) displays altered ligand-binding kinetics. CHO cells expressing the normal or mutant AR were incubated with the indicated concentrations of tritiated DHT in the presence or absence of a 200-fold excess of unlabeled steroid for 1 h at 37 C. After this incubation, the cells were assayed to determine the quantity of bound labeled steroid. The data presented represent the quantity of specifically bound DHT (femtomoles bound per milligram of cellular protein). In these comparisons, low levels of specific binding can only be detected at the highest DHT concentrations. Immunoblot analyses (inset) demonstrate that the cells stably expressing the normal AR contain approximately 4-fold more immunoreactive AR than cells expressing the mutant AR.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this report we describe a 61-yr-old man with absence of virilization, minimal pubertal development, hypospadias, and unilateral cryptorchidism, whose biochemical profile assessed during acute illness indicated HH. However, the presence of hypospadias, family history of an X-linked mode of inheritance of ambiguous genitalia, and prior elevated gonadotropin and T levels all suggested the diagnosis of PAIS. This case demonstrates that acute illness and/or corticosteroid use can induce HH and thereby mask the typical biochemical phenotype of the PAIS patient characterized by elevated gonadotropin and T levels. Molecular analysis confirmed the diagnosis and revealed a novel, partially inactivating mutation (Ser740Cys) in the LBD of the AR protein.

The patient exhibited most of the clinical features characteristic of congenital HH. He had microphallus, unilateral cryptorchidism, undervirilization, small testes, a hypogonadal T level, and undetectable gonadotropin levels. The key clinical finding inconsistent with congenital HH was the presence of severe hypospadias. Indeed, placental human chorionic gonadotropin stimulation of intratesticular T, which is required for normal virilization of the internal and external genitalia (11), is intact in patients with congenital HH; consequently, severe hypospadias is not observed (12). In contrast to hypospadias, cryptorchidism and microphallus, which are also part of the phenotypic spectrum of intersex disorders, may occur in patients with congenital HH (12). This finding indicates that endogenous LH stimulation of T secretion participates in the inguino-scrotal descent of the testes and the growth of the phallus during the late fetal and early neonatal periods (13). Thus, in this case the presence of severe hypospadias suggested an anomaly of sexual differentiation, the differential diagnosis of which includes Leydig cell hypoplasia (14), 5{alpha}-reductase deficiency (15), 17{alpha}-hydroxylase deficiency (16), and androgen insensitivity (17). After careful discussion with the patient, we ultimately obtained the family pedigree, which was consistent with an X-linked disorder. Although the clinical phenotype and mode of inheritance were consistent with the diagnosis of PAIS, the biochemical profile of HH was discordant. Typically patients with AIS have elevated T levels, which first become evident at the time of puberty. LH is also increased, signaling androgen resistance at the level of the hypothalamo-pituitary unit (17). We hypothesized that severe illness induced transient HH, which, in turn, obscured the typical hypergonadotropic profile of PAIS. Subsequent measurement of his gonadotropin levels after the stress had passed and his glucocorticoid dose had been decreased confirmed this hypothesis.

Stress is well known to have a negative effect on reproduction across species (18). A biphasic response to stress has been observed in males. In the acute phase, an immediate and direct Leydig cell suppression of T production occurs with increased or normal LH levels (19). It has been suggested that hormones secreted during stress, such as CRH, ACTH, glucocorticoids, catecholamines, and cytokines (IL-1 and IL-2) may have a direct gonadal effect, inhibiting steroidogenesis (20, 21, 22, 23). When the stress becomes prolonged, gonadotropins become suppressed, further decreasing T levels (6, 24). The exact mechanism underlying stress-induced HH is not fully understood. A centrally mediated inhibition of GnRH release has been proposed via the opiate or dopaminergic pathways (25, 26, 27). Studies in experimental animals support a direct central effect of both IL-1 and CRH in suppressing GnRH secretion (28, 29). Alternatively, HH could be the consequence of a decrease in pituitary responsiveness to GnRH due to a direct effect of corticosteroids on the gonadotropes (30, 31). The biphasic response to stress was not observed in this case, as hormonal assessment of the HPG axis was not performed until 5 d after his admission for acute MI. Interestingly, the magnitude of T suppression seems to correlate with the severity of illness (1); this is reminiscent of the euthyroid sick syndrome, where T3 levels reflect the severity of illness (32).

In the present case, high dose corticosteroid therapy is also likely to have contributed to the suppression of the HPG axis. Indeed, the administration of corticosteroids has been shown to suppress T secretion in men (33, 34, 35). The role of corticosteroids in this case is underscored by the submaximal increase in T levels after recovery from the patient’s MI, most likely due to the continued low dose of corticosteroid for temporal arteritis. As gonadotropin secretion seemed to have recovered at follow-up, it is possible that moderate doses of corticosteroid may have a direct inhibitory gonadal effect.

The proband in this case presented with undervirilization, perineoscrotal hypospadias, cryptorchidism, microphallus, and gynecomastia consistent with PAIS. To date, more than 300 mutations in the AR have been identified to cause AIS (36). Molecular analysis of the AR gene in the proband revealed a novel mutation (Ser740Cys) located at the edge of the fourth helix of the LBD. This region shows a high degree of conservation across species and within members of the steroid receptor family (37). Although cysteine 740 does not interact directly with the ligand (37, 38), the substitution of a serine for a cysteine residue would be anticipated to disturb adjacent structures and the interaction of the receptor with ligand. In keeping with this expectation, activation of the mutant AR by physiological ligands such as DHT is considerably weaker than that of the normal AR and approaches that of the normal AR only at high concentrations of DHT. By contrast, activation of the mutant AR by a potent androgen agonist, mibolerone, is near normal. These findings are consistent with the results of ligand binding assays in which the specific binding of mibolerone could be measured in whole cell binding assays, even under conditions in which the specific binding of DHT could not be detected. These results support a destabilizing effect of the Ser740Cys mutation on the AR-ligand complex, as has been observed for other mutant ARs (9).

In conclusion, we describe for the first time a patient with PAIS presenting with transient HH induced by severe illness that masked the typical hypergonadotropic profile of PAIS. This case further emphasizes the critical role of stress in men in suppressing the HPG axis and demonstrates the need for caution in interpreting gonadotropin levels during acute illness.


   Footnotes
 
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{alpha}-dihydrotestosterone; HH, hypogonadotropic hypogonadism; HPG, hypothalamic-pituitary- gonadal; LBD, ligand-binding domain; MI, myocardial infarction; PAIS, partial androgen insensitivity syndrome; T, testosterone.

Received August 6, 2003.

Accepted December 4, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals