madman
Super Moderator
Abstract
The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as the constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings, and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism.
Delay of puberty
The process of puberty and its delay
Physiological pubertal development encompasses a sequential series of pubertal stages, usually occurring between the age of 8 and 13 years in females, and 9 and 14 years in males. The first signs of pubertal development are represented by testicular enlargement (testicular volume >3 mL) in males and breast budding (thelarche) in females. The appearance of pubic and axillary hair is mainly dependent upon adrenal androgens and, if isolated, should not be interpreted as the beginning of gonadotrophin-dependent puberty [1, 2]. However, in some ethnic populations pubarche may be the first sign of pubertal onset in a large proportion of children.
The mechanisms involved in the timing of puberty are complex and currently not fully understood, but several intrinsic (e.g. genetic) and environmental cues are involved in this process [3, 4].
Pubertal delay refers to the absence of the first signs of pubertal development beyond the normal age distribution (>2–2.5 standard deviation above the mean of the reference population) or, when pubertal progress arrests after an initial physiological start [ 5]. A considerable delay in pubertal onset is associated with a significant somatic and psychological impact on the adolescent [6].
Causes of delayed puberty
Delay of puberty is very common. Constitutional delay of growth and puberty (CDGP) is the most frequent form and is a paraphysiological self-limited condition. Highly variable conditions include the various causes of primary and central hypogonadism (Table 1).
*Hypergonadotropic hypogonadism
*Central hypogonadism
*Clinical features
*Hormones and stimulation tests
*Genetics
*Priming
Conclusions: How can one approach the differential diagnosis?
From the above, it is clear that there is no strong and unequivocal evidence to guide us in the differential diagnosis and management of CDGP and CHH. However, according to the pathophysiology of these two conditions, we propose a tentative flow-chart that could lead through this tangle of tests and approaches (Fig. 1).
First of all, girls and boys with pubertal delay who do not have any of the typically associated features can be reassured before 13 or 14 years, respectively [8, 48, 49], as these ages are considered the upper limit of physiological puberty. If no sign of puberty has emerged at these ages, or if puberty does not progress appropriately according to puberty nomograms for girls and boys, respectively [50, 51], the determination of gonadotropins and bone age can be useful as a first diagnostic approach. High gonadotropins point to a primary gonadal defect and karyotype is a key step for the definition of these cases. In the case of gonadotropins that are inappropriately low for the hypogonadal state a significant bone age delay is indicative of a complete pubertal immaturity and in the absence of particular phenotypes a CDGP is the most likely condition. Based on the above-reported data and the potential benefits for psychological wellbeing and final height [42], LDSS priming should be proposed to promote a jump start of spontaneous puberty in CDGP after a thorough discussion with the patient and their parents. Certainly, if differential diagnoses of CHH or hypergonadotropic hypogonadism are reached, appropriate steroid or gonadotropin treatment should be given in a timely manner at ages corresponding to physiological puberty in order to minimize psychologically and somatic consequences.
The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as the constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings, and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism.
Delay of puberty
The process of puberty and its delay
Physiological pubertal development encompasses a sequential series of pubertal stages, usually occurring between the age of 8 and 13 years in females, and 9 and 14 years in males. The first signs of pubertal development are represented by testicular enlargement (testicular volume >3 mL) in males and breast budding (thelarche) in females. The appearance of pubic and axillary hair is mainly dependent upon adrenal androgens and, if isolated, should not be interpreted as the beginning of gonadotrophin-dependent puberty [1, 2]. However, in some ethnic populations pubarche may be the first sign of pubertal onset in a large proportion of children.
The mechanisms involved in the timing of puberty are complex and currently not fully understood, but several intrinsic (e.g. genetic) and environmental cues are involved in this process [3, 4].
Pubertal delay refers to the absence of the first signs of pubertal development beyond the normal age distribution (>2–2.5 standard deviation above the mean of the reference population) or, when pubertal progress arrests after an initial physiological start [ 5]. A considerable delay in pubertal onset is associated with a significant somatic and psychological impact on the adolescent [6].
Causes of delayed puberty
Delay of puberty is very common. Constitutional delay of growth and puberty (CDGP) is the most frequent form and is a paraphysiological self-limited condition. Highly variable conditions include the various causes of primary and central hypogonadism (Table 1).
*Hypergonadotropic hypogonadism
*Central hypogonadism
*Clinical features
*Hormones and stimulation tests
*Genetics
*Priming
Conclusions: How can one approach the differential diagnosis?
From the above, it is clear that there is no strong and unequivocal evidence to guide us in the differential diagnosis and management of CDGP and CHH. However, according to the pathophysiology of these two conditions, we propose a tentative flow-chart that could lead through this tangle of tests and approaches (Fig. 1).
First of all, girls and boys with pubertal delay who do not have any of the typically associated features can be reassured before 13 or 14 years, respectively [8, 48, 49], as these ages are considered the upper limit of physiological puberty. If no sign of puberty has emerged at these ages, or if puberty does not progress appropriately according to puberty nomograms for girls and boys, respectively [50, 51], the determination of gonadotropins and bone age can be useful as a first diagnostic approach. High gonadotropins point to a primary gonadal defect and karyotype is a key step for the definition of these cases. In the case of gonadotropins that are inappropriately low for the hypogonadal state a significant bone age delay is indicative of a complete pubertal immaturity and in the absence of particular phenotypes a CDGP is the most likely condition. Based on the above-reported data and the potential benefits for psychological wellbeing and final height [42], LDSS priming should be proposed to promote a jump start of spontaneous puberty in CDGP after a thorough discussion with the patient and their parents. Certainly, if differential diagnoses of CHH or hypergonadotropic hypogonadism are reached, appropriate steroid or gonadotropin treatment should be given in a timely manner at ages corresponding to physiological puberty in order to minimize psychologically and somatic consequences.
