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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0050
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 2900-2905
Copyright © 2006 by The Endocrine Society

Adult Height in Patients with Permanent Growth Hormone Deficiency with and without Multiple Pituitary Hormone Deficiencies

Mohamad Maghnie, Linda Ambrosini, Marco Cappa, Gabriella Pozzobon, Lucia Ghizzoni, Maria Grazia Ubertini, Natascia di Iorgi, Carmine Tinelli, Sabrina Pilia, Giuseppe Chiumello, Renata Lorini and Sandro Loche

Departments of Pediatrics, (M.M., L.A., N.d.I., R.L.), University of Genova, Instituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini, 16147 Genova, Italy; Department of Pediatrics (M.C., M.G.U.), Bambino Gesù, 00165 Rome, Italy; Department of Pediatrics (G.P., G.C.), Instituto di Ricovero e Cura a Carattere Scientifico, Fondazione Centro San Raffaele, Università Vita-Salute, 20132 Milan, Italy; Department of Pediatrics (L.G.), University of Parma, 43100 Parma, Italy; Biometry-Scientific Direction (C.T.), Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy; and Ospedale Regionale per le Microcitemie (S.P., S.L.), 09121 Cagliari, Italy

Address all correspondence and requests for reprints to: Mohamad Maghnie, M.D., Ph.D., Associate Professor of Pediatrics, Department of Pediatrics, Instituto di Ricovero e Cura a Carattere Scientifico, G. Gaslini, University of Genova, Largo Gerolamo Gaslini, 5, 16147 Genova, Italy. E-mail: mohamadmaghnie{at}ospedale-gaslini.ge.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported.

Objectives: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD.

Design and Setting: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit.

Patients and Methods: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 µg/liter after an insulin tolerance test or peak GH levels less than 5 µg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height SD score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal.

Results: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis.

Conclusions: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
IT HAS LONG been recognized that untreated hypogonadal subjects are taller than average (1), whereas, to the contrary, subjects affected by precocious puberty show decreased adult height (2). Likewise, patients with gonadotropin deficiency who are treated later in life end up taller than patients with isolated GH deficiency (IGHD) and spontaneous puberty (3, 4, 5, 6, 7), whereas untreated children with severe IGHD reach an adult height that is lower than that of untreated patients with multiple pituitary hormone deficiency (MPHD) (8, 9, 10). However, these patients, show eunuchoid features (3), which are related to both hypogonadism and the late induction of puberty (3, 4, 5).

Taken together, these observations have led to the hypothesis that delaying the onset of puberty might increase adult height in patients with GH deficiency (GHD) as well as children with idiopathic short stature. However, delaying pubertal maturation through long-term treatment with GnRH analogs, alone or in combination with GH, has provided conflicting results (11, 12, 13, 14). In addition, the late induction of puberty may have adverse effects on both bone metabolism (15) and psychosocial adaptation (1).

A number of recent studies have shown that a high proportion of patients with childhood-onset isolated GHD and normal magnetic resonance imaging (MRI) of the hypothalamic pituitary region show normalization of GH response to stimulation when reevaluated at the attainment of adult height (16, 17, 18, 19, 20, 21). But because retesting was not always carried out in earlier studies (4, 5), or in many of the most recent reports (22, 23, 24, 25, 26, 27), it is likely that patients with normal pituitary function were included in these study analyses.

To our knowledge, a comparison between the adult height of patients with MPHD in whom sex steroid therapy was started at an appropriate age and that of patients with unequivocally permanent IGHD has not yet been reported. The present retrospective study was designed to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in patients with permanent IGHD as opposed to patients with MPHD. We thus investigated clinical presentation, patterns of puberty (either spontaneous or pharmacologically induced), morphologic characteristics of the hypothalamic-pituitary region at MRI, and adult height in patients with hypopituitarism in whom a diagnosis of GHD was confirmed after adult height achievement.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We reviewed the databases of five pediatric endocrinology units and identified 88 young adults with GHD (31 females, 57 males) who had been treated with GH during childhood and had subsequently reached adult height. The patients were subdivided into two groups: patients with IGHD (n = 39, 26 males, 13 females) and patients with MPHD, including GHD (n = 49, 31 males, 18 females). Twenty-four of the 49 patients with MPHD (17 males, seven females) had TSH, ACTH, and GnRH deficiency; nine (seven males, two females) had TSH and GnRH deficiency; 14 (six males, eight females) had GnRH deficiency; and two (one male, one female) had ACTH and GnRH deficiency. The main clinical characteristics of the patients are summarized in Table 1Go.


