Growth hormone treatment during the transition period

INTRODUCTION — The effects of growth hormone deficiency (GHD) differ markedly depending on the life phase. During childhood and puberty, the most important effects of growth hormone (GH) are on linear growth and higher doses of GH are required for replacement therapy than in adulthood because the dose-response curve for growth is right-shifted compared with that for the metabolic effects. During adulthood, GHD is associated with altered body composition and diminished quality of life and much lower GH doses (relative and absolute) are required to counteract these effects.

The transition period refers to the interval between these phases, during which clinical care for an individual with GHD focuses on the following questions:

●Which individuals with childhood GHD will remain deficient as adults?

●When and how should testing be performed to determine whether an individual has persistent GHD?

●How should patients be monitored during and after the transition period to determine appropriate dosing for GH therapy?

●What are the benefits of GH replacement therapy once linear growth has ceased?

These questions are not relevant to the disorders in which GH is given for reasons other than GHD, including being born small for gestational age, chronic kidney disease, Turner syndrome, Prader-Willi syndrome (which may represent a GH-deficient state), Noonan syndrome, and idiopathic short stature. For these disorders, GH therapy is generally stopped when linear growth is complete, with the possible exception of Prader-Willi syndrome (where some affected patients have GHD, but virtually all have excessive fat and diminished lean body mass), for which GH is sometimes continued into adulthood to regulate body composition (increase lean body mass) [1-3]. (See "Prader-Willi syndrome: Management", section on 'Recombinant growth hormone treatment'.)

Management of individuals with GHD during the transition period is discussed below. The diagnosis and management of GHD during the childhood and adult phases are discussed in separate topic reviews. (See "Diagnosis of growth hormone deficiency in children" and "Treatment of growth hormone deficiency in children" and "Growth hormone deficiency in adults".)

DEFINITION OF TRANSITION PERIOD — For individuals with GHD, the "transition period" is loosely defined as occurring from the mid- to late teenage years until six to seven years after reaching near-adult height.

ANTICIPATORY GUIDANCE — Planning for management of GHD during the transition period should start at the initial diagnosis of GHD. In the past, most pediatric endocrinologists only planned to treat the child with GHD until near-adult height was reached (ie, growth less than 2.0 to 2.5 cm/year, which corresponds to the downward slope of height velocity after passing peak height velocity). However, individuals with persistent GHD benefit from continuing GH treatment into adulthood because GH is required to achieve full adult body composition, regional distribution of body fat, and accrual of normal bone mineral content.

Therefore, the following issues should be discussed in detail with the family before GH treatment is begun:

●The child may require ongoing GH treatment during the transition period.

●The child should be retested for GHD during late adolescence (usually when they reach near-adult height). The exception is the child with one of the genetic, organic, or structural disorders that predictably leads to permanent GHD [4]. (See 'Genetic, organic, or structural causes of GHD' below.)

●If the child remains GH-deficient when retested, they will be referred to an endocrinologist who evaluates and treats adults with GHD.

●For individuals who remain GH-deficient during adulthood, lower doses of GH (both absolute and relative to body weight) are required for treatment as compared with childhood.

This discussion prepares the patient and family for the retesting and possible referral to another endocrinologist, when the appropriate time arrives. The pediatric endocrinologist typically initiates the process for retesting.

PREDICTING RISK FOR CONTINUING GROWTH HORMONE DEFICIENCY

Isolated growth hormone deficiency — Among children diagnosed with isolated GHD during childhood, more than two-thirds will have normal results when retested for GHD during late adolescence or adulthood [5]. These discrepancies are probably due in part to the inherent imprecision in diagnosing GHD, which is reflected in the low reproducibility of the stimulation test results. In addition, a mild GHD may not have clinically important effects during adulthood, because adults require only minimal concentrations of GH to affect its metabolic benefits.

Because the majority of patients with isolated GHD will be GH-sufficient by late adolescence or adulthood, it is important to repeat the GH stimulation testing during the transition period to determine if they require ongoing therapy [4,6-9]. (See 'Testing for continuing growth hormone deficiency' below.)

