Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between the visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function.

In GH-deficient children showing ectopic posterior pituitary hyperintense signal (EPP), the anatomical details of the pituitary-hypothalamic region and the relationship between the visibility of the pituitary stalk and anterior pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the pituitary stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7+/-5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of pituitary stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P<0.05). Although the EPP was found at the median eminence in all group 2 patients, it was visualized in group 1 at different levels of the pituitary stalk in 60% of cases (8 of 14; at the proximal end of the pituitary stalk, n = 4; in the middle of the pituitary stalk, n = 2; at the distal end of the pituitary stalk, n = 2). This demonstrates that the ectopic posterior pituitary migration abnormality may be complete or partial. In conclusion, although the pathogenesis of GH deficiency with EPP remains unclear, these results suggest that in cases of GH deficiency associated with ectopic posterior pituitary hyperintense signal, patients with no visible pituitary stalk on MRI after gadolinium injection present a more severe form of the disease in childhood associated with multiple anterior pituitary hormone deficiency, whereas visibility of the pituitary stalk is related to isolated GH deficiency. Nevertheless, careful follow-up of these latter patients is necessary, as the natural history of the disease is not established until adulthood.     

Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R,GH-1, or PROP-1 genes

Pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI) are frequently observed in patients with GH deficiency (GHD), but their pathogenesis remains controversial. We performed pituitary stimulation tests, MRI, and studied GH-1, GHRH receptor (GHRH-R), and Prophet of Pit-1 (PROP-1) genes in 76 patients with GHD. Of 33 patients with isolated GHD, 4 had GH-1 deletions and 4 had GHRH-R mutations; of 43 patients with combined pituitary hormone deficiency, 1 had PIT-1 and 5 had PROP-1 mutations. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequency of consanguinity (57 vs. 2%, P < 0.001), familial cases (21 vs. 3%, P < 0.05), and lower frequency of breech delivery or hypoxemia at birth (0 vs. 39%, P < 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P < 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations against 13% without mutations (P < 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP-1 and PIT-1 mutations and suggestive of hypothalamic origin in 81% without mutations. Perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies. In contrast, GH-1, GHRH-R, and PROP-1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. We conclude that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiological diagnosis of GHD.     

Dynamic MRI in the congenital agenesis of the neural pituitary stalk syndrome: the role of the vascular pituitary stalk in predicting residual anterior pituitary function

OBJECTIVE Magnetic resonance imaging (MRI) without contrast medium is unable to give detailed information on the hypothalamic-pituitary structures. MRI using gadopentetate dimeglumine (Gd-DTPA), and dynamic MRI, were performed in patients with hypopituitarism previously diagnosed as having anterior pituitary hypoplasia, ectopic posterior pituitary and unidentified pituitary stalk (1) to determine whether Gd-DTPA improves the delineation of hypothalamic-pituitary structures; (2) to verify whether, if so, such improvement can be correlated with residual pituitary function in patients subjected to long-term follow-up; and (3) to identify the hypothalamic-pituitary vascular network in such cases. PATIENTS Eighteen patients (13 males, 5 females) aged 10–26.4 years with unidentified pituitary stalk at first MRI study were evaluated. Eight had isolated GH deficiency (IGHD), and 10 had multiple pituitary hormone defect (MPHD) with the progression to complete anterior pituitary deficits seen by the age of 15 years in 8 patients (1 had GH and FSH–LH deficiency and 1 had GH, TSH and FSH–LH deficiency). RESULTS The MRI revealed a very thin pituitary stalk in 7 patients (38.8%), 6 with IGHD (75%) and 1 (10%) with MPHD (GH and FSH-LH deficiency), after Gd-DTPA administration. Reassessment of anterior pituitary function showed that the thyroid, adrenal and gonadal functions were intact in the 6 patients with IGHD and pituitary stalk identified by Gd-DTPA as well as in one IGHD patient with no evidence of pituitary stalk. In one 10-year-old with IGHD at the time of presentation (6 years) and no pituitary stalk seen after Gd-DTPA, subclinical hypothalamic hypothyroidism and suspected hypogonadotropic hypogonadism were documented. Partial ACTH deficiency was recorded In the patient with TSH and FSH–LH deficiency with no pituitary stalk. After Gd-DTPA, patients with absent pituitary stalk had a risk of developing MPHD 27 times greater than had those with an identified pituitary stalk (relative risk r=27, 95% confidence interval 1.9–368.4, Fisher’s exact test P=0.009). Dynamic MR images obtained every 4.6 s revealed rapid enhancement of hypothalamic-pituitary structures and allowed the determination of the times to initial enhancement of ectopic posterior pituitary and hypoplastic anterior pituitary which ranged between 9.2 and 18.4 s, and that of complete anterior pituitary (32.2–41.4 s). The time to maximum enhancement of anterior pituitary was significantly longer than in controls (35.5±3.8 s vs 25.2±1.6 s, P<0.0001). CONCLUSIONS MRI with Gd-DTPA proved more sensitive in identifying the vascular component of pituitary stalk and added new information about the partial preservation of hypothalamo-hypophyseal portal vessels. The vascular pituitary stalk is easily recognized after Gd-DTPA in most IGHD patients, but exceptionally in MPHD; this sheds light on the possible normal course of affected patients. The neural component of the pituitary stalk is lacking regardless of whether patients have IGHD or MPHD, indicating that the term congenital agenesis of the neural pituitary stalk is more appropriate than pituitary stalk interruption. The times to enhancement of ectopic posterior pituitary and residual anterior pituitary obtained by the fast-framing MRI technique disclose dynamic changes in regional blood supply which appear direct, arterial and mainly independent of the portal system     

