Utility of magnetic resonance in the etiologic diagnosis of hypopituitarism

The diagnosis of hypothalamic-pituitary disorders relies on a combination of clinical and biochemical data and imaging techniques. During the last decade, computed tomography (CT) has been the best technique for the evaluation of the hypothalamuspituitary region, but in recent years magnetic resonance (MR) has improved the diagnostic efficiency of CT. We retrospectively review the clinical records of 40 hypopituitary patients from the endocrinology unit of our hospital. The aim of the present study was to establish the role of MR in the etiologic diagnosis and anatomic definition of hypopituitarism, when compared with CT. Secondarily, we studied the different pituitary hormones in this condition. The diagnoses were: 12 postsurgical hypopituitarism, 10 empty sella turcica, 7 Sheehan's syndrome, 5 idiopathic hypopituitarism, 3 pituitary disgenesis, 2 craniopharyngioma and 1 macroprolactinoma. GH was the most commonly affected hormone, followed by gonadotrophins, corticotrophin and thyrotrophin (100%, 94%, 76% and 68% respectively). In 24 patients both MR and CT studies were performed. MR was diagnostic in 22 patients, and CT in 15 patients (p < 0.05). MR offered improved diagnostic or anatomical data in 16 patients of the 24 in whom both techniques were performed (p < 0.05). We conclude that MR allows a better definition of the hypothalamus-pituitary region than CT, contributing to the etiologic diagnosis and improving the anatomical findings. Empty sella turcica should be considered a common cause of hypopituitarism.     

Cryotherapy in the treatment of spring conjunctivitis

A 15-year-old boy had growth failure and failure of sexual development. The probable onset was at age 10. Endocrine studies showed hypopituitarism with deficiency of growth hormone and follicle-stimulating hormone, an abnormal response to metyrapone, and deficiency of thyroid function. Luteinizing hormone level was in the low-normal range. Posterior pituitary function was normal. Roentgenogram showed a large sella with some destruction of the posterior clinoids. Transsphenoidal exploration was carried out. The sella was empty except for a whitish membrane; no pituitary tissue was seen. The sella was packed with muscle. Recovery was uneventful, and the patient was given replacement therapy. On histologic examination,the cyst wall showed low pseudostratified cuboidal epithelium and occasional squamous metaplasia. Hemosiderin-filled phagocytes and acinar structures were also seen. The diagnosis was probable rupture of an intrasellar epithelial cyst, leading to empty sella syndrome.     

"Born from the flank"--discussion concerning "cesarean section" in animals in the Talmud

We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.     

The primary empty sella an endocrine study on 12 cases

Twelve patients (10 women and 2 men) with a primary empty sella turcica were studied. Endocrine function tests were performed as follows: growth hormone (GH) was measured after insulin-induced-hypoglycaemia, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after LH-releasing hormone, thyrotrophin (TSH) and prolactin after thyrotrophin-releasing hormone; pituitary reserve of adrenocorticotrophin (ACTH) was determined by measurement of plasma cortisol after lysine-vasopressin and 11 deoxycortisol after metyrapone. Five of the patients (group A) had no endocrine disturbance. Seven patients (group B) had a hypothalamo-pituitary disorder. Two of them had panhypopituitarism which appeared in one case after meningoencephalitis and in the other after a severe cranial trauma. In two cases an amenorrhoea-galactorrhoea syndrome with increased prolactin level (68 and 230 ng/ml) led to a diagnosis of a prolactin producing adenoma, which was confirmed by surgery. Finally three cases of amenorrhoeagalactorrhoea, with normal prolactin level, and/or diabetes insipidus remained unexplained. However, no causal relationship could be demonstrated between the pituitary disturbance and the "empty sella". Primary empty sella turcica is therefore a neuroanatomical and neuroradiological entity with no endocrine implication. A pituitary disorder might suggest a microadenoma or an incidentally associated disease.     

