PHIL HERNON said:
if taken every other day as opposed to every day, it comes back much quicker. With everyday use, in some cases, it never came back to the same level. A doctor would have to be Houdini to tell you what is going to happen when you stop taking GH, especially the amounts I see some people take.
Phil,
Is this the one you seen? I couldnt get the graphs but it looked well done.
raj
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Prevention of Growth Deceleration after Withdrawal of Growth Hormone Therapy in Idiopathic Short Stature
Meir Lampit and Ze’ev Hochberg
Department of Pediatrics, Meyer Children’s Hospital, Haifa 31096, Israel
Address all correspondence and requests for reprints to: Dr. Ze’ev Hochberg, Division of Pediatric Endocrinology, Meyer Children’s Hospital, P.O. Box 9602, Haifa 31096, Israel. E-mail: .
[email protected]
Abstract
The treatment of children with idiopathic short stature by daily injections of human GH (hGH) is followed after its withdrawal by a growth deceleration with normal serum GH and IGF-I levels. The present study was designed to understand and prevent growth deceleration. We hypothesized that this phenomenon is due to tolerance at the target organ level, that tolerance develops in response to the unphysiological pharmacokinetics of daily-injected hGH, and that alternate day hGH therapy will prevent it. Thirty-eight prepubertal children with idiopathic short stature, aged 3.3–9.0 yr, were studied. Their heights were less than -2 SD score, growth rate was above the 10th percentile for age, bone age was less than 75% of chronological age, and the stimulated serum GH concentration was greater than 10 µg/liter. The children were matched for sex, height, and growth velocity SD score to receive daily or alternate day hGH at the same weekly dose of 6 mg/m2 for a period of 2 yr. The 1st and 2nd year mean growth velocities were 3.4 and 2.3 SD score for the daily therapy group and 3.0 and 2.0 SD score for the alternate day group, respectively (P = NS). Over the initial 6 months after withdrawal of therapy, and growth velocity decelerated to a nadir of -3.9 SD score in the daily therapy group, whereas it decelerated in the alternate day group to only -0.2 SD score (P < 0.01). Over the entire 2 yr off therapy the latter group maintained mean growth rates of -0.2 to -1.2 SD score, similar to their pretreatment velocities. The daily group recovered slowly to resume their mean pretreatment rate only on the fourth semiannual evaluation off therapy. The cumulative 4-yr growth velocity (2 yr on and 2 yr off therapy) of the alternate day group was greater than that of the daily therapy group (mean, 0.9 vs. 0.3 SD score; P < 0.002). At the end of the 4-yr therapy period, the adult height prediction of the alternate day group was greater than that of the daily group by a mean 6.5 cm (P = 0.06). It is concluded that growth deceleration after withdrawal of hGH therapy in idiopathic short stature is due to tolerance to GH and IGF-I in response to the unphysiological pharmacokinetics of daily-injected hGH and that alternate day therapy allows for an alternate day physiological GH profile, thus preventing tolerance during therapy and growth deceleration thereafter.
THE TREATMENT OF children with idiopathic short stature or intrauterine growth retardation by daily injections of human GH (hGH) is associated with development of tolerance for the GH-IGF-I axis and dependence, followed after its withdrawal by deceleration of growth to rates that are slower than pretreatment values (1, 2, 3, 4). The withdrawal syndrome also includes a decline in resting cardiac output (4), an increase in fat mass (4), a decrease in metabolic rate (5), and a negative balance of nitrogen, phosphorus, sodium, and potassium (5). The withdrawal deceleration of growth is time dependent, being more pronounced after prolonged hGH treatment; the dose is of no consequence, but the daily schedule of injections may be important (6). After discontinuation of daily hGH therapy for 30–36 months the markedly subnormal growth persists for as long as 18 months (4).
The mechanism by which chronic exposure to hGH leads to tolerance, dependence, and a withdrawal syndrome is unclear and does not involve the suppression of hormone secretion. During the nadir of growth velocity, which follows the withdrawal of prolonged drug therapy, serum GH levels remain normal, as do serum IGF-I and IGF-binding protein-3 levels (4). Moreover, endogenous pulsatile secretion of GH resumes within days even after long-term hGH therapy (7). The tolerance may be in GH signal transduction in selective target organs in response to the disappearance of the unique pulsatile pattern of serum GH during GH therapy. Indeed, daily sc administration of GH results in an unphysiological serum GH profile, with peak levels at 4 h and a slow decline over the course of the following 12–24 h. This pattern can be regarded as continuous administration, rather than the physiological GH pulses, with a frequency of about eight per day.