The relation between pituitary magnetic resonance imaging findings and GH, TSH, PRL dynamics in patients with idiopathic GH deficiency

The relation between pituitary magnetic resonance imaging (MRI) findings and anterior pituitary function was studied in 36 patients with classic idiopathic GH deficiency. These patients were divided into three groups based on MRI findings which were compared with those of 14 normal short children; i.e. normal stalk (N = 6), narrowed stalk (N = 20), and transected stalk (N = 10). The transected and narrowed stalk groups showed significantly delayed TSH responses to TRH compared with the normal stalk group and with the normal short children. Further, the mean maximal TSH increment in the narrowed and transected stalk group was slightly greater than that in normal short children. In contrast, there were no differences in basal plasma GH and PRL levels and their responses to GHRH and TRH among the three groups. When the patients were divided into normal anterior pituitary and atrophic pituitary groups regardless of stalk changes or when they were divided into groups of stalk changes (narrowing and transection) with and without pituitary atrophy, no differences in GH, TSH and PRL dynamics between the groups were observed. These results indicate that pituitary thyrotrope functions, but not somatotrope and lactotrope functions, in patients with idiopathic GH deficiency are more closely correlated to stalk changes than to anterior pituitary changes observed on MRI.     

Untreated hypopituitarism due to absence of the pituitary stalk with normal adult height: report of two cases

Patients with congenital multiple pituitary hormones deficiency (MPHD) occasionally present with pituitary stalk interruption and ectopic posterior lobe on magnetic resonance imaging (MRI). Very rarely normal adult height despite growth hormone deficiency (GHD) has been described in these patients. We report two patients with evidence of congenital MPHD, who remained untreated until adulthood. They both failed to develop spontaneous puberty, and they demonstrated very low growth velocity until adulthood when they continued to grow, with a final height of 176 and 169 cm when they sought medical attention in our department at the age of 45 and 33 yr, respectively. At that time a hypoplastic pituitary, absence of pituitary stalk, and ectopic posterior pituitary lobe were found on MRI, and the laboratory investigations, including dynamic tests for pituitary hormone reserve, revealed MPHD with severe GHD. In conclusion, these cases illustrate that very rarely patients with untreated MPHD can reach normal adult height. Some postulations about the pathophysiology of this phenomenon are discussed.     

The pituitary stalk transection syndrome: multifaceted presentation in adulthood

The pituitary stalk transection syndrome was characterized after introducing the MRI scan in the evaluation of children with hypopituitarism. Its prevalence and natural history into adulthood have not been clearly established. We present 4 cases of stalk transection syndrome diagnosed by the adult endocrinologist that reflect its pleiotropic manifestations. In all cases, MRI showed pathognomonic findings with small anterior pituitary, diminutive or absent infundibulum and ectopic posterior pituitary at the median eminence. Clinical presentation occurred in childhood or the second decade of life. The hormonal deficits were variable in severity and onset, with adrenal insufficiency diagnosed in the second and forth decade in three patients, and absent in another. Growth hormone deficiency was diagnosed before age 10 in three cases and at age 20 in one case with normal spontaneous linear growth. Hypothyroidism had onset in the first or second decade of life and hypogonadism was diagnosed during work-up for lack of pubertal development in all cases. The pituitary stalk transection syndrome should be considered in patients who were previously thought to have idiopathic GH deficiency or multiple pituitary hormone deficiencies. Presence of MRI characteristics compatible with the pituitary stalk transection syndrome should prompt a full pituitary hormonal evaluation. Long-term follow-up by the adult endocrinologist is warranted as new hormone deficiencies might appear later in life.     

Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe

OBJECTIVE: LHX4 and HESX1 are important in early stages of pituitary development and their mutations can be associated with an ectopic posterior lobe (EPL) in the pituitary of patients with hypopituitarism. The EPL can be located at the median eminence or at the path of the pituitary stalk. The aim of this study was to analyse LHX4 and HESX1 and characterize the hormonal deficiency profiles, establishing relationships with magnetic resonance imaging (MRI) findings in these patients. PATIENTS AND DESIGN: Sixty-two patients with hypopituitarism associated with EPL were submitted to evaluation of pituitary function, analysis of MRI with EPL location and molecular analysis of LHX4 and HESX1 using polymerase chain reaction (PCR), digestion with restriction enzyme and automatic sequencing. RESULTS: Forty-two patients had a nonvisualized pituitary stalk (NPS), and 20 a visualized pituitary stalk (VPS). Most patients (95%) with NPS had combined pituitary hormone deficiency (CPHD), with ACTH deficiency in 85%. In patients with VPS, CPHD was found in 50% and ACTH deficiency occurred in only 20%. The frequency of the location of EPL was similar in patients with VPS and NPS: 35% at median eminence and 65% at the path of the stalk. No mutations in LHX4 and HESX1 were identified. Three new polymorphisms in LHX4 were found. CONCLUSIONS: ACTH deficiency is frequent in patients with hypopituitarism and NPS (85%), the location of EPL at the median eminence was not predictive of the hormonal profile [isolated GH deficiency (IGHD) or CPHD], and LHX4 and HESX1 genes mutations remain rare causes of hypopituitarism associated with EPL.     

Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults

GH secretion was reevaluated after completion of GH treatment at a mean age of 19.2 +/- 3.2 yr in 35 young adults with childhood-onset GH deficiency (GHD). The patients were subdivided into 4 groups according to their first pituitary magnetic resonance imaging (MRI) findings: group I, 11 patients with isolated GHD (IGHD) and normal pituitary volume (280 +/- 59.4 mm3); group II, 7 patients with IGHD and small pituitary gland (163.1 +/- 24.4 mm3; P = 0.0009 vs. group I); group III, 13 patients (5 with IGHD and 8 with multiple pituitary hormone deficiency) with congenital hypothalamic-pituitary abnormalities such as pituitary hypoplasia (95.8 +/- 39.3 mm3; P < 0.00001 vs. group I and P = 0.003 vs. group II), pituitary stalk agenesis, and posterior pituitary ectopia; and group IV, 4 patients with multiple pituitary hormone deficiency secondary to craniopharyngioma. Pituitary MRI and GH secretory status were reevaluated after GH withdrawal using arginine, insulin induced-hypoglycemia, and sequential arginine-insulin tests. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were determined at the time of retesting and 6, 12, and 24 months after discontinuation of treatment in the patients with permanent GHD and after 6 months in those with normal GH responses to stimulation. The patients in groups I and II showed a normal response to stimulation after completion of GH treatment regardless of pituitary size, whereas all patients in groups III and IV still had a GH response of less than 3 microg/L to any of the tests. Pituitary volume normalized in 6 of 7 patients in group II, whereas in all patients in group III MRI studies confirmed the initial findings. Mean IGF-I and IGFBP-3 concentrations at the time of retesting were significantly higher in groups I and II than in groups III and IV. In patients of groups III and IV, mean IGF-I was significantly decreased after 6 and 12 months, whereas IGFBP-3 was significantly decreased 12 months after treatment withdrawal. Our results confirm that a high proportion of children with IGHD and normal or small pituitary show normalization of GH secretion at the completion of GH treatment, whereas GHD is permanent in all patients with pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia. IGF-I and IGFBP-3 determinations shortly after GH withdrawal had limited value in the diagnosis of GHD of childhood onset associated with congenital hypothalamic-pituitary abnormalities, but became accurate after 6-12 months. We suggest that patients with GHD and congenital hypothalamic-pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary gland should be retested well before the attainment of adult height.     

Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene

Genomic DNA from 18 patients with combined pituitary hormone deficiency was screened for 2-bp deletion (A301,G302) in PROP1 gene by BcgI restriction endonuclease analysis of PCR-amplified exon 2 gene fragments. Two unrelated female patients were homozygous for this 2-bp deletion. Patient 1 presented at 8.8 yr with severe short stature (-2.9 SD score), slightly enlarged sella turcica at x-rays, and diffusely enlarged pituitary gland (height, 8 mm vs. 4.5 +/- 0.6 mm in matched controls) with hyperintense enhanced signal at T1 weighted image at coronal and sagittal views at magnetic resonance imaging (MRI). MRI repeated at age 15 yr revealed a marked reduction of pituitary height (2 mm vs. 5.3 +/- 0.8 mm in matched controls). Patient 2 presented at 27 yr with short stature (-5.5 SD score) without pubertal development, normal sella turcica, and a pituitary gland of reduced size (height, 5 mm vs. 6.1 +/- 0.3 mm in matched controls) of normal intensity at MRI. Both patients had normal pituitary stalk and normally located neurohypophysis. Hormonal features were characterized by GH, TSH, PRL, LH, and FSH deficiencies. Patient 1 had normal cortisol secretion at 8.8 yr, and at 16.6 yr had developed partial cortisol deficiency, whereas patient 2 maintained normal cortisol secretion at 28.4 yr. We conclude that 1) a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced signal at T1 at MRI can be suggestive of PROP1 deficiency; 2) pituitary morphology can change during follow-up of patients with PROP1 gene mutation; and 3) hormonal deficiencies could include the adrenal axis.     

Long-term follow-up evaluation of magnetic resonance imaging in the prognosis of permanent GH deficiency

OBJECTIVE: In patients with GH deficiency (GHD), magnetic resonance imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, pituitary stalk agenesis (PSA) and ectopia of the posterior pituitary (PPE). The MRI anomalies have been more frequently reported in patients with multiple pituitary hormone deficiency (MPHD) than in subjects with isolated GH deficiency (IGHD). The aim of this work was to define which MRI anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD. DESIGN: To investigate the relationship between the neuroradiological images and endocrine findings, we clinically re-evaluated 93 out of the 121 GHD patients with IGHD and MPHD previously studied. RESULTS: No additional hormone deficiencies were observed in 55 out of 60 patients initially classified as having IGHD with a normal (15 cases) or reduced (40 cases) pituitary gland size, without other MRI abnormalities. The remaining five children, who had initially shown an apparently IGHD in spite of PSA and PPE, developed a MPHD over time. In 33 MPHD patients with (25 cases) or without (8 cases) MRI abnormalities, the associated hormone deficiencies were confirmed during follow-up. CONCLUSIONS: The IGHD patients showing PSA and PPE inevitably develop additional hormone deficiencies, while IGHD subjects having no MRI abnormalities maintain IGHD. Moreover, the anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD.     

Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency

OBJECTIVE In patients with congenital GH deficiency (GHD), magnetic resonance Imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, absence of the stalk and ectopia of the posterior pituitary (PPE). Our study was aimed at investigating the possible relationship between neuroradioiogical Images and the presence of Isolated GH or multiple pituitary hormone deficiency. DESIGN We studied 121 patients, aged 0.3–25 years, with Isolated GHD (IGHD, 81 cases) or multiple pituitary hormone deficiency (MPHD, 40 cases). Of 81 IGHD patients, 50 were at prepubertal and 22 at pubertal age, while 9 had a delayed onset of puberty. Out of 40 MPHD patients, 25 were at prepubertal age and 15 at the age of puberty. RESULTS Pituitary hypoplasia, defined as a gland with a height of less than ?2 SD for age, was observed more frequently in prepubertal (66%) than pubertal (18%) IGHD patients. It was also found in the majority of MPHD patients of prepubertal (76%) and pubertal age (80%), and of IGHD patients with delayed onset of puberty (100%). Mean ± SEM pituitary height was significantly lower (P < 0.001) In both prepubertal IGHD (?2.70 ± 0.20 SD) and MPHD children (?3.10 ± 0.39 SD) than in IGHD patients with normal onset of puberty (?1.55 ± 0.2 SD). A significantly greater pituitary height was observed in IGHD patients with normal onset of puberty (?1.55 ± 0.20 SD) than In MPHD patients at the age of puberty (?4.38 ± 0.61 SD, P < 0.001) and in IGHD subjects with delayed onset of puberty (?4.06 ± 0.41 SD, P < 0.001). An Important Increase (P < 0.02) in the height of the pituitary gland was found in 6 of the 9 patients with delayed puberty when they were re-evaluated after completing their spontaneous pubertal development. The frequency of other MRI abnormalities (PPE, stalk transection) was significantly higher in MPHD patients than In IGHD patients (P < 0.001). CONCLUSION Our results confirm the usefulness of MRI In the evaluation of children affected by GH deficiency. The association of gland hypoplasia with other MR abnormalities could suggest the presence of multiple anterior pituitary deficiencies. Finally, puberty seems to play an important role in the increase of pituitary size in multiple pituitary hormone deficiency and isolated GH deficiency patients.     

