Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communications
Pituitary and Hypothalamic Hormones
Hormones of the Anterior Pituitary - Glycoprotein Hormone Group

The most complex protein Hormones known to date are the pituitary and placental glycoprotein hormones: thyroid-stimulating hormone (thyrotropin; TSH), luteinizing hormone (lutropin; LH), follicle-stimulating hormone (follitropin; FSH), and chorionic gonadotropin (CG). All of these hormones influence various biological processes while exhibiting marked structural similarities. This group of hormones is present in all mammals; hormones with comparable Functions have also been found in lower forms, and molecules possessing human TSH and CG (hCG) activity have even been discovered in Bacteria. Like other Peptide and Protein hormones, these compounds interact with Cell-surface receptors and activate adenylate cyclase, thereby utilizing cAMP as an intracellular mediator.

Each of the hormones in question consists of two subunits, α and β, joined by a non-covalent bond. The α-subunits of all these hormones are identical within a given species, and significant interspecies Homology is also observed. Specific biological activity is determined by the β-subunit, which is likewise highly conserved among different hormones, though to a considerably lesser extent than the α-subunit. The β-subunit on its own is inactive, and receptor recognition involves interaction with specific domains on both subunits. Intermolecular and interspecies molecular hybrids retain full activity; for example, the TSH_α–LH_β hybrid exhibits LH activity, whereas the human TSH_α–mouse TSH_β hybrid exhibits mouse TSH activity. Thus, Species Differences in the α- and β-subunits do not affect their ability to associate or the biological function of the β-subunit domain. Each subunit is synthesized through the participation of its own mRNA, derived from a separate Gene. It is believed that all hormones in this group evolved from a common precursor gene that gave rise to two molecules, α and β, the latter of which subsequently enabled The Emergence of various distinct hormones.

Quite a bit is known about The Structure of these compounds. For instance, it has been established that the C-terminal pentapeptide of the α-subunit is crucial for receptor binding, but not for association with the β-subunit. A distinctive feature of the glycoprotein hormone group is the glycosylation of their molecules. In each glycoprotein hormone, the α-subunit contains two complex asparagine-linked Oligosaccharides, while the β-subunit contains one or two. Glycosylation may be necessary for the proper interaction between the α- and β-subunits. The α-subunit contains 5 disulfide (S-S) bonds, whereas the β-subunit contains 6.

Free α-subunits have been detected in the Pituitary Gland and Placenta. It has been established that the Introduction/27.html">Translation of the α- and β-subunits is mediated by distinct mRNAs, which Supports METABOLISM/2.html">THE CONCEPT OF separate regulation of their synthesis and the rate-limiting role of the β-subunit in whole hormone assembly. All of these molecules are synthesized as preproneurohormones (or preprohormones) and undergo post-translational Processing within The Cell to yield glycosylated Proteins.

Gonadotropins (FSH, LH, hCG)

These hormones regulate gametogenesis and steroidogenesis in the Gonads. All of them are Glycoproteins with a Molecular Weight of approximately 25,000.

A. Follicle-stimulating hormone (FSH, follitropin). FSH binds to specific receptors on the Plasma Membranes of target Cells: ovarian follicular cells and Sertoli cells in the Testes. This process activates adenylate cyclase and leads to elevated cAMP production. FSH stimulates follicular growth, prepares follicles for the ovulation-inducing action of LH, and enhances LH-stimulated estrogen secretion. In males, it binds to Sertoli cells, inducing the synthesis of androgen-binding protein, which is presumably involved in The transport of testosterone to the seminiferous tubules and the Epididymis; this mechanism achieves the high local testosterone concentration required for Spermatogenesis. FSH stimulates the growth of the seminiferous tubules and testes and plays a vital role in initiating spermatogenesis. In the absence of FSH, the testes atrophy and sperm production ceases. The hormone also enhances estradiol synthesis in isolated Sertoli cells, although the physiological significance of this process in males remains unclear. Plasma FSH concentration is low in children and rises during Puberty. The onset of pulsatile FSH and LH secretion, particularly during Sleep, indicates the entry into puberty. In females, FSH levels fluctuate cyclically, with the peak occurring during or just prior to ovulation, reaching up to 10 times the baseline level.

B. Luteinizing hormone (LH, lutropin). LH binds to specific Plasma Membrane Receptors and stimulates The production of progesterone by corpus luteum cells and testosterone by Leydig cells. cAMP acts as the intracellular signal mediating LH action. This nucleotide mimics the effects of LH, which include enhancing The conversion of acetate to squalene (a Cholesterol synthesis precursor) and increasing The formation of 2α-hydroxycholesterol from cholesterol—a mandatory step in The Biosynthesis of progesterone and testosterone. Although There is a close correlation between LH binding and cAMP production, steroidogenesis can occur even with a very modest increase in cAMP concentration. Consequently, spare receptors are involved in this response (see Fig. 43.3). Prolonged exposure to LH leads to desensitization, likely caused by the downregulation of LH receptors.

An estradiol-dependent surge in LH secretion mid-cycle triggers ovulation in women, after which LH is required to maintain the corpus luteum—a transformed follicle that, alongside estradiol, begins to produce progesterone. Following the Fertilization and implantation of the ovum, the function of LH is assumed by the placental hormone human chorionic gonadotropin (hCG). During the first 6–8 weeks, Pregnancy is sustained by the corpus luteum; subsequently, the placenta itself begins producing progesterone in quantities sufficient to maintain the pregnancy, while hCG production continues.

