Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis

Acquired PRL deficiency occurs when the anterior pituitary is functionally destroyed, and it usually accompanies other pituitary hormone deficiencies. We retrospectively investigated in an outpatient endocrine clinic of a major tertiary medical center the prevalence and clinical characteristics of acquired PRL deficiency in patients with diseases of the hypothalamic-pituitary axis. The study included 100 consecutive patients, 61 men and 39 women, aged 4-79 yr at diagnosis. Patients were divided by PRL level to normal (>5 ng/ml), mild (3-5 ng/ml), and severe deficiency (<3 ng/ml). Twenty-seven patients (27%) had PRL deficiency, 13 mild deficiency and 14 severe deficiency. Patients with severe PRL deficiency tend to be younger at diagnosis (mean age, 37.5+/-21.8 yr) than patients with normal PRL (46+/-18.5 yr; ns). Underlying diseases including pituitary apoplexy, non-functioning pituitary adenoma, craniopharyngioma, and idiopathic hypogonadotropic hypogonadism were associated with PRL deficiency. The incidence of severe PRL deficiency rose with an increase in the number of other pituitary hormone deficits (ACTH, TSH, gonadotropin, vasopressin), from 0 in patients with no other deficits to 38% in patients with 4 deficits (p=0.006). Patients with severe deficiency had a mean of 3 hormone deficits compared to 1.8 in the other groups (p=0.006). PRL deficiency was significantly associated with TSH, ACTH and GH deficiency. CONCLUSIONS: PRL deficiency is common in patients with hypothalamic-pituitary disorders, especially pituitary apoplexy and craniopharyngioma. Acquired severe PRL deficiency can be considered a marker for extensive pituitary damage and a more severe degree of hypopituitarism.     

THYROTROPHIN, PROLACTIN AND GROWTH HORMONE RESPONSES TO TRH IN BARBITURATE COMA AND IN DEPRESSION

The effects of 200 microgram thyrotrophin-releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear-cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderated rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TRH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.     

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     

Growth hormone-releasing peptide-2 infusion synchronizes growth hormone, thyrotrophin and prolactin release in prolonged critical illness

OBJECTIVE: During prolonged critical illness, nocturnal pulsatile secretion of GH, TSH and prolactin (PRL) is uniformly reduced but remains responsive to the continuous infusion of GH secretagogues and TRH. Whether such (pertinent) secretagogues would synchronize pituitary secretion of GH, TSH and/or PRL is not known. DESIGN AND METHODS: We explored temporal coupling among GH, TSH and PRL release by calculating cross-correlation among GH, TSH and PRL serum concentration profiles in 86 time series obtained from prolonged critically ill patients by nocturnal blood sampling every 20 min for 9 h during 21-h infusions of either placebo (n=22), GHRH (1 microg/kg/h; n=10), GH-releasing peptide-2 (GHRP-2; 1 microg/kg/h; n=28), TRH (1 microg/kg/h; n=8) or combinations of these agonists (n=8). RESULTS: The normal synchrony among GH, TSH and PRL was absent during placebo delivery. Infusion of GHRP-2, but not GHRH or TRH, markedly synchronized serum profiles of GH, TSH and PRL (all P< or =0.007). After addition of GHRH and TRH to the infusion of GHRP-2, only the synchrony between GH and PRL was maintained (P=0.003 for GHRH + GHRP-2 and P=0.006 for TRH + GHRH + GHRP-2), and was more marked than with GHRP-2 infusion alone (P=0.0006 by ANOVA). CONCLUSIONS: The nocturnal GH, TSH and PRL secretory patterns during prolonged critical illness are herewith further characterized to include loss of synchrony among GH, TSH and PRL release. The synchronizing effect of an exogenous GHRP-2 drive, but not of GHRH or TRH, suggests that the presumed endogenous GHRP-like ligand may participate in the orchestration of coordinated anterior pituitary hormone release.     

