Characterization of a pituitary stone

Calcification of the pituitary is unusual and functional studies of such cases have not been previously reported. We have been able to document persistent prolactin secretion both in vivo and in vitro in a patient with a severely calcified pituitary adenoma (“pituitary stone”), and have also documented prolactin granules within the calcified tissue mass. Normal menstrual function was restored after surgical removal of the “stone,” and galactorrhea subsided although the prolactin response to thyrotropin-releasing hormone (TRH) remained abnormal. Two years after surgery the menstrual cycle has remained regular, but galactorrhea has recurred, emphasizing the need for prolonged follow-up in patients with prolactin-producing adenomas, despite apparent surgical cure. The in vitro studies showed that human pituitary tissue is secretory in culture and thus may serve as a useful tool for physiologic studies of the pituitary cell.     

Hexarelin as a test of pituitary reserve in patients with pituitary disease

BACKGROUND: The insulin tolerance test (ITT) is the reference standard for the diagnosis of cortisol and growth hormone (GH) deficiency, but problems have occurred in small children in inexperienced hands and it is contraindicated in patients with cardiac disease and epilepsy. Hexarelin is a growth hormone-releasing peptide with GH-, ACTH/cortisol- and prolactin-releasing effects which involve both hypothalamic and direct pituitary mechanisms. We therefore investigated whether it could be used to test GH and ACTH/cortisol reserve in patients with pituitary disease. METHODS AND SUBJECTS: The changes in GH and cortisol in response to insulin-induced hypoglycaemia (intravenous human Actrapid 0.15 IU/kg) and hexarelin (2 microg/kg) in 19 patients with possible pituitary disease (5 males, mean age 39 years, range 21-70) were compared. The patients' responses during the hexarelin test were also compared to normal ranges of GH and cortisol responses established in healthy volunteers following hexarelin administration. RESULTS AND DISCUSSION: GH peak levels were significantly higher after hexarelin than after hypoglycaemia (mean +/- SEM; 67.1 +/- 16 vs. 26.9 +/- 6.8 mU/l respectively; P < 0. 001), while cortisol levels were significantly lower (420 +/- 34 vs. 605 +/- 50 nmol/l; P < 0.001). The peak responses of both hormones correlated significantly between the hexarelin and insulin-induced hypoglycaemia tests (r = 0.80, P < 0.001 for cortisol). Peak GH levels after hexarelin and ITT showed a significant positive correlation with IGF-I levels (r = 0.84 and r = 0.77, P < 0.001 for both). All patients with a subnormal GH response to hexarelin (<41.4 mU/l) had a peak GH response to ITT of <9 mU/l, and only one patient had a normal (although borderline) response to hexarelin with a subnormal GH response to the ITT. Although 17 of the 19 patients had corresponding cortisol responses to hexarelin and the ITT test (either failing or passing both), two patients had normal cortisol responses to hexarelin but subnormal responses to the ITT. A peak serum cortisol level following hypoglycaemia of >580 nmol/l is indicative of normal cortisol reserve, as established in patients undergoing surgery; only five of the normal volunteers and one of the thirteen patients with a normal ACTH/cortisol reserve on ITT had a peak cortisol >580 nmol/l in response to hexarelin. CONCLUSION: Adult patients who have a subnormal peak GH response to hexarelin are likely to be GH deficient on an insulin tolerance test. However, our data suggest that the hexarelin test is not a useful test of ACTH/cortisol reserve. The hexarelin test could be a useful first/screening test to diagnose adult GH deficiency, particularly in patients in whom an insulin tolerance test is contraindicated or who are already ACTH deficient and in whom the GH reserve alone is of interest.     

Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study.