Permanent central diabetes insipidus with complete regression of pituitary stalk enlargement after 4 years of follow-up

A 14 year-old patient was admitted because of a history of polyuria and polydipsia. A diagnosis of central diabetes insipidus (CDI) accompanied by growth hormone (GH) and gonadotropin deficiency was made. Hypophyseal magnetic resonance imaging (MRI) of the patient demonstrated isolated pituitary stalk enlargement. Although GH deficiency and gonadotropin deficiency were transient, CDI was persistent despite the regression of the pituitary stalk enlargement over the 4 years of follow-up.     

Clinical characteristics, etiologies and pathophysiology of patients with severe short stature with severe GH deficiency: questionnaire study on the data registered with the foundation for growth science, Japan

In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 micro/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.     

Development of growth hormone and adrenocorticotropic hormone deficiencies in patients with prenatal or perinatal-onset hypothalamic hypopituitarism having invisible or thin pituitary stalk on magnetic resonance imaging

A gradual loss of anterior pituitary hormones is suspected in patients treated with irradiation due to brain tumors. Development of growth hormone deficiency (GHD) with age has been documented in patients with idiopathic GHD. A gradual loss of adrenocorticotropic hormone (ACTH) secretion has been also shown in a patient with severe GHD and an invisible pituitary stalk on magnetic resonance imaging (MRI). The purpose of this longitudinal and cross-sectional study was to evaluate the gradual loss of growth hormone (GH) and ACTH in a homogeneous group of patients with hypopituitarism. Twenty-eight patients (23 males, 5 females) from four hospitals were diagnosed as having prenatal or perinatal-onset hypothalamic hypopituitarism. They had an abnormal pituitary stalk on MRI (invisible in 18 patients, thin in 10 patients) without any other organic disease of the brain. Each patient had GHD upon initial evaluation. Height (n=20) was analyzed as standard deviation score (SDS). Longitudinal (n=8) and cross-sectional (n=28) GH secretion capacity was evaluated by GH peaks, in response to insulin tolerance test (ITT) and growth hormone releasing factor test (GRF test). Longitudinal (n=10) and cross-sectional (n=28) ACTH secretion capacity was evaluated by cortisol peaks in response to ITT. Height SDS decreased each year in all the untreated patients after birth. GH peaks decreased gradually with age. Longitudinal data showed decreased GH peaks with age in seven out of eight patients using ITT and in all four patients using GRF tests. Cortisol peaks also decreased gradually together with signs and symptoms for adrenal deficiency such as general fatigue. Cortisol peaks of less than 414 nmol/L (15 microg/dl) in response to ITT were seen in 24% of the tests before age 10 and 56% before age 25. In conclusion, GHD and ACTH deficiency developed gradually in patients with prenatal or perinatal-onset hypothalamic hypopituitarism who had invisible or thin pituitary stalks examined by MRI.     

MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature

BACKGROUND: Disturbances in the GH/IGF-I axis are reported in 25-60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls. PATIENTS AND METHODS: MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non-SGA children with isolated GH deficiency (IGHD group; n = 24) and non-SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF-I and IGFBP-3 levels was evaluated. RESULTS: Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic-pituitary region in contrast to 58% of the non-SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non-SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF-I and IGFBP-3 levels. CONCLUSION: Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.     