Genetic, organic, or structural causes of GHD — By contrast, GHD is permanent in virtually all patients with the following causes of GHD [6]:

●Genetic GHD (either isolated or as part of a more complex pituitary hormone deficiency syndrome). Genetic GHD is usually recognized by the presence of affected relatives and confirmed by molecular testing for the causative genes, which include POU1F1 (Pit-1), PROP1, and GH1. Patients with pathogenic variants in GH1 tend to develop neutralizing antibodies shortly after initiation of GH treatment, causing a characteristic rapid loss of the growth response to GH. (See "Diagnosis of growth hormone deficiency in children", section on 'Molecular genetics of growth hormone deficiency' and "Treatment of growth hormone deficiency in children", section on 'Growth response to recombinant human growth hormone therapy'.)

●Structural causes (eg, associated with midline craniofacial anomalies such as optic nerve hypoplasia/septo-optic dysplasia). GHD is highly likely to be permanent in patients with congenital anomalies, eg, agenesis of the hypothalamic-pituitary stalk (infundibulum), in the sellar or suprasellar region, as shown by magnetic resonance imaging [10,11]. An exception is the finding of an ectopic posterior pituitary, which is not consistently associated with permanent GHD [6].

●Organic causes of GHD:

•GHD following brain surgery and radiation therapy for craniopharyngioma or other brain tumors.

•GHD following irradiation therapy to the brain for hematologic malignancies (which is especially common with doses >40 Gy) [10,12]. Infants or young children are particularly vulnerable to developing permanent GHD after brain radiation; some also develop precocious puberty (especially girls).

•Multiple pituitary hormone deficiencies. As an example, for those with deficiencies of three or more pituitary hormones, the likelihood of persistent GHD is greater than 95 percent [13].

Because patients with these characteristics are very likely to have permanent GHD, extensive testing for GHD during the transition period is not necessary [6,10]. Instead, the ongoing deficiency can be confirmed by discontinuing GH therapy for approximately one month and then measuring the serum concentration of insulin-like growth factor 1 (IGF-1). If the IGF-1 concentration is below -2 standard deviations (SD) from the mean, ongoing GHD is confirmed and no further testing is necessary. In this case, the patients should have ongoing GH replacement during adolescence and adulthood, at age-appropriate doses. (See 'Insulin-like growth factor 1' below and 'Dosing and monitoring GH therapy during the transition and into young adulthood' below.)

Other predictors — Patients who have very low GH peaks during stimulation tests done as children (GH <3 ng/mL) are more likely to have permanent GHD as compared with those with higher peak stimulated levels [14].

TESTING FOR CONTINUING GROWTH HORMONE DEFICIENCY

When should retesting be done? — The optimal timing for testing for continuing GHD during the transition period has not been established. Each of the following approaches has merit:

●Retesting in mid-puberty. This approach is based on the hypothesis that entry into puberty stimulates GH secretion in those children who would eventually become GH-sufficient [15,16]. If the patient is no longer GH-deficient, then retesting at this time would reduce the length of GH treatment by three years or more [17].

●Retesting as near-adult height is reached (ie, when the height velocity decreases to less than 2.0 to 2.5 cm/year), generally occurring in late puberty. This is the most commonly used approach.

●Retesting at the end of the transition phase (age in mid-20s). Disadvantages of this approach are that patients without ongoing GHD would have several years of unnecessary treatment and those with ongoing GHD would be treated for several years with the higher doses required for growth stimulation rather than the lower dose required for metabolic effects in an adult. Therefore, this approach is not optimal for patients with isolated GHD, the majority of whom will not need ongoing GH treatment as adults.

For patients who have a history of cranial irradiation, the results of initial retesting should not be considered definitive, because radiation tends to cause progressive damage to the hypothalamus (mostly) and pituitary. Since GH deficiency may evolve over time, the diagnosis needs to be considered if suggested by clinical, laboratory, or radiologic data. Patients should also undergo ongoing monitoring for evidence of other pituitary hormone deficiencies during this period. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Hypothalamic-pituitary dysfunction'.)

Tests to evaluate for continuing GHD — Patients with isolated GHD, or those with deficiencies of GH and involvement of only one additional hypothalamic-pituitary-hormonal axis, should be evaluated to determine if their GHD is permanent [6,8]. The first step is to measure a serum level of insulin-like growth factor 1 (IGF-1) during a trial off of GH therapy. Those with a low level should be further evaluated with a GH stimulation test.

