Delayed puberty

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The main aims of treatment are ensuring attainment of secondary sexual characteristics and induction of the pubertal growth spurt.

Most patients have temporary delay of puberty, particularly boys who have constitutional delay in puberty, and are best observed with serial monitoring. If a specific underlying disorder causing pubertal delay is identified, such as a chronic illness, stress, malnutrition, or excessive exercise, it must be treated. Patients with a pituitary tumour need urgent evaluation and a neurosurgical review. Surgery is indicated in most instances.

Hormone therapy is reserved for patients with confirmed organic gonadotrophin deficiency (hypogonadotrophic hypogonadism), for those with a gonadal abnormality (e.g., Turner's syndrome, Klinefelter's syndrome), and for those with constitutional delay who have severe delay or abnormal psychosocial adjustment. Typically, those with constitutional delay require only a short course to activate puberty. Patients with organic delay require early diagnosis and treatment to achieve normal development and optimal height, avoid issues of psychosocial adjustment with peers, and optimise potential for future fertility where possible. Patients should be treated by a paediatric endocrinologist experienced in the management of delayed puberty.

It is often difficult, following investigations at the time of delay, to distinguish between constitutional delay and organic gonadotrophin deficiency, as the basal gonadotrophin concentrations may be low in both groups. Thus, it does not clarify whether an individual will progress in puberty spontaneously or has a permanent defect. Some patients with delay are presumed to have organic gonadotrophin deficiency and are treated with sex steroids throughout puberty, but they are re-evaluated after completion of growth and puberty. Those with constitutional delay will reveal normal gonadotrophin concentrations on re-testing, but those with organic gonadotrophin deficiency will continue to have low serum gonadotrophin concentrations. Re-evaluation after a period of treatment to ascertain the need for long-term hormone replacement is therefore indicated in those patients with ambiguous results in pre-puberty.

Temporary delay

Constitutional delay

Patients need monitoring to assess for progression of pubertal signs and an increased height velocity. Treatment is often not required.
Some boys have severe delay or abnormalities of psychosocial adjustment. These patients may benefit from a short (3- to 6-month) course of depot testosterone to induce puberty. Adverse effects associated with testosterone treatment include erythrocytosis, weight gain, and prostate hyperplasia.[1] While these are rare, they should be monitored during treatment. Once activated, puberty often progresses spontaneously despite withdrawal of treatment.
Girls, too, often do not require any treatment apart from serial monitoring. However, if required, in those with severe delay or psychosocial concerns, a short (3- to 6-month) course of estradiol therapy may be offered. They are then allowed to progress spontaneously after discontinuation of treatment.

Chronic illnesses, malnutrition, eating disorders, excessive exercise, stress

Treatment of the underlying cause may resolve the pubertal delay, with subsequent spontaneous pubertal progression. In those with a severe delay, treatment may be instituted with a short course of sex steroids until spontaneous pubertal development recovers.

Organic (permanent) delay

Pubertal induction must be carried out in as physiological a manner as possible to allow normal development and achievement of the optimum growth potential. Patients with an organic (permanent) cause need lifelong sex-steroid replacement. Pubertal induction and lifelong hormone replacement is almost certainly required in patients with congenital gonadotrophin deficiency (although ‘reversal’ of the phenotype is seen in approximately 10% of patients) and in males with anorchia.[53]

Patients with acquired gonadotrophin deficiency (following radiation, pituitary surgery, trauma, or iron overload); those with congenital gonadal abnormalities such as cryptorchidism (males), Klinefelter's syndrome (males), Turner's syndrome (females), and other forms of gonadal dysgenesis (e.g., XY gonadal dysgenesis, 45X/46XY mixed gonadal dysgenesis); and those with acquired gonadal abnormalities such as testicular damage following torsion or surgery, autoimmune disorders, chemotherapy, or viral infections (e.g., mumps in males) also need induction of puberty and lifelong hormone replacement therapy, depending on the severity of the disease. Re-evaluation at the end of growth and puberty to ascertain the need for long-term replacement may be indicated in some of those patients who had ambiguous results pre-puberty.

Pubertal induction

Males

Pubertal induction is carried out gradually, with a low starting dose of intramuscular testosterone therapy that is increased until adult levels are reached. Doses are typically increased gradually over approximately 2 years, at 6-month intervals.
The serum levels of testosterone achieved through the intramuscular route are not physiological. Some boys report symptoms of irritability, aggression, and hypersexuality in the days following the injection.
Serum total testosterone levels should be checked 1 week after therapy to assess whether the doses are therapeutic.

Males with Klinefelter's syndrome usually do not require pubertal induction, and only require testosterone supplementation if they manifest with symptoms of hypogonadism, have low-normal serum testosterone, and raised gonadotrophins.[54]

Males with permanent hypogonadotrophic hypogonadism can have pubertal induction with GnRH or gonadotrophin therapy, rather than testosterone, to mimic physiology and facilitate testicular development and sperm production.[55][56] Doses are increased gradually to induce puberty over 1 to 3 years. Combination therapy with recombinant follicle-stimulating hormone (rFSH) and human chorionic gonadotrophin (hCG) are most commonly used. Careful monitoring is required to target physiological serum concentrations of FSH and testosterone, and such regimes should be limited to experienced centres.[56]

Females

Females require gradually increasing doses of oestrogen treatment, with cyclic progesterone therapy introduced when adequate oestrogenisation has occurred (usually 2-3 years) or at the onset of uterine breakthrough bleeding. Puberty should not be induced using contraceptive pills or patches because the doses of oestrogen are too high and the androgenic progestogens impair optimal breast development.
The preferred preparations are either transdermal or oral estradiol in the smallest available dose. However, synthetic oral oestrogen may also be used as an alternative. Transdermal delivery avoids first-pass effects on the liver.[57]
Various brands exist for both transdermal and oral preparations. The dose is increased gradually over approximately 2 years, at 6-month intervals, to a full adult dose and/or until breast development is satisfactory.
Cyclic progesterone therapy is introduced when adequate oestrogenisation has occurred or at the onset of uterine breakthrough bleeding, to induce menstruation.
Girls with Turner's syndrome may also require growth hormone and/or oxandrolone treatment to achieve adequate final height.[58] See Turner's syndrome.

Ongoing treatment