Assessment of testicular function in boys and adolescents

[madman]

Abstract

Objective: The hypothalamic‐pituitary‐testicular axis is characterized by the existence of major functional changes from its establishment in fetal life until the end of puberty. The assessment of serum testosterone and gonadotrophins and semen analysis, typically used in the adult male, is not applicable during most of infancy and childhood. On the other hand, the disorders of the gonadal axis have different clinical consequences depending on the developmental stage at which the dysfunction is established. This review addresses the approaches to evaluate the hypothalamic-pituitary-testicular axis in the newborn, during childhood, and at pubertal age.

Design: We focused on the hormonal laboratory and genetic studies as well as on the clinical signs and imaging studies that guide the aetiological diagnosis and the functional status of the gonads.

Results: Serum gonadotrophin and testosterone determination are useful in the first 3–6 months after birth and at pubertal age, whereas AMH and inhibin B are useful biomarkers of testis function from birth until the end of puberty. Clinical and imaging signs are helpful in appraising testicular hormone actions during fetal and postnatal life.

Conclusions: The interpretation of results derived from the assessment of hypothalamic-pituitary-testicular in pediatric patients requires a comprehensive knowledge of the developmental physiology of the axis to understand its pathophysiology and reach an accurate diagnosis of its disorders.




1 | INTRODUCTION

1.1 | Scope of the review

The hypothalamic‐pituitary‐testicular axis shows significant functional changes from fetal life to adulthood. While its assessment in the adult most frequently relies on the determination of serum testosterone and gonadotrophins and on semen analysis, this diagnostic strategy is inappropriate in most pediatric patients, especially during infancy and childhood 1 Furthermore, the impact of disorders of testicular function has different clinical consequences according to the stage of development at which the dysfunction is established.2 In this review, we will address the different diagnostic approaches to evaluate testicular function, including the hormonal laboratory and genetic studies as well as the clinical and imaging signs to be sought for as the expected consequences of gonadal dysfunction at different stages of postnatal life.


1.2 | Physiology of the prenatal and postnatal male gonadal axis




2 | ASSESSMENT OF TESTICULAR FUNCTION IN PREPUBERTY AND PUBERTAL AGE

2.1 | Patients with DSD

2.1.2 | Genetic studies
2.1.3 | Hormonal laboratory




2.2 | Newborns/infants with micropenis and/or cryptorchidism

2.2.1 | Physical examination and imaging
2.2.2 | Hormonal laboratory
2.2.3 | Genetic studies




2.3 | Patients born preterm or small for gestational age

2.3.1 | Physical examination and imaging
2.3.2 | Hormonal laboratory




2.4 | Boys with precocious pubertal maturation

2.4.1 | Physical examination and imaging
2.4.2 | Hormonal laboratory
2.4.3 | Genetic studies




2.5 | Adolescents with delayed or arrested puberty

2.5.1 | Physical examination and imaging
2.5.2 | Hormonal laboratory
2.5.3 | Genetic studies




2.6 | Boys and adolescents with miscellaneous conditions affecting testicular function




3 | CONCLUDING REMARKS

The assessment of the gonadal function in boys and adolescents differs significantly from the usually done in the adult male. The accurate knowledge of the developmental physiology of the axis is essential for the understanding of its pathophysiology and the diagnosis of the diverse conditions affecting it. While serum gonadotrophins and testosterone may be informative in the first 3–6 months after birth and at pubertal age, serum AMH and inhibin B are the most useful biomarkers during childhood. Both reflect Sertoli cell activity, the most relevant cell population in the prepubertal testis. At the age of puberty, the decline in serum AMH reflects a normal (or precocious) elevation of intratesticular androgen concentration, while the increase in serum inhibin is indicative of spermatogenic development in the seminiferous tubules.

 

[madman]

FIGURE 1 Developmental changes in serum levels of the pituitary‐testicular axis and their impact on anatomical aspects. In the first trimester of fetal life, testicular hormones are responsible for the virilization of the internal and external genitalia, independently of fetal gonadotrophins. Afterward, luteinizing hormone (LH) drives testosterone (T) secretion by Leydig cells, and follicle-stimulating hormone (FSH)regulates Sertoli cell proliferation and anti‐Müllerian hormone (AMH) and inhibin B levels. While T is needed for the descent of the testes to the scrotum and the enlargement of the penis, FSH provokes a modest increase in testicular size. All hormone levels increase after birth and remain high for 3–6 months. Thereafter, serum LH and T decline to undetectable levels during childhood, but AMH and inhibin B remain clearly detectable. Puberty is characterized by a reactivation of gonadotrophin and T secretion. T inhibits AMH production, whereas FSH and pubertal spermatogenesis upregulate inhibin B secretion. Testicular size increases dramatically, due to germ cell proliferation. Reprinted, with permission, from Salonia et al.1 © 2019 Springer Nature Limited. O, orchidometer; US, ultrasonography. [Color figure can be viewed atwileyonlinelibrary.com]

 

[madman]

FIGURE 2 Ontogeny of the hypothalamic‐pituitary‐testicular axis, and the clinical impact of hypogonadism on clinical presentation. The tests differentiate in the first trimester of fetal life, independently of pituitary gonadotropins. Androgens and AMH drive male genital differentiation; in their absence, female differentiation of the genitalia occurs. Hypogonadism in this period leads to ambiguous or female genitalia in XY individuals. In the second and third trimesters, androgens stimulate testicular descent and penile enlargement. Hypogonadism, either primary or central, results in micropenis, cryptorchidism, and/or microorchidism. In newborns, gonadotrophin and steroid secretion are active. Hypogonadism results in reduced penile enlargement. During childhood gonadotrophins and testosterone are low or undetectable. Hypogonadism established in this period does not result in clinically evident signs. During puberty, the gonadal axis is reactivated and results in the development of secondary sex characteristics. Hypogonadism results in absent or incomplete pubertal development. Reprinted, with permission, from Grinspon et al.4 © 2019 Elsevier Limited. [Color figure can be viewed at wileyonlinelibrary.com]

 

[madman]

TABLE 1 Reference ranges of hormones of the pituitary‐testicular axis according to age and pubertal stage.

 

[madman]

TABLE 2 Clinical and laboratory consequences of fetal‐onset male hypogonadism.

 

[madman]

TABLE 3 Hormonal laboratory assessment in boys with suspicion of precocious puberty.

 

[madman]

TABLE 4 Laboratory consequences of postnatal‐onset male hypogonadism.

 

[madman]

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