Enlargement of the pituitary gland is a frequent cause of incidentaloma and of referrals to endocrinologists for hormonal evaluation and therapeutic advice. In neuroradiological series, 25-50% of healthy women who are 18-35 yr old have a convex superior pituitary contour, but pituitary height exceeds 9 mm in less than 0.5% of cases. This study was performed to provide thorough clinical and hormonal data and long-term endocrinological and imaging follow-up data on subjects with incidentally discovered pituitary hypertrophy (height > 9 mm). Seven eugonadal nulliparous women, 15-27 yr old, referred between 1989 and 1998 with incidentally diagnosed pituitary gland enlargement (height > 9 mm) and a suspected pituitary tumor, were studied. At presentation and at yearly intervals, PRL plasma levels and corticotropic, somatotropic, and thyrotropic pituitary function were measured; and pituitary dimensions and signal on magnetic resonance imaging (MRI), before and after iv gadolinium-diethylene-triamine-pentaacetic acid injection, were assessed. PRL plasma levels were normal; and corticotropic, somatotropic, and thyrotropic pituitary function was considered normal in all cases. In all the women, the upper boundary of the pituitary was convex, on MRI, and touched the optic chiasm in four cases. The width and anteroposterior diameter of the gland were normal. The pituitary itself seemed normal, with a homogeneous signal, on plain and dynamic studies with iv contrast injection. Despite normal initial hormone values, two women underwent surgery, by the transsphenoidal approach, in another center. During surgery, the pituitary seemed normal in both cases, with no evidence of tumoral or inflammatory processes. Biopsy specimens showed the morphologic characteristics of a normal, nonhyperplastic pituitary gland. All seven women were seen at yearly intervals for 2-8 yr (median, 4 yr). Clinical and hormonal status remained stable, as did the structure and size of pituitary, on serial MRI. No tumor formation occurred, supporting the diagnosis of physiologic hypertrophy of the pituitary gland. In conclusion, these observations suggest that careful examination of MRI results may help to distinguish physiologic pituitary hypertrophy from pituitary tumors and infiltrating lesions. The former diagnosis is confirmed by normal baseline pituitary function in extensive hormonal tests. Correct identification of such patients is important to avoid unnecessary pituitary surgery and costly MRI surveillance.     

Macroprolactinemia presenting like a pituitary tumor

A serum prolactin level greater than 200 ng/ml is almost pathognomonic of a pituitary tumor in a nonpregnant woman. A patient with a three-year history of documented serum prolactin levels of 350 to 400 ng/ml and no evidence of a pituitary adenoma on computed axial tomographic scanning was recently studied. Detailed evaluation included a 24-hour prolactin profile that revealed blunting of the nocturnal augmentation of prolactin release, low-dose dopamine infusion resulting in normal inhibition of prolactin secretion, and a thyrotropin-releasing hormone bolus that showed a blunted stimulation of prolactin release. Analysis of circulating prolactin by column chromatography of her serum revealed that greater than 85 percent of her circulating immunoreactive prolactin had a molecular weight greater than 100,000 daltons (macroprolactin). This contrasts with other hyperprolactinemic states in which 85 percent of the serum prolactin elutes in a 22,000-dalton peak. Hence, macroprolactinemia is apparently a nonprogressive condition and a novel cause of massive hyperprolactinemia.     

Normal pituitary function and reserve after selective transsphenoidal removal of a thyrotropin-producing pituitary adenoma

A 37-yr-old woman with recurrent hyperthyroidism after partial thyroid ablation was found to have an enlarged sella turcica and elevated serum thyrotropin (TSH) and prolactin (PRL) levels measured by radioimmunoassay. Serum growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol levels were within normal limits and responded appropriately to provocative stimuli both before and after surgery. Preoperatively, the administration of thyrotropin-releasing hormone (TRH) (200 μg i.v.) and metoclopramide (MCP) (10 mg p.o.) induced a more than twofold increase in serum PRL levels, whereas TSH was only modestly affected. Bromocriptine (2.5 mg p.o.) and l-dopa (500 mg p.o.) suppressed TSH and PRL values to less than 50% of their initial values. After selective transsphenoidal removal of a pituitary adenoma, signs and symptoms of hyperthyroidism disappeared and TSH and PRL returned to normal. The postoperative administration of TRH and MCP produced a normal response for both PRL and TSH. Postoperatively, bromocriptine induced a parallel decrease in the serum level of both hormones, whereas l-dopa decreased PRL but had no effect on the serum TSH level. This case provides evidence that hyperthyroidism caused by a pituitary adenoma can be successfully treated by transsphenoidal surgery with preservation of normal pituitary function and reserve.     