SERUM THYROTROPHIN RESPONSE TO THYROTROPHIN-RELEASING HORMONE IN NORMAL CHILDREN AND IN PATIENTS WITH SHORT STATURE AND VARIOUS ENDOCRINE OR GENETIC DESEASES

The TSH response to TRH has been investigated in a group of forty-two children, including eight normal controls, eight patients with short stature and without growth hormone deficieny, twelve hypopituitary patients, seven patients with thyroid disorders and seven others with various diseases, including four cases of Turner's syndrome. All children with short stature and without GH deficiency demonstrate a normal response to TRH. The same conclusion arises from the data obtained in most of the cases with isolated GH deficiency. In one out of three cases of organic hypopituitarism, the maximal TSH response was delayed to 60 min after injection. Patients with Turner's syndrome have a normal response to TRH while the pituitary response was definitely enhanced in one case of pseudohypoparathyroidism.     

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.     

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.     

Hypothalamic-pituitary function in growth hormone-deficient patients with pituitary stalk transection

We compared 1.5 T magnetic resonance (MR) image findings with hypothalamic-pituitary function in 11 patients with idiopathic pituitary dwarfism, each of whom had a history of perinatal abnormalities, and 1 patient with posttraumatic pituitary dwarfism. MR imaging revealed transection of the pituitary stalk in all patients and the formation of an ectopic posterior lobe at the proximal stump in 9 patients, none of whom had polydipsia or polyuria. Three patients without an ectopic posterior lobe had diabetes insipidus. The 5 patients who had small pituitary glands (less than 2 mm in height) had hypothyroidism with low serum TSH concentrations and low serum cortisol responses to insulin-induced hypoglycemia; however, 7 patients with normal-sized pituitary glands had normal thyroid and adrenal function. The serum GH response to GHRH did not correlate with the size of the pituitary gland. The patients with small pituitary glands had delayed or prolonged serum TSH responses to TRH and impaired serum LH and FSH responses to GnRH; 4 of the patients with normal-sized pituitary glands had normal serum TSH, LH, and FSH responses. Only 2 patients had high basal serum PRL concentrations. The endocrinological data suggest that reestablishment of the hypothalamo-hypophyseal portal circulation, which cannot be seen by MR imaging, may occur. We suggest that the primary cause of idiopathic pituitary dwarfism in many patients is injury to the pituitary stalk at birth.     

Induction of hypothyroidism and hypoprolactinemia by growth hormone producing rat pituitary tumors.

The GH3 rat pituitary tumor cell line which secretes both growth hormone (GH) and prolactin (PRL) stopped releasing PRL when transplanted to animals; furthermore, it suppressed PRL production by the hosts' pituitary glands. When the same tumor was transferred back to cell culture, PRL production resumed. The PRL to GH ratio in cell culture medium and cells ranged from 5 to 1 while in the tumor and serum of the host animals it averaged 0.09 and 0.001, respectively. To investigate further this phenomenon, female rats were transplanted with GH3 tumors (T) and compared to intact normal (N) and to thyroidectomized (Tx) rats. T animals were larger and had splanchnomegaly but smaller pituitaries and thyroids. Serum PRL concentrations in the basal state were decreased, as were levels of triiodothyronine (T3), thyroxine (T4), and free T4 index. Despite reduced serum thyroid hormone concentrations, and in contrast to Tx animals, the serum thyrotropin (TSH) level in T rats was not elevated and they did not show a supranormal TSH response to thyrotropin-releasing hormone (TRH) administration. The PRL response to TRH in T animals was completely abolished while all N and Tx animals responded by a significant increase in serum PRL. Serum corticosteroids and estrogens were normal in T rats. Pituitary content of PRL was decreased and that of TSH increased in T rats. Tx animals, however, had a reduced pituitary content of PRL, TSH, and GH. When GH3 cells were grown in cell culture media containing serum from T animals, there was a reduction of PRL content in cells and released in the medium. Addition of T3 to the T serum did not alter its suppressive effect on PRL nor did rat GH added to N serum alter PRL production and release in vitro. In a preliminary experiment, rats injected ip with 50 mug hGH in two divided doses for eighteen days, suppressed serum T4 and T3 concentrations; pituitary content of TSH was significantly increased and that of PRL slightly decreased. Injection with 250 mug oPRL or saline, on the same schedule and for the same length of time, had no significant effect on the levels of serum thyroid hormones. Thus, GH, but also possibly other substance(s) secreted by GH3 tumors in vivo a) suppress the production of tumor and pituitary PRL; b) suppress the release of TSH, causing mild hypothyroidism; c) inhibit the PRL and TSH responses to TRH; and d) decrease the production of PRL in tissue culture. Although no simple and unifying theory could explain these findings, an hypothesis implicating somatomedin is presented.     