In analogy to another endocrine tolerance and withdrawal syndrome, alternate day therapy with glucocorticoids prevents tolerance to that hormone to a substantial degree. Interestingly, glucocorticoid withdrawal syndrome can also occur while the hypothalamic-pituitary-adrenal axis is intact (8), indicating that tolerance to glucocorticoids has developed at the target organ level (9).
The present study was based on the hypotheses that 1) growth deceleration after withdrawal of hGH therapy in idiopathic short stature is due to tolerance at the target organ level; 2) tolerance is due to the unphysiological pharmacokinetics of daily-injected hGH; and 3) alternate day hGH therapy will allow for alternate day physiological GH secretion and prevent tolerance during therapy and growth deceleration thereafter. To investigate these hypotheses, the present study enrolled patients with idiopathic short stature for either daily or alternate day therapy schemes and compared their growth responses over 2 yr of hGH therapy and after its withdrawal.
On the applied side of hGH therapy in patients with idiopathic short stature or intrauterine growth retardation, the first 2 yr of treatment are the most effective, with minimal further gain thereafter (10). It makes sense to limit such therapy to a period of 2 yr if it were not for the ensuing growth deceleration. It was further hypothesized that despite the documented superiority of the modern approach of daily hGH injections over the old alternate day scheme, the prevention of growth deceleration would reward the children’s growth in the long run.
Subjects and Methods
Thirty-eight prepubertal children with idiopathic short stature, aged 3.3–9.0 yr, were studied (Table 1). Criteria for the diagnosis were height less than -2 SD score, growth velocity greater than the 10th percentile for age, bone age less than 75% of chronological age, normal chemistry and thyroid function, and serum GH concentration more than 10 µg/liter after an arginine stimulation test. Birth weight and parents’ heights were not limited by the inclusion criteria.
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Table 1. Clinical characteristics of 20 patients who received daily injections of hGH, compared with 18 patients who received alternate-day therapy at an identical weekly dose per square meter of body surface area
The children were matched by sex, height SD score, and growth velocity SD score to receive either daily or alternate day sc injections of hGH (BioTropin, Bio-Technology General Corp., Rehovot, Israel) at the same weekly dose of 6 mg/m2 body surface area. The protocol was approved by the Helsinki committees of the Rambam Medical Center and the Israel Ministry of Health. Legal consents were obtained from the parents. hGH therapy was given for 2 yr and was withdrawn thereafter, and growth was followed for an additional 2 yr. At the end of 2 yr on and 2 yr off therapy, patients were all still prepubertal. All 38 children completed the 4 yr of study.
The children were measured at 3-month intervals, dose was adjusted to the body surface area, and bone age was assessed yearly (by the Greulich and Pyle method).
Serum GH was measured by a double antibody RIA kit (hGHK-2 Sorin Biomedica, Salussia, Italy), with a sensitivity of 0.3 µg/liter and intra- and interassay variabilities of 7.7% and 11%, respectively.
The body mass index (kilograms per meter squared) is expressed as the SD score for age. Results are expressed as the mean ± SD. Statistical significance was evaluated by t test, and P < 0.05 was considered significant.
Results
During hGH therapy, both groups accelerated their growth substantially, and the growth velocity was greater during the first than during the second year (Fig. 1). The first and second years’ mean growth velocities were 3.4 and 2.3 SD score for the daily therapy group and 3.0 and 2.0 SD score for the alternate day group, respectively (P = NS). Over the initial 6 months after withdrawal of therapy, growth velocity decelerated to a nadir of -3.9 SD score in the daily therapy group, whereas it decelerated in the alternate day group to only -0.2 SD score (P < 0.01). Over the entire 2 yr off therapy the latter group maintained a mean growth velocity of -0.2 to -1.2 SD score, similar to their pretreatment velocity. The daily group recovered slowly to resume their pretreatment rate only on the fourth semiannual evaluation off therapy (Fig. 1). Calculation of the cumulative 4-yr growth velocity indicated that over the entire 2-yr period on and 2-yr period off hGH therapy, the alternate day group’s growth was greater than that of the daily therapy group (mean, 0.9 vs. 0.3 SD score; P < 0.002; Fig. 2).