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  		TABLE 1. Characteristics of patients with either IGHD or MPHD

 
All patients were regularly seen at 6-month intervals, and at each visit they underwent a complete physical examination, with height and weight measurement and pubertal staging. A testicular volume of more than 4 ml in boys and the appearance of breast buds in girls were taken to indicate the onset of puberty. In patients with MPHD (n = 49), the onset of puberty was considered when breast buds appeared (Tanner II stage) after the start of sex steroid administration. Seven females who failed to progress with puberty were Tanner stage II when sex steroids were started; they were included in the MPHD group. The duration of puberty was calculated as the time interval between Tanner stages II and IV or V.

Height was recorded using a wall-mounted Harpenden stadiometer and reported both in centimeters and in a SD score (SDS) related to chronological and bone age according to Tanner (28). These measurements were calculated at the time of GHD diagnosis, Tanner stage II, and the attainment of adult height, which was defined as a growth velocity of less than 1 cm per year. We also calculated parentally adjusted height SDS, i.e. the difference between height SDS for chronological age and target height SDS (average of the parents’ heights plus 6.55 cm for boys and –6.5 cm for girls). The difference between adult height SDS and baseline height SDS was taken as the absolute height SDS gain. Pubertal height gain was calculated as the difference between adult height and height at Tanner stage II. The body mass index (kilograms per square meter) expressed as the SDS for sex, and age was calculated at the time of diagnosis and the end of therapy. Bone age was determined by the method of Greulich and Pyle (29) at the first visit and the time of adult height attainment.

Anterior pituitary function

The diagnosis of GHD was confirmed by failure of GH to rise more than 10 µg/liter after two provocative tests (insulin tolerance test, levodopa, arginine, GHRH, clonidine). All patients were tested for GH after administration of arginine (0.5 g/kg iv over 30 min), insulin (0.1 U/kg administered iv), levodopa (500 mg/m2 administered orally), or clonidine (0.10–0.15 mg/m2 administered orally). Blood sample measurements of serum GH were obtained at 0, 30, 60, 90, and 120 min. Pituitary-thyroid function was evaluated every 6–12 months by measuring serum-free T4, free T3, and TSH. Hypothyroidism was defined as low or low-normal serum TSH concentration and low serum-free T4 and free T3 concentrations. Plasma ACTH and serum cortisol values were measured in the morning at presentation in all patients and every 6–12 months in the patients with MPHD. ACTH deficiency was defined as either a morning serum cortisol concentration of less than 3.6 µg/dl (100 nmol/liter) or an impaired cortisol serum concentration rise inferior to 20 µg/dl (550 nmol/liter) during insulin-induced hypoglycemia. Serum FSH and LH were measured before and 30, 60, and 120 min after the iv administration of 100 µg/m2 of GnRH in patients with suspected hypogonadotropic hypogonadism. Hypogonadism was confirmed in both sexes by lack of puberty and no increase in FSH and LH in response to GnRH. Ultrasonography was used to identify female patients with a prepubertal uterus. All hormone measurements were carried out by means of standard RIAs.

Childhood treatment

In the patients with isolated GHD, GH was administered in five to seven sc doses per week at a median dose of 0.2 mg/kg·wk (range 0.17–0.21 mg/kg·wk), which was the dose used consistently during the study period. The median treatment age was 9.5 yr in males (range, 6.1–11 yr) and 9.6 yr in females (range 4.9–11.7 yr). One male received pituitary GH in three sc doses per week for 3.7 yr, and two females received pituitary GH administered in three sc doses per week for 0.6 yr and 3.3 yr, respectively. The other patients received recombinant human GH only.

In the patients with MPHD, GH was administered sc at a median dose of 0.18 mg/kg·wk (range 0.16–0.20 mg) five to seven times per week. The median treatment age was 11.5 yr in males (range 9–15 yr) and 8.8 yr in females (range 7.4–9.6 yr). Ten males and three females received pituitary GH administered in three sc doses per week for a median of 4.6 yr in males (range 3.3–8.7 yr) and a median of 9 yr in females (range 4.75–10 yr). The other patients received recombinant human GH only. Patients with MPHD were receiving conventional replacement treatment.