Hypothalamic-pituitary dysfunction in growth hormone-deficient patients with pituitary abnormalities

Hypothalamic-pituitary function was studied in 45 patients with idiopathic GH deficiency (GHD), 33 of whom had pituitary abnormalities on magnetic resonance imaging: pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe in 8 patients with isolated GHD (IGHD) (group I) and in 12 patients with multiple pituitary hormone deficiency (MPHD) (group II); isolated pituitary hypoplasia in 13 patients with IGHD (group III); no evidence of pituitary abnormalities in the remaining 12 patients with IGHD (group IV). Sellar and pituitary volumes were significantly lower in groups I, II, and III than in group IV (P less than 0.001). No significant differences were observed between group I and group II in the GH response to GHRH1-44 expressed both as peak serum GH and area under the curve. Mean GH peak in group III and IV was significantly higher than that in group I (P less than 0.005) and II (P less than 0.001), as were the mean AUC (P less than 0.005), suggesting hypothalamic defect. Delayed peak serum TSH after TRH was found in all patients of group II, and overt hypothyroidism in 11 of them. Furthermore, basal hyperprolactinemia was present in 6 patients and adrenal insufficiency in 7 cases of group II. Finally, a reduced response of FSH to GnRH was observed in all these patients (P less than 0.005 vs. each of the other groups), and clinical hypogonadism was present in all of them. We suggest that: 1) A high incidence of pituitary abnormalities seems to be present in idiopathic GHD patients; 2) Pituitary hormone deficiencies are more dependent on the type of the hypothalamic-pituitary abnormality than on the size of the pituitary per se: the association of pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe should possibly be considered a distinct entity reflecting an early abnormality in hypothalamic development; 3) The majority of patients with IGHD or MPHD probably have a primary hypothalamic releasing hormone deficiency even if pituitary hypoplasia is associated; 4) Magnetic resonance imaging may have a role in the diagnosis and prognosis of patients with GHD through differentiation between patients who are at risk for developing MPHD vs. those who are candidates for having a persistently isolated GHD.     

Neurohypophyseal function of an ectopic posterior lobe in patients with growth hormone deficiency

We studied the neurohypophyseal function of 20 patients with complete GH deficiency owing to pituitary stalk transection by means of the water deprivation and the hypertonic saline infusion test. In T1-weighted magnetic resonance images, high-signal intensity of the posterior lobe of the hypophysis was missing in all the patients. An ectopic posterior lobe was observed at the proximal stump of the transected stalk in 17 patients, whereas the 3 patients without ectopic posterior lobe had overt diabetes insipidus or intractable nocturnal enuresis. After water deprivation, 3 patients with large ectopic posterior lobes (length along the pituitary stalk axis exceeding 5 mm) showed urinary osmolality and plasma AVP levels as high as those of 13 patients with partial GH deficiency in whom magnetic resonance images revealed no abnormalities. On the other hand, 14 patients with small ectopic posterior lobes (length less than 5 mm) showed significantly lower urinary osmolality and plasma AVP levels than the patients with large ectopic posterior lobes (p less than 0.01 and p less than 0.01, respectively) and the patients with partial GH deficiency (p less than 0.01 and p less than 0.01, respectively). Urinary osmolality in the patients with small ectopic posterior lobes, however, was higher than that in 3 patients without ectopic posterior lobes (p less than 0.01). During the hypertonic saline infusion test, peak plasma AVP levels in the patients with small ectopic posterior lobes were significantly lower than those in the patients with partial GH deficiency (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin

OBJECTIVE: To determine the specific morphology of the pituitary gland in children with severe isolated GH deficiency due to GH-1 gene mutations (IGHD type II). DESIGN: The pituitary gland morphology in magnetic resonance imaging (MRI) of children with IGHD type II was analyzed and compared with the findings in a group of children with comparably severe IGHD of unknown origin. In addition, the birth histories of both groups were studied. SUBJECTS: Thirteen children with IGHD type II were diagnosed in seven European children's hospitals and they carried a corresponding GH-1 gene mutation. For comparison, we selected from a group of 66 MRI-studied GH-insufficient subjects diagnosed in our clinic, all children with severe IGHD (all GH peaks <4 microg/l) who had no GH-1 gene mutation, no first-grade relative with IGHD and no septo-optic dysplasia. METHODS: Sagittal and coronal images of the brain were analyzed for the presence of any malformation of the pituitary gland and the intracranium. The height of each adenohypophysis was measured in a strict midline sagittal image for quantification of the gland's size. In addition, patients' files were reviewed for birth trauma or breech delivery. RESULTS: Normal MRI morphology of the pituitary gland was observed in all patients of the familial IGHD type II group (P<0.003) in which, however, five of thirteen patients (38%) exhibited a mild hypoplasia of their gland (mean sagittal adenohypophysial height -1.0+/-0.03 SD score (SDS)). In contrast, the pituitary gland in the idiopathic group showed a definitive malformation with hypoplasia of pituitary stalk and adenohypophysis in all cases, while ectopia of the neurohypophysis was present in nine of the ten cases. The adenohypophysis was significantly smaller in the idiopathic group (mean sagittal adenohypophysial height -3.2+/-0.3 SDS) (P<0.0001). All thirteen birth histories in the familial group (IGHD type II) were unremarkable while, in the idiopathic group, three of eight available birth histories recorded a breech delivery or traumatic birth (37.5%) (P<0.05). CONCLUSIONS: This study shows for the first time that MRI pituitary morphology may correlate with the etiology of severe IGHD: normal morphology suggests the presence of GH-1 gene mutations, while severe hypoplasia with malformation have other causes which might include so far unknown genetic defects as well as traumatic insults.     