Nelson's syndrome: frequency, prognosis, and effect of prior pituitary irradiation

Previous reports differ regarding the frequency and course of pituitary tumors occurring after adrenalectomy for bilateral adrenal hyperplasia (Nelson's syndrome). In this report, 120 patients who were adrenalectomized for bilateral adrenal hyperplasia were followed for 2 to 20 years. Nine of the 120 developed Nelson's syndrome (8%), the tumors appearing 6 months to 16 years after adrenalectomy. In the majority of cases, the course was benign; seven patients are living an average of 9.7 years after discovery of their tumors. Finally, contrary to previous reports, pituitary irradiation before adrenalectomy did not prevent Nelson's syndrome. Twenty of 120 patients had pituitary irradiation as the initial treatment for bilateral adrenal hyperplasia and two subsequently developed pituitary tumors. Thus, after adrenalectomy for bilateral adrenal hyperplasia, all patients, regardless of previous pituitary irradiation, should be followed indefinitely with periodic X rays of the sella turcica for the possible occurrence of Nelson's syndrome.     

CT abnormalities of the pituitary in hyperprolactinaemic women with normal or equivocal sellae radiologically

Sixteen young women with hyperprolactinaemia and normal or equivocal sella in radiographs underwent computed tomography using a Siemens Somatom II. In all but one case an abnormality was found. The sella was full in seven and partially empty in nine. A tumour was visible in six of the full and in four of the partially empty sellae. All but one of the 10 tumours was unilateral, and in seven the pituitary stalk was deviated away from the tumour. After administration of intravenous contrast (Urografin) four tumours showed diffuse enhancement, four ring enhancement, and two enhanced less than adjacent normal pituitary tissue. Two of the tumours have been subsequently shown histologically to be prolactinomas. Prolactin response to thyrotrophin-releasing hormone predicted a tumour in seven out of eight with visible tumours but also in three out of four without visible tumours; using metoclopramide, a tumour was predicted in six out of seven with tumours, but again in three out of four without visible tumours. Such results question the value of dynamic tests for the discrimination of tumours. We conclude that practically all women with sustained hyperprolactinaemia and a normal or equivocal sella radiologically have pituitary disease.     

Failures, problems and hopes in the transformation of health services. I. Causes of erroneous decisions in the beginning phases of transformation

Vascular damage is a well known cause of hypopituitarism since Sheehan's report of postpartum pituitary necrosis; it has subsequently been reported that also sickle-cell anemia, eclampsia, pituitary apoplexy and other pathologies may induce failure of the anterior hypophysis through this mechanism. The antiphospholipid syndrome (APS) is characterized by widespread arterial and venous thrombosis with resulting different clinical features; Addison's disease due to adrenal thrombosis is the only endocrine involvement reported so far in this syndrome. We report here a case of global anterior pituitary insufficiency which developed soon after cerebral ischaemic stroke in a 62 year aged woman with Lupus aicoagulant activity (LAC) and large atrial thrombosis; underlying pathologies were excluded by appropriate investigations. Therefore in our opinion this is the first case in which anterior hypopituitarism is reported in the clinical constellation of APS and the second type of endocline involvement.     

The accuracy of CT and MR evaluation of the sella turcica for detection of adrenocorticotropic hormone-secreting adenomas in Cushing disease

PURPOSE: To document the accuracy of CT and MR of the sella turcica for detecting adrenocorticotropic hormone-secreting adenomas in Cushing disease. METHODS: The radiologic findings of the sella turcica prior to transsphenoidal surgery are reviewed in 141 patients who had biochemical evidence of pituitary-dependent Cushing disease. Axial thin-collimation CT scans with sagittal and coronal reformations before and after contrast enhancement were obtained in 125 patients. Seventy-eight patients had MR examinations with a 1.5-T superconducting magnet. In 11 of the patients gadolinium-enhanced MR scans were also obtained. The preoperative interpretation of the imaging studies was correlated with the surgical findings and patients follow-up. RESULTS: The sella turcica was enlarged in 43 cases (30%). In 125 patients reformatted or direct coronal thin-collimation CT scans were available. Seventy-eight of the patients had MR. In the 12 patients with pituitary macroadenomas, the accuracy of CT (n = 10) and MR (n = 10) in respect to detection of the lesion was 100%. Of the 98 microadenomas assessed by CT, 47 (48%) were directly depicted as distinct hypodense lesions. In only 31 of 73 cases (42%), however, could CT predict the precise anatomic location and extent of the lesions. Only patients in whom the hypercortisolism was corrected by later surgery were considered for the correlation analysis. Of the 52 microadenomas assessed by MR, 28 (53%) were directly depicted as distinct lesions of reduced signal intensity on T1-weighted images, and in only 21 of 41 cases (52%) did MR show good correlation to the surgical findings. Some degree of partially empty sella was found in 22% of the patients. CONCLUSIONS: Although both the sensitivity and the diagnostic accuracy of imaging methods of the sella turcica have been considerably improved in comparison with previous reports, they still provide only a minor contribution to the diagnosis and differential diagnosis of Cushing syndrome.     