Reevaluation of GH secretion

Reevaluation of GH secretion was carried out in all but four patients by repeating GH stimulation tests at the attainment of adult height or when growth velocity dropped to less than 1 cm per year in the last year of therapy. The four patients who refused retesting had a high likelihood of permanent GHD. In fact, three of them had IGHD and structural hypothalamic-pituitary abnormalities including posterior pituitary ectopia at the level of the median eminence, anterior pituitary hypoplasia, and pituitary stalk agenesis; the other patient, with posterior pituitary ectopia, anterior pituitary hypoplasia, and pituitary stalk agenesis and MPHD, had an IGF-I of less than –2 SDS, suggestive of permanent GHD (30). The diagnosis of permanent severe GHD was based on serum peak GH levels of less than 3 µg/liter after insulin tolerance test. In the subjects in whom the insulin tolerance test was contraindicated, the diagnosis of permanent severe GHD was formulated on the basis of a GH peak of less than 5 µg/liter after the following tests: arginine; clonidine; levodopa; GHRH (GHRH 1–29; GEREF, Serono, Italy; 1 µg/kg iv at time 0) plus pyridostigmine (120 mg pyridostigmine, Mestinon; Hoffmann-La Roche, Basel, Switzerland; at –60 min administered orally); GHRH (GHRH 1–29, GEREF; 1 µg/kg iv at time 0) plus arginine (0.5 g/kg, L-arginine monohydrochloride administered iv, from time 0 over 30 min). Blood sample measurements were obtained at –60, 0, 15, 30, 45, 60, and 90 min.

Subjects with MPHD were receiving conventional replacement therapy for pituitary deficits: L-T4 75–200 µg/d, hydrocortisone 20–25 mg/d in two to three separate doses, testosterone enanthate 150–250 mg im every 2 or 3 wk for males and ethynyl estradiol (first 21 d, 5 µg/d orally, n = 2) or transdermal 17ß-estradiol patches (n = 8) with medroxyprogesterone acetate (5–10 mg, 12th to 21st d) for females; in the subject with central diabetes insipidus, desmopressin acetate (desamino-D-arginine-8-vasopressin) was administered orally three times daily.

Imaging studies

MRI scans were obtained for all patients using a spin-echo technique with a 1.5-T superconductive system. Sagittal and coronal T1-weighted images were obtained whose sections were 3.0 mm thick. The MRI of the hypothalamic-pituitary area in the patients with IGHD showed a normal anterior pituitary gland in five patients, pituitary hypoplasia in three, and ectopic posterior pituitary gland mainly at the level of the median eminence in the remaining 31 subjects. In the patients with MPHD, MRI showed pituitary hypoplasia in seven patients and the classic triad including ectopic posterior pituitary gland, anterior pituitary hypoplasia, and pituitary stalk agenesis in 40 patients, of whom two had septooptic dysplasia. One female subject had a pituitary Rathke’s cyst and another showed pituitary stalk thickening.

Statistical analysis

Data are nonnormally distributed and reported as median and interquartile range (IQR); IQR is the distance between the 25th and 75th percentile and encompasses the middle 50% of observations. A comparison between groups was performed using the Mann-Whitney U test (when comparing two groups) or the Kruskal-Wallis ANOVA (when comparing more than two groups). Correlations among the variables were analyzed with the Spearman r coefficient and P < 0.05 was considered statistically significant. All tests were two sided. Analyses were carried out with Statistica for Windows software (StatSoft, Inc., Tulsa, OK).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical characteristics of the patients at the time of diagnosis

The main clinical data of the 88 patients at the time of GHD diagnosis are summarized in Table 1Go. All subjects were prepubertal at the time of presentation. Because no differences were found in clinical features and outcome between patients with GH and gonadotropin deficiency (n = 11 patients) and those with GH and additional pituitary hormone deficiencies, the data from these patients were pooled and analyzed together. All patients with GH and at least one additional hormone deficiency were thus included in the MPHD group. The patients started GH therapy when prepubertal at a similar chronological age. The clinical characteristics of patients with isolated GHD or MPHD, including median chronological age, bone age, body mass index, and height, were similar (Table 1Go).

Clinical characteristics of the patients during puberty

The clinical characteristics of the 88 patients from the start of puberty up to adult height achievement are reported in Table 1Go. Patients with IGHD entered puberty spontaneously, whereas the MPHD patients underwent induced puberty when chronological age, bone age, and height values were similar to those of the isolated GHD subjects. The duration of puberty was significantly longer in females with MPHD than those with IGHD (5.4 vs. 2.5 yr, P = 0.03). There was no significant difference in pubertal height gain between patients with IGHD or MPHD. Although a standard protocol was not established among the five centers involved, our retrospective analysis revealed that the patients were treated at similar chronological ages with similar doses of sex steroids.