In males, LH increases testosterone production, which, together with FSH, stimulates spermatogenesis. Systemic effects of the hormone include The Development of secondary sex characteristics and the growth and maintenance of accessory reproductive Organs, including the prostate, vas deferens, and Seminal Vesicles.

In the interstitial cells of non-germinal ovarian Tissues, LH can induce the formation of several androgens and their precursors, notably androstenedione, dehydroepiandrosterone, and testosterone. Patients with polycystic Ovary syndrome (Stein–Leventhal syndrome) exhibit elevated LH levels, increased androgen production, reduced fertility, weight gain, and excessive body and facial Hair growth. This syndrome is believed to stem from hyperactivity of the ovarian stroma.

C. Human chorionic gonadotropin (hCG). hCG is a glycoprotein synthesized by the syncytiotrophoblast Cells of the placenta. It possesses the characteristic αβ-dimer structure of this hormone group and is most closely related to LH. Blood and urine levels of hCG rise sharply shortly after implantation (see above), making its detection the basis for numerous pregnancy diagnostic tests.

D. Regulation of LH and FSH secretion. The secretion of LH and FSH is regulated by sex Steroid Hormones via a classic negative feedback loop. Prolonged administration of Sex Hormones suppresses LH and FSH release. Conversely, castration or physiological ovarian atrophy during menopause is accompanied by hypersecretion of both gonadotropins. Their secretion can also be regulated via a positive feedback mechanism: estradiol (or progesterone/20α-hydroxyprogesterone in certain species) triggers or 'licenses' the ovulatory surge of LH release. LH and FSH secretion is episodic, which is particularly evident during puberty. Mean plasma levels of both hormones fluctuate widely, peaking around the middle of the Menstrual cycle.

The release of LH and FSH is controlled by a single hypothalamic factor known as gonadotropin-releasing hormone (GnRH, gonadoliberin). It is a decapeptide whose N-terminal amino acid, pyroglutamate, is a cyclized derivative of glutamate (Table 45.2). The release of gonadoliberin is inhibited by the target-organ hormones testosterone and estradiol, as well as by endorphins. Gonadoliberin exerts a direct effect on the anterior pituitary, stimulating gonadotropin secretion via a calcium-phospholipid-dependent mechanism. Although separate releasing factors have not been found for FSH and LH, the plasma concentrations of the two gonadotropins do not always change in parallel. Men with impaired spermatogenesis at stages following secondary spermatocyte formation exhibit elevated FSH levels. These and other findings have led to the hypothesis that a testicular factor exists which specifically suppresses FSH release (termed inhibin). Inhibin has now been purified, and its physiological role has been demonstrated. Various gonadoliberin analogues are currently being evaluated for their ability to stimulate fertility or, conversely, exert a contraceptive effect.

Thyroid-stimulating hormone (TSH, thyrotropin)

A. Structure and MECHANISM OF ACTION. Thyroid-stimulating hormone is a glycoprotein with an αβ-dimer structure and a molecular weight of approximately 30,000. Like Other Hormones in this family, it binds to plasma Membrane receptors and activates adenylate cyclase. The ensuing rise in cAMP levels mediates the action of TSH on thyroid hormone biosynthesis. The Link Between cAMP and the trophic effects of TSH on The Thyroid Gland remains less well understood.

Thyrotropin exerts a profound influence on thyroid function. Its rapid effects (manifesting within minutes) include The stimulation of all stages of triiodothyronine (T₃) and thyroxine (T₄) biosynthesis, such as iodide uptake and organification, iodothyronine Condensation, and thyroglobulin Hydrolysis. In addition, TSH elicits chronic effects in the thyroid gland that require several days to develop. These include increased synthesis of proteins, Phospholipids, and Nucleic Acids, as well as an increase in the size and number of thyroid cells. The long-term metabolic effects of TSH are driven by the production and action of the THYROID HORMONES themselves.

B. Regulation of TSH secretion. TSH release is regulated by a negative feedback system involving target-organ hormones (triiodothyronine and thyroxine) as well as the hypothalamic thyrotropin-releasing hormone (TRH). The regulatory pathway is illustrated in detail in Figure 46.4.

TRH (thyroliberin) is a neutral tripeptide composed of pyroglutamic acid, Histidine, and prolinamide (Table 45.2). It lacks species Specificity; chemical methylation of the histidine residue at the third position results in an eightfold increase in TRH activity. This hormone stimulates TSH secretion and elevates cAMP levels within the first minute, though its action appears to be more intimately linked to a Ca²⁺-phospholipid-dependent mechanism, much like GnRH (gonadoliberin). Prolonged exposure of cells to TRH likewise leads to their desensitization.

Like Somatostatin, thyroliberin is present in numerous extra-hypothalamic tissues, where it may function as a neurotransmitter. The hormone is used clinically in cases of hypothyroidism to differentiate between a pituitary or hypothalamic Water/144.html">Origin of the disease: in the latter case, patients respond to exogenous thyroliberin with an increase in thyrotropin secretion, whereas patients with pituitary-origin hypothyroidism lack this response. Due to its rapid clearance from plasma (t_1/2 ~ 4 min), thyroliberin (TRH) is not utilized for long-term therapy.