Prolactin-secreting pituitary carcinoma with implants in the cheek pouch and metastases to the ovaries. A case report and literature review

BACKGROUND: Prolactin-secreting pituitary carcinomas are uncommon, locally destructive neoplasms that rarely metastasize outside the central nervous system. The authors report a case of a prolactin-secreting tumor that initially presented as the empty sella syndrome. Two recurrences along transsphenoidal surgery tracts in cheek pouches were followed by distant metastases later in the abdomen and pelvis. Only 10 previous cases of either extracranial or intracranial metastases from prolactin-secreting pituitary carcinomas have been reported. No metastases below the diaphragm have been reported previously. METHODS: The patient's cheek pouch implants, lymph node metastases, ovarian metastases, and uterine metastases were studied with prolactin-specific immunohistochemistry. RESULTS: Long term treatment with bromocriptine, several debulking surgeries, extensive local radiation therapy (external beam and proton beam), and cytotoxic chemotherapy had little impact. Tamoxifen, however, may have slowed tumor growth. CONCLUSION: Tamoxifen may have efficacy in the treatment of prolactin-secreting pituitary carcinomas.     

High signal in the adenohypophysis on T1-weighted images presumably due to manganese deposits in patients on long-term parenteral nutrition

Hypermanganesaemia is reported in patients on long-term parenteral nutrition. Deposition of manganese, giving high signal on T1-weighted images, may involve the basal ganglia. MRI in nine patients (mean age 51 years, range 31-75 years) on long-term parenteral nutrition (mean duration 30 months, range 6-126 months), demonstrated high signal in the anterior pituitary gland on T1-weighted sagittal and coronal images. The gland appeared normal on T2-weighted images. Signal intensity in the basal ganglia on T1-weighted images was increased in all patients. Endocrine assessment showed no significant abnormality. Neurological examination showed a mild parkinsonian movement disorder in one patient. Hypermanganaesemia was present in all nine (1.3-2.8 micromol/l, mean 1.87 micromol/l). The high signal in the anterior pituitary gland was probably related to deposition of paramagnetic substances, especially manganese.     

Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion

Leptin, a circulating hormone secreted by adipocytes, communicates peripheral nutritional status to hypothalamic centers affecting satiety, energy expenditure, and body weight. The intact leptin receptor (OB-R), a single membrane-spanning peptide containing an approximately 300-amino acid intracellular domain, is highly expressed in the hypothalamus, whereas shorter OB-R isoforms with truncated cytoplasmic regions resulting from alternative splicing have also been identified. We studied expression of OB-R isoforms in human fetal pituitaries, adult anterior pituitaries, and human pituitary adenomas. Using RT-PCR, messenger ribonucleic acid expression of the OB-R intact isoform was detected in fetal anterior pituitary tissues, but not in adult anterior pituitary glands, whereas both fetal and adult tissues expressed the short forms. Messenger ribonucleic acid of both intact and short OB-R isoforms were expressed in 4 of 5 GH-secreting, all 9 PRL-secreting, and 26 of 29 nonfunctioning pituitary adenomas. Recombinant human leptin (3-6 nmol/L) specifically stimulated GH secretion from primary human fetal pituitary cultures by 40-90% (P < 0.05) without altering fetal ACTH, PRL, or gonadotropin secretion. Thus, the intact OB-R is selectively expressed in human fetal and adult pituitary tumor tissues, but not in normal adult pituitary. Leptin specifically stimulates GH release from normal fetal somatotrophs, substantiating the functionality of its intact receptor in the fetal pituitary. Thus, pituitary adenomas appear to revert to a fetal phenotype of leptin receptor expression.     

