BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 15. INTEGRATION OF METABOLIC PATHWAYS. HORMONES

15.6. Hormones of the Adenohypophysis

Adenohypophysis Hormones are classified according to their Structure into: 1) simple Proteins, 2) Glycoproteins, and 3) POMC (pro-opiomelanocortin) derivatives.

Growth Hormone (GH), also known as somatotropic hormone (STH), and prolactin (PRL) are simple proteins consisting of a single polypeptide chain with a high degree of Primary Structure Homology.

GH is synthesized in pituitary somatotrophs and, unlike other tropic hormones, lacks a specific target endocrine gland. Its primary Functions are to promote linear growth and exert anabolic effects. Human GH consists of 191 amino acid residues and contains two Disulfide Bonds. The rate of GH secretion depends on The ratio of somatoliberin (GHRH) to Somatostatin concentrations. Upon entering the bloodstream, GH binds to the GH-binding protein, which is homologous to the extracellular domain of The Cell-membrane GH receptor. The growth-promoting effects of GH are mediated by Insulin-like Growth Factors (IGFs), which are synthesized predominantly in the Liver under its influence. IGF-1 and IGF-II are structurally related single-chain proteins similar to proinsulin, circulating primarily in complexes with IGF-binding proteins. IGF-1 receptors possess intrinsic Tyrosine kinase activity. Both IGFs are involved in fetal development; however, in the postembryonic period, IGF-I plays the primary role in growth regulation by stimulating the proliferation of Cells in all Tissues, especially Cartilage and bone. Additionally, GH enhances Protein Synthesis while inhibiting its degradation. It also exerts a lipolytic effect to supply tissues with energy during fasting or in the postabsorptive state, and decreases tissue sensitivity to insulin, thereby promoting insulin resistance. Both GH and IGFs regulate the Hypothalamus and adenohypophysis via a feedback mechanism. In addition to somatostatin, GH secretion is inhibited by progesterone, glucocorticoids, and obesity.

GH hypersecretion in adults causes acromegaly, hypersecretion in children typically leads to gigantism, and hypersecretion during the late stages of Puberty results in tall stature. Almost all patients with acromegaly present with GH-secreting pituitary adenomas. In most cases, the transformation of somatotropic cells is triggered by Mutations in the $G_{s\alpha}$ protein Gene. The mutant protein continuously stimulates adenylyl cyclase, leading to enhanced proliferation of somatotrophs and increased GH production. Absolute or relative GH deficiency results in reduced IGF-I production and is one of the most common causes of growth retardation in children. Furthermore, growth delays may stem from GH resistance caused by mutations in the receptor gene.

Prolactin consists of 198 amino acid residues and is synthesized in lactotrophic cells. Its primary target Organs are the Mammary Glands. Prolactin stimulates mammary gland growth during Pregnancy and Lactation postpartum, processes that also involve progesterone, cortisol, and several Other Hormones. Prolactin secretion is tonically inhibited by hypothalamic dopamine and stimulated by estrogens, thyroliberin (TRH), and neural impulses originating from the nipples.

The family of glycoprotein hormones includes follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). These hormones consist of two subunits: the $\alpha$-subunits are identical and contain 92 amino acid residues each, whereas the $\beta$-subunits vary in structure and molecular weight, which depends largely on the number of carbohydrate residues. Both subunits are glycosylated.

FSH and LH are synthesized in gonadotropic cells, contain 115 amino acid residues each in their $\beta$-chains, and regulate sex hormone synthesis, secretion, and gametogenesis. In the Ovaries, FSH stimulates estrogen secretion as well as follicular growth and maturation. LH triggers ovulation, corpus luteum formation, and progesterone Synthesis and Secretion. In the Testes, LH stimulates Leydig cells and testosterone synthesis, whereas FSH stimulates Sertoli cells, Spermatogenesis, and inhibin synthesis. The production of LH and FSH is regulated by gonadotropin-releasing hormone (GnRH) and modulated by Sex Hormones via both positive and negative feedback loops.

TSH is synthesized in thyrotrophic cells, and its primary function is to stimulate the synthesis of THYROID HORMONES in The Thyroid Gland. By binding to receptors on the membrane of thyroid cells, TSH activates adenylyl cyclase, thereby stimulating the uptake of inorganic iodide into the thyroid gland, the synthesis of thyroglobulin, The oxidation of iodine, and the iodination of tyrosines within thyroglobulin. TSH also promotes glandular growth and Blood supply. The synthesis and secretion of TSH are controlled by thyroliberin. Stress and elevated ambient temperatures exert a stimulatory effect on TSH secretion. The synthesis and secretion of TSH are regulated via a negative feedback mechanism.

The family of pro-opiomelanocortin (POMC) derivatives comprises hormones synthesized from a single precursor molecule (Fig. 15.8). The POMC molecule consists of 256 amino acid residues. Initially, a signal peptide (26 amino acid residues) is cleaved from the N-terminus, after which subsequent proteolysis yields corticotropin (adrenocorticotropic hormone, ACTH), $\alpha$- and $\beta$-melanocyte-stimulating hormones (MSH), $\beta$- and $\gamma$-lipotropins (LPH), and endorphins.

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Fig. 15.8. Peptide Hormones derived from POMC

ACTH consists of 39 amino acid residues. It stimulates the function, growth, and blood supply of the adrenal cortex, as well as the synthesis of Adrenal Cortical Hormones, primarily glucocorticoids. ACTH secretion is regulated by the stimulatory action of corticoliberin (CRH) and the negative feedback of cortisol. Cortisol also inhibits the secretion of corticoliberin.

MSH stimulates melanin synthesis in mammals. The $\beta$-lipotropin molecule contains 91 amino acid residues and exhibits fat-mobilizing activity. Specific proteolysis of $\beta$-lipotropin yields a series of biologically active, opioid-like compounds: met-enkephalin, $\alpha$-, $\gamma$-, $\delta$-, and $\beta$-endorphins. Among these, $\beta$-endorphin is the most potent analgesic.

Reduced secretion of adenohypophyseal hormones leads to systemic disorders. TSH deficiency causes secondary hypothyroidism, LH and FSH deficiency leads to secondary hypogonadism, and ACTH deficiency results in secondary adrenal insufficiency and hypopigmentation.