GHRH plus arginine in the diagnosis of acquired GH deficiency of childhood-onset

We evaluated the GH-releasing effect of GHRH plus arginine (ARG) in 36 patients (22 males and 14 females) with acquired GH deficiency including idiopathic inflammatory pituitary stalk thickness (n = 15), Langerhans cell histiocytosis (LCH) affecting the hypothalamic-pituitary area (n = 11), and craniopharyngioma (n = 10). All of the patients (mean age, 9.6 +/- 3.1 yr; range, 5.6-20.8) showed GH response less than 10 microg/liter after 2 pharmacological stimuli and were tested with GHRH plus ARG at a mean age of 11.2 +/- 4.1 yr. Twenty-nine patients had vasopressin deficiency, 10 had TSH deficiency, 8 had gonadotropin deficiency, and 4 had ACTH deficiency. The median peak GH response to insulin test was 2.1 microg/liter (range, 1.1-2.9), whereas it was 1.5 microg/liter (range, 1.3-2.4) after ARG. The median peak GH response to insulin was significantly lower in the patients with craniopharyngioma (1.4 microg/liter; range, 0.8-1.7) than in the patients with idiopathic pituitary stalk thickness (2.2 microg/liter; range, 1.0-2.4) or with LCH (2.6 microg/liter; range 2.0-4.3, P = 0.02). The median peak GH response to ARG was significantly lower in the patients with idiopathic inflammatory pituitary stalk thickness (1.3 microg/liter; range, 0.8-1.8) than in those with craniopharyngioma (1.5 microg/liter; range, 1.1-1.6) or with LCH (2.8 microg/liter; range, 1.9-3.2, P = 0.00007). The median peak GH response after GHRH plus ARG was significantly lower in the overall patient population (8.3 microg/liter; range, 4.4-28.4) than in the age-matched controls (49.8 microg/liter; range, 39.9-81.6, P < 0.00001). The median peak GH response was significantly lower in the patients with craniopharyngioma (4.6 microg/liter; range, 3.6-6.3) than in those with LCH (8.9 microg/liter; range, 4.4-28.4) or with idiopathic pituitary stalk thickness (12.6 microg/liter, range, 6.4-24, P = 0.07). Ten patients had a GH response of more than 20 microg/liter after GHRH plus ARG. There was a trend toward a decrease in peak GH response to GHRH plus ARG (r = -0.57, P = 0.06) as patient age increased. For cut-off values of 20 microg/liter, the sensitivity of GHRH plus ARG was 75% (95% CI, 57.8-87.9%) and the specificity was 96.4% (95% CI, 89.9-99.2%); whereas, for cut-off values of 24.2 microg/liter, sensitivity was 86.1% (95% CI, 70.5-95.3%), and specificity was 95.2% (95% CI, 88.2-98.7%). The median IGF-I level did not differ between the children with idiopathic pituitary stalk thickness (57 microg/liter; range, 46-68), those with LCH (55 microg/liter; range, 34-63), and those with craniopharyngioma (41 microg/liter; range, 39-49). The present study confirmed the diagnostic potential of the GHRH-plus-ARG test in children with acquired GH deficiency caused by hypothalamic-pituitary lesion. It stimulates GH secretion to a greater extent in those patients with GH deficiency with primary involvement of the hypothalamic area, e.g. patients with idiopathic pituitary stalk thickness or LCH, than in those with both hypothalamic and pituitary lesion, as in craniopharyngioma. In some patients, the GHRH-plus-ARG test stimulates GH response to a so-called: normal value, suggesting that pituitary responsiveness to GHRH plus ARG may fail to recognize acquired GHD. Finally, the number of pituitary hormone deficits and the patient's age affect the GH response to GHRH plus ARG.     