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Figure 1. Growth velocity of children treated with alternate day GH () or with a daily GH regimen () before, during, and 2 yr after stopping therapy. Values are the mean ± SD. *, P < 0.05; **, P < 0.01.
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Figure 2. Pretreatment and cumulative 4-yr growth velocity of children treated with alternate day GH () or with a daily GH regimen (). Values are the mean ± SD. *, P < 0.002.
Bone maturation during daily and alternate day therapy was comparable (Fig. 3). During growth deceleration, bone maturation was slower in the daily dose group (mean annual bone age increase during the first year 0.7 yr) compared with the alternate day group (mean 1.0 yr; P < 0.05). Over the entire 4-yr period the mean annual increase in bone age was 0.97 yr in the daily group and 1.05 yr in the alternate day group (P = NS).
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Figure 3. Annual bone age advancement in children treated with alternate day GH () or with a daily GH regimen () before, during, and 2 yr after stopping therapy. Values are the mean ± SD.
The mean pretreatment height SD score was similar at -2.6 and -2.8 in the alternate day and daily hGH groups, respectively (Fig. 4). It was still similar at -1.4 and -1.3 SD scores, respectively, at the end of hGH therapy; it remained unchanged 2 yr later at -1.3 SD score for the alternate day group, but decreased to -1.8 SD score in the daily hGH group.
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Figure 4. Height SD score of children treated with alternate day GH () or with a daily GH regimen () before, during, and 2 yr after stopping therapy. Values are the mean ± SD. *, P < 0.05; **, P < 0.01.
Due to the young age of some children, it was not possible to calculate height prediction before therapy. At the end of the 4-yr period, the adult height prediction of the alternate day group was greater than that of the daily group by a mean 6.5 cm (P = 0.06).
Discussion
As the collaborative Israeli study of efficacy and safety of hGH therapy was analyzed (10), we realized that in 65 boys with GH deficiency or idiopathic short stature, aged 3–15 yr, the child’s age was the most significant determinant of therapy outcome; over the course of 3 yr boys in the prepubertal age group gained an average 8 cm of predicted adult height, pubertal boys over the age of 12 yr showed a negative correlation of their predicted height gain against age, and boys over the age of 14 yr showed a loss of predicted height during hGH therapy (10). As others did, we observed a maximal response during the initial 2–3 yr of therapy. The consequence of that study was the hypothesis that in idiopathic short stature, a 2- to 3-yr period of therapy might be beneficial and that the window of opportunity ends before the onset of puberty. In the follow-up study we showed the short-term efficacy of 2–3 yr of hGH therapy in prepubertal children, but identified the well known phenomenon of growth deceleration after treatment withdrawal (4). To understand the mechanism of GH dependence and its withdrawal syndrome, we then studied the GH – IGF-I axis and observed it to be normal during the withdrawal syndrome (4). Assuming that the withdrawal syndrome is related to tolerance that might have developed toward hGH or IGF-I, we tried to prevent it by alternate day treatment. Moreover, hGH doses used in therapy often stimulate IGF-I to supraphysiological serum levels, suggesting that target tissues IGF-I may also be higher than normal. The mechanism seems, therefore, to rest with hGH and IGF-I action at their target tissues. We now show that alternate day therapy with hGH in children with an intact GH-IGF-I axis prevents the withdrawal syndrome.
The design of the study paid special attention to the young age group and conclusion of therapy before the onset of puberty, as well as to matching the two treatment groups by height and growth velocity SD scores. In our previous study we did not observe a different response of patients with intrauterine growth retardation or familial short stature compared with children with normal birth weight and parental height, and the current study followed the same design; inclusion criteria did not include either birth weight or parents’ height. Due to the young age of many of the patients, we could not calculate pretreatment height prediction, and therefore, the final predictions made 4 yr later give unreliable estimates of the true final height gain.
