An apparent cluster of congenital hypopituitarism in central Massachusetts: magnetic resonance imaging and hormonal studies.

Between 1980 and 1989, five infants (four males and one female) with congenital hypopituitarism were born within a relatively sparsely populated area of central Massachusetts, an incidence 25-fold greater than expected. In all infants the pituitary stalk was undetectable on magnetic resonance imaging, and a bright spot on T-1 weighted imaging, probably representing posterior pituitary tissue, was found ectopically located inferior to the median eminence. The height of the anterior pituitary remnant on magnetic resonance imaging varied from undetectable to 4 mm, and similarly, on hormonal testing a spectrum of deficiencies of GH, TSH, ACTH, and gonadotropin was observed. The magnitude of the hypopituitarism was less in the three patients whose anterior pituitary remnant was greater than 2 mm, and in them, TRH testing resulted in exaggerated TSH and PRL responses, suggestive of hypothalamic disease. In contrast, in the other two patients in whom the anterior pituitary remnant was less than 2 mm in height, hypopituitarism was more severe, and TRH administration resulted in little if any TSH or PRL response, characteristic of pituitary disease. The size of the anterior pituitary remnant correlated significantly with that of the ectopic posterior pituitary bright spot (P less than 0.005). We conclude that patients with congenital hypopituitarism may exhibit a spectrum of hormonal responses, varying from findings typical of hypothalamic to those characteristic of primary pituitary disease. The pattern of hormonal responsiveness is dependent on the quantity of residual anterior pituitary tissue and probably results from abnormal transport of the hypothalamic hypophyseal releasing hormones rather than to any putative hypothalamic abnormality. The significant correlation between the size and function of the anterior pituitary gland and the size of the ectopic posterior pituitary remnant suggests that the fetal pituitary gland may secrete a factor necessary for the growth and descent of the neuroepithelium to form the infundibulum and posterior pituitary gland.     

Expression and function of ErbB receptors and ligands in the pituitary

The role of ErbB family in discreet pituitary functions is reviewed. Several ErbB receptor ligands, EGF, TGFα, and heregulin are differentially expressed in normal gonadotroph and lacto-somatotroph lineages, and other elements of the anterior pituitary. ErbB receptors, i.e. EGFR and ErbB2, are also localized to the anterior pituitary with preferential EGFR lactosomatotroph expression. EGF regulates CRH and ACTH secretion and corticotroph proliferation as well as exhibiting autocrine and paracrine effects on gonadotrophs and on lactosomatotroph proliferation, gene and protein expression, and hormonal secretion. EGF and EGFR are expressed in both functioning and non-functioning pituitary adenomas, with higher expression in more aggressive tumor subtypes. ErbB2 receptor is detected in all tumor subtypes, particularly in invasive tumors. ErbB tyrosine kinase inhibitors regulate hormonal secretion, cell morphology, and proliferation in lacto-somatotroph tumors, reflecting the emerging application of targeted pituitary therapeutics.     

Hypophysitis superimposed on a non-functioning pituitary adenoma: diagnostic clinical, endocrine, and radiologic features

Pituitary adenomas are common neoplasms requiring medical and/or surgical treatment when associated with hormonal hypersecretion. Treatment of non-functioning pituitary adenomas is necessary when symptoms of mass effect or hormonal deficits occur. However, therapeutic options, including surgical resection and/or radiotherapy, can be associated with significant complications. Hence, it is important to consider disorders that could present in a similar manner to pituitary adenomas, for which surgery is not the indicated therapeutic approach. We describe herein a 38-yr-old woman who presented with a pituitary lesion that was considered to be a non-functioning pituitary adenoma. Due to lack of hormonal deficits and/or compression of adjacent structures, we opted for conservative management and followup with consecutive magnetic resonance imaging. Fifteen months after initial diagnosis, considerable enlargement of the lesion was noted, extending mainly superiorly and indenting the optic chiasm. Repeated endocrine investigation revealed partial anterior pituitary insufficiency. The patient underwent trans-sphenoidal resection of the pituitary lesion; histology revealed a null cell pituitary adenoma and lymphocytic hypophysitis (LYH) of the non-neoplastic adenohypophysial gland. Post-operatively, complete anterior and partial posterior pituitary insufficiency developed. This case illustrates the effects of new-onset LYH in a patient with a pre-existing non-functioning pituitary adenoma. Being aware of this rare possibility is important, as enlargement of the pituitary lesion may not be caused by expansion of the preexisting tumor, but by the onset of LYH of the nonneoplastic pituitary tissue.     