External pituitary irradiation as a cause of TRH deficiency in patients with pituitary adenomas

The influence of external pituitary irradiation (XRT) on thyrotroph function and PRL secretion was studied in twenty-five patients with pituitary adenomas, of whom eight had acromegaly. Twenty-one patients had undergone subtotal operative removal of their adenomas 8-190 weeks (median 12 weeks) before XRT. Following irradiation there was a significant reduction in peak serum TSH levels in response to i.v. TRH (P less than 0.05, compared with before XRT). Peak TSH levels returned to normal at 3 months. Similarly a transient reduction in TRH-stimulated beta-TSH release was observed. Serum T3 and T4 concentrations also fell after XRT, the levels at 3 months being significantly lower than control values (P less than 0.02), though no difference was seen at 6 and 12 months. A delayed (hypothalamic) serum TSH response to TRH (60 greater than 20-min level) developed at 6 months. In contrast, PRL concentrations (basal and TRH stimulated) were not altered during the 12 months following XRT. These findings demonstrate that thyrotroph function can be transiently impaired following external pituitary irradiation. None of the patients studied required T4 replacement therapy. The development of a delayed TSH response to i.v. TRH may indicate endogenous TRH deficiency. It was not associated with supra-sellar tumour enlargement in our patients and may be due to hypothalamic damage by irradiation.     

Rosai-Dorfman disease presenting as a pituitary tumour

A 45-year-old woman had pyrexia, headaches, collapse and hyponatraemia. Intracerebral abscess, bacterial meningitis and subarachnoid haemorrhage were excluded. She was given intravenous antibiotics and gradually recovered. One month later she was readmitted with diplopia, headache and vomiting. Serum sodium was low (107 mmol/l) and a diagnosis of inappropriate ADH secretion was made. MRI scan showed a suprasellar tumour arising from the posterior pituitary gland. A skin rash gradually faded. Serum cortisol, prolactin, gonadotrophins and thyroid hormone levels were low. A pituitary tumour was removed trans-sphenoidally, she had external pituitary radiotherapy, and replacement hydrocortisone and thyroxine. She was well for 12 months when she developed progressive weakness and numbness of both legs. Examination suggested spinal cord compression at the level of T2 where MRI scanning showed an intradural enhancing mass. This spinal tumour was removed and her neurological symptoms disappeared. Nine months after this she developed facial pain and nasal obstruction. CT scan showed tumour growth into the sphenoid sinus and nasal cavities. A right Cauldwell-Luc operation was done and residual tumour in the nasal passages was treated by fractionated external radiotherapy and Prednisolone. Histological examination of the specimens from pituitary, spinal mass, and nasal sinuses showed Rosai-Dorfman disease, a rare entity characterized by histiocytic proliferation, emperipolesis (lymphophagocytosis) and lymphadenopathy. Aged 48 she developed cranial diabetes insipidus. Although Rosai-Dorfman syndrome is rare, it is being reported with increasing frequency, and should be borne in mind as a possible cause of a pituitary tumour.     

The pituitary gland: a brief history

The functions of the pituitary gland as an important constituent of the endocrine system were not understood until the latter part of the nineteenth century and the first half of the 20th century. At one time, the pituitary was deemed to be the “leader of the endocrine orchestra,” but more recent studies have shown that its secretions are influenced by external stimuli and that it is largely under the control of the hypothalamus.     

Hyperthyroidism due to a TSH-secreting pituitary tumor

A 28-year-old female with a 12-year history of goiter is presented. She had both clinical and laboratory evidence of hyperthyroidism, and her serum TSH was persistently and markedly elevated after treatment with antithyroid drugs. A TRH stimulation test resulted in no further rise in serum TSH after cessation of medication. Menses were regular and serum prolactin levels were normal. Serum LH and FSH responses to LHRH stimulation test were normal. No other evidence of pituitary or peripheral endocrine deficiencies existed. She underwent a subtotal thyroidectomy followed by 131I therapy three years later. A pituitary adenoma with sphenoidal and suprasellar extension was completely removed by transphenoidal approach. On light microscopy, it was mostly composed of chromophobic cells with occasional calcification showing sinusoidal pattern. On electron microscopy, most of the cells contained fine granules, which suggested thyrotroph. The immunoperoxidase technique revealed TSH beta in the cytoplasm of some adenoma cells. Three days postoperatively the patient's serum TSH levels returned to normal. TRH stimulation test produced a normal response in serum TSH. The patient was diagnosed hypothyroid by laboratory findings and is currently on thyroid replacement therapy. The patient became pregnant and delivered twice prior to the operation for pituitary adenoma. The previously reported TSH secreting adenomas associated with hyperthyroidism were reviewed.     