Dependence, often associated with drug abuse, is a biological phenomenon with both psychological and physiological components. During the period of addictive substance use, the body adjusts to a new level of pathologic homeostasis or allostasis. When the drug is abruptly discontinued, this equilibrium is disturbed, and the organism reacts with a constellation of manifestations collectively called a withdrawal syndrome. Dependence is preceded by a phase of tolerance, which signifies a progressively decreased response to the effect of a drug, necessitating ever larger doses to achieve the same effect. Tolerance is largely due to compensatory responses of the organism that mitigate the drug’s pharmacological action. It may result from functional adjustment due to compensatory changes in an effector enzyme or a signal transduction system or from metabolic adjustment due to increased disposition of the drug after chronic use. Endocrine tolerance and withdrawal syndromes have been reported for several hormones (9). The mechanism may lie partly at the inhibitory effect of the drug on endogenous hormone secretion. Yet, GH secretion is normal in children during the withdrawal syndrome (4, 7). It must have to do, then, with the effect of hGH at the target organ, and in the case of childhood growth, the target organ is the growth plate. The molecular and cellular bases of endocrine tolerance and withdrawal syndromes are only partly understood (9). Relatively short-term dependence and addiction result from adaptations in specific target cells caused by prolonged exposure to a supraphysiological level of a hormone or a drug of abuse. The best established mechanism of adaptation is up-regulation of second messenger pathways. Acute opiate exposure inhibits a neuronal cAMP pathway, whereas chronic exposure leads to a compensatory cAMP up-regulation (11). Adaptation in protein kinase A, receptor-G protein coupling, and other components of this signal transduction pathway have also been shown to be involved in the case of opiates and cocaine (12). Long-lasting molecular and cellular adaptations may involve other mechanisms. By analogy with other models of long-term memory and long-term drug addiction and abstinence, such long-lived adaptations to hormones may involve relatively stable changes in molecular switches and transcription factors, such as those implicated in persistent drug-induced long-term neural and behavioral plasticity that occur through alterations in the expression of other genes (9, 11).
The prevention of GH tolerance and withdrawal syndrome by alternate day therapy may implicate the pulsatile nature of GH secretion and serum profile. The latter is preserved in the alternate day regimen and is abrogated by daily treatment. We have previously shown the essential role of GH pulsatility for proper function of the GH receptor. Continuous administration of GH to rats, unlike its pulsatile delivery, up-regulates GH receptors (13, 14) and GH-binding protein (15). In the human, too, GH administration has an up-regulatory effect on GH-binding protein (16), which reflects to a great extent the expression of the GH receptor (17). Moreover, it was shown in a mouse model that hormone pulsation is essential for the signal transduction of GH (18). GH pulses induce synchronized pulses of activated STAT5b, its nuclear translocation, and expression of sex-specific liver CYP genes (19, 20). Long-term interference with GH pulsatility may induce long-lived adaptations to GH that may involve relatively stable changes in molecular switches.
GH tolerance is not ubiquitous, as IGF-I and IGF-binding protein-3 levels did not decrease after withdrawal below their pretreatment levels in this (data not shown) and a previous study (4). A possible site of long-term plasticity is the chondroprogenital (reserve) layer of the growth plate. GH promotes differentiation of chondroprogenitor cells to become proliferating chondroblasts in isolated epiphyseal cartilage cells (21) and in epiphyseal organ culture (22) as reviewed recently (23). Chronic exposure to hGH might exhaust these cells, whereas alternate day therapy might enable an intermittent recovery for these cells. The results of the present study suggest that after daily hGH therapy for 24 months, such stable changes may last for over a year.
This paper suggests, but cannot prove, that alternate day therapy is superior if one chooses to treat children with idiopathic short stature over a prepubertal window of 2 yr. This suggestion is based on the cumulative growth velocity over the 2 yr of treatment and 2 yr off treatment. Furthermore, the small differences in bone maturation between the groups imply that the 4-yr effect would translate into similar changes in the ultimate adult height, although final conclusions will have to await actual adult heights.
It has been more than a decade since the original description of growth deceleration following withdrawal of GH therapy in children with intact GH secretion (1, 2, 3, 4). This report demonstrates that this deceleration can be prevented by alternate day therapy, suggesting that reduced growth velocity after cessation of daily GH treatment results from tolerance related to the unphysiological nature of such treatment. Although alternate day GH administration is somewhat less growth stimulating than daily therapy, this is more than compensated by the prevention of growth deceleration during the 2 yr after stopping GH administration.
Acknowledgments
Footnotes
Abbreviation: hGH, Human GH.
Received December 21, 2001.
Accepted April 23, 2002.
References
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