Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas.

Jameson, J. Larry; Klibanski, Anne; Black, Peter McL.; Zervas, Nicholas T.; Lindell, C M; Hsu, Dora W.; Ridgway, E. Chester; Habener, Joel F.

doi:10.1172/jci113228

Cited by 142 publications

(39 citation statements)

References 29 publications

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“…Activin receptors were demonstrated in a variety of tissues in which activin binding sites were demonstrated in a previous ligand binding study [9]. A number of studies have shown that most non-functioning adenomas are potentially gonadotropinomas and secrete varying amounts of gonadotropins, although they remain clinically and endocrinologically silent [15][16][17]. Taking these into consideration, most of our non-functioning adenomas which expressed ACTR 2 mRNA could be silent gonadotroph adenomas.…”

Section: Resultsmentioning

confidence: 98%

Expression of Inhibin .ALPHA., and .BETA.A Subunit and Activin Type II Receptor mRNAs in Various Human Pituitary Adenomas.

Demura¹,

Tajima²,

Suzuki³

et al. 1995

Endocr J

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Abstract. Inhibin and activin are known to be involved in the pituitary hormone secretion as well as proliferation of the pituitary. We studied the expression of inhibin a, and 13A subunit and activin type II receptor (ACTR 2) mRNAs in human pituitary adenomas to determine the significance of inhibin and activin in pituitary hormone secretion. Tumor tissues were homogenized immediately after resection in guanidinium thiocyanate to extract total RNA. PCR was performed with reversely transcripted cDNA and respective amplification primers. DNA bands obtained for inhibin a, f3A and ACTR 2 by agarose gel-electrophoresis were 367, 285, and 389 bp, respectively. Messenger RNAs for inhibin f3A were demonstrated in all of the pituitary tissues studied, namely in 3 GH, 2 ACTH, 6 PRL and 1 FSH producing adenomas and 17 non-functioning adenomas. Inhibin a mRNAs were detected in 10 of 12 functioning adenomas and 15 of 17 non-functioning adenomas. ACTR 2 mRNAs were found in 11 out of 17 nonfunctioning adenomas, but only found in 3 out of 12 functioning adenomas. These results suggested local production of activin, a homodimer of /3-subunits, and inhibin, a heterodimer of a and f3 subunits, in most of the pituitary adenomas regardless of their hormone secretion. On the other hand, a significantly higher incidence of ACTR 2 in non-functioning adenomas than in functioning adenomas suggested that activin had its main site of action in non-functioning adenomas, which could be potential gonadotropinomas.

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Section: Resultsmentioning

confidence: 98%

Expression of Inhibin .ALPHA., and .BETA.A Subunit and Activin Type II Receptor mRNAs in Various Human Pituitary Adenomas.

Demura¹,

Tajima²,

Suzuki³

et al. 1995

Endocr J

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“…In patients with gonadotropin levels consistent with postmenopausal status, the presence of a gonadotropinoma was considered unlikely on the basis of the simultaneous elevation of both LH and FSH, which is unusual in this type of tumor, and/or absence of abnormal gonadotropin response to TRH, which characterizes gonadotropinomas (19,20). However, since gonadotropinomas and NFPA share a number of biochemical and morphological characteristics (14,15,(19)(20)(21)(22), this possibility cannot be excluded. From the analysis of data obtained in normal subjects and in patients with NFPA in the 50-80 year age range, accuracy of FSH and LH measurement for the diagnosis of NFPA was very high, both FSH and LH showing a high sensitivity and specificity (about 90%).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, diagnosis of NFPA generally occurs when the tumor has reached the stage of macroadenoma and signs and symptoms of expanding mass and hypopituitarism, particularly hypogonadism, are present (12,13). In fact, although several lines of evidence indicate that NFPAs are derived from the proliferation of cells which synthesize glycoprotein hormones and/or their a and b subunits, only very rarely does this synthetic capacity result in an in vivo hypersecretion, while in the great majority of patients signs and symptoms of hypogonadism prevail (14,15). Since the majority of patients present with NFPA in middle or old age, hypogonadal status is generally confused with the normal decline of gonadal function, particularly in women.…”

