Co-expression Of Growth Hormone Research Articles

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.

Ectopic Co-expression of Growth Hormone Releasing Hormone and Pituitary Adenylate Activating Peptide in Skeletal Muscle Enhance Animal Growth*

Growth hormone (GHRH) and pitutary adenylate cyclase activating peptide (PACAP) are the members of the PACAP/Glucagon superfamily, who are related in both sequence and function. Their stimulation of GH secretion and animal growth is concerned. A series of expression plasmid, pIRES1-GHRH-PACAP (P-G-P), pIRES1-GHRH (P-G) and pIRES1-PACAP(P-P), were constructed, extracted and purified, then transfected into CHO cell line with Lipofectamine. The expression was examined by RT-PCR, dot-ELISA and Western blotting. The biological activity of expression products was detected in rats. At 8 h after injection of transfection supernatant, serum IGF-Ⅰ concentrations in P-G-P group were significantly higher than that in other groups(P 0.05). PLGA encapsulating plasmid microspheres were prepared and injected intramuscularly into rabbit legs. Growth behavior and IGF-1 level were measured at day 0, 15, 30 and 45 after injection. Greater body weights gain and higher serum IGF-Ⅰlevels were observed in three plasmid microsphere injection groups, compared with control group. At day 30, the body weight gain in P-G-P group was greater than saline group (81%, P 0.01), P-G microsphere group (15%, P 0.05) and P-P microsphere group (7%, P 0.05), serum IGF-Ⅰ concentration in P-G-P microsphere group showed a 16.68% increase to P-G microsphere (P 0.05), a 17.14% increase to P-P microsphere(P 0.05) and a 50.46% increase to control (P 0.05). These results suggest that co-expression of GHRH and PACAP in one expression plasmid might exert an additive stimulation of GH secretion and growth when delivered into rabbit skeletal muscle with PLGA microsphere. The results may provide a new approach to regulate animal growth.

Commentary: Classification and grading of pituitary tumors. Observations of two working neuropathologists

As part of the World Health Organization (WHO) ‘‘blue book’’ series, the recently updated endocrine volume includes a 38-page chapter on pituitary tumors [3], divided into concise multi-authored sections. New developments, remaining shortcomings, and future directions of research have been summarized by Al-Shraim and Asa in the current issue [1]. Overall, this newest ‘‘blue book’’ is superbly written, provides a wealth of useful information, and is sold at a readily affordable price, making it a bargain to anyone even remotely interested in pituitary pathology. As with other issues of the WHO series, current molecular data are well integrated with classic pathology and the entities are beautifully illustrated. The pituitary falls under the purview of both endocrine and neuropathology. However, given its intracranial location, the gland is biopsied by neurosurgeons. Therefore, despite crossing subspecialty boundaries, neuropathologists must be well acquainted with this area of endocrine pathology. In the current summary, we attempt to represent the working neuropathologist’s perspective. Pituitary adenomas can be classified on the basis of their gross/radiographic features (macrovs microadenoma, invasive vs noninvasive), hormone status (functional vs nonfunctional), cytology (acidophil, basophil, chromophobe), grade (typical, atypical, carcinoma), immunohistochemical/ultrastructural cell type (lactotroph, somatotroph, corticotroph, gonadotroph, thyrotroph), and molecular attributes (transcription factor, growth factor, and or tumor suppressor gene expression). Practicing neuropathologists are also aware of the wide morphological spectrum encountered routinely. Depending upon the histological pattern, particularly in nonfunctioning adenomas, one can consider diagnoses such as ependymoma, oligodendroglioma, meningioma, or even carcinoma, particularly if one is unaware of the sellar origin of the tissue sample. Despite the limitations of classifying adenomas by their tinctorial characteristics, as discussed in the introductory chapter of the WHO book [3], a more complete discussion of helpful morphological features is worthy of re-emphasis. For example, calcospherites (prolactinomas), eosinophilia or fibrous bodies (growth hormone adenomas), paranuclear vacuolation (acidophil stem cell adenoma), cytoplasmic basophilia or Crooke’s hyaline (corticotroph adenomas), pseudorosette formation (gonadotroph adenomas), and oncocytic change (gonadotroph or null cell adenomas) serve as clues to tumor subtype. Synaptophysin immunoreactivity was also emphasized as a more consistent broad spectrum neuroendocrine marker for pituitary adenoma than chromogranin [3]. This distinctive immunophenotypic feature is generally under appreciated. As common as pituitary adenomas are, it is surprising to see the current inter-institutional variation in diagnostic approach. This ranges from a single hematoxylin and eosin section and a final diagnosis of ‘‘pituitary adenoma’’ in virtually every case, to the ‘‘Cadillac approach’’ of a full pituitary hormone immunostain panel in nearly all instances and electron microscopy in selected cases. An interesting point highlighted in the review of Al-Shraim and Asa [1] is the histogenetic link between transcription factor expression in normal development and pituitary adenomas. Work in this area [4] has advanced our understanding of plurihormonal adenomas, such as the coexpression of growth hormone, prolactin and thyrotropin in the majority of acromegalyassociated adenomas, as well as the gonadotroph-like properties of so-called ‘‘null cell’’ adenomas. NonetheA. Perry (&) Division of Neuropathology, Washington University School of Medicine, Campus Box 8118, 660 S. Euclid Ave, 63110-1093 St. Louis, MO E-mail: aperry@wustl.edu Tel.: +1-314-3627426 Fax: +1-314-3624096

