Detection of mRNA of prolactin and ACTH in clinically nonfunctioning pituitary adenomas

Clinically nonfunctioning pituitary adenomas have been thought to synthesize some pituitary hormones as shown by studies involving cell culture, immunocytochemistry, or measurement of hormone levels in tumor homogenates. Nevertheless, they are not associated with hypersecretion of pituitary hormones. To further clarify hormone synthesis in such pituitary adenomas, the presence of messenger ribonucleic acid (mRNA) of prolactin (PRL) growth hormone, and adrenocorticotropic hormone (ACTH) in the cytoplasm of 16 nonfunctioning adenomas was determined by means of a hybridization technique, and compared to the immunocytochemical findings. In three adenomas (19%) PRL mRNA was detected and in one case (6%) ACTH mRNA was detected. The hybridization technique appears to be more sensitive than immunohistochemistry for detection of specific mRNA's in assigning the hormone synthesis potential to clinically nonfunctioning tumors. The results suggest that PRL and ACTH are synthesized in some cases of clinically nonfunctioning pituitary adenomas and that hybridization techniques are useful to investigate hormone synthesis in pituitary adenomas. The ability to demonstrate PRL mRNA in tumor tissues allowed differentiation between hyperprolactinemia caused by synthesis of PRL in the tumor and that due to hypersecretion from the adjacent normal pituitary.     

Kinetics of secretion of luteinizing hormone subunits and free alpha, and effects of gonadotropin releasing hormone

While GnRH is known to stimulate release of pituitary gonadotropins, its acute effects on the kinetics of secretion of the various hormones and subunits are not well characterized. Pulse-chase experiments were therefore performed to compare the time course of secretion of newly synthesized LH subunits and free alpha from rat pituitary quarters, and to study the effects of GnRH. After a 1-h pulse labeling with [35S]cysteine in the presence or absence of 10(-8) M GnRH, cultures were chased with excess unlabeled cysteine for 1, 2, 4, 8, or 20 h. Tissue lysates and media were immunoprecipitated sequentially with antisera to PRL, GH, LH beta and LH alpha, and the products were analyzed by gel electrophoresis. Labeled LH alpha was completely secreted by 4 h of chase without GnRH, and by 2 h with GnRH, as shown by its appearance in media and depletion from pituitary. Newly synthesized LH beta was depleted only at 8 h with GnRH from pituitary, suggesting much slower secretion. Incorporation of 35S into LH beta was approximately half that into LH alpha. Newly synthesized free alpha subunit was secreted between 4 and 20 h without GnRH, and by 8 h with GnRH. Free alpha incorporated a similar amount of radioactivity as LH beta. GnRH had no effect on the timing of the secretion of labeled total protein, PRL, GH, or TSH subunits. The amount of label incorporated during the pulse was greatest for PRL, approximately 15% of total protein label. GH incorporated approximately 20% as much label as PRL, with the glycoprotein subunits somewhat lower. The total amount of 35S incorporated into each protein studied was not affected by GnRH. The data indicate that short term in vitro GnRH exposure during a 1-h pulse labeling and chase acts to accelerate early secretion of LH alpha, LH beta and free alpha but does not affect overall protein synthesis. The peptide hormones PRL and GH incorporated the greatest amount of label and were the most briskly secreted hormones, while LH alpha led the glycoprotein subunits in the amount of incorporation and rapidity of secretion.     

Immunohistochemical and ultrastructural study of clinically nonfunctioning pituitary adenomas

Sixty-five clinically nonfunctioning pituitary adenomas were studied by immunohistochemistry, and 12 cases were also analyzed by electron microscopy. Thirty-nine cases (60%) were immunohistochemically identified as hormone-producing adenomas. Six adenomas produced multiple hormones. Electron microscopy found seven null cell adenomas and five oncocytomas. The oncocytomas had a significantly higher incidence of hormone expression that the null cell adenomas. These results indicate that clinically nonfunctioning pituitary adenomas produce hormones, even though blood hormone levels are normal or low. Furthermore, the evidence of multihormonal production implies that two or more cell lineages including a protein hormone-producing type and a glycoprotein hormone-producing type may exist in the same nonfunctioning pituitary adenoma.     