Human fetal pituitary gland in holoprosencephaly and anencephaly

The normal prenatal development of the human pituitary gland and the gland-supporting sella turcica has recently been investigated. The sella turcica area constitutes a developmental boundary area in the cranial base. Posterior to the area the cranial base has developed close to the notochord, and anterior to the region the cranial base development is dependent chiefly on neural crest cell migrations. In the present study the sella turcica region was analyzed in two fetuses with holoprosencephaly (cyclopia and median cleft) and four fetuses with anencephaly combined with rachischisis in the neck region (GA 16-20 weeks). The sella turcica region was investigated radiologically and histologically. Adenohypohyseal gland tissue was localized by immunohistochemical hormonal marking. In both types of malformation an open craniopharyngeal canal was seen in the base of the sella turcica with adenohypophyseal glandular tissue located in the sella turcica, in the canal, and in the pharyngeal connective tissue at the external side of the cranial base. In conclusion, severe malformations of the pituitary gland occur in both holoprosencephaly, which is a polytopic field defect located anterior to the sella turcica, and in anencephaly associated with notochordal insufficiency posterior to the sella turcica. This might indicate that the sella turcica area, bounding different developmental fields, is involved in various craniofacial malformations. It is consequently recommended that examination of the pituitary gland should become a part of the routine autopsy of prenatal material when malformations in the face, brain, and cranial base occur.     

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients

OBJECTIVE: The purpose of this study was to determine, among six second-trimester maternal serum analytes, the best three-analyte combination for fetal Down syndrome detection. STUDY DESIGN: With use of commercially available assay kits, medians for free beta-human chorionic gonadotropin, CA 125, and dimeric inhibin A were established in stored sera from 45 to 50 euploid pregnancies at each week of gestation from 14 to 22 weeks and from 33 Down syndrome pregnancies. Maternal serum alpha-fetoprotein, unconjugated estriol, and intact human chorionic gonadotropin levels measured in each sample before storage were retrieved. All 20 possible three-analyte combinations were evaluated in the multiple-marker screening test for Down syndrome. RESULTS: The mean maternal age of the study population was 35.6 +/- 5.3 years. The best three-analyte combination was maternal serum alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A: 97% of Down syndrome cases were detected at a false-positive rate of 16%. At a slightly higher false-positive rate (18%) maternal serum alpha-fetoprotein, estriol, and intact human chorionic gonadotropin detected only 79% of cases. CONCLUSIONS: Of six second-trimester maternal serum analytes, the best three-analyte combination for fetal Down syndrome detection was maternal serum alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A. This retrospective analysis should now be confirmed prospectively.     

Nuclear magnetic resonance measurement of skeletal muscle: anisotrophy of the diffusion coefficient of the intracellular water

Four cases of chiasmal syndrome resulting from chromophobe adenoma with normal-sized sella turcica are reported. The predominantly suprasellar growth of these tumors was probably the result of a well-pneumatized sphenoid sinus and/or a congenitally deficient diaphragma sellae. In patients with chiasmal syndrome, a high suspicion of a surgically treatable lesion must be maintained in spite of radiographs showing a normal-sized sella. In spite of the difficulties presented by normal variations, subtle findings should be searched for on the plain films and given additional weight in the patient with a chiasmal syndrome. An aggressive diagnostic work-up, including pneumoencephalography with thin-section tomography, should be pursued in all such patients before accepting some alternate explanation, such as demyelinating disease, for visual impairment.     

Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand

PATIENTS AND METHODS: The role of cerebral magnetic resonance imaging (MRI) in the diagnosis of growth hormone (GH) deficiency in children has been studied in 100 children. The diagnosis of GH deficiency was assessed at a mean age of 6.7 +/- 4.1 years: morphological abnormalities of the hypothalamic-pituitary (HP) region have been studied in three different groups: in the first group (70 cases), the neurohypophysis was present and normally located; in the second group (ten cases) it was missing; in the third group (20 cases) the neurohypophysis was ectopic (truncated stalk syndrome with ectopic neurohypophysis, small antehypophysis, thin or non-visualized stalk). RESULTS: In the majority of cases, children presenting with only one morphological abnormality of the HP region (ectopic neurohypophysis or small antehypophysis or non-visualized or thin stalk) had an isolated GH deficiency. When multiple morphological abnormalities were present, anterior pituitary deficiency was multiple in more than half the cases. Cerebral midline anomalies (above all Chiari I malformation and basipharyngeal canal) had been observed in 20% of the children presenting with GH deficiency. In the majority of cases (95%), these anomalies were associated with one or more abnormalities of the HP region. A familial case is reported: morphological anomalies of the HP region were different for both siblings. Genetic factors are evoked. CONCLUSION: The severity of the hormone deficiency is correlated to the ectopic location of the neurohypophysis, the thin appearance or non visibility of the pituitary stalk and the associated midline anomalies.     

