The Diagnosis of Growth Hormone Deficiency in Children and Adults

I. Introduction II. GHD in Children A. Clinical aspects B. Radiology C. GH provocative tests D. Physiological assessment of GH secretion E. IGFs F. IGFBPs G. Newer strategies for assessment of GH status H. Practical approach to the diagnosis of GHD III. GHD in Adults A. Clinical aspects B. GH provocative tests C. Physiological assessment of GH secretion D. IGF-I and IGFBP-3 E. Obesity F. Elderly G. Childhood onset H. Newer strategies for assessment of GH status I. Practical approach to the diagnosis of GHD GH REPLACEMENT therapy has been offered to GH-deficient children for more than 30 yr, but it only became a licensed indication for GH-deficient adults in the United States, a number of European countries, and New Zealand in 1996. Thus, in contrast to the longstanding pediatric literature and interest in the biochemical diagnosis of GH deficiency (GHD), the concerns of the endocrinologist treating adults have been addressed only recently. The type of underlying pathophysiology differs in childhood-onset compared with adult-onset GHD. In childhood, the commonest etiology is isolated idiopathic GHD (1, 2), a blanket term, which includes some children with distinctive pathophysiology that may be demonstrated radiologically, and others in whom the pathological insult is unknown and the explanation for the GHD ill-understood. In contrast, adult-onset GHD is most frequently due to a pituitary adenoma and/or treatment with surgery or radiotherapy (3, 4); isolated idiopathic GHD acquired in adult life has never been reported. In childhood the differential diagnosis is dominated by alternative causes of poor growth (5–9), whereas difficulties in the diagnosis of adult-onset GHD (10–12) exist in the obese and in the elderly. The purpose of this review is to evaluate the usefulness of a variety of clinical and biochemical approaches to the diagnosis of GHD in children and adults. In studies that contain GH measurements in milliunits/liter, the conversion into nanograms/ml has assumed an equivalence of 2 U/mg unless stated otherwise by the authors. GH secretion is a continuum (13) between normality and abnormality (Fig. 1); therefore, with rare exception, the diagnosis of GH deficiency must be made on arbitrary grounds. The more severe the GHD, the less arbitrary the diagnosis, whereas the“ lesser degrees of GHD” (GH insufficiency) merge into normality. Until 1985, replacement therapy consisted of pituitary-extract GH obtained from human cadavers; the supply was limited and thus the diagnostic strategy was directed initially at detecting severe GHD. Subsequently, recombinant DNA-derived GH became available, the supply of which is unlimited. Unfortunately, compared with other endocrine therapies, GH replacement is expensive. Thus, at the present time in certain countries, children with all forms of GH insufficiency from severe to mild are considered for GH replacement, whereas in other countries, because of economic restraints, only with severe GHD have a of GH some of the in diagnostic to the diagnosis of GHD in of the between for and of GH with from C. Children with GHD present with and a growth for and causes of poor growth to be considered and at from the of life to The and at are by the time of onset and the of GHD the in growth is with the of GHD. with of GH secretion with a GH present the of with a and a growth the for children with GH insufficiency present at an with less growth and a growth the for The clinical is to between GH insufficiency and of normality whereas the is or the is of normality is idiopathic a to a of children with underlying and is in growth and In the of adult may be with the and The of growth is growth measurements a between the with GH insufficiency and the have with in a of children that is in from to that is to growth (Fig. Thus, the of this of children the for from to the of the that a that be by the with between in the of children for and to for from D. with from the from growth may be other in the and clinical that to a diagnosis of idiopathic GHD or GHD. is a between idiopathic GHD and a of forms of GHD may that the diagnosis is in other of the The of in the and and the of of or the of of a in the and the diagnosis of GHD in a In children with GHD of the growth be but time have for to be the growth is more than the the GH-deficient has the The is with a and this is to the of GH on growth at the of the and the is In the may be and the of onset is in and is and the of is to the and of GHD. of the may a a or of the pituitary due to an The pituitary may or and the pituitary may be The more severe the the more that pituitary other than GHD, are present is by degrees of of the and of the The