Anterior pituitary glandular kallikrein: trypsin activation and estrogen regulation

Discrepant reports exist regarding the presence of glandular kallikrein or other trypsin-like serine proteases in the pituitary. The existence of pituitary kallikreins in latent forms could explain these discrepancies. I report that trypsin treatment of rat anterior pituitary homogenates activates two serine proteases which generate kinins from kininogen and selectively cleave chromogenic substrates for kallikreins. One protease (enzymatically and immunologically resembling glandular kallikrein) and activated 5-fold by trypsin and was 20 times more abundant in female than in male lobes due to hormonal regulation by ovarian estrogens. The second kallikrein (activated 20-fold by trypsin) was unaffected by estrogens. The results demonstrate that rat anterior pituitary kallikreins predominantly exist in latent forms requiring activation for detection. Additionally, glandular kallikrein is a major estrogen-induced protein in the rat anterior pituitary. No other member of this large protease family is known to be regulated by estrogens.     

Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.     

Estrogens modulate the inhibitory effect of tumor necrosis factor-alpha on anterior pituitary cell proliferation and prolactin release

Considering that tumor necrosis factor-alpha (TNF-alpha) is involved in normal tissue homeostasis and that its receptors are expressed in the anterior pituitary, we examined the effect of this cytokine on pituitary cell growth. Because anterior pituitary function depends on hormonal environment, we also investigated the influence of gonadal steroids in the effects of TNF-alpha on cell proliferation and the release of PRL from anterior pituitary cells. In addition, the release of TNF-alpha and its action on the release of PRL from anterior pituitary cells of rats at different stages of the estrous cycle was evaluated. In minimum essential medium D-valine, a medium that restricts fibroblastic proliferation, TNF-alpha (10 and 50 ng/mL) reduced 3H-Thymidine incorporation, DNA content, and active cell number. TNF-alpha failed to affect proliferation of cells from ovariectomized (OVX) rats. However, it significantly inhibited growth of cells from OVX rats cultured with 17beta-estradiol (E2) (10(-9) M) and from chronically estrogenized rats. TNF-alpha decreased the release of PRL from cells of intact rats, especially in proestrous, OVX rats cultured with E2 and chronically estrogenized rats. The release of anterior pituitary TNF-alpha was higher in proestrous rats. These results indicate that TNF-alpha plays an inhibitory role in anterior pituitary cell growth and the release of PRL in an estrogen-dependent manner.     

Involvement of Catecholestrogens in the release of pituitary hormones

Catecholestrogens (CE), natural metabolic products of 17?-estradiol and estrone, were assayed in anterior and posterior pituitary lobes and in the median eminence of the rat. The highest CE values were found in the median eminence and the lowest in the anterior pituitary. The CE concentrations in pars nervosa and pars intermedia of the posterior pituitary were quite similar. No sexual difference in the CE content was found in median eminence, anterior and posterior pituitary lobes. The highest CE concentrations were found in the median eminence and pars intermedia of lactating rats. During the estrous cycle median eminence CE showed maximal values in the morning of the proestrus, while anterior pituitary CE showed a decrease in the afternoon of the proestrus. Posterior pituitary lobe CE content did not change throughout the stages of the estrous cycle. Ovariectomy decreased CE content in the anterior pituitary but did not change the CE content in pars nervosa and pars intermedia of the posterior pituitary lobe. Estrogen therapy in ovariectomized animals increased CE content in pars nervosa. In the lactating rats, the separation of mothers from their pups for 4 h increased CE content in the posterior lobe and showed no variations in the anterior lobe. When pups were replaced and allowed to suckle for 5 and 30 min, CE content decreased in both the anterior and posterior pituitary lobes. Pars nervosa CE varied with suckling in the same way as the whole posterior lobe did. Pars intermedia and median eminence, both of which exhibited high CE values in the lactating rats, showed no CE variations in the model of separation/suckling. Parallel studies of COMT activity showed no variations in any model and in any pituitary lobe except anterior pituitary during the estrous cycle: COMT activity at Diestrus 2 was significantly low. The results obtained suggest that the CE are involved in the hormonal changes taking place in rat sexual cycle and lactation.     

Hypothalamic-pituitary sarcoidosis.

Patients with sarcoidosis may develop hypopituitarism secondary to granulomatous infiltration of the pituitary and hypothalamus. All degrees of anterior pituitary insufficiency can occur, ranging from selective deficiency to panhypopituitarism; diabetes insipidus occurs frequently. Commonly associated neurologic manifestations are cranial neuropathies, aseptic meningitis, and visual field defects. Although neurologic deficits respond well to corticosteroids, hormonal abnormalities generally persist despite therapy.     