Section: Introductionmentioning

confidence: 99%

Effect of aging on serum gonadotropin levels in healthy subjects and patients with nonfunctioning pituitary adenomas

et al. 2000

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Objective: Nonfunctioning pituitary adenomas (NFPA), which represent about one-quarter of human pituitary tumors, occur in middle or old age. Determination of gonadotropin levels, which are not expected to be high during the early postmenopause in normal women and which are low in women with NFPA, is important to distinguishing hypogonadal status due to the normal decline of gonadal function from that due to hypothlalamic-pituitary dysfunction. The aim of the study was to verify whether this difference still persists in old subjects, despite the physiological decline of gonadotropins in the last decades of life. Design and methods:The study included 154 healthy subjects (aged 50-104 years) and 47 patients with NFPA (aged 50-80 years). Blood samples were collected after an overnight fast and hormone levels were measured by two immunofluorimetric assays. Results: In healthy women the highest serum levels of gonadotropins were present in the 50-60 year age group, with a slight but progressive age-associated decrease in serum FSH and LH being observed thereafter. In healthy men serum gonadotropin levels were stable up to 70 years, increased up to 75-85 years and thereafter gradually decreasing. Female patients with NFPA showed levels of gonadotropins which were far lower than controls. Only three patients had levels of both FSH and LH above the 2.5 centile for normal subjects. A high sensitivity and specificity of gonadotropin measurements (about 90%) for the diagnosis of NFPA was observed in female patients aged 50-80 years. In male subjects, a large overlap of gonadotropin values in NFPA and controls, namely over the 50-70 years age range, was observed. Conclusions: Our study demonstrates that despite the gradual decline of gonadotropin levels in healthy postmenopsausal women, the reduction of both FSH and LH persists in old patients with NFPA, suggesting that measurement of gonadotropin levels could prove useful in the evaluation of pituitary lesions even in old women. More subtle differences seem to occur in male subjects.

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“…Many hormones present in the multi-hormonal pituitary adenomas are often clinically mute and do not alter the serum hormone levels [41]. For some of these tumors a monoclonal origin has been demonstrated [42].…”

Section: Discussionmentioning

confidence: 99%

Somatotroph to thyrotroph cell transdifferentiation during experimental hypothyroidism ‐ a light and electron‐microscopy study

Radian

Coculescu

Morris

2003

J Cellular Molecular Medi

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Somatotroph and thyrotroph pituitary cells share a common precursor cell expressing the transcription factor Pit1 in ontogeny. Cells expressing both thyrotropin (TSH) and growth-hormone (GH) are found in adult rat pituitary and in human pituitary adenomas in acromegaly, and these tumors contain both thyrotropin-releasing hormone (TRH) and the TRH receptors (TRHR). It has been shown that stimulation of TSH expression in primary hypothyroidism promotes changes suggestive of somatotroph to thyrotroph cell transdifferentiation. We tested this hypothesis and the role of TRH in experimental primary hypothyroidism in rats. Adult female Long-Evans rats, 6 months old, were administered the antithyroid drug methimazole (0,1% w/v) in the drinking water for 42 days. Animals were sacrificed by perfusion fixation under anaesthesia at weekly intervals and pituitary tissue processed in acrylic resin for immunofluorescence and immuno-electronmicroscopy for TSH, GH and TRHR. In the hypothyroid rat pituitary immunofluorescent somatotrophs were greatly reduced in number and gradually replaced by thyrotrophs during methimazole administration. Colocalization of GH and TSH in the same cell was noted. Immunoelectronmicroscopy demonstrated the development of enlarged thyrotrophs with dilated rough endoplasmic reticulum containing an electron-dense material and intracisternal granules, both of which are immunoreactive for TSH ('thyroidectomy cells'). The somatotrophs showed reduced GH immunoreactivity and also the presence of TSH-type, small-size secretory granules. This suggests that the greatly increased number of TSH-cells in methimazole-induced-hypothyroidism is due, at least partially, to the transdifferentiation of somatotroph into thyrotroph cells. TRHR immunofluorescence was expressed in many somatotrophs in normal rat pituitary and unlike immunoreactive GH, its expression was enhanced during hypothyroidism. The number of TRHR-immunoreactive cells increased in parallel with the number of TSH-immunoreactive cells. This indicates a role for TRH stimulation in the transdifferentiation process. Taken together, these data suggest that, in addition to the cell mutation mechanism involving an early totipotential progenitor cell, transdifferentiation of existing somatotroph cells also plays a part in the pathogenesis of multihormonal GH-secreting adenomas.

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Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas.

Cited by 142 publications

References 29 publications

Expression of Inhibin .ALPHA., and .BETA.A Subunit and Activin Type II Receptor mRNAs in Various Human Pituitary Adenomas.

Expression of Inhibin .ALPHA., and .BETA.A Subunit and Activin Type II Receptor mRNAs in Various Human Pituitary Adenomas.

Effect of aging on serum gonadotropin levels in healthy subjects and patients with nonfunctioning pituitary adenomas

Somatotroph to thyrotroph cell transdifferentiation during experimental hypothyroidism ‐ a light and electron‐microscopy study

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