Effect of simultaneous administration of GHRH (1-40) and TRH on GH, PRL and TSH secretion in normal man

The GHRH test represents a new tool in the study of secretion in man. Nine normal fasting males received on separate occasions in random order 1) GHRH 1-40 (1 microgram/Kg bw) iv at time 0; 2) TRH (6 micrograms/min) infusion between -30 and +120 min; 3) GHRH 1-40 (1 microgram/Kg bw) iv at time 0 plus TRH (6 micrograms/min) infusion between -30 and +120 min. Blood samples were drawn for GH, PRL and TSH at -90, -60, -30, 0 min and then every 15 min for 2 h. GHRH significantly increased GH in all subjects. The same GH response was found during GHRH plus TRH test. No effect was found either on PRL and TSH secretion after GHRH administration, or on GH pattern after TRH administration. A significant decrease of TSH, but not of PRL response was observed after GHRH plus TRH administration in comparison to TRH alone. These results underline that the inhibitory effect exerted by TRH on GH secretion during some experimental conditions is not linked to a pituitary interference between GHRH and TRH. The difference in TSH secretion, following GHRH plus TRH in comparison with TRH alone, could be due to a GHRH-induced central inhibitory mechanism, probably GHRH-related.     

Hyperresponsiveness of TSH and prolactin and impaired responsiveness of GH in Japanese patients with isolated ACTH deficiency]

Two hundred and forty-one cases of isolated ACTH deficiency have been reported in Japan since 1969. Pituitary hormone responsiveness to stimulation tests before and after hydrocortisone supplementation was investigated in these cases. Plasma ACTH level showed no or little change in response to lysine vasopressin, metyrapone, CRF or insulin-induced hypoglycemia in 97.3-100% of the cases. Serum GH level changed little or not at all in response to GRF, insulin-induced hypoglycemia, glucagon, 1-dopa and arginine in 26.9, 29.3, 40.0, 50.0 and 56.1%, respectively. Serum TSH and prolactin (PRL) levels showed hyperresponse to TRH in 34.7 and 35.6%, respectively. After hydrocortisone therapy, GH secretion was more responsive than before therapy in 78.9% of the cases. After supplementation, TSH level was less responsive to TRH stimulation than before therapy in 59.3% of the cases. After hydrocortisone supplementation, TSH response to TRH decreased in 75% of ACTH-deficient patients without primary hypothyroidism but did not decrease in more than half of those with primary hypothyroidism. TSH response to TRH decreased after supplementation in 76.5% of the patients with TSH hyperresponsiveness before therapy, and increased after therapy in 66.7% of those with normal TSH responses before therapy. After supplementation, PRL response to TRH was less than that before therapy in 43.5% of ACTH--deficient patients, and greater than that before therapy in 30.4%. PRL response to TRH decreased after therapy in 66.7% of the patients with PRL hyperresponsiveness before therapy, and increased in 63.6% of those with normal PRL response before therapy. Primary hypothyroidism and Hashimoto's thyroiditis were complicated in 21.6 and 11.6%, respectively, of the 241 patients with isolated ACTH deficiency. In patients who had TSH hyperresponsiveness and/or high basal TSH levels and PRL hyperresponsiveness and/or high basal PRL levels, primary hypothyroidism was complicated in 58.4 and 42.3%, respectively. Hashimoto's thyroiditis was complicated in 29.8 and 20.5%, respectively, of these patients. Pituitary cell antibody (PCA) was detected in 36.6% of ACTH-deficient patients who were examined. Pituitary cell surface antibody (PCSA) to AtT-20 cells and GH3 cells was detected in 50.0 and 28.0% of the examined cases, respectively. The prevalence of PCA and PCSA did not differ between TSH-hyperresponsive patients and those with normal TSH basal levels and response, whereas PCA and PCSA were significantly more prevalent in PRL-hyperresponsive patients than in those with normal PRL levels and response. An empty sella was found in 30.2% of the examined case.(ABSTRACT TRUNCATED AT 400 WORDS)     