may be GH secretion is and are of the provocative tests of GH than a GH to GH The for of GH are the and The GH by to the of and the forms of GH obtained than with the The between the for GH and the of normality and abnormality be in In a in which the GH was in the in was a of on the of and in the between pediatric to is in GH and to In this is in a of of pediatric GH treatment than GH tests to to GH therapy in a with a growth which type of GH and GH in children of The for assessment of GH status was of this the that the be at the it a to GH that the between and GHD is and is to GH The the of in a it with other and the of the which in is In that GH provocative to the strategy of a with a growth to GH provocative tests be that the for this in a the GH was to children the from to a of GH therapy than to the diagnosis of severe GHD the Thus, a of other into the GH diagnostic and variety of of tests has been in some provocative are or in The approach may be and more but is to that the are more the tests are in than with or for a a GH provocative is an to between GHD and in growth and in is a in GH secretion due to the in children with GH secretion or in but a in GH secretion with GH to provocative the in GH Thus, in a of with a growth is a in the differential In a with GH provocative tests severe GHD GH and a of with GH exist to the of in GH to the at the between the of GH insufficiency and be is a of the GH to the of provocative the to a GH was it was at on the of studies by in which of children GH-deficient a GH to an whereas all GH-deficient children a GH to the The GH was to GH became more and with the of only is normality but the GH is to normality of the In more have but have the of (Fig. GH to and and and in children of or GH in at time by The of the was whereas the and of between and and and from for a provocative or from the provocative in the GH from E. The The of tests and the that GH secretion the to the of the GH and GH in the diagnosis of GHD. The is to an and The are by the of the and the of by the Unfortunately, an GH to may in to a of children in a of the of provocative tests to GH status in the GH to was from that in to an or to and The is in clinical of the and of provocative GH measurements of GH tests for a of and of for GH are expensive. a be an and of GH have been in children of a poor between GH secretion and GH provocative tests In some of studies a of children GH children are by GH to tests but GH may be for the of GH The of GH children with of growth is and the is to be in adult The pathophysiology and of or has been from the of this into the endocrine The or a GH is more for GH status than provocative GH tests is is that GH are the is than that with the GH to a variety of provocative tests that the of a GH is in a for growth must be with a of GH with other of GH growth more between normality and or children compared with the GH a pediatric in the have the or to GH and have for with rare exception, GH a to GH in the because of the of or have of GH to has to interest in the of GH in the diagnosis of GHD The is to and in the of to and and the of which for of the in GH but it has that GH may other tests in to severe GHD, it to the between GH insufficiency and idiopathic The IGFs are to of the and of GH The of the IGF-I is the due to the of with a of the for GH status with a of the IGF-I and to the that GH tests may by from the of IGFBPs has been by a variety of approaches the with an of the for an IGF-I or that to IGFBPs of IGF-I may in a with or GHD. The IGF-I is by and of IGF-I in children than of the of IGF-I to between and GH-deficient children is less in this the of and IGF-I the diagnostic of IGF-I but with normality a GH the to between children with GHD and with an IGF-I at the of the a of of and of of and with an IGF-I of The IGF-I in compared with of and that of IGF-I was in the diagnosis of childhood GHD the by more in than an of and in children less than and between and yr, In the studies the IGF-I for and but the of studies exist that the IGF-I with GH by provocative GH the diagnostic of IGF-I the of has been the that is less GH than the for is in children and Thus, the of in detecting GHD is the of IGF-I and a diagnostic In a of GH-deficient and of the GH-deficient children IGF-I the whereas of children IGF-I in of GH-deficient children but in of the from that of GH-deficient children IGF-I and but only of children and of children of IGF-I and In pediatric endocrine in the assessment of children with the IGFBP-3 is the of IGFBP-3 of a of an and an and IGFBP-3 are GH IGFBP-3 IGF-I and of IGFBP-3 is less than for the of status on IGFBP-3 is less than for IGF-I The IGFBP-3 of the IGFBPs from and are to the of a of a with a a of GH status The