Morphological classification of pituitary adenomas and its value for clinical diagnosis]

Pituitary adenomas should be classified not only by their tinctorial affinities but also by their degree of differentiation. Then useful correlation to the clinical data can be obtained; On this principle our own collection of 299 tumors was classified in undifferentiated acidophilic, highly differentiated acidophilic GH cell-, highly differentiated acidophilic prolactin cell-adenomas, in undifferentiated mucoid cell-, highly differentiated mucoid ACTH cell-, highly differentiated mucoid TSH cell-adenomas, in chromophobic adenomas of small cell type and of large cell type, and in oncocytic adenomas. 95% of the cases with acromegaly based on undifferentiated acidophilic or highly differentiated GH cell adenomas. All patients with hypothalamic-hypophyseal Cushing's syndrome or Nelson's syndrome had undifferentiated mucoid cell adenomas or highly differentiated ACTH cell adenomas. In cases with hyperprolactinemia prolactin cell adenomas or chromophobic adenomas of large cell type with ultrastructurally demonstrated very highly developed rough endoplasmic reticulum or endocrinologically inactive chromophobic adenomas of small cell type were found. In the latter cases the prolactin is probably produced not by the tumor but by the surrounding tumor-free pituitary tissue.     

Melanin-concentrating hormone stimulates human growth hormone secretion: a novel effect of MCH on the hypothalamic-pituitary axis

Melanin-concentrating hormone (MCH), a 19-amino acid orexigenic (appetite-stimulating) hypothalamic peptide, is an important regulator of energy homeostasis. It is cleaved from its precursor prepro-MCH (ppMCH) along with several other neuropeptides whose roles are not fully defined. Because pituitary hormones such as growth hormone (GH), ACTH, and thyroid-stimulating hormone affect body weight and composition, appetite, insulin sensitivity, and lipoprotein metabolism, we investigated whether MCH exerts direct effects on the human pituitary to regulate energy balance using dispersed human fetal pituitaries (21-22 wk gestation) and cultured GH-secreting adenomas. We found that MCH receptor-1 (MCH-R1), but not MCH receptor-2, is expressed in both normal (fetal and adult) human pituitary tissues and in GH cell adenomas. MCH (10 nM) stimulated GH release from human fetal pituitary cultures by up to 62% during a 4-h incubation (P < 0.05). Interestingly, neuropeptide EI (10 nM), which is also cleaved from ppMCH, increased human GH secretion by up to 124% in fetal pituitaries. A milder, albeit significant, induction of GH secretion by MCH (20%) was seen in cultured GH-secreting pituitary adenomas. A comparable stimulation of GH secretion was seen when cultured mouse pituitary cells were treated with MCH. Treatment of cultured GH adenoma cells with MCH (100 nM) induced extracellular signal-regulated kinases 1 and 2 phosphorylation, suggesting activation of MCH-R1. In aggregate, these data suggest that MCH may regulate pituitary GH secretion and imply a potential cross-talk mechanism between appetite-regulating neuropeptides and pituitary hormones.     

Growth hormone releasing hormone-sensitive adenylate cyclase activity in growth hormone-producing pituitary adenoma: correlation to the response of plasma growth hormone to growth hormone releasing hormone in patients with acromegaly

The correlation between response of plasma GH to GHRH and the GHRH-induced stimulation of the intracellular adenylate cyclase (AC) activity in pituitary adenoma cell membranes in acromegalic patients was investigated. Each peak plasma GH level after iv administration of GHRH ranged from 1.1 to 13.8 times the basal level in 13 acromegalic patients. On the other hand, the maximal stimulation of intracellular AC activity (cAMP production) induced by GHRH varied from 1.4 to 6.4 times the control level in each GH-producing pituitary adenoma cell membrane. A significant positive correlation (r = 0.89, P less than 0.005) between plasma GH response to GHRH and intracellular cAMP production stimulated by GHRH was observed in nine of the acromegalic patients. In contrast, the response of plasma GH to GHRH was significantly blunted, despite a fairly large production of intracellular cAMP stimulated by GHRH, in the other four acromegalic patients. These results suggest that GHRH-induced GH release from GH-producing pituitary adenomas of patients with acromegaly may be regulated not only by GHRH receptor-adenylate cyclase system but also modified by several other factors including somatostatin and Sm-C.     