Idiopathic central diabetes insipidus is associated with abnormal blood supply to the posterior pituitary gland caused by vascular impairment of the inferior hypophyseal artery system

Central diabetes insipidus (CDI) has been linked to vascular central nervous system damage, although the pathophysiology of the mechanism has never been perfectly understood. Indeed, the vascular system of human pituitary gland has rarely been the subject of rigorous investigation except at postmortem. Recently, studies of pituitary gland blood supply have been carried out by means of a time evaluation of pituitary gland enhancement with noninvasive dynamic magnetic resonance (MR) imaging after contrast medium injection. In the present study, we decided to investigate the status of posterior pituitary blood supply by evaluating vascular pituitary patterns in a group of 19 patients with idiopathic CDI in whom previous standard MR imaging had failed to identify causal specific lesions. The control group was composed of 55 subjects with a median age of 12 yr (range, 4.2-17 yr) who had idiopathic isolated GH deficiency and normal pituitary morphology and 15 young adults (18-25 yr) who had normal pituitary gland and no endocrine dysfunction. Nineteen patients (12 females and seven males), ranging in age at the time of diagnosis of CDI from 0.5-14.9 yr (median, 5 yr), were examined with dynamic MR imaging between 1990 and 1997 at a median age of 14.1 yr (range, 5.0-26.3 yr). CDI was diagnosed according to clinical findings of polyuria and polydipsia, water deprivation test, and desmopressin acetate therapeutic trial. All of the patients had permanent CDI and were being treated with satisfactory results with desmopressin, two to three times daily, either intranasally or orally. The previous MR imaging findings of the 19 CDI patients had shown the absence of posterior pituitary hyperintensity, normal pituitary stalk, and normal anterior pituitary size. Enhancement of the straight sinus, representing a temporal reference point and occurring in normal subjects simultaneously to that of the posterior pituitary gland, was observed in all subjects after iv gadopentetate dimeglumine administration, with no substantial differences between patients and controls. However, the enhancement of the posterior pituitary lobe occurred simultaneously with the enhancement of the straight sinus in all of the controls but in only 14 of the 19 patients with CDI. In the remaining five patients, the enhancement of the straight sinus was not associated with the expected contrast enhancement of the posterior pituitary gland, suggesting abnormal blood supply to the posterior pituitary lobe. This is in keeping with vascular impairment of the inferior hypophyseal artery system and suggests that abnormal blood supply to the posterior pituitary gland is associated with what, until now, has been considered idiopathic CDI.     

Hypothalamic origin of idiopathic hypopituitarism

Two adult male patients with anterior pituitary insufficiency of unknown etiology were studied during acute challenge with thyrotropin releasing hormone (TRH) and aqueous vasopressin (AVP). Each patient had previously documented thyrotropin (TSH) adrenocorticotropin (ACTH) and gonadotropin deficiencies dating back to childhood. Plasma growth hormone (GH) was undetectable in each following insulin and arginine stimuli. Intravenous administration of synthetic TRH produced in both patients a prompt rise in serum TSH similar to the response observed in normal subjects. AVP injection was followed by a significant elevation of plasma 17-hydroxycorticosteroids in each patient and a rise in plasma GH in one of them. These results demonstrate that the adenohypophysis of these two patients could respond to stimuli of hypothalamic origin. It is concluded that the anterior pituitary failure was due to a deficiency of hypothalamic “releasing factors” caused by a disorder of hypothalamic function of unknown etiology.