Determination of uric acid in scalp hair for non-invasive evaluation of uricemic controls in hyperuricemia

A 29-year-old man with Kallmann syndrome suddenly developed decreased semen volume, azoospermia, and facial hair loss after 11 years of successful human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) treatment. Anti-hCG antibody was not detected in the patient's serum. A high serum level of luteinizing hormone (LH) with nasal LH-releasing hormone analogue administration failed to increase serum testosterone to a sufficient level. Testosterone injection after cessation of hCG and hMG therapy was able to improve semen volume, but not azoospermia. Resumption of hCG and hMG therapy after 6 months cessation partially restored spermatogenesis. The secondary failure of hCG and hMG therapy suggests a decrease of testicular sensitivity to LH as well as hCG.     

Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome

We evaluated growth parameters and hypothalamic-pituitary-gonadal and growth functions in five children with Bardet-Biedl syndrome (BBS). Three of the five children had stature below the fifth percentile for age. Their growth hormone (GH) response to provocation was defective, and computed tomographic (CT) scanning revealed empty sellae in all of them. All the children were obese (body mass index [BMI] > 95th percentile for age). Three had hypercholesterolemia. Their basal serum testosterone concentration and testosterone response to 3-day human chorionic gonadotropin (HCG) stimulation were significantly lower than the levels in 12 age-matched obese normal children. Testosterone secretion failed to respond to HCG therapy for 4 weeks. Both basal gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadotropin responses to LH-releasing hormone (LHRH) stimulation were normal and did not differ among the two study groups. It appears that primary hypogonadism is a cardinal feature of BBS, and it may be accompanied by hypothalamic and pituitary abnormalities.     

MRI: incidence and evaluation of size and form criteria in hypophysis-healthy probands and in patients with detectable microadenomas

Magnetic resonance imaging (MRI) was performed in 42 patients with proven microadenomas and in 42 patients with normal pituitary hormone analysis. The normal MRI--anatomy of the pituitary gland and its possible variations with measurement of the volume and comparison of the anatomy with that of the gland after changes caused by microadenomas has to our knowledge not yet described. In this study we measured the height, coronary and sagittal diameter of the pituitary gland in both groups as well as other indirect signs of microadenomas (asymmetry of the gland, sella turcica, and the stalk). The pituitary volume indicates the expansion of microadenomas much better than the gland height (and the other diameters). Normal pituitary glands showed a significant lower volume (525 +/- 137 mm3 [R = 225-800 mm3]) than patients with proven microadenomas (734 +/- 393 mm3 [R = 335-2800 mm3], p < 0.001). The normal pituitary gland and sella turcica show a large variety of anatomic variations. These variations are less frequent in healthy subjects (10-21%) than in patients with microadenomas (48-71%). The described criteria are of some value in diagnosis of a suspected gland hypertrophy or microadenoma. In 75% of the patients with normal pituitary parameters and in 12% of the patients with microadenomas no indirect adenoma criteria was found in our study.     

Empty sella and headache

Empty sella is an anatomical condition caused by herniation of the subarachnoid space into the pituitary fossa through an incompetent sellar diaphragm. Headache seems to be one of the most frequently reported symptoms. We studied 13 headache patients (12 females, 1 male) presenting with primary empty sella (PES) on CT scan. The characteristics of the headache were analyzed and plasma levels of pituitary hormones or cortisol assessed. We confirmed the nonspecific nature of the headache in PES even though the majority of our patients complained of daily headache, mostly localized anteriorly. Hormone plasma levels were within normal range in all the patients assessed. However, four patients reported earlier endocrine disorders and more than half of the patients presented with obesity. In our opinion, PES should be suspected in middle-aged overweight women with daily headache even in the absence of endocrine symptomatology.