Immunocytochemical localization of bioregulatory peptides in marmoset testes.

Immunocytochemical localization of neuropeptides (beta-endorphin, substance P, arginine vasopressin, oxytocin), pituitary hormones (adrenocorticotropin, prolactin, growth hormone, follicle stimulating hormone (FSH), gonadal inhibin, gastrin, and human chorionic gonadotrophin (hCG)) was carried out in marmoset testis during development. Both intensity of immunostaining and distribution of these peptides in testicular compartments viz. seminiferous tubules and Leydig cells changed dramatically during development. In vitro biosynthesis of inhibin and FSH was increased by hCG, whereas prolactin (5 micrograms) and prostatic inhibin peptide suppressed the synthesis of these hormones.     

The pathogenesis of acromegaly. Clinical and immunocytochemical analysis in 75 patients

A series of 75 patients with acromegaly and immunocytochemically characterized pituitary adenomas has been analyzed. Tumors secreting growth hormone (GH) only were found in 21% of cases. The remainder had tumors immunoreactive for more than one pituitary hormone: GH and prolactin in 31%; GH, prolactin, and glycoprotein in 40%; and GH and glycoprotein in 8%. Microadenomas were surgically treated in 17 patients with a success rate of 82%. Overall, normalization of basal GH secretion (to less than or equal to 5 ng/ml) was achieved in 54% of cases. The implications of these findings for the pathogenesis and neurosurgical management of acromegaly are discussed.     

Ectopic pituitary adenomas with normal anterior pituitary glands

Two patients with ectopic pituitary adenomas and biopsy-proven normal anterior pituitaries are described. Both tumors were located in the sphenoid sinus. One tumor produced prolactin, and the other one was a plurihormonal adenoma that produced predominantly adrenocorticotropin and to a lesser extent thyroid stimulating hormone and alpha subunit. The patient with the plurihormonal tumor, who had Cushing's disease, was cured by surgery while the patient with the prolactinoma was treated by surgery and medical therapy. A review of these two cases and an additional nine cases from the literature of ectopic pituitary adenomas in patients with normal intrasellar anterior pituitaries indicate that these uncommon tumors are capable of secretory function and may be the only cause of excessive pituitary hormone production.     

Prolactin and growth hormone-producing pituitary adenomas. An immunohistochemical and ultrastructural study

Thirteen prolactin and five growth hormone-producing pituitary adenomas were studied by immunohistochemistry and electron microscopy. The immunohistochemical localization of prolactin and growth hormone correlated well with elevated serum levels of pituitary hormones in all cases. Ultrastructural characterization by granule density and secretory activity was studied in relation to the serum levels of pituitary hormones and the sizes of the tumors. This indicated that markedly elevated serum hormone levels were related to larger tumors with high secretory activity, as indicated by abundant endoplasmic reticulum and well-developed Golgi complexes rather than to the numbers of cytoplasmic granules in the tumors. Two patients with prolactin-producing adenomas had been treated with bromocryptine before surgery. Both tumors showed evidence of degeneration, including cytoplasmic vacuolization. In one case the tumor had an increased number of secretory granules, while in the other case there were few viable cells and an abundance of amyloid deposits. The effects of bromocryptine therapy on pituitary tumor morphology in these two cases include an increased number of pituitary granules, and cellular degenerative changes.     

