Pituitary and Placenta

The components of the GH axis located at the level of the pituitary gland are the GHRH receptor, the GHS receptor, pituitary transcription factors, and GH (Table 2). The GHRH receptor has been localized to human chromosome 7p15 (18). GHRH receptors on somatotrophs are typical G-protein-coupled receptors containing seven transmembrane-spanning domains with three extracellular and three cytoplasmic loops (19,20). On binding GHRH, the receptor activates a Gs protein with a resultant increase in cAMP and intracellular Ca2+ (21,22). Via these intracellular signaling pathways, GH synthesis and release are induced.

Recently the GHS receptor was cloned and also shown to be a G-protein-coupled receptor (23). The GHS receptor, unlike the GHRH receptor, does not activate intracellular cAMP, but appears to act via protein kinase C activation (24). The endogenous ligand for this receptor is unknown.

Fig. 1. GH axis. Simplified, schematic representation of the growth hormone axis. Growth hormone (GH) synthesis and release from somatotrophs is predominantly regulated by two hypotha-lamic hormones, growth hormone releasing hormone (GHRH) and somatostatin (SRIF). GHRH stimulates GH transcription, synthesis, and release via a Gs-protein coupled receptor (GHRH-R). SRIF antagonizes this effect via a Gi-protein coupled receptor (SRIF-R). GHRH activation of the heterotrimeric Gs-protein results in increased cAMP accumulation and activation of protein kinase A (PKA). PKA in turn phosphorylates and activates the cAMP response element binding protein (CREB) that binds to cAMP response elements in the promotor region of the Pit-1 gene to enhance transcription. Pit-1 augments GH-1 gene transcription leading to increased growth hormone synthesis. GH, acting via its receptor (GH-R), increases the synthesis and release of insulin-like growth factor 1 (IGF-1), which mediates somatotrophic effects via the IGF type 1 receptor (IGF-R type 1). The regulation of the other pituitary transcription factors such as Rpx and PROP-1 in somatotrophs has not yet been fully characterized. Asterisks denote recognized abnormalities in this axis.

Fig. 1. GH axis. Simplified, schematic representation of the growth hormone axis. Growth hormone (GH) synthesis and release from somatotrophs is predominantly regulated by two hypotha-lamic hormones, growth hormone releasing hormone (GHRH) and somatostatin (SRIF). GHRH stimulates GH transcription, synthesis, and release via a Gs-protein coupled receptor (GHRH-R). SRIF antagonizes this effect via a Gi-protein coupled receptor (SRIF-R). GHRH activation of the heterotrimeric Gs-protein results in increased cAMP accumulation and activation of protein kinase A (PKA). PKA in turn phosphorylates and activates the cAMP response element binding protein (CREB) that binds to cAMP response elements in the promotor region of the Pit-1 gene to enhance transcription. Pit-1 augments GH-1 gene transcription leading to increased growth hormone synthesis. GH, acting via its receptor (GH-R), increases the synthesis and release of insulin-like growth factor 1 (IGF-1), which mediates somatotrophic effects via the IGF type 1 receptor (IGF-R type 1). The regulation of the other pituitary transcription factors such as Rpx and PROP-1 in somatotrophs has not yet been fully characterized. Asterisks denote recognized abnormalities in this axis.

Recent advances in the molecular ontogeny of the pituitary gland have identified a number of nuclear transcription factors necessary for normal anterior pituitary gland and, more specifically, somatotroph development. It is clear that a cascade of transcription factors is involved in differentiation of specific pituitary cell populations.

Early in embryogenesis Rpx, (Rathke pouch homeobox, also known as HESX1, homeobox gene expressed in ES cells) is expressed in the mouse in visceral endoderm, neural ectoderm, and Rathke's pouch (25). This is a member of the paired-like class of homeobox genes. The human gene for Rpx is found at 3p21.2-p21.1 (26).

Other early transcription factor genes important in the formation of thyrotrophs, lactotrophs, and somatotrophs are LHX3 (lim homeobox 3); LHX4; OTX (orthodenticle homolog 1); and PROP-1 (prophet of pit-1) (27). The LHX genes are expressed in embryonic and adult mouse pituitaries and appear to be involved in establishing and maintaining differentiated pituitary cells (28,29). OTX1 is a homeobox-containing gene that may activate transcription of GH, follicle stimulating hormone, luteinizing hormone, and the a-glycoprotein subunit genes (30). PROP-1 is a paired domain protein, whose expression occurs immediately before and in the same tissues as pit-1. PROP-1 function is necessary for pit-1 expression. In humans, the PROP-1 gene is found on the distal portion of chromosome 5q (31).

Pit-1 is a 33kd pituitary-specific transcription factor that is necessary for GH, thyroid-stimulating hormone (TSH), and prolactin gene transcriptional activation, and for somatotroph, lactotroph, and thyrotroph establishment (32). The protein is a product of the POU-domain gene family and has three regions: a transcriptional activation domain, a 60 amino acid sequence necessary for high-affinity DNA binding known as the POU homeodomain (POU-HD), and a 76 amino acid highly-conserved region that potentiates POU-HD binding, known as the POU specific domain (33). In humans, the gene encoding pit-1 has been mapped to chromosome 3p11.

GH is a single 191 amino acid polypeptide chain, which is nonglycosylated but contains two disulfide bridges. The GH-1 gene that codes for GH is part of a 50-kb cluster of five genes that evolved from a series of three sequential gene duplications (34). Located on chromosome 17q22-24, in 5'-3' order these genes are: GH-1, chorionic somatomam-motropin-like (CS-L), CS-A, GH-2, and CS-B (Fig. 2). Except CS-L, each gene produces a unique 217 amino acid prohormone that is cleaved to a mature 191 amino acid hormone. CS-L was originally categorized as a pseudogene. Subsequent investigations have found that it is translated and undergoes alternative splicing, but the resultant protein products appear to be nonfunctional (35).

The GH-1 gene is expressed in the anterior pituitary and yields a major 22-kb product (GH-N), a minor 20-kb product, and some post-translational variants. The GH-2 product, known as GH variant (GH-V), only differs from GH-N by 13 amino acids that are distributed along its peptide chain (36). It is expressed as at least four alternatively spliced mRNAs in the placenta and is continuously secreted during the second half of pregnancy (37,38). Placental GH-V accounts for the majority of radioimmunoactive growth hormone detected in the maternal circulation, with maternal pituitary GH-1 function being suppressed (39). In vitro, it is a potent GH analogue and likely assists during pregnancy in optimizing maternal transfer of nutrients to the fetus.

CS-A and CS-B are placentally expressed and encode human chorionic somatomam-motropin (hCS, also known as human placental lactogen). HCS is produced in massive amounts by syncytiotrophoblastic cells, but, unlike GH-V, has, on a weight-for-weight basis, only 0.5% the affinity for the GH receptor as GH-N (40). It is similar in structure (85% amino acid homology with two disulfide bonds) to GH-N (41). HCS production is shared by CS-A and CS-B genes. Deletion of both of these genes is necessary to have hCS deficiency.

Fig. 2. Map of GH gene family: GH-1 ; CS-L; CS-A; GH-2; CS-B. Schematic representation of the GH gene cluster located on chromosome 17q22-24. The tissue where normal transcription occurs is also shown. CS, chorionic somatomammotropin.
Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Post a comment