Adult height and clinical characteristics at the time of GH withdrawal

The clinical characteristics of the 88 patients at the time of GH withdrawal are summarized in Table 1Go. There were no significant differences in chronological age, height velocity, and body mass index between patients with IGHD and MPHD. Females with MPHD stopped GH therapy later than those with IGHD (20 vs. 16.5 yr, P = 0.005). The duration of GH treatment was significantly longer in males with multiple hormone deficiencies than those with IGHD (11.5 vs. 9.5 yr, P = 0.03). Total pubertal height gain and adult height were similar in both groups (Fig. 1Go). Likewise, an analysis of the differences between the adult height SDS minus baseline SDS revealed that the gain in height SDS was similar between patients with IGHD and those with MPHD. In 68 subjects (34 with IGHD, 34 with MPHD), adult height was in the normal range by Tanner standards (28). All subjects reached their target height (target height SDS ± 1.5 SD), and 20 patients (10 with IGHD, 10 with MPHD) exceeded it.


Figure 1
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  		FIG. 1. Pattern of growth in the cohort [males (A) and females (B)] with permanent GHD from the time of diagnosis to adult height. The upper and lower limits of each rectangle indicate the 75th and 25th height SDS percentiles, respectively; the small squares inside the rectangles indicate median values. The vertical lines extending from the rectangles represent maximum and minimum height SDS values.

 
Correlations

Adult height correlated significantly with height SDS at diagnosis and height SDS at the onset of puberty in both IGHD (P = 0.001 and P < 0.001) and MPHD (P = 0.035 and P < 0.001) subjects. It correlated weakly with the duration of GH treatment only in patients with MPHD (P = 0.032). Adult height correlated significantly with pubertal height gain only in patients with IGHD (P = 0.002).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We have shown in this study that the adult height of patients with permanent severe IGHD treated with GH is similar to that of patients with MPHD treated with sex steroids at an appropriate age (14 and 13.5 yr, respectively, in boys and girls). Patients with GHD, when left untreated, generally show growth failure and adult short stature (8, 9, 10). In earlier studies on adult height in patients with GHD, the frequency of injections was two to three per week, the dosage was variable, and it was often not adjusted for body size, and nonetheless, despite these inadequate treatment schedules, patients who received GH grew taller than those who did not (3, 22, 23). In more recent studies, in which the frequency of injections was six to seven per week and the dose standardized for body weight, adult height values showed a further improvement (23, 24, 25, 26, 27). In our study, adult height ranged between –0.4 and –0.9 SDS, well within the normal range, and was similar to that reported by Blethen et al. (24), who used a slightly higher GH dose (0.3 mg/kg·wk).

Several studies on the treatment of GHD have compared the adult height of patients with IGHD and spontaneous puberty with that of patients with GHD and gonadotropin deficiency (3, 4, 5, 6, 7, 8, 24). These earlier studies (3, 4, 5) reported significantly higher adult heights in patients with MPHD than in those with IGHD with spontaneous puberty. In the studies by Frish and Birnbacher (6), a higher (although not statistically significant) mean adult height was reported in subjects with MPHD, compared with those with IGHD. Blethen et al. (24) also reported similar outcomes. Nonetheless, none of these prior studies matches ours for number and clinical characteristics of patients or its experimental design. Our study is the largest one to date to report the adult heights of patients with IGHD and MPHD whose GH secretion was reevaluated at the attainment of adult height. Reevaluation of GH secretion was carried out in all patients in one previous study (6) and in only a few patients in another study (3). This point is crucial because several reports have shown that a high proportion of patients with childhood-onset GHD show normalization of GH response to stimulation when retested at the attainment of adult height (16, 17, 18, 19, 20, 21). Indeed, the diagnosis of GHD remains challenging in young adults, although a GH cut-off level after insulin-induced hypoglycemia has now been established (30, 31). In our study the high frequency of congenital hypothalamic-pituitary abnormalities, including ectopic posterior pituitary gland at the level of the median eminence, is suggestive of permanent GHD (21). It is possible, therefore, that many of the patients with IGHD included in the aforementioned reports (3, 4, 5, 24) may have had normal pituitary function. In this regard we have previously shown that a high number of subjects who failed GH stimulation tests showed normal responses when retested after a few months (32).

