COMPOSITION AND ONTOGENY OF THE ANTERIOR PITUITARY

Three reviews serve as a background for the next two sections. One is a chapter entitled "Functional Anatomy of the Hypothalamus and Pituitary" in Endotex, a Web textbook by the Endocrine Society, downloadable at https://www.ncbi.nlm.nih.gov/books/NBK279126/. A second review is in Science [29], and a third review is in Endocrine Reviews [30].

Anterior pituitary structure, cell types, and dopamine receptors

The anterior pituitaiy is composed of nests of cuboidal hormone-producing cells located adjacent to venous sinusoids. The sinusoids, which are part of the secondary capillary plexus of the hypophysial portal, are lined with fenestrated epithelium that collects the secretory products of the pituitary cells. As previously discussed, the pituitary gland lies outside the BBB. Thus, in addition to the releasing/inhibiting hormones that reach the anterior pituitary from the hypothalamus via the hypophysial portal vasculature, peripheral hormones and modulators can reach the anterior pituitary from the systemic circulation and provide feedback information.

The long-held dogma that the mammalian anterior pituitary is devoid of innervation has been challenged by several reports. In fact, peptidergic nerve fibers were detected in anterior pituitaries of humans, monkeys, dogs and rats [31]. Large numbers of nerve fibers containing substance P (SP), calcitonin gene-related peptide (CGRP), and galanin (GAL), were seen in the human pituitary stalk. These nerve fibers run along the pituitary stalk and enter the anterior pituitary; some GAL-immunoreactive fibers reach the center of the human anterior pituitary. Older publications from the 1990s reported expression of tyrosine hydroxylase (TH) in anterior pituitaries from rats and humans. Yet, there was no follow up on these findings, and the identity of the cells that express TH and whether the enzyme was functional and locally generated DA remain unknown.

As listed in Table 5.1, the anterior pituitary contains five discrete hormone producing cell types, each of which produces its respective hormone(s): somatotrophs (GH), lactotrophs (PRL), corticotrophs (ACTH), thyrotrophs (TSH), and gonadotrophs (both LH and FSH). The older classification of the anterior pituitary cells was based on their staining properties: acidophils for somatotrophs and lactotrophs, basophils for thyrotrophs and gonadotrophs, and chromophobes for corticotrophs. Following the introduction of specific immunocytochemical methods for each of the pituitary hormone, this staining classification became obsolete. All secretory anterior pituitary cells also exhibit spontaneous and extracellular calcium-dependent electrical activity, but differ with respect to the patterns of firing and associated calcium signaling and hormone secretion.

Table 5.1 Anterior pituitary hormones

ACTH: adrenocorticotropic hormone; FSH: follicle-stimulating hormone; GH: growth hormone; LH: luteinizing hormone; PRL: prolactin; TSH; thyroid stimulating hormone.

Figure 5.7 shows the primary targets of each pituitary hormone: thyroids for TSH, male and female gonads for LH and FSH, adrenals for ACTH, and multiple targets for PRL and GH. A detailed discussion on each hormone, its regulation, release, and feedback from its targets is presented in the subsequent sections. In addition to the classical protein hormones, the anterior pituitary synthesizes a wide variety of peptides, growth factors, cytokines, binding proteins and neurotransmitters that cany out paracrine and/or autocrine functions in the control of pituitary secretion and/or cell proliferation.

Figure 5.7 Anterior pituitary hormones. Shown are the six protein hormones of the anterior pituitary, their target organs/ glands and their primary functions. ACTH: adrenocorticotropic hormone; FSH: follicle- stimulating hormone; GH: growth hormone; LH: luteinizing hormone; PRL: prolactin; TSH: thyroid stimulating hormone.

The relative expression of DA receptors (DARs) in the human pituitary is D2R»>D4R»D5R>DlR, while D3R is undetectable [32]. Clinically nonfunctioning pituitary tumors (non-hormone secreting) showed a predominance of D2R, low expression of D4R, and undetectable D l R, D3R and D5R [33]. On the other hand, a recent study reported expression of D5R in nonfunctioning human pituitary adenomas as well as in rat (GH3) and mouse (MMQ) lactotroph/ somatotroph cell lines [34]. In non-tumorous rat [35-37] and human [32,38] anterior pituitaries, D2R was primarily expressed in the lactotrophs. Both long and short D2R isoforms were found in the normal human pituitaiy [39]. D2R is expressed at variable levels in other hormone-producing cells, including gonadotrophs, corticotrophs, thyrotrophs and somatotrophs [38,40].

Folliculostellate cells are non-endocrine, star-shaped cells, devoid of secretory granules that are dispersed among of endocrine cells of the anterior pituitary. They are glial-like cells derived from neuroectodermal origin and are identified by several markers: vimentin, S-100 protein, and GFAR The cells are organized into follicles, possess phagocytic properties, and communicate with each other and with endocrine cells through gap- junctions. Their long processes generate a three-dimensional (3D) network, used for the transmission of signals throughout the pituitary and which help in the coordination of its functions.

Folliculostellate cells produce signaling proteins such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF), insulin-like growth factor (IGF), and transforming growth factors (TGF-a and -p). They also express cytokines such as interleukin-6 and leukemia inhibitory factor (LIF) and produce nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and follistatin. It has been reported that folliculostellate cells specifically influence the function of gonadotrophs and lactotrophs. There are no published records whether folliculostellate cells express TH or DA receptors.

Stem cells that do not produce hormones have also been identified in the adult anterior pituitary. The cells are identified by expression of established stem cell markers and are located primarily in the marginal zone around the pituitary cleft. The pituitary stem cells are presumably involved in cell regeneration after pituitary injuiy and have a role in pituitary tumor formation. In one study [41], progenitor/stem cells were isolated from nonfunctioning human pituitary tumors (NFPTs). Approximately 70% of the NFPTs formed spheres that co-express the stem cell markers DAX1, SF1, and ERG1. Upon in vitro incubation, D2R as well as somatostatin (SSTR2) agonists inhibited their proliferation, suggesting the maintenance of anti-proliferative effects of DA and somatostatin. This finding is supported by another study [42], reporting on co-expression of D2R and somatostatin receptors in stem cells isolated from nonfunctioning human pituitary adenomas. The authors indicated that stem cells with similar properties also exist in murine models of pituitary adenomas.