Testing is not necessary for patients with multiple (three or more) pituitary hormone deficiencies or an established genetic or structural cause other than an ectopic posterior pituitary gland. In this setting, the GHD can be presumed to be permanent and GH therapy continued [6,8]. (See 'Genetic, organic, or structural causes of GHD' above and 'Dosing and monitoring GH therapy during the transition and into young adulthood' below.)

Insulin-like growth factor 1 — The first step is to measure the serum concentration of IGF-1. GH therapy should be stopped for approximately one month prior to IGF-1 testing.

For patients with isolated GHD, or those with deficiencies of GH and only one additional pituitary hormone, a low IGF-1 result (<-2 standard deviations [SD] for age and sex) suggests the possibility of permanent GHD. These patients should be further evaluated with a GH stimulation test to confirm the diagnosis (see 'Growth hormone stimulation testing' below). A normal IGF-1 result (>0 SD) suggests that permanent GHD is unlikely and GH therapy can be stopped.

For patients with multiple (three or more) pituitary hormone deficiencies or an established genetic or structural cause other than an ectopic posterior pituitary, permanent GHD is likely. As a result, a consensus guideline suggests that testing is not necessary for these patients [6]. However, some experts still prefer to confirm a low IGF-1 during the transition period to establish the diagnosis of permanent GHD. If IGF-1 is low (<-2 SD), stimulation testing is not necessary for this group of patients [8].

Growth hormone stimulation testing — For patients with isolated GHD (or those with deficiencies of GH and one other pituitary hormone) and a low IGF-1 level, stimulatory testing is indicated to determine if GHD is persistent. GH therapy should be stopped for at least one month prior to testing [6,8]. For this purpose, one stimulation test is generally considered sufficient (although two different stimulants are recommended for the initial diagnosis of GHD in children). Several different stimuli have been used for this purpose:

●Insulin – The insulin tolerance test (ITT; or insulin-induced hypoglycemia test) remains widely regarded as the "gold standard" test for the diagnosis of adult GH deficiency. Because it induces hypoglycemia, it is contraindicated in patients with coronary or cerebrovascular disease or those at risk for seizures, such as patients who have had transcranial surgery for craniopharyngioma. In adult patients with multiple pituitary hormone deficiencies tested with ITT, a peak GH response of <5.1 mcg/L has approximately 95 percent specificity and sensitivity for detecting GHD, which is somewhat better than those for glucagon stimulation [8,10,18,19]. The cutoff values for adolescents may be slightly higher than those in adults [8,20]. (See "Growth hormone deficiency in adults", section on 'Insulin-induced hypoglycemia'.)

●Glucagon – A common approach is to use glucagon (1 mg) for a stimulation test [8,10]. Sampling is continued for three or four hours because there are some late responders to this stimulus. Published reports indicate a sensitivity of 97 to 100 percent and a specificity of 88 to 100 percent [21], but the evidence base for this test is limited. The GH response to glucagon stimulation depends on body mass index as well as glycemic dynamics [22,23]. Moreover, a separate study reported that 14 percent of the patients would have been misclassified by the glucagon stimulation test compared with the ITT [24].

●Macimorelin – Macimorelin acetate is a single-dose, oral ghrelin receptor agonist with GH secretagogue activity. It is approved by the US Food and Drug Administration for testing adults with suspected GHD. In adults, macimorelin has high reproducibility, sensitivity, and specificity, similar to testing with an ITT [8,25]. Compared with the ITT, testing with macimorelin has the advantages of having minimal adverse effects (it does not induce hypoglycemia) and taking less time, but the disadvantage of very high cost. The safety and efficacy of macimorelin in children and adolescents have not yet been established, with clinical trials in progress. (See "Growth hormone deficiency in adults", section on 'Provocative tests'.)

For all of these stimulation tests, the optimal cutoff and predictive value results in lean individuals differ markedly from those with obesity [8,26]. Individuals with obesity and without GHD have a blunted response to stimulation testing (lower peak value) as compared with lean individuals, and stimulation tests are somewhat less accurate [6].

Decision to treat in individuals who remain GH-deficient as adults — Stopping GH therapy during adolescence in a patient with ongoing GHD affects adult body composition. Muscle mass and bone mineral accrual are diminished, and regional distribution of body fat is altered, with increased total body fat and a greater proportion in the deep visceral compartment, changes that are associated with increased cardiovascular risk [10,27,28]. The effects of GH on bone mineral density are particularly important during early adulthood, when bone mass normally continues to accumulate. In addition, adult GHD is associated with subjective symptoms including diminished quality of life, especially energy and vitality [29]. Continued treatment with GH prevents most of these consequences [30,31].