Penfluridol decreases secretagogue-induced TSH, GH, and LH secretion in vitro: a possible role for calcium-calmodulin

This study was designed to investigate the effects of penfluridol, a potent neuroleptic calmodulin inhibitor, on basal and secretagogue-stimulated secretion of thyroid-stimulating hormone (TSH), growth hormone (GH), and luteinizing hormone (LH). The drug had no effect on basal TSH or LH release, but decreased GH release in a dose-related manner. TSH, LH, and GH secretion stimulated by calcium ionophore A23187 or 50 mM K+ was decreased by penfluridol as was TSH and GH release stimulated by dibutyryl-cAMP (dbcAMP). Penfluridol reversibly abolished the stimulatory effect of thyrotropin-releasing hormone (TRH) on TSH release in perifused dispersed pituitary cells. The compound inhibited hormonal release without affecting hormonal synthesis and cellular morphology (trypan blue exclusion test). Penfluridol appears to inhibit hormonal secretion by interfering with the calcium-calmodulin system in the anterior pituitary; therefore calmodulin may be an important link in the stimulus-secretion coupling of adenohypophyseal hormones.     

Anterior hypopituitarism is rare and autoimmune disease is common in adults with idiopathic central diabetes insipidus

Objective Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood‐onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. Design and patients We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. Results One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty‐three percent had at least one autoimmune disease in addition to central diabetes insipidus. Conclusions Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.     

Hypopituitarism Following Closed Head Injury

We describe four young patients (age 19–34 years) with hypopituitarism following closed head injury. The diagnosis was made by demonstration of low basal pituitary hormone levels and dynamic tests showing low pituitary reserve. The time interval between the injury and diagnosis of hypopituitarism was between three weeks and two months demonstrating the difficulty and complexity of making this diagnosis. Three of our patients (all patients suffering from anterior pituitary hormone deficiency) had ACTH deficiency, a condition which may be life threatening if left undiagnosed; these patients also demonstrated central hypothyroidism. Hypogonadotrophic hypogonadism occurred in three of the patients and was treated with hormonal replacement. Diabetes insipidus was the only insult in one of our patients, accompanied other hormonal deficits in two, and did not appear at all in another patient. Information about skull damage was available for three of the patients, and included skull base and facial bone fractures, probably reflecting the extent of injury necessary to cause hypopituitarism. All patients regained normal lives with adequate hormonal replacement therapy.     

The renin-angiotensin system in the pituitary gland.

There is evidence that angiotensin II, in addition to being generated in the circulating blood, is synthesized in the anterior pituitary lobe and other endocrine tissues. Angiotensin II produced locally may act on pituitary cell receptors to modulate or mediate the action of other hormonal factors. However, tissue angiotensins may be synthesized by a different mechanism than most other neuroendocrine peptides. A precise understanding of the mode of formation of local angiotensin II is necessary for the comprehension of its physiologic role in the pituitary gland.     

Dopaminergic regulation of the estrogen-induced glandular kallikrein in the rat anterior pituitary

Glandular kallikrein is a major estrogen-induced protein of the rat anterior pituitary. A second kallikrein-like protease in the rat anterior pituitary (kallikrein A) is not affected by estrogens, nor is a third pituitary protease which cleaves a trypsin substrate but not kallikrein substrates. This study examined whether any of the pituitary proteases are regulated by dopaminergic mechanisms. Ovariectomized female rats were treated for 5-10 days with reserpine (a catecholamine depleting agent), haloperidol (a dopamine receptor blocker) or bromocriptine (a dopamine receptor agonist); some rats also received 1 or 2 micrograms estradiol benzoate every 48 h. Following activation of latent proteases with trypsin, anterior pituitary extracts were assayed for kallikrein activity before and after fractionation on DEAE-Sephadex to separate the two kallikrein-like proteases. Reserpine or haloperidol doubled glandular kallikrein levels in anterior pituitaries from estrogen-treated rats. Reserpine or haloperidol had little or no effect in the absence of estrogen (estrogen produced a 5- to 7-fold increase in glandular kallikrein in the absence of drug treatment). Bromocriptine markedly attenuated the ability of estrogen to induce glandular kallikrein. Further, bromocriptine blocked the ability of reserpine to increase glandular kallikrein levels, and haloperidol attenuated the effect of bromocriptine. Other anterior pituitary proteases were unaffected by either estrogen, haloperidol, reserpine or bromocriptine. The results demonstrate that the estrogen induction of glandular kallikrein in the rat anterior pituitary is modulated by inhibitory dopaminergic mechanisms. Prolactin is the only pituitary hormone which exhibits a similar profile of hormonal and neuroendocrine regulation; this suggests a possible link between glandular kallikrein and prolactin.     

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.     

