Is Growth Hormone Deficiency in Ectopic Neurohypophysis Permanent?

Anatomical abnormalities of the hypothalamic-pituitary axis, as detected by cerebral magnetic resonance imaging (MRI) in children with isolated growth hormone deficiency (GHD) or multiple pituitary hormone deficiencies (MPHD) are a landmark of a group of patients with hypopituitarism. Leger et al reported a prospective study of a group of such 18 patients who had in common MRI markers of ectopic neurohypophysis with defects of the pituitary stalk. The researchers followed the patients until adulthood, after completion of GH treatment. The initial diagnosis of GHD was based on a GH peak of <10 µg/L after provocative stimuli. At retesting, the same criteria were applied, but GHD was considered as severe if the peak value was <5 µg/L. The important finding at reevaluation was the presence of normal or only partially deficient GH secretion with a peak value of >5 µg/L in 7 patients; 6 out of whom had isolated GHD. Among the 11 patients with severe GHD at retesting, only one had isolated GHD. Therefore, MPHD, regardless of etiology, was a strong predictor of permanent GHD after adolescence.

The MRI structure of the hypothalamic-pituitary axis differed among both groups. It should therefore be recalled that the main anatomical finding in the so-called pituitary stalk interruption syndrome is the ectopic location of the bright spot of the neurohypophysis. This spot may be located in its upper position at the median eminence or at a lower level along the pituitary stalk with a hypoplastic anterior pituitary. The ectopic neurohypophysis was found at the median eminence level in 10 out of 11 patients with permanent, severe GHD. In contrast, it was located along the stalk in all but one of the patients with normal or partially reduced GH response at retesting.

Cerebral MRI (T1-weighted images). A, Sagittal slice; B, coronal slice; normal morphology of anterior pituitary and pituitary stalk is seen. The hyperintense signal of the posterior pituitary is in the normal location. C, Sagittal slice; D, Coronal slice; a normal anterior pituitary with a thin pituitary stalk is seen. The ectopic posterior pituitary hyperintense signal is located along the stalk (at a proximal level of the pituitary stalk; arrow). E, Sagittal slice; F, coronal slice; hypoplastic anterior pituitary with no visible pituitary stalk after gadolinium injection. The ectopic pituitary hyperintense signal is at the median eminence (arrow). Reprinted with permission Leger J, et al. J Clin Endocrinal Metab. 2005;90:650-656. Copyright ©2005. The Endocrine Society. All rights reserved.

The authors concluded that increased GH secretion may be observed in adult patients with less severe MRI anatomical defects. These individuals need to be retested at the completion of GH treatment. In contrast, the patients who persisted with severe GHD formed a subgroup with their neurohypophysis at the median eminence with lack of or poor visibility of the pituitary stalk. Retesting may not be necessary in these patients, especially if there is MHPD.

Editor’s Comment: The authors studied a group of non-acquired GHD patients identified by MRI-detectable anatomical defects of the hypothalamic-pituitary axis. This type of patient is of theoretical as well as practical interest. It was first hypothesized that all patients with such MRI-detectable defects would show permanent GHD and eventually be candidates for life-long GH therapy. It is now shown that a subgroup (approximately 40%) with isolated GHD in childhood may appear as normal, or moderately affected, at retesting after growth is completed. Furthermore, the patients with GHD appear to present an anatomical defect detectable in the MRI which can be considered as less severe: the pituitary stalk is eventually visible and the neurohypophysis has partly “migrated” downward. These findings may help predict a more favorable outcome. In contrast, those presenting with MPHD with an ectopic neurohypophysis located in the median eminence usually present persistent GHD into adulthood. However, a word of caution is necessary as some of the patients with isolated GHD may develop other pituitary defects at any age. They require a lifetime follow-up, even if GH secretion has apparently returned to normal. These data should be considered for future guidelines of GH treatment.

The pathogenesis of the pituitary stalk interruption syndrome with pituitary insufficiency remains unknown in most cases. This defect has been reported in some patients with identified molecular defects of transcription factors controlling the early pituitary development.^1-3Although it was not the scope of this study, it seems important to not consider pituitary dysfunction as a stable condition. As also shown in other studies, the switch from isolated GHD to multiple defects remains possible at any age.^4,5 It will be of great interest to follow the patients who had an apparent recovery reported by Leger et al to document their reproductive function. Finally, patients with this illness are candidates for genetic studies and long-term follow-up to provide a more complete and eventually significant description of their hypothalamic-pituitary function throughout life.

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Table of Contents 21-3 Is Growth Hormone Deficiency in Ectopic Neurohypophysis Permanent?
Volume 21, Issue 3, September 2005 © 2005 Prime Health Consultants, Inc.