between of IGFBP-3 and the of of IGF-I and that IGFBP-3 GH status more than IGF-I and some of children with GHD IGFBP-3 the In contrast, of children IGFBP-3 the In a more of the usefulness of IGFBP-3 in the diagnosis of GHD, and and of and in children less than of and and in between and be in other studies the IGFBP-3 between GHD and normality in children and with GHD has been that the of the to the of IGF-I and IGFBP-3 in the diagnosis of GHD are in with GHD the that in most is between the IGFBP-3 and the of GH the was from the GH in of GHD and idiopathic and IGFBP-3 in The of IGF-I and IGFBP-3 the of in a with GHD that in with forms of GH all have a IGFBP-3 and most have a IGF-I have GH with a or of the for the GH which to GH the IGFBP-3 and the severe growth IGFBP-3 with the Thus, IGF-I and IGFBP-3 are to the diagnosis of severe GHD, the the alternative of and between IGF-I and IGFBP-3 compared with the GH to tests in children to have lesser degrees of GHD. The of provocative tests of GH may the in the GH status by the GH and it may be that IGF-I and IGFBP-3 are less than the GH to provocative in children with GH The of the provocative tests of GH and the are The of GH a of the of the pituitary in the a of GH than provocative is in the GH to to in The of in with that of and has been The of with the to a GH and the GH to the and and In a of the of GH provocative the GH to an and in children with or In this the of or only a GH than the of the GH provocative but the in tests was GH in or in with the for between children with GHD and the a GH to tests GHD due to is a in that in most children with isolated GHD, the of pathophysiology is to be than is the to the and In contrast to the approach of a of of with or is that the GH to an of in children The is but the of GH in or a of the The of this diagnostic approach between children with GHD and but the only children with of children GH to tests and GH than to the GH to provocative that the GH is and that of a the number and of GH and the GH to and to an The for a a poor GH to and a GH the are a GH be in the diagnostic assessment of GH status in a with a growth alternative of the GH status of the has been in The approach has been the to for GH therapy on less than the and growth less than for GH was in most children it was for the of than children have been with GHD GH with and with other forms of In the to the of GH therapy to with less than the and of GH therapy was to for and for New have from to less than for GH between and has been and is in the The approach with a has in a with a number of and a the of children with GHD only because of of the for and other but a of GH for growth in children with severe GHD GH be that the for the to in the from this The in which GH status to be is the with and a growth the in whom other causes of poor growth have been The diagnostic is to between idiopathic GHD and idiopathic the of and to the for IGF-I and IGFBP-3 and GH to provocative of a for GHD of the GH provocative in and poor of GH provocative tests or GH The most is in that GHD and a by the of of all and biochemical in children with diagnostic GH treatment may the growth in Thus, the growth to GH the of GH therapy to the diagnosis of the GH of GH therapy the growth of children with GH between and is from that of children with GH in of The most approach to the assessment of GH status GH and on tests in with or in of the to GH insufficiency with with this GH provocative and GH is the of GHD that the of the diagnostic the with severe GHD is to be with the Thus, of IGF-I and IGFBP-3 and tests of GH all in children with severe GHD. GH to be a diagnostic only in children with severe GHD and is in with a lesser of GHD. In most is by the of a IGF-I and IGFBP-3 in with a GH provocative The of a GH provocative to the diagnosis of severe GHD. In a with IGF-I and IGFBP-3 but a GH to a provocative a GH provocative to between GH insufficiency and the of the GH provocative is it that the diagnosis of GH insufficiency has been provocative tests GH the diagnosis of GH insufficiency have been be that this approach is because may be in the growth to GH therapy between children with of biochemical In the GH biochemical assessment of pituitary and are in this may to other than with the a GH to at provocative it is more but that a with GH to provocative tests is more to of of of endocrine less and is that of a IGF-I in the of or GH to provocative The may be with a number of clinical with acquired GH a severe and for a but the clinical is dominated by the and differential diagnosis is an a variety of in the that may in a with a IGF-I and or GH to provocative The a in the GH in of GH in the GH and growth and growth with of the IGF-I In (GH is an and is by severe