madman
Super Moderator
Abstract
Clinical manifestations and the need for treatment vary according to age in males with hypogonadism. Early fetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in fetal life presents with micropenis, cryptorchidism, and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between the constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relatively short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective in inducing an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.
Introduction
The concept of male hypogonadism is often associated with low testosterone production by the testes. This notion derives from adult endocrinology; indeed, during adulthood, testosterone is the most conspicuous testicular hormone because of its circulating levels and target organ actions. Conversely, in pediatric endocrinology, basal serum testosterone determination is helpful only during the first months following birth and after mid-puberty.1 During the rest of infancy and childhood, serum testosterone is physiologically below the detectable levels using classical assays, and anti-Müllerian hormone (AMH)2–4 and inhibin B4 are more adequate biomarkers to initially screen testicular function (Figure 1).
*The ontogeny of the hypothalamic-pituitary-testicular axis: its importance for the diagnosis of male hypogonadism
-The prenatal period: consequences of fetal-onset hypogonadism
-Childhood: male hypogonadism may remain unnoticed
-Adolescence: pubertal delay
*Pharmacotherapy for male hypogonadism
Medicines used
-Androgenic drugs
-DHT
-Nandrolone and oxandrolone
-Aromatase inhibitors
-Gonadotrophin formulations
*Pharmacotherapy in neonates and infants
-Treatment of newborns/infants with DSD
-Treatment of newborns/infants with primary hypogonadism and completely virilized genitalia
-Treatment of newborns/infants with central hypogonadism
*Pharmacotherapy in childhood
*Pharmacotherapy at pubertal age
-Treatment of patients with DSD or delayed puberty due to primary hypogonadism
-Treatment of patients with constitutional delay of puberty or central hypogonadism
-Androgen therapy
-Aromatase inhibitors
-Gonadotrophins and GnRH
Concluding remarks and research agenda
All treatments used in pediatric patients with hypogonadism are off-label. Testosterone administration IM is the most frequently used therapy in order to provoke genital enlargement in childhood or the full development of secondary sexual characteristics and growth spurt in adolescents. While this is the only possibility for patients with primary hypogonadism, the administration of gonadotrophins or GnRH may represent a more physiological therapy in boys with central hypogonadism. Clinical trials with long-term follow-up are needed to assess whether gonadotrophin treatment yields better results than initial androgen replacement followed by gonadotropin treatment in adulthood when fertility is sought. Other possibilities based on recently developed technologies, such as Leydig cell133 or spermatogenic134 development in vitro, represent stimulating alternatives.
Clinical manifestations and the need for treatment vary according to age in males with hypogonadism. Early fetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in fetal life presents with micropenis, cryptorchidism, and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between the constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relatively short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective in inducing an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.
Introduction
The concept of male hypogonadism is often associated with low testosterone production by the testes. This notion derives from adult endocrinology; indeed, during adulthood, testosterone is the most conspicuous testicular hormone because of its circulating levels and target organ actions. Conversely, in pediatric endocrinology, basal serum testosterone determination is helpful only during the first months following birth and after mid-puberty.1 During the rest of infancy and childhood, serum testosterone is physiologically below the detectable levels using classical assays, and anti-Müllerian hormone (AMH)2–4 and inhibin B4 are more adequate biomarkers to initially screen testicular function (Figure 1).
*The ontogeny of the hypothalamic-pituitary-testicular axis: its importance for the diagnosis of male hypogonadism
-The prenatal period: consequences of fetal-onset hypogonadism
-Childhood: male hypogonadism may remain unnoticed
-Adolescence: pubertal delay
*Pharmacotherapy for male hypogonadism
Medicines used
-Androgenic drugs
-DHT
-Nandrolone and oxandrolone
-Aromatase inhibitors
-Gonadotrophin formulations
*Pharmacotherapy in neonates and infants
-Treatment of newborns/infants with DSD
-Treatment of newborns/infants with primary hypogonadism and completely virilized genitalia
-Treatment of newborns/infants with central hypogonadism
*Pharmacotherapy in childhood
*Pharmacotherapy at pubertal age
-Treatment of patients with DSD or delayed puberty due to primary hypogonadism
-Treatment of patients with constitutional delay of puberty or central hypogonadism
-Androgen therapy
-Aromatase inhibitors
-Gonadotrophins and GnRH
Concluding remarks and research agenda
All treatments used in pediatric patients with hypogonadism are off-label. Testosterone administration IM is the most frequently used therapy in order to provoke genital enlargement in childhood or the full development of secondary sexual characteristics and growth spurt in adolescents. While this is the only possibility for patients with primary hypogonadism, the administration of gonadotrophins or GnRH may represent a more physiological therapy in boys with central hypogonadism. Clinical trials with long-term follow-up are needed to assess whether gonadotrophin treatment yields better results than initial androgen replacement followed by gonadotropin treatment in adulthood when fertility is sought. Other possibilities based on recently developed technologies, such as Leydig cell133 or spermatogenic134 development in vitro, represent stimulating alternatives.