Anatomical abnormalities of the hypothalamic-pituitary axis, as detected by cerebral magnetic resonance imaging (MRI) in children with isolated growth hormone deficiency (GHD) or multiple pituitary hormone deficiencies (MPHD) are a landmark of a group of patients with hypopituitarism. Leger et al reported a prospective study of a group of such 18 patients who had in common MRI markers of ectopic neurohypophysis with defects of the pituitary stalk. The researchers followed the patients until adulthood, after completion of GH treatment. The initial diagnosis of GHD was based on a GH peak of <10 µg/L after provocative stimuli. At retesting, the same criteria were applied, but GHD was considered as severe if the peak value was <5 µg/L. The important finding at reevaluation was the presence of normal or only partially deficient GH secretion with a peak value of >5 µg/L in 7 patients; 6 out of whom had isolated GHD. Among the 11 patients with severe GHD at retesting, only one had isolated GHD. Therefore, MPHD, regardless of etiology, was a strong predictor of permanent GHD after adolescence. The MRI structure of the hypothalamic-pituitary axis differed among both groups. It should therefore be recalled that the main anatomical finding in the so-called pituitary stalk interruption syndrome is the ectopic location of the bright spot of the neurohypophysis. This spot may be located in its upper position at the median eminence or at a lower level along the pituitary stalk with a hypoplastic anterior pituitary. The ectopic neurohypophysis was found at the median eminence level in 10 out of 11 patients with permanent, severe GHD. In contrast, it was located along the stalk in all but one of the patients with normal or partially reduced GH response at retesting. Cerebral MRI (T1-weighted images). A, Sagittal slice; B, coronal slice; normal morphology of anterior pituitary and pituitary stalk is seen. The hyperintense signal of the posterior pituitary is in the normal location. C, Sagittal slice; D, Coronal slice; a normal anterior pituitary with a thin pituitary stalk is seen. The ectopic posterior pituitary hyperintense signal is located along the stalk (at a proximal level of the pituitary stalk; arrow). E, Sagittal slice; F, coronal slice; hypoplastic anterior pituitary with no visible pituitary stalk after gadolinium injection. The ectopic pituitary hyperintense signal is at the median eminence (arrow). Reprinted with permission Leger J, et al. J Clin Endocrinal Metab. 2005;90:650-656. Copyright ©2005. The Endocrine Society. All rights reserved. The authors concluded that increased GH secretion may be observed in adult patients with less severe MRI anatomical defects. These individuals need to be retested at the completion of GH treatment. In contrast, the patients who persisted with severe GHD formed a subgroup with their neurohypophysis at the median eminence with lack of or poor visibility of the pituitary stalk. Retesting may not be necessary in these patients, especially if there is MHPD. Leger J, Danner S, Simon D, Garel C, Czernichow P. Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood? J Clin Endocrinol Metab. 2005;90:650−656. Editor’s Comment: The authors studied a group of non-acquired GHD patients identified by MRI-detectable anatomical defects of the hypothalamic-pituitary axis. This type of patient is of theoretical as well as practical interest. It was first hypothesized that all patients with such MRI-detectable defects would show permanent GHD and eventually be candidates for life-long GH therapy. It is now shown that a subgroup (approximately 40%) with isolated GHD in childhood may appear as normal, or moderately affected, at retesting after growth is completed. Furthermore, the patients with GHD appear to present an anatomical defect detectable in the MRI which can be considered as less severe: the pituitary stalk is eventually visible and the neurohypophysis has partly “migrated” downward. These findings may help predict a more favorable outcome. In contrast, those presenting with MPHD with an ectopic neurohypophysis located in the median eminence usually present persistent GHD into adulthood. However, a word of caution is necessary as some of the patients with isolated GHD may develop other pituitary defects at any age. They require a lifetime follow-up, even if GH secretion has apparently returned to normal. These data should be considered for future guidelines of GH treatment. The pathogenesis of the pituitary stalk interruption syndrome with pituitary insufficiency remains unknown in most cases. This defect has been reported in some patients with identified molecular defects of transcription factors controlling the early pituitary development.^1-3Although it was not the scope of this study, it seems important to not consider pituitary dysfunction as a stable condition. As also shown in other studies, the switch from isolated GHD to multiple defects remains possible at any age.^4,5 It will be of great interest to follow the patients who had an apparent recovery reported by Leger et al to document their reproductive function. Finally, patients with this illness are candidates for genetic studies and long-term follow-up to provide a more complete and eventually significant description of their hypothalamic-pituitary function throughout life. Raphaël Rappaport, MD References - (linked to ) Sloop KW, Walvoord EC, Showalter AD, Pescovitz OH, Rhodes SJ. Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia J Clin Endocrinol Metab. 2000;85:2701-2708. Netchine I, Leger J, Rappaport R. In Rappaport R, Amselem S, eds. Hypothalamic-pituitary development: genetic and clinical aspects. Basel: Karger, 2001:94–108. Woods KS, Cundall M, Turton J, et al. Over- and underdosage of SOX3 Is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005;76:833–848. Birkebaek NH, Patel L, Wright NB, et al. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003;88:5281-5286. Maghnie M, Uga E, Temporini F, et al. Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol. 2005;152:735-741.