growth and IGF-I and IGFBP-3 or GH secretion The all with of in the of the GH Subsequently, have been some of whom have of in the of the of the GH that is for or that may the biochemical to other in the from that of GH are in that the GH with a GH the GH be with a and a to an IGF-I to of GH The thus with of the IGF-I and IGFBP-3 with severe growth and of the with a IGF-I and or GH secretion is to of for a of the GH or IGF-I or of less of the GH are to in the of to the growth of the of the an arbitrary for the biochemical of GH is the growth and of children the a of GH replacement, compared with children the in the or of than the other in the term, term, or explanation the and in growth in children with GHD a IGFBP-3 and more frequently an GH to an than to other GH provocative tests children for a in the of GH and IGF-I is the for of GH secretion in children with and other and a of the biochemical in this review and In in the that between GHD and normality The between normality and abnormality is more to be and for IGF-I and IGFBP-3 and GH tests than more on the of or of of GH Until the yr, the for an in adults with of the was to secretion to the for a time was to GH in adult was interest in the GH by the with the that an GH to an a of in the the of with the that GH replacement therapy adults with GHD and the of of have in the diagnosis of GHD in adults. therefore, the diagnostic strategies to the have been in adults with or GHD in adult life is with in the an and and of life the of clinical is or that is of GHD in adult this is of with pituitary in whom and may be or is that the of with GHD in adult life differs in adults with childhood-onset compared with adult-onset is in an adult of GH-deficient that the diagnostic usefulness the growth of a the of of in with a of the or in have surgery and/or radiotherapy to this GH is the of the pituitary to be by pathological which that in a with pituitary the of GHD present is the in the pediatric in whom pituitary are this is of in adults in whom pituitary and/or treatment are the most causes of GHD a number of the has been the the this is because the is the only GH provocative in which has been by the a for the in the assessment of the in of with pituitary an alternative of GH status be in have been studies of the GH to in adults the GH status of to by with and a GH from to and that was at than the at GH the in from to and GH to but with an and the GH was from the to of the considered to be a GH to the whereas the GH or in GH from to of less than and and was the of the the this may be have demonstrated that the GH to an is in than in is in contrast to the GH to that is in compared with is a on the GH to certain provocative that in on the be from the studies that have been The to be a more for GH compared with and In to an all in the and a GH of than in the by all but with a GH in of of the of is by the that the studies GH that are in of to in GH that a GH than a GH than 30 with of the a GH in of and the between and to of the to a GH in of in to the of the GH provocative tests in the pediatric of this review to the diagnosis of GHD in but is in the of GHD to be present GH replacement is In countries, children with all of GHD from of GH secretion to GH insufficiency are offered a of GH GH replacement therapy has only been for adults with severe GHD. the of the diagnostic in GHD in the adult with pituitary the an In clinical of GH replacement, the diagnostic for GHD between a GH to a provocative of less than and some to the a that severe GHD be a GH of less than an The of the of this diagnostic a variety of of GHD in and for and with the with GH to an GH from and IGF-I and IGFBP-3 (Fig. was a of the GH to an between the and GH-deficient of or a GH and with a than In contrast to the was a of and IGFBP-3 between of tests of GH deficiency in and GH to GH IGF-I IGFBP-3 for GH and IGF-I with from D. with the of the an in an endocrine is with a of are certain of in whom this be with or an and because of the of with an in the of the of of GH that endocrine must diagnostic of the to the in adults with pituitary to an clinical that the of the growth in that the of the of adult this the that in all the forms of in adult GHD is the of pituitary and in with pituitary GHD is In adult with pituitary only the but the of GHD is to the number of pituitary Thus, that the GH to an in of adult with isolated GHD and GHD and pituitary was and (Fig. was a in the GH of the with the between and and and was between the and of in and of and in a GH less than the between GHD and pituitary have been of GH status has been by GH or GH The of the GH in to an in into to the of number of pituitary in from A. A. of GH by demonstrated a of between and GH-deficient adults. of