TRANSITION IN ENDOCRINOLOGY: Induction of puberty

Abstract

Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary-gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo-pituitary-gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5-10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative ('watch-and-wait') management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated 'red flag' clinical features. These 'red flags' comprise findings indicating lack of prior 'mini-puberty' (such as cryptorchidism or micropenis), or the presence of non-reproductive congenital defects known to be associated with specific hypogonadal syndromes, e.g. anosmia, deafness, mirror movements, renal agenesis, dental/digital anomalies, clefting or coloboma would be compatible with Kallmann (or perhaps CHARGE) syndrome. In children, interventions (whether in the form or treatment or simple reassurance) have been historically

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…174,175 Sex steroid therapy (that is, testosterone in male individuals and estradiol before estradiol + progesterone in female individuals) induces the characteristic changes of puberty, which includes psychosocial development (Table 4).…”

“…Virilization is typically the primary objective of treating CHH 174 in order to diminish the psychological suffering caused by sexual infantilism. 97,98,176 Accordingly, prompt initiation of therapy after diagnosis is important and usually involves an injectable testosterone ester (aromatizable androgen such as enanthate, cypionate or undecanoate) or transdermal testosterone application with the precise protocol depending on the age at diagnosis and local practice.…”

“…Such regimens help mimic natural puberty and maximize statural growth while affording time for psycho sexual development and minimizing the risk of precocious sexual activity. 95,174 Adult endocrinologists often see patients with CHH in late adolescence or early adulthood when the main complaint is the lack of pubertal development. 94 In such cases, the therapeutic approach is often more incisive than for younger patients, involving higher initial testosterone doses (200 mg testosterone enanthate monthly, then every 2-3 weeks) than those used by paediatric endocrinologists to induce more rapid virilization (Box 4).…”

“…The use of specific low-dose estradiol formulations (for example, 0.1 mg daily) are important. 174 Transdermal estradiol administration is started (from age 10 years at the earliest) at low doses (typically 0.05-0.07 μg/kg nocturnally), with the goal of mimicking estradiol levels during gonadarche. In older girls, when breast development is a high priority, the starting dose of transdermal estradiol can be 0.08-0.12 μg/kg.…”

Pubertal breast development in primary school girls in Sokoto, North-western Nigeria

“…Its onset requires an intact hypothalamic-pituitary-gonadal axis, the reactivation of the secretion of pulsatile gonadotrophin-releasing hormone from its stage of childhood quiescence, and the stimulation of luteinising hormone and follicle-stimulating hormone secretion, which in turn activate the production of the gonadal sex steroid, oestradiol, in girls. [1][2][3] The external sign of puberty onset in girls is the appearance of breast buds, because breast tissue is the primary target of oestradiol. This usually occurs between 10 and 11 years of age.…”