RECOVERY OF PITUITARY FUNCTION FOLLOWING SURGICAL REMOVAL OF LARGE NONFUNCTIONING PITUITARY ADENOMAS*

Pituitary function was evaluated in eleven patients with large nonfunctioning pituitary adenomas before and 3 months after surgical adenomectomy. The longest anteroposterior dimension from the anterior wall to the dorsum of the sella on a lateral skull x-ray ranged between 22 and 45 mm. All adenomas were confirmed histologically and had negative immunostaining for GH, PRL, ACTH and HCG. Based on the pre- and post-operative pituitary function, the patients were divided into two groups. Group I included eight patients who had hypopituitarism pre-operatively of whom five had partial recovery of pituitary function while three had persistent hypopituitarism. Group II included three patients who had normal pituitary function pre- and post-operatively. Five patients of group I had high normal or slightly elevated serum PRL levels while one had a normal level and two patients had low levels pre-operatively. TRH but not perphenazine resulted in a variable but definite rise in serum PRL preoperatively in patients with normal or elevated PRL level. In contrast, neither stimulus resulted in a rise in serum PRL in two patients with low basal levels. Serum PRL levels were normal in six patients and low in two others post-operatively. Serum TSH levels were low in all eight patients with hypothyroidism. TRH resulted in a sustained release of TSH in three patients and was without effect in two patients pre-operatively. Of eight patients with pre-operative hypothyroidism, five recovered normal function and three remained hypothyroid. Of six patients with adrenal insufficiency pre-operatively, two recovered normal pituitary—adrenal function while only two of eight patients recovered gonadal function post-operatively. None of the eight patients recovered GH responsiveness to stimulation. All patients that recovered pituitary function had normal or slightly elevated serum PRL pre-operatively. Our data indicate that recovery of pituitary function in patients with large pituitary adenomas and hypopituitarism may occur after surgical removal of the adenoma. One of the possible mechanisms of hypopituitarism in this setting would be interruption of the hypothalamic pituitary portal circulation by the large adenoma. An additional factor might be pressure necrosis and destruction of normal pituitary cells by the expanding adenoma. The extent of that might determine the degree of recovery of pituitary function.     

Sequential contrast-enhanced magnetic resonance imaging in the diagnosis of growth hormone deficiencies

The purpose of the present study was to assess the presence and the time-course of contrast-enhancement in the pituitary gland and pituitary stalk of 24 patients with isolated growth hormone (GH) deficiency and multiple pituitary hormone deficiency. The patients were evaluated clinically (auxological measurements), endocrinologically (spontaneous GH secretion and GH stimulation tests) and with conventional MRI scans. In addition, fast-framing dynamic magnetic resonance imaging (MRI) with Gd-DTPA enhancement was used to quantitate the time course of contrast enhancement within the neurohypophysis, pituitary stalk, postero-superior adenohypophysis and antero-inferior adenohypophysis. In 3 patients without evidence of abnormalities at normal conventional MRI scans (normal anterior lobe and pituitary stalk, normal posterior lobe) and a high response to the GRF provocation test, sequential time-resolved Gd-enhanced MRI demonstrates reduced contrast enhancement in the pituitary stalk. These findings are consistent with impairment in stalk vasculature, presumably located at the level of the portal venous system, and could play a role in the pathogenesis of pituitary hormonal deficiency.     

Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas

Detailed pituitary function studies were conducted on 26 patients with large nonfunctioning pituitary adenomas before and 2-3 months after transsphenoidal adenomectomy. Basal serum PRL, GH, TSH, LH, FSH, and ACTH levels were measured, and dynamic studies of their secretion were made. Preoperatively, GH deficiency was found in all 26 patients (100%), hypogonadism in 25 patients (96%), hypothyroidism in 21 patients (81%), and adrenal insufficiency in 16 patients (62%). Serum PRL levels were low (1.5-4 ng/ml) in 5 patients, normal (5-20 ng/ml) in 9 patients, and mildly elevated (21-53 ng/ml) in the remaining 12 patients. After selective adenomectomy, variable improvement in pituitary function occurred in 17 patients, worsening in 1 patient, and persistence of hypopituitarism in 8 patients. After surgery, normal thyroid function was documented in 12 of the 21 patients (57%) who were hypothyroid preoperatively. Similarly, 6 of the 16 patients (38%) with adrenal insufficiency recovered normal adrenal function, and 8 of the 25 patients (32%) with hypogonadism recovered normal gonadal function. GH deficiency persisted in all but 4 patients (15%). Serum PRL levels decreased in all patients, and only 5 had midly elevated levels after surgery. The presence of a normal or mildly elevated serum PRL level before surgery in these patients was of value in predicting possible recovery of pituitary function after surgery; none of the 5 patients with low preoperative serum PRL levels had any improvement in pituitary function after surgery. A rise in serum TSH levels after TRH administration before surgery also was helpful in predicting possible recovery from hypopituitarism. Most patients who had a rise in serum TSH level in response to TRH stimulation preoperatively recovered some pituitary function after adenomectomy. In contrast, no improvement in pituitary function occurred in patients who had blunted responses to TRH preoperatively. Improvement in pituitary function occurred more often in patients with tumors measuring 25 mm or less than in those with larger tumors. In conclusion, significant improvement in pituitary function may occur after surgical adenomectomy for nonsecreting pituitary tumors. A rise in serum TSH levels in response to TRH stimulation preoperatively suggested the presence of viable pituitary tissue in these patients with hypopituitarism. The presence of a normal or mildly elevated serum PRL level before surgery also suggested the presence of functioning pituitary lactotrophs. These observations suggest that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Thyrotropin-releasing hormone stimulates growth hormone release from the anterior pituitary of hypothyroid rats in vitro