Receptors and neurohormones in human pituitary adenomas

In order to go further into the pathogenesis of human pituitary adenomas, we studied receptors for neurohormones (thyroliberin, TRH; dopamine, DA; somatostatin, SRIH), for estradiol and epidermal growth factor (EGF) thought to influence hormone secretion and/or cell growth. The following results were obtained: (1) the receptors listed above, with the exception of EGF receptors in the adenomas, are present in normal pituitary tissue and in prolactin (PRL)- and growth hormone (GH)-secreting adenomas; (2) they are functional and their affinities are not different in normal or tumoral tissues; (3) their density is variable and depends on the type of secreting adenoma (GH or PRL), the size of the tumor and the plasma level of the hormone which is secreted, and (4) in nonsecreting adenomas, only TRH receptors are found with characteristics identical to those observed in secreting adenomas. We also showed that TRH is contained in normal and tumoral pituitary tissues. TRH and SRIH are released in vitro from adenomatous cells in large amounts, suggesting their possible synthesis by the pituitary. In both cases a local regulation is observed. TRH release is stimulated in the presence of DA while SRIH is inhibited in the presence of TRH. This neuropeptide release may be implicated in the pituitary hormone regulation through a paracrine or an autocrine mechanism. Thus, the neurohormone receptors found in pituitary adenomas should be dependent on a more complex regulation than it has been envisaged till now.     

Plasma alpha-subunit levels during the treatment of pituitary adenomas with the somatostatin analog (SMS 201-995)

The effect os SMS 201-995 (Sandostatin), a long-acting somatostatin analog, on different types of pituitary adenomas including alpha-subunit elevation is illustrated in this report. Treatment induced a fall in hCG levels in a woman with a pituitary adenoma producing only alpha-subunit. In 3 acromegalic patients, there was only a partial drop in GH and alpha-hCG. The same effect was observed in a woman with menopausal FSH and LH levels. SMS reduced plasma TSH and alpha-hCG in a case of thyrotropic adenoma. Two patients exhibiting FSH- and alpha-hCG-secreting adenomas did not respond to acute administration of SMS 201-995. More patients have to be treated before a definitive statement can be made on the usefulness of somatostatin analogs in the management of different types of pituitary adenomas.     

Localization of Carboxyl Ester Lipase in Human Pituitary Gland and Pituitary Adenomas

Carboxyl ester lipase (CEL) is an enzyme that hydrolyzes a wide variety of lipid substrates, including ceramides, which are known to show inhibitory regulation of pituitary hormone secretion in experimental models. Because no studies on CEL expression in human pituitary and pituitary adenomas have been reported in the literature, we investigated CEL expression in 10 normal pituitary glands and 86 well-characterized pituitary adenomas [12 FSH/LH cell, 17 α-subunit/null cell, 6 TSH cell, 21 ACTH cell, 11 prolactin (PRL) cell, and 19 GH cell adenomas] using IHC, immunoelectron microscopy, Western blotting, and quantitative RT-PCR. In normal adenohypophysis, CEL was localized in GH, ACTH, and TSH cells. In adenomas, it was mainly found in functioning GH, ACTH, and TSH tumors, whereas its expression was poor in the corresponding silent adenomas and was lacking in FSH/LH cell, null cell, and PRL cell adenomas. Ultrastructurally, CEL was localized in secretory granules close to their membranes. This is the first study demonstrating CEL expression in normal human pituitary glands and in functioning GH, ACTH, and TSH adenomas. Considering that CEL hydrolyzes ceramides, inactivating their inhibitory function on pituitary hormone secretion, our findings suggest a possible role of CEL in the regulation of hormone secretion in both normal and adenomatous pituitary cells. (J Histochem Cytochem 58:881–889, 2010)     

Expression of leptin receptor isoforms and effects of leptin on the proliferation and hormonal secretion in human pituitary adenomas

OBJECTIVE: To pursue whether leptin regulates anterior pituitary cells, we studied the ex vivo expression of several isoforms of the leptin receptor (OB-R) as well as the in vitro effects of leptin administration in human pituitary adenomas. METHODS: OB-R mRNA expression and in vitro response to leptin were studied in 39 pituitary macroadenomas. RESULTS: All 4 OB-R subtypes were expressed in most adenomas. The expression was significantly more pronounced in GH-secreting adenomas as compared to non-functioning tumor cells (p < 0.05). Leptin administration in vitro did not significantly influence cell proliferation or the secretion of GH, FSH, LH or alpha-subunit. CONCLUSIONS: (1) Several isoforms of the OB-R, including the signal transducing full-length receptor, are expressed in most human pituitary adenomas. (2) This expression ex vivo is not associated with significant effects of leptin in vitro.     

Pituitary surgery for the management of acromegaly

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.     

Growth hormone-releasing hormone and somatostatin in normal and tumoral human pituitaries.