Hypothalamic and pituitary function

The endocrine system consists of groups of cells (glands) that secrete messengers (hormones), which affect distant groups of cells (target organs). It controls mainly basal processes. Hormonal action may be on receptors in the target cell membrane (e.g. leading to alterations in membrane channel properties), in which case it is rapid, or it may affect gene function and thus protein synthesis, in which case the onset of action is relatively slow. Endocrine function is controlled via single and multiple feedback mechanisms from products of the various target organs. It is largely under the control of the hypothalamus via the pituitary gland. Releasing factors and hormones from the hypothalamus act on the pituitary, which produces its own hormones (antidiuretic hormone, oxytocin, growth hormone and prolactin) as well as hormones and releasing factors that affect other endocrine glands (adrenocorticotrophic hormone, thyroid stimulating hormone, luteinizing hormone and follicle stimulating hormone). Growth hormone controls skeletal growth via the release of insulin-like growth factors from the liver; it promotes anabolism, but also antagonizes the hypoglycaemic effect of insulin. Antidiuretic hormone secretion is stimulated by changes in osmolality and is a sensitive mechanism for conserving fluid via its action on the kidney. Oxytocin stimulates uterine contraction, and prolactin stimulates milk production. Luteinizing and follicle stimulating hormones affect the growth of the gonads.     

Clinically silent hypersecretion of growth hormone in patients with pituitary tumors

Hypersecretion of growth hormone (GH) was found in three women aged 25 to 35 years old, with somatotroph adenomas without clinical stigmata of acromegaly. The patients had previously been diagnosed as having nonfunctioning pituitary macroadenomas, with extrasellar extension. Concentrations of GH were elevated preoperatively in all subjects and could not be suppressed during oral glucose tolerance testing. Somatomedin-C concentrations were elevated in two patients. Immunocytochemical studies of surgically obtained tumor tissue demonstrated sparse positive staining for GH in all subjects. Gel-chromatographic analysis of serum and tumor tissue samples demonstrated that the immunoactive GH was authentic GH. On pathological examination, the tumor was cellular in all cases, consisting of partly acidophilic and partly chromophobic cells. Electron microscopic analysis of one tumor showed a cell composition not previously described. These studies further characterize GH hypersecretion in a subset of patients with clinically nonfunctioning pituitary macroadenomas.     

Immunohistochemical localization of pituitary peptides in the rat pyloric antrum mucosa

Several peptides normally produced in the anterior pituitary lobe were searched in rat antral mucosa by immunocytochemistry. Peptides derived from pro-opiomelanocortin were tested: some endocrine cells were immunoreactive with ACTH 17-39 antiserum, and only a few elements were stained with ACTH 1-24 and beta LPH antisera. No immunoreactive cells were observed using alpha MSH, beta MSH and beta endorphine antisera. Using an antiserum against beta endorphin, a few cells and nerve fibres were immunostained. The other pituitary hormones were also tested: numerous antral cells contained immunoreactive GH, and some cells immunoreactive PRL or compounds chemically related to these hormones. No cells were stained with antisera directed against glycoproteic hormones. This work showed that several peptides previously localized in the pituitary gland were found in the antral mucosa. Further studies are needed to identify the cell types containing these peptides and to determine their origin.     

Rational Design of Competitive Prolactin/Growth Hormone Receptor Antagonists

There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.     

The immunocytochemical detection of protein hormones in human prostatic tissues

The immunocytochemical detection of four pituitary protein hormones in tissue from 13 patients with benign prostatic hyperplasia has been described. There have been marked differences in the distribution and intensity of reaction product attributable to the various hormonal antisera. The intracellular presence of endogenous prolactin and FSH in the epithelial cytoplasm has been suggested together with the stromal localization of growth hormone and prolactin. Minimal diffuse staining over most cellular components was observed with the LH antiserum. This technique has provided an invaluable means of studying the potential involvement of pituitary protein hormones in the control of prostatic function and disease.     

Multiple adenomas of the human pituitary. A retrospective autopsy study with clinical implications

In a review of autopsy material from two centers, 20 pituitary glands were found containing multiple adenomas. In total, 44 adenomas were identified histologically; 16 glands contained double tumors and in four glands triple adenomas were found. Size was measured in 30 tumors, all of which were microadenomas. Thirty-four adenomas were located in the lateral wings and 10 lay in the median wedge. Forty-one tumors were chromophobic and three were basophilic. Immunocytochemical analysis of the 44 tumors demonstrated the presence of prolactin in 11, adrenocorticotropic hormone in three, growth hormone in one, and alpha-subunit as well as follicle-stimulating hormone and luteinizing hormone in one. Of the 20 patients studied, there were 11 men and nine women, with an average age of 69 years. All patients died from various nonendocrine causes. With the exception of one patient who appeared mildly acromegalic, no correlation was observed between pituitary morphology and clinical data. This study found a 10.4% frequency of adenomas in pituitaries studied randomly at autopsy. Multiple tumors were encountered in 0.9% of cases. Despite its low frequency, adenoma multiplicity may underlie surgical failure in cases in which one adenoma is removed and the other is left behind.     

Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients

Patients affected by the multiple endocrine neoplasia type I syndrome (MEN1) display a high incidence of pituitary adenomas, though it is still unknown whether these pituitary tumors have specific pathologic features that would distinguish them from sporadic pituitary adenomas. Pituitary tissue specimens of 77 MEN1 patients from the GTE (Groupe d'étude des Tumeurs Endocrines) register were compared with unselected 2509 non-MEN1 sporadic pituitary tumors and also to a control subgroup of 296 cases, where 1 MEN1 tumor was matched with 4 sporadic tumors of the same hormonal immunoprofile. Sex, age, size, and invasiveness of tumors, and menin gene mutations were documented. Histologic analysis took into account 33 items, including immunocytochemical data, the proliferative marker Ki-67, and an examination of the juxtatumoral pituitary. MEN1 tumors were significantly larger and more often invasive by histology. MEN1 patients with large pituitary tumors (grade IV) were younger than non-MEN1 patients. MEN1 tumors had no other characteristic histologic features and no predominance of any one hormone producing subtype. However, plurihormonal adenomas versus monohormonal and nonimmunoreactive adenomas were more frequent in MEN1 tumors (39%) than in the control non-MEN1 group (P = 0.001). Especially, the growth hormone and prolactin plurihormonality with unusual association with follicle-stimulating hormone, luteinizing hormone, or adrenocorticotropic hormone was more frequent in MEN1 tumors. In addition, multiple adenomas were significantly more frequent (4% vs. 0.1%; P < 0.0001), especially prolactin-adrenocorticotropic hormone. Somatotroph hyperplasia, with or without a microadenoma was found in only 3 MEN1 patients, with growth hormone-releasing hormone hypersecretion by a pancreatic tumor in 2 of them. All types of mutation were observed, including frameshifts, nonsenses, missenses, and 1 case of germline MEN1 encompassing large deletion, strongly suggesting the absence of any phenotype-genotype correlation.     

Hyperthyroidism with an FSH-and TSH-secreting pituitary adenoma

A 34-year-old man was found to have elevated thyroxine (T4), triiodothyronine (T3), calculated free T4, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and alpha subunits of TSH and FSH. A computed tomography scan of the head showed a 16-mm macroadenoma of the pituitary gland. There was no evidence of loss or excess secretion of other pituitary hormones. The large chromophobe adenoma was removed via a transphenoidal approach. The patient has been taken off all medication. Thyroid function has returned to normal and there has been no loss of pituitary secretory capacity of other pituitary hormones. The occurrence of a combined TSH- and FSH-secreting pituitary adenoma is rare; to the authors' knowledge, only one case has been documented in the literature.     

Endocrine effects of vasopressin in critically ill patients

Vasopressin, also called antidiuretic hormone, is a 9 amino-acid peptide, synthesized from a precursor containing neurophysin II, by neurones from the supra-optic and peri-ventricular nuclei, and then stored in the posterior hypophysis. Vasopressin regulates plasmatic osmolality and volaemia via V2 receptors at the levels of the kidney, and vascular smooth muscle tone via V1a arterial receptors. Both its synthesis and release from hypophysis vesicles depend on variations in plasma osmolality, volaemia, and arterial blood pressure. In addition, vasopressin interacts with the main hormonal systems involved in the response to stress, including the hypothalamic-pituitary adrenal axis, other anterior pituitary hormones, mainly prolactin and growth hormone, the renin-angiotensin system, and regulates insulin synthesis and glucose metabolism. Interestingly, during critical illness, exogenous administration of vasopressin showed little effects on the circulating levels of these various hormones, except an increase in prolactin. The absence of endocrine effects of vasopressin during critical illness is unclear and may relate to an already maximal hormonal stimulation or to down-regulation of vasopressin receptors.     