We have examined the interaction of thyroid hormone and TRH on GH release from rat pituitary monolayer cultures and perifused rat pituitary fragments. TRH (10(-9) and 10(-8)M) consistently stimulated the release of TSH and PRL, but not GH, in pituitary cell cultures of euthyroid male rats. Basal and TRH-stimulated TSH secretion were significantly increased in cells from thyroidectomized rats cultured in medium supplemented with hypothyroid serum, and a dose-related stimulation of GH release by 10(-9)-10(-8) M TRH was observed. The minimum duration of hypothyroidism required to demonstrate the onset of this GH stimulatory effect of TRH was 4 weeks, a period significantly longer than that required to cause intracellular GH depletion, decreased basal secretion of GH, elevated serum TSH, or increased basal secretion of TSH by cultured cells. In vivo T4 replacement of hypothyroid rats (20 micrograms/kg, ip, daily for 4 days) restored serum TSH, intracellular GH, and basal secretion of GH and TSH to normal levels, but suppressed only slightly the stimulatory effect of TRH on GH release. The GH response to TRH was maintained for up to 10 days of T4 replacement. In vitro addition of T3 (10(-6) M) during the 4-day primary culture period significantly stimulated basal GH release, but did not affect the GH response to TRH. A GH stimulatory effect of TRH was also demonstrated in cultured adenohypophyseal cells from rats rendered hypothyroid by oral administration of methimazole for 6 weeks. TRH stimulated GH secretion in perifused [3H]leucine-prelabeled anterior pituitary fragments from euthyroid rats. A 15-min pulse of 10(-8) M TRH stimulated the release of both immunoprecipitable [3H]rat GH and [3H]rat PRL. The GH release response was markedly enhanced in pituitary fragments from hypothyroid rats, and this enhanced response was significantly suppressed by T4 replacement for 4 days. The PRL response to TRH was enhanced to a lesser extent by thyroidectomy and was not affected by T4 replacement. These data suggest the existence of TRH receptors on somatotrophs which are suppressed by normal amounts of thyroid hormones and may provide an explanation for the TRH-stimulated GH secretion observed clinically in primary hypothyroidism.     

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.     

Evaluation of anterior pituitary function in patients with posttraumatic diabetes insipidus

Serum LH, FSH, TSH, PRL, GH, and cortisol were measured in 10 patients with posttraumatic diabetes insipidus both basally and after a combined insulin-induced hypoglycemia, LRH and TRH test. Two patients did not show hormonal abnormalities, while 8 patients had deficiencies of 1 or more hormones. The most frequent abnormality was GH deficiency (50%), followed by TSH (40%), ACTH (30%), FSH (30%0, and LH (20%). These results indicate that anterior pituitary dysfunction frequently accompanies posttraumatic diabetes insipidus.     

Growth and adult height in GH-treated children with nonacquired GH deficiency and idiopathic short stature: the influence of pituitary magnetic resonance imaging findings

We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests >10 microg/liter). The mean GH dose was 0.44 IU/kg.wk (0.15 mg/kg.wk), given for a mean duration of 4.6 yr. Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak <5 microg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 +/- 0.9 vs. +1.3 +/- 0.8 SD score; P < 0.01), and reached greater final height (-1.1 +/- 1.0 vs. -1.7 +/- 1.0 SD score; P < 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies. GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 +/- 0.8, +0.9 +/- 0.6, and +0.7 +/- 0.9 SD score, respectively; P < 0.01, by ANOVA), these patients reached a similar final height (-1.7 +/- 1.0, -2.1 +/- 0.8, and -2.1 +/- 1.0 SD score, respectively; P = 0.13). Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.