Brain stem cells adopt a pituitary fate after implantation into the adult rodent pituitary gland

Fetal brain stem cells (RSCs) have been induced to express pituitary phenotypes in vitro in co-cultures with GH(3) cells and by exposure to GH(3)-conditioned media. In the current studies, we graft RSCs into the pituitary glands of adult rat to investigate whether grafted RSCs can be induced by the native gland to acquire pituitary properties. Grafted cells survive for 4 weeks and express Pit-1, GH, FSH, LH, ACTH, TSH and to a lesser extent PRL indicating that inductive influences are operative in vivo as well. This demonstrates that pluripotential cells can be induced to acquire properties of tissues different from their organ of origin likely through the action of cell-cell contact and local tissue factors.     

Evidence for a role of pituitary ATP receptors in the regulation of pituitary function.

Despite a rapidly increasing acceptance for a role of ATP as an extracellular mediator in several biological systems, the present report shows that ATP may mediate physiological responses in pituitary cells. We have now been able to demonstrate a specific action of ATP receptors to mediate the release of luteinizing hormone from gonadotropes and have coupled them with further studies that clearly show that ATP can be exocytotically released from cultured rat pituitary cells. Both ATP and UTP (100 microM) caused a > 14-fold increase in the rate of luteinizing hormone release from superfused cells. Adenosine 5''-[alpha, beta-methylene]triphosphate and 5''-[beta,gamma-methylene triphosphate were ineffective, and 2-methylthio-ATP had only a modest stimulatory effect. Homologous and heterologous desensitization occurred with UTP and ATP, and these did not have additive effects. Thus, nucleotides can be effective stimulators of luteinizing hormone release through a single class of ATP receptor (P2U subtype). The calcium ionophore A23187 provoked release of a substantial amount of ATP from pituitary cells in a concentration- and Ca(2+)-dependent manner, which was desensitized by pretreatment with A23187. This implies a possible paracrine and/or autocrine mechanism by which nucleotides may exert their effects on pituitary cells. In conclusion, we have provided strong evidence for a novel role of extracellular nucleotides as mediators in pituitary--in particular, in gonadotrope--function.     

Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors

OBJECTIVE: The long-term outcome of non-functioning pituitary adenoma (NFPA) patients is not clearly established, probably due to the low annual incidence and prolonged natural history of these rare tumors. The aim of this study was to evaluate clinical data at presentation and long-term post-surgery and radiotherapy outcome in a cohort of patients with NFPA. DESIGN AND METHODS: A computerized database was developed using Access 2000 software (Microsoft Corporation, 1999). Retrospective registration of 295 NFPA patients was performed in seven Endocrinological Centers of North West Italy. Data were analyzed by STATA software. RESULTS: The main presenting symptoms were visual defects (67.8%) and headache (41.4%) and the most frequent pituitary deficit was hypogonadism (43.3%), since almost all tumors were macroadenomas (96.5%). Surgery was the first choice treatment (98% of patients) and total debulking was achieved in 35.5%. Radiotherapy was performed as adjuvant therapy after surgery in 41% of patients. At the follow-up, recurrence occurred in 19.2% of patients without post-surgical residual tumor after 7.5 +/- 2.6 years, regrowth in 58.4% of patients with post-surgical remnant after 5.3 +/- 4.0 years and residue enlargement in 18.4% of patients post-surgically treated with radiotherapy after 8.1 +/- 7.3 years. CONCLUSIONS: Our database indicates that the goal of a definitive surgical cure has been achieved during the last decade in a low percentage of patients with NFPA. This tumor database may help to reduce the delay between symptom onset and diagnosis, to assess prognostic parameters for the follow-up of patients with different risk of recurrence and to define the efficacy and safety of different treatments and their association with mortality/morbidity.     

Nonfunctioning pituitary tumors and pituitary incidentalomas.

Clinically nonfunctioning adenomas (CNFAs) range from being completely asymptomatic, and therefore detected at autopsy or as incidental findings on head MRI or CT scans performed for other reasons, to causing significant hypothalamic/pituitary dysfunction and visual field compromise because of their large size. Patients with incidental adenomas should be screened for hypersecretion and hyposecretion. In the absence of hypersecretion, hypopituitarism, or visual field defects, patients may be followed by periodic screening by MRI for enlargement. Symptomatic patients with CNFAs are generally treated by transsphenoidal resection. Postoperative MRI scans are done at 3 to 4 months after surgery to assess for completeness of resection and then repeated yearly for 3 to 5 years and subsequently less frequently to assess for regrowth. The regrowth rate may be substantially reduced with the use of dopamine agonists and radiotherapy.