Pituitary tumors

Opinion statement  Pituitary adenomas are the most common intrasellar tumors. With the exception of prolactinomas, first-line treatment is almost always surgical. Prolactinomas are usually treated with dopamine agonists such as cabergoline or bromocriptine. Somatostatin analogues, such as octreotide and lanreotide, can be adjunctive to surgical therapy in acromegaly, although they can be used as primary therapy in selected cases. Pegvisomant, a growth hormone receptor antagonist, is reserved for acromegalic patients who are resistant to treatment with somatostatin analogues. No effective medical therapy is available for adenomas that secrete adrenocorticotropic hormone, and occasionally bilateral adrenalectomy is required to resolve severe hypercortisolemia. Radiation therapy (fractionated or radiosurgery) can be used for residual or recurrent pituitary tumors. Asymptomatic, nonfunctioning pituitary adenomas may be followed without any intervention, but surgery is typically indicated if there are symptoms of mass effect on the optic chiasm or endocrine dysfunction. In the hands of an experienced pituitary neurosurgeon, the prognosis for endocrinologic recovery and visual improvement is good.     

Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization

OBJECT: The goal of this study was to determine factors associated with endocrine normalization after radiosurgery is performed in patients with hormone-producing pituitary adenomas. METHODS: Between 1990 and 1999, 43 patients with hormone-producing pituitary adenomas underwent radiosurgery: 26 patients with growth hormone (GH)-producing tumors, nine with adrenocorticotrophic hormone-producing tumors, seven with tumors that produced prolactin (PRL) alone, and one with a tumor that secreted both GH and PRL. The median patient age was 42 years. Thirty-seven patients (86%) had undergone surgery earlier and in 30 (70%) there was tumor extension into the cavernous sinus. The product-limit method was used to calculate endocrine normalization while patients were not receiving any hormone-suppressive medication. The median follow-up period after radiosurgery was 36 months (range 12-108 months). In 20 patients (47%) there was normalization of hormone secretion at a median of 14 months (range 2-44 months) after radiosurgery; no correlation was found between tumor type and cure. Actuarial cure rates were 20, 32, and 61% at 1, 2, and 4 years posttreatment. Multivariate analysis demonstrated that the absence of hormone-suppressive medications at the time of radiosurgery (relative risk 8.9, 95% confidence interval [CI] 1.2-68.7, p = 0.04) and maximum radiation doses greater than 40 Gy (relative risk 3.9, 95% CI 1.3-11.7, p = 0.02) correlated with an endocrine cure. A new anterior pituitary deficiency developed in seven patients (16%), temporal lobe necrosis was identified in two patients, an asymptomatic internal carotid artery stenosis was detected in two patients, and unilateral blindness occurred in one patient. CONCLUSIONS: Radiosurgery provides an endocrine cure for many patients with persistent or recurrent hormone-producing pituitary adenomas. Further study is needed to determine whether pituitary hormone-suppressive medications have a radioprotective effect.     

A rare association between acromegaly and pheochromocytoma

The occurrence of multiple endocrine tumors is rare; however, they may be found with hereditary diseases such as multiple endocrine neoplasia (MEN). The endocrine tumors involved with these diseases are well documented. We present a case of a patient with a pheochromocytoma and a growth hormone (GH) secreting pituitary adenoma. This association is not described with any of the known MEN syndromes. The association may be a cross-over MEN syndrome or a secondarily induced GH-secreting pituitary adenoma from a pheochromocytoma producing growth hormone releasing hormone (GHRH) instead of catecholamines.     

The hypothalamic anterior pituitary relationships and their tumors. A review

The hypothalamic pituitary axis is reviewed in relation to the regulation of the secretion of prolactin, growth, and adrenocorticotrophic hormones by the anterior pituitary lactotrophic, somatotrophic, and corticotrophic cells, respectively. The signs and symptoms, diagnosis, and treatment of tumors arising from these three separate anterior pituitary cells are discussed in the context of current literature.