the less than the of the GH-deficient Thus, of to between GHD and and at of the was due to the number of and with that the of of the GH a to the the of of the the but an between and GHD in adults less than of from GH-deficient the GH GH in GH-deficient and in the GH in GH-deficient but the that of GH in GHD was of the in from a in the than in the that the by GH in GH-deficient was Thus, the GH but the or the GH between GH-deficient and the only GH-deficient and only the GH by a GH studies GH have the to of the that and GH are to to the to GHD in an is less from alternative of assessment of GH GH from in GH-deficient by the of pituitary and a GH of less than to an a of the for GHD was in adult yr, between and yr, and an the of The in IGF-I life are to of the onset of is a 2 to in IGF-I by a that adult are by the a with to IGF-I but less IGFBP-3 to a the and in Thus, in the adult with GHD, IGF-I and IGFBP-3 measurements only be are The usefulness of an IGF-I in the diagnosis of adult GHD is a of it has that at some of the between studies is by the of the onset of GHD. that of IGF-I and of IGFBP-3 in adult-onset GHD yr, the of for the of in a of yr, with GHD by a GH of less than to a provocative and with other of pituitary that an IGF-I In the the adults consisted of a of childhood-onset and adult-onset GHD on childhood-onset GHD and GH status in adult GH replacement in of the an IGF-I the with a number of IGFBP-3 the (Fig. the in a of childhood-onset and adult-onset GHD that are between forms of GHD that the IGF-I in of GH-deficient but in childhood-onset than adult-onset GHD have made In it is or the of GHD was in the childhood-onset and adult-onset Thus, from the of the of onset of GHD, it is that the of GHD the of IGF-I IGF-I and IGFBP-3 in with GH deficiency and of in with from H. G. C. E. A. of growth deficiency in adults this have the IGF-I of the of adults with and adult-onset GHD by in the of the of GHD. of the IGF-I with GH is due to the of GH provocative tests in that the IGF-I have been in the of pituitary into with and (Fig. In of the is a of adult-onset and childhood-onset GHD a of IGF-I status with degrees of GHD. The are for in the and in the childhood-onset IGF-I is than the adult-onset IGF-I in of the that for a of GHD, the IGF-I is in adults with childhood-onset compared with adult-onset The explanation for this is it the that an IGF-I is more to be of diagnostic in childhood-onset than in adult-onset GHD. IGF-I in adults with childhood-onset GHD or adult-onset GHD into and to be made in the with adult-onset isolated GHD. that of a GH of less than to an In the of are in the with adult-onset of whom have an IGF-I strategy to which GH-deficient a of GH therapy must for with isolated GHD, on an may severe a of GHD a with Obesity is that may be to from GHD in the is that is by of GH and that may and GH secretion GH in obese to be that of an in of by is with GH secretion due to GH and in at a GH secretion by in in the in to be a of GH secretion in IGF-I in are are or IGF-I in adults and IGF-I in obese In the of IGF-I in an in IGF-I to was for in a GH secretion has been is that a studies with a that and is of that the GH to a variety of GH but it GH secretion in obese The of of is at the pituitary in and that is a more in GH secretion in a of with GHD compared with a of obese In the obese with pituitary and other pituitary a GH to of the provocative tests may GHD or In this clinical between the is with of at the present GH secretion in adults is compared with that in adults GH secretion by from adult life and an that GH secretion may in certain is with in to in with GH a in in severe and a in and The of the in adults with GHD and that are of the has some to that may be due to GHD The in GH secretion and the with have been and the In the clinical this a number of the GH status of with pituitary be from that of the adults with GHD to with GH replacement the of The of pituitary with and thus pituitary is in the elderly. have that GH secretion is in the with pituitary compared with of GH secretion in with and in for The the of the GH the GH to and the IGF-I in the than in the of the of GH was between the of the of or GH secretion a with a of whereas all of in which GH secretion is to be most a GH be with Thus, a of the by was that and of the GH in the of and the of the Subsequently, the GH an 2 GH secretion was the in all and the of GH secretion in all but pituitary and GH was in the by to the of in adults with GHD, GH to a than GH between and unless the was to with the most severe of GHD, with or more pituitary in whom the GH was from In the GH on the obtained the provocative GH a (Fig. between the GH to and the the GH which was more in the than in the between the