In order to further understand the role of endogenous pituitary neuropeptides in pituitary hormonal content and secretion, GHRH, SRIH and GH contents were quantified in GH adenomas obtained from acromegalic patients with plasma GH levels either high (greater than 5 micrograms/l, range 11 to 550 micrograms/l, n = 11) or in the normal range (less than 5 micrograms/l, range 1 to 3.3 micrograms/l, n = 4). Values were compared to those found in normal human pituitaries. No relationship was found between GHRH content and plasma GH or between SRIH and GH content when considering together adenomas and normal pituitaries. Results showed that there is a positive relationship between GHRH and GH content: when GHRH content is high, GH content is also high (normal pituitaries and GH adenomas of acromegalic patients with high plasma GH) and when GHRH content is low, GH content is also low (GH adenomas of acromegalic patients with plasma GH in the normal range). Conversely, SRIH content is negatively related to plasma GH levels: when SRIH is present, plasma GH is in the normal range; when SRIH is undetectable, plasma GH is high.     

PKC and ERK are differentially involved in gonadotropin-releasing hormone-induced growth hormone gene expression in the goldfish pituitary

Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus and stimulates the synthesis and secretion of gonadotropin hormones. In addition, GnRH also stimulates the production and secretion of growth hormone (GH) in some fish species and in humans with certain clinical disorders. In the goldfish pituitary, GH secretion and gene expression are regulated by two endogenous forms of GnRH known as salmon GnRH and chicken GnRH-II. It is well established that PKC mediates GnRH-stimulated GH secretion in the goldfish pituitary. In contrast, the signal transduction of GnRH-induced GH gene expression has not been elucidated in any model system. In this study, we demonstrate, for the first time, the presence of novel and atypical PKC isoforms in the pituitary of a fish. Moreover, our results indicate that conventional PKC alpha is present selectively in GH-producing cells. Treatment of primary cultures of dispersed goldfish pituitary cells with PKC activators (phorbol ester or diacylglycerol analog) did not affect basal or GnRH-induced GH mRNA levels, and two different inhibitors of PKC (calphostin C and GF109203X) did not reduce the effects of GnRH on GH gene expression. Together, these results suggest that, in contrast to secretion, conventional and novel PKCs are not involved in GnRH-stimulated increases in GH mRNA levels in the goldfish pituitary. Instead, PD98059 inhibited GnRH-induced GH gene expression, suggesting that the ERK signaling pathway is involved. The results presented here provide novel insights into the functional specificity of GnRH-induced signaling and the regulation of GH gene expression.     

Central effects of ghrelin on serum growth hormone and morphology of pituitary somatotropes in rats

Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor, was originally purified from rat stomach; subsequently, ghrelin neurons were found in the arcuate nuclei of rats. Central effects of the peptide on GH release, however, remain to be clarified. The aim of the present study was to determine the morphologic features of GH-producing pituicytes and serum GH concentration after central administration of ghrelin. Five injections of rat ghrelin or phosphate-buffered saline (PBS; n = 10 rats/group) were given every 24 hrs (1 microg of ghrelin in 5 microl of PBS) into the lateral cerebral ventricle of male rats. Significant (P < 0.05) increases in absolute and relative pituitary weights occurred in ghrelin-treated rats versus controls (58% and 41%, respectively). Morphometric parameters (i.e., the volume of GH cells, volume of their nuclei, and volume density) all significantly (P < 0.05) increased by 17%, 18%, and 19%, respectively, in the ghrelin-treated group versus controls. Terminal serum concentration of GH was significantly (P < 0.05) increased by 15% with ghrelin treatment. The results clearly document that daily nanomolar doses of ghrelin into the lateral cerebral ventricle stimulate GH cell proliferation and promote GH release. Thus, achieving pharmacologic control of central ghrelin receptors is a promising modality to modulate the actions of GH.     

Five-year follow-up of a 13-year-old boy with a pituitary adenoma causing gigantism--effect of octreotide therapy