For these reasons, for most patients with GHD during childhood who also have evidence of GHD when retested during the transition period, we suggest treatment with GH during adulthood. This will include most patients with underlying genetic, organic, or structural causes of GHD. By contrast, continued GH treatment in adulthood is not necessary for patients who remain asymptomatic when GH is withdrawn, particularly if the results of GH testing during the transition period are equivocal [10]. Treatment with GH is not recommended in patients with active malignancy. (See "Growth hormone deficiency in adults", section on 'Clinical manifestations'.)

Dosing and monitoring GH therapy during the transition and into young adulthood — The dose of GH required for growth during childhood and adolescence is higher in terms of absolute dose and far higher per kilogram of body weight (or per m² body surface area) compared with doses required to treat GHD during adulthood. The relatively high doses of GH are continued until linear growth is nearly complete (ie, the growth rate decelerates to 2.0 to 2.5 cm/year). A few adolescents with suboptimal growth on standard doses of GH are treated with "pubertal dosing" in the range of 70 micrograms/kg/day to mimic physiology and maximize linear growth (as compared with the usual prepubertal dose of 40 micrograms/kg/day). Studies of long-term effects using these high pubertal doses of GH are lacking. (See "Treatment of growth hormone deficiency in children", section on 'Duration of therapy'.)

After linear growth is complete, the patient is transitioned to "adult dosing" if ongoing GH treatment is indicated. The starting dose for an adult is approximately 200 to 300 micrograms/day (total dose). Women will often require a larger dose than men (in the range of 600 to 900 micrograms/day and more if they are receiving oral estrogens).

To optimize the GH dose for an adolescent during the transition period, we begin with the adult dose and then titrate to a serum IGF-1 level in the upper portion of the normal range for age and sex. In our practice, we measure serum IGF-1 concentrations one to two months after beginning the adult dose of GH and titrate the GH dose until the IGF-1 level is within the appropriate range without side effects, such as those related to fluid retention [32]. (See 'Adverse effects' below.)

Monitoring of therapy should follow the plan noted in the paragraph just above. When the appropriate dose is attained without side effects, the frequency of visits can decrease to one to two per year. At each visit, the history is reviewed for possible treatment-emergent adverse events, IGF-1 level, fasting glucose level, hemoglobin A1c, and a lipid profile. Since GH affects body composition and the regional distribution of body fat, we also obtain a dual-energy x-ray absorptiometry (DXA) scan for body composition and bone mineral density at the onset of therapy. If the initial results are abnormal, we repeat the scan periodically (eg, at least 18 months later) to objectively define the response to therapy [10,32].

Individuals with GHD during childhood caused by radiation therapy should be followed with serial stimulation tests during adulthood, even if the test during the transition period suggested no residual GHD. This is because the damage to the hypothalamus and pituitary function caused by radiation may continue to progress over 5 to 10 years after the end of the radiation therapy.

A quality-of-life inventory may be helpful in patients with somatic and psychological complaints because reduced quality of life can be an indication for GH therapy in GH-deficient adults. Quality of life is usually assessed via self-administered questionnaires that reflect a variety of health-related, economic, and social factors. Disease-specific quality-of-life assessment questionnaires have been validated and are now widely used [10,33,34]. (See "Growth hormone deficiency in adults", section on 'Quality of life'.)

ADVERSE EFFECTS — GH therapy of adults with GHD has generally been regarded as being quite safe [35]. The following possible adverse effects should be considered:

●Concerns remain regarding the potential for cancer risk and tumor regrowth [10,32,36]. Therefore, GH therapy is not recommended for patients with active malignancy. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)

●Although GH treatment decreases insulin sensitivity, abnormal fasting glucose levels rarely occur.

●Since the thyroid and adrenal axes may be affected by GH therapy, it is prudent to periodically check for dysfunction by measuring free T4 (thyroxine), not thyroid-stimulating hormone (TSH), and an early-morning cortisol concentration [10,32]. Patients with GHD due to radiation therapy are particularly at risk because they may experience progressive damage over time, affecting the thyroid and/or adrenal axes.