In the present study, the mean age of the patients at the start of treatment was considerably lower than that reported in the previous studies (3, 4, 5, 24). Moreover, whereas the mean age at the start of sex steroid replacement in the earlier studies (3, 4, 5, 6) ranged from 18.5 to 20.5 yr in boys and 18.5 to 19.5 yr in girls, all our patients received sex steroid replacement at an earlier and more physiological age (median age 14 and 13.5 yr in boys and girls, respectively). It is worth pointing out that the etiology of GHD and the presence or absence of spontaneous (as opposed to induced) puberty did not affect the patients’ outcome in the study by Blethen et al. (24). In this latter study, the mean age at start of treatment was higher, but the age at onset of puberty and the mean adult height of the patients (–0.7 SD score) were similar to those of the patients in the present study.

Our findings and those of Blethen et al. (24) indicate that the induction of puberty at a physiological age in patients with MPHD does not affect adult height, in agreement with the evidence that early or late maturing normal children achieve similar heights (33, 34). Moreover, males with isolated hypogonadotropic hypogonadism who started treatment between the ages of 10 and 17 yr reached an adult height similar to that of normal males. Conversely, their adult height was moderately increased if treatment was started after 18 yr of age (35). Thus, the higher adult height of patients with MPHD (3, 5) can be accounted for by the late induction of puberty. In addition, Burns et al. (3) have shown that patients with gonadotropin deficiency or those with MPHD had an eunuchoid body build, with more growth in leg than trunk length. Similar findings have been reported in patients with hypogonadism (1) as well as in patients with absence of estrogen receptor (36) or aromatase deficiency (37).

As a whole, these observations have led to the recognition that estrogens play a pivotal role in the maturation of the growth plate and in epiphyseal fusion (38), suggesting that prolonging the period of growth could increase adult height. In this respect, treatment with GnRH analogs for 3.5 yr increased the adult height of adolescents with severe short stature by 0.6 SDS (4.2 cm), with height gain correlating positively with the duration of arrested bone maturation during treatment (12). However, patients with delayed puberty (15), hypogonadism (39), or estrogen deficiency (36, 37) show a substantial decrease of bone mineral density, a phenomenon that also follows long-term treatment with GnRH analogs in normal adolescents (12) as well as adult men (40). Therefore, postponing sex steroid treatment by GnRH analogs may cause abnormal body proportions and osteoporosis in patients that may in turn lead to increased risk of fractures later in life. In addition, abnormal psychosocial adaptation in adolescence due to the late appearance of secondary sexual characteristics is a factor that should not be underestimated (1). It has recently been shown, in fact, that late maturation among males may be associated with a late-onset pathway for deviant behavior and/or substance abuse (41).

In our study, the duration of puberty was similar in males with IGHD and those with MPHD, but it was longer in females with MPHD (5.4 yr) than those with IGHD (2.5 yr). This might be ascribed to the earlier start of GH treatment in girls with IGHD, compared with girls with MPHD (7.9 vs. 10.9 yr). However, total pubertal height gain and adult height were similar in males with IGHD and those with MPHD as well as females with IGHD and MPHD. Adult height correlated with height at the onset of puberty in both groups of patients, whereas it correlated with total pubertal height gain in patients with IGHD only. It is well known that adult height results from the sum of the height reached at the start of puberty and the pubertal height gain (4). Our findings indicate that height at the onset of puberty has a major impact on adult height, emphasizing the need for optimization of prepubertal growth. The positive correlation between adult height SDS and height SDS at diagnosis indicates that the smaller the height deficit at diagnosis, the better the final outcome. Indeed, the age of the patients at diagnosis and the duration of GH treatment do not seem to have any major impact on adult height. Almost all patients reached their target height and some of them even exceeded it.

In conclusion, the results of the present study show that adult height in patients with permanent IGHD and spontaneous puberty is similar to the adult height of patients with MPHD and induced puberty. Moreover, the adult height of the great majority of patients was within the normal range. Consequently, postponing the induction of puberty in view of its potential adverse events is not justified. Thus, early diagnosis and intervention are essential to optimize height outcome in patients with permanent IGHD or MPHD.


   Footnotes
 
The authors warrant that they have seen and approved this manuscript and that their contributions meet the requirements criteria for authorship. The authors have nothing to declare.

First Published Online May 9, 2006

Abbreviations: GHD, GH deficiency; IGHD, isolated GHD; IQR, interquartile range; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; SDS, SD score.

Received January 9, 2006.

Accepted May 1, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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