Co-expression of GH and GHR isoforms in prostate cancer cell lines.

Prostate cancer is a significant cause of morbidity and mortality in Western males. While it is known that androgens play a central role in prostate cancer development and progression, other hormones and growth factors are also involved in prostate growth. Insulin-like growth factor-I (IGF-I) plasma levels have been associated with prostate cancer risk, and growth hormone (GH), a major factor regulating IGF levels, also appears to have a role in prostate cancer cell growth. Most significantly, GH has been shown to increase the rate of cell proliferation in prostate cancer cell lines. We have now demonstrated the co-expression of GH and GH receptor (GHR) mRNA isoforms in the ALVA41, PC3, DU145, LNCaP prostate cancer cells by reverse transcription polymerase chain reaction. Sequence analysis has confirmed that these cell lines express the pituitary form of GH mRNA and also the placental mRNA isoform. These prostate cancer cell lines also express the full-length mRNA for the GHR and the exon 3 deleted isoform. We have also demonstrated the presence of GH and GHR proteins in these cell lines by immunohistochemistry. GH expression has not been described previously in human prostate cancer cells. The co-expression of GH and its receptor would enable an autocrine-paracrine pathway to exist in the prostate that would be capable of stimulating prostate growth, either directly via the GHR or indirectly via IGF production. The GH axis in the prostate could therefore be an important additional target for the future development of prostate cancer therapies.

Co-Expression of Bovine Growth Hormone (GH) and Human GH Antagonist Genes in Transgenic Mice

Bovine growth hormone (bGH) transgenic (Tg) mice have been shown to possess enhanced growth phenotypes and exhibit severe glomerulosclerosis. One amino acid substitution in GH, i.e. G119R in bGH or G120R in human (h) GH, results in GH antagonists (GHAs). GHA-Tg mice exhibit dwarf phenotypes and normal kidneys. In order to investigate the possibility of GHAs as pharmaceutical agents for the treatment of human diseases with excessive GH levels, we cross bred mice that express bGH with those that express hGHA. Double positive Tg mice were identified that express both genes although at different levels. Kidney histological studies revealed that the double positive Tg mice with high GHA/GH expression ratios possessed normal or near normal kidneys, whereas those with low GHA/GH ratios exhibited glomerulosclerosis similar to GH-Tg mice. Thus, co-expression of GH and GHA genes in vivo results in animal phenotypes and kidney histopathologies which are a reflection of the relative expression levels of each gene.

Co-expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice.

Bovine growth hormone (bGH) transgenic (Tg) mice have been shown to possess enhanced growth phenotypes and exhibit severe glomerulosclerosis. One amino acid substitution in GH, i.e. G119R in bGH or G120R in human (h) GH, results in GH antagonists (GHAs). GHA-Tg mice exhibit dwarf phenotypes and normal kidneys. In order to investigate the possibility of GHAs as pharmaceutical agents for the treatment of human diseases with excessive GH levels, we cross bred mice that express bGH with those that express hGHA. Double positive Tg mice were identified that express both genes although at different levels. Kidney histological studies revealed that the double positive Tg mice with high GHA/GH expression ratios possessed normal or near normal kidneys, whereas those with low GHA/GH ratios exhibited glomerulosclerosis similar to GH-Tg mice. Thus, co-expression of GH and GHA genes in vivo results in animal phenotypes and kidney histopathologies which are a reflection of the relative expression levels of each gene.