•GH therapy may unmask preexisting central hypothyroidism because GH increases the peripheral conversion of T4 to T3 (triiodothyronine). This abnormality is recognized by a fall of the serum free T4 level into the subnormal range [32,37].

•GH therapy may unmask secondary adrenal insufficiency because GH reduces the activity of 11-beta-hydroxysteroid dehydrogenase type 1, the enzyme that converts inactive cortisone to cortisol. Similarly, in a patient with central adrenal failure, initiation of GH therapy may require an increase in the dose of hydrocortisone [32,38].

●Other reported adverse effects of GH are peripheral edema, arthralgias, carpal tunnel syndrome, and paresthesias. However, these were mostly reported in patients with adult-onset GHD and were dose-related. (See "Growth hormone deficiency in adults", section on 'Side effects'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Growth hormone deficiency and other growth disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: My child is short (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition of transition period – Only a minority of children with growth hormone deficiency (GHD) will remain deficient as adults and require ongoing GH therapy. The "transition period" between these phases is loosely defined as occurring from mid- to late teens until six to seven years after reaching near-adult height. (See 'Definition of transition period' above.)

●Natural history of GHD – The likelihood of persistent GHD during adulthood depends on the underlying cause:

•Idiopathic, isolated GHD – Among children with isolated GHD, more than two-thirds will have normal results when tested for GHD as adults. Because the majority of these patients with isolated GHD during childhood will be GH-sufficient as adults, it is important to repeat the GH stimulation test during the transition period to determine if they will require ongoing therapy. (See 'Testing for continuing growth hormone deficiency' above.)

•Genetic, structural, or organic GHD – By contrast, GHD is usually permanent in patients with genetic causes of GHD (recognized by a family history of GHD), structural causes of GHD (eg, optic nerve hypoplasia), or organic GHD (eg, caused by brain surgery, brain tumors, or intracranial irradiation or associated with multiple pituitary hormone deficiencies). (See 'Genetic, organic, or structural causes of GHD' above.)

●Retesting for GHD during the transition period – If an organic disease was not identified during childhood, testing during the transition period helps to distinguish between the above groups.

•Timing – Retesting for GHD during the transition period is usually done when near-adult height is reached (ie, when the growth rate decelerates to less than 2.0 to 2.5 cm/year), occurring in late puberty. Earlier retesting (eg, in mid-puberty) may be beneficial for patients with mild isolated GHD because many of these patients will have become GH-sufficient by mid-puberty and can stop GH treatment. (See 'When should retesting be done?' above.)

•Method – Retesting for GHD during the transition period usually employs the insulin tolerance test (ITT), which induces hypoglycemia to stimulate GH release, or glucagon. A peak GH response of <5 ng/mL suggests permanent GHD. (See 'Tests to evaluate for continuing GHD' above.)

•Caveats

-For patients with genetic, organic, or structural causes of GHD (other than ectopic posterior pituitary), testing for GHD during the transition period is not necessary, because these patients are very likely to have permanent GHD. However, some experts choose to confirm ongoing GHD by documenting a low serum concentration of insulin-like growth factor 1 (IGF-1) during at least a one-month trial off of GH. (See 'Genetic, organic, or structural causes of GHD' above.)

-For patients who have a history of cranial radiation therapy, the results of retesting should not be considered definitive, because radiation tends to cause progressive damage to the hypothalamus and pituitary. Patients who are GH-sufficient during the transition period may develop increasing GHD over time and should be followed and retested for GHD periodically. (See 'When should retesting be done?' above.)

●Treatment

•Indications – For most patients with GHD during childhood who also have evidence of GHD when retested during the transition period, we suggest treatment with GH during adulthood (Grade 2B). However, GH treatment in adulthood is not required for asymptomatic patients without underlying genetic, organic, or structural causes of GHD, particularly if the results of GH testing are equivocal. (See 'Decision to treat in individuals who remain GH-deficient as adults' above.)

•Dosing – Compared with GH dosing for children, GH doses for adults are lower in terms of absolute dose and far lower per kilogram of body weight or per m² body surface. The starting dose for an adult is approximately 200 to 300 micrograms/day. Women will often require a larger dose. To optimize the GH dose for an adolescent during the transition period, we begin with the adult dose and then titrate to an IGF-1 level in the upper portion of the normal range for age and sex. (See 'Dosing and monitoring GH therapy during the transition and into young adulthood' above.)