The spectrum of hypopituitarism caused by PROP1 mutations

Mutations in the PROP1 gene are responsible for a high proportion of cases of multiple or combined anterior pituitary hormone deficiencies in humans. The physical and hormonal phenotypes of affected individuals are not uniform. The diagnosis is seldom considered during the first year of life. Growth failure is usually evident later in childhood. Deficiency of growth hormone (GH) tends to precede deficiency of thyroid-stimulating hormone (TSH). While most affected individuals fail to enter puberty without sex hormone replacement, some enter puberty but then develop pubertal arrest with a loss of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses to GnRH. Partial deficiency of corticotrophin (ACTH) is a late finding. Imaging of the pituitary may disclose either a small anterior pituitary gland or an intrapituitary mass. The mechanisms responsible for delayed loss of hormone production and the occasional overgrowth of the pituitary represent important areas for future research.     

Ontogeny of pituitary-gonadal interactions current advances and controversies.

The different compartments of the fetal hypothalamic-pituttary-gonadal axis, the hypothalamus, anterior pituitary, and gonads, probably start their embryonic development independently, and become fully interactive as the last link o f their maturation. The developing hypothalamic-pituitary-gonadal axis offers a good model for studies on the mechanisms of regulation of fetal hormonal systems. It is evident that fetal hormonal functions are not the same as those of the adult on a smaller scale, but that there are fundamental differences between the fetus and adult in basic features of the mechanisms o f reproductive hormone action.     

Dopamine receptor activation inhibits estrogen-stimulated transforming growth factor-alpha gene expression and growth in anterior pituitary, but not in uterus.

Transforming growth factor-alpha (TGF alpha) has been localized to the anterior pituitary, specifically to the lactotroph and somatotroph cell populations, by our previous studies. Since pituitary lactotrophs are known to undergo growth in response to estrogens, we have used an estradiol-induced pituitary hyperplasia/adenoma model. Estradiol treatment resulted in induction of TGF alpha mRNA in anterior pituitary, evident by 48 h, preceding actual macroscopic growth, which attained a maximum greater than 500% by 12 weeks. This rapid effect of estradiol also enhanced PRL mRNA, but did not affect other species of mRNA encoding for proenkephalin, D2 receptor mRNA, or hexosaminidase-A. TGF alpha mRNA remained elevated for the duration of rapid pituitary growth. D2 receptor activation by its agonist bromocriptine resulted in marked attenuation of TGF alpha mRNA preceding regression of growth. Coadministration of bromocriptine with estradiol resulted in an involution of pituitary size, indicating the overriding influence of dopamine in spite of a continued estrogenic stimulus. Epidermal growth factor receptor mRNA was not affected by any of these manipulations, suggesting that the receptor was not coregulated in this tissue similarly to TGF alpha. Estradiol also induced uterine TGF alpha mRNA and marked growth of the organ, but TGF alpha in this location was not regulated by dopamine. These results indicate that TGF alpha in the anterior pituitary is rapidly induced by estrogen in a time course preceding the growth of the gland. Estrogen-induced TGF alpha is rapidly attenuated by D2 dopamine receptor activation and is accompanied by a regression of pituitary growth. Interaction between these opposing hormonal/transmitter responses will determine the growth potential of the anterior pituitary.     

A case of lymphocytic infundibuloneurohypophysitis showing diabetes insipidus followed by anterior hypopituitarism associated with thrombasthenia

We report a case of a 42-year old male patient with diabetes insipidus followed by anterior hypopituitarism associated with thrombasthenia. The patient had been diagnosed with thrombasthenia since the age of 19. He was admitted and diagnosed as diabetes insipidus in 1995. Although T1-weighted image of magnetic resonance imaging (MRI) showed empty sella and partial pituitary stalk hypertrophy, the anterior pituitary functions were normal at that time. Three years later, he was re-admitted after an episode of general malaise and impotence in 1998. Endocrinological studies revealed adrenal insufficiency, hypothyroidism and hypogonadism. T1-weighted image of MRI demonstrated the thickening of pituitary stalk and neurohypophysis. Analysis of anti-pituitary antibodies by immunoblotting identified a major band at 61.5 kDa. The diabetes insipidus was controlled by desmopressin acetate and the shrinkage of pituitary stalk was seen after hormonal replacement therapy including glucocorticoid and thyroid hormone. We suggested that this case represented lymphocytic infundibuloneurohypophysitis, in which a chronic inflammatory process occurred in infundibulum and/or neurohypophysis and that hypopituitarism developed possibly due to damage to the pituitary portal vessels caused by a thickened pituitary stalk, although a pituitary biopsy was not done because of the risk of bleeding in thrombasthenia. The pituitary autoantibodies in sera from patients with hypopituitarism may be helpful to characterize the patient with lymphocytic hypophysitis.