BACKGROUND/AIM: In children, there is little experience with octreotide therapy for pituitary tumors, especially growth hormone (GH) producing adenomas. We report on a 13-year-old boy with gigantism due to a GH-producing pituitary adenoma caused by a Gsalpha mutation on the basis of McCune-Albright syndrome. METHODS: At the age of 6.5 years a GH- and prolactin-producing pituitary adenoma was diagnosed. The adenoma was surgically removed. Immediately thereafter, the small adenoma residuum was treated with octreotide (2 x 100 microg/day s.c.). RESULTS: During therapy with octreotide, the growth rate dropped to normal values; however, rose again after 2 years of treatment. The insulin-like growth factor I (IGF-I) levels remained above the 95th percentile, the GH level mostly >2 microg/l. After 5 years of octreotide therapy, GH (6.9 microg/l), IGF-I (620 microg/l), IGF-binding protein 3 (5.4 mg/l), and prolactin (17.0 ng/ml) levels were still elevated. The growth velocity was +2.4 SDS (standard deviation score), the pubertal status was mature, and the bone age was 14.3 years (prospective final height 208 cm). A magnetic resonance imaging scan showed an unchanged residual 4-mm rim of adenoma at the pituitary site. Side effects from octreotide therapy were not reported by the patient or his family. The therapy was changed to the long-acting release octreotide analog octreotide-LAR. After 1 year of treatment with octreotide-LAR, the GH level was 1.0 microg/l, and the prospective final height dropped by 10 cm. CONCLUSIONS: This case demonstrates that combined surgical and medical treatment can influence the prognosis of childhood gigantism; however, the prognosis of this rare condition remains uncertain.     

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.     

A single amino acid change in the glycoprotein of lymphocytic choriomeningitis virus is associated with the ability to cause growth hormone deficiency syndrome.

Persistent infection of C3H/St mice with certain strains of lymphocytic choriomeningitis virus (LCMV) causes a growth hormone (GH) deficiency syndrome (GHDS) manifested as growth retardation and hypoglycemia. Infected mice show high levels of viral replication in the GH-producing cells in the anterior pituitary leading to decreased synthesis of GH mRNA and protein despite the absence of detectable virus-induced cell structural damage. Virus clones isolated from the GHDS-negative LCMV WE strain can cause the disease, while others cannot. The genetic basis of this phenotypic difference is a nucleotide substitution resulting in a single amino acid difference in the viral glycoprotein. Reassortant studies indicate that the single amino acid substitution (Ser-153 to Phe) is sufficient to allow infection of the GH-producing cells and cause GHDS. These results show that a single change in the genome can affect viral pathogenicity by altering the tropism of the virus.     

The molecular weight forms of rat growth hormone secreted in response to growth hormone-releasing factor

The different molecular weight forms of immunoreactive growth hormone (irGH) secreted by the anterior pituitary of rats were evaluated during basal and stimulated secretion in vitro and in vivo. Anterior pituitary cells maintained in a monolayer culture system secreted only a 22,000-Da form of GH based on Sephacryl S-200 column chromatography. This was also true for the irGH secreted in response to growth hormone-releasing factor and prostaglandin E2 stimulation. In contrast, the molecular weight forms of irGH found in plasma under basal conditions included an approximately 90,000-Da form as well as the expected 22,000-Da form. The concentrations of both forms increased following growth hormone-releasing factor stimulation although there was a shift in the ratio of the forms secreted. These results suggest that the larger molecular weight forms of rat GH observed in plasma may be the result of some postsecretory process which occurs in blood and suggests a possible regulatory function for the larger molecular weight forms as it pertains to the bioavailability of GH in vivo.     

Effect of glucagon on growth hormone secretion in rats

Gentled rats injected subcutaneously with glucagon (20 microgram/100 g body weight) showed a significant decrease in plasma growth hormone (GH) at 15 min after glucagon injection. A subcutaneous injection of 50% glucose did not cause the early suppression as shown at 15 min after glucagon injection, but at 30 min after glucose injection a tendency to decrease in plasma GH was observed. In urethane anesthetized rats, a subcutaneous administration of glucagon (1 microgram or 10 microgram/100 g body weight) failed to elicit an increase in plasma GH. In vitro incubation of anterior pituitary fragments with glucagon failed to decrease the release of GH, suggesting that glucagon does not act directly on the anterior pituitary.     

垂体腺瘤的临床与病理观察(附22例报告)

目的探讨垂体腺瘤(pituitary adenoma)的临床与病理特点。方法回顾性分析22例垂体腺瘤患者的临床资料。结果内分泌检查结果:22例垂体腺瘤患者中,催乳激素(PRL)值升高者8例;促性腺激素(GnH)水平改变者8例;生长激素(GH)升高者1例;出现Cushing综合症者2例;激素水平正常者3例。免疫组化结果:22例垂体腺瘤患者中8例PRL阳性;7例卵泡刺激素(FSH)/黄体生成素(LH)阳性;1例GH阳性;1例GH/PRL阳性;1例FSH/PRL阳性;无功能者4例。结论应用病理和内分泌功能分类相结合的方法,对垂体腺瘤进行分类,具有十分重要的实际应用价值。