human Chorionic gonadotropin (hCG)
hCG is structurally related to the pituitary hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH). The glycoprotein hormones lutropin (LH), follitropin (FSH), thyrotropin (TSH), and choriogonadotropin (CG) are heterodimers, which consist of a common alpha subunit and a unique beta subunit that confer the receptor specificity of the ligand. The subunits combine non-covalently early in the secretory pathway, and formation of the heterodimer is crucial for binding to the receptors.
Gonadotropins of urinary origin have been used for a long time. Recombinant forms of human LH (hLH) and hCG have been produced (in mammalian cells) and are being tested in clinical studies for human use; recombinant human FSH (hFSH) is available in several countries. At a cellular level the two hormones are roughly equivalent. In vivo, the main difference is the much longer half-life of hCG. hCG has a half-life of 8 hours compared to LH half-life of 30 minutes.
hCG has a stimulatory effect on testicular steroidogenesis and has been widely used for evaluating male Leydig cell function. The hCG stimulation test with assessment of serum testosterone (T) is used for evaluation of testicular function. However, considerable variability exists in the protocols for HCG stimulation tests. In the most commonly used protocols HCG is administered daily for several days.
A retrospective study was undertaken to estimate the diagnostic value of stimulated estradiol (E2) levels in the assessment of Leydig cell function. Serum T and E2 before and after repeated daily hCG injections in adult men with clinically suspected or established primary hypogonadism were studied. After hCG administration serum T increased gradually with peak levels after 72 hours. In contrast, serum E2 concentrations reached their maximal levels 24 hours after the first injection. Peak E2 levels after 24 hours correlated significantly with peak T levels after 3 days.
DOSE - In another study the circulating androgen response after 1 and 3-dose HCG regimens was examined. A single weight or body surface area based HCG dose, 100IU/kg. or 5,000 IU/1.7m2., with androgen measurement after 3 or 4 days was found to be reliable in testicular evaluation.
A 2005 study, 30-year retrospective study, showed long-term administration of hCG/hMG for 12 to 240 months resulted in sperm production in only 36% of the small testis, <4cc, subjects but in 71% of the large testis, >4cc, subjects. Noteworthy, doses ranging from 750 to 1500 IU of hCG, divided into one to three weekly doses, were necessary to restore and maintain normal testosterone serum levels in hypogonadotropic hypogonadic male subjects.
The production rate of testosterone increases in presence of rhCG, but the increase does not asymptote to a maximum level but instead decreases at higher concentrations of rhCG. Conventional assessment of Leydig-cell androgen secretion is based on acute injection of human chorionic gonadotropin (hCG). However, compared with endogenous LH pulses, hCG stimulation is supraphysiological. In particular, hCG kinetics and LH/hCG receptor occupancy are prolonged, resulting in steroidogenic desensitization. Desensitization is apparently due to receptor down-regulation in the testis.
TESTICULAR SIZE - Subcutaneous doses of 1000–2500 IU hCG applied twice a week and 75–150 IU hMG applied three times a week. Testicular size after 5–12 months of therapy bilateral testicular volumes increased from an initial mean of 6.86ml (group Ia) è 14.96ml (Ia); 4.46ml (group Ib) è 15.36ml (Ib); and 14.06ml (group II) è 28.36ml (II).
The primary physiological effect of the gonadotropins is the promotion of gametogenesis and/or gonadal steroid production. In the male, endogenous production of CG does not occur, and LH stimulates the de novo synthesis of androgens, primarily testosterone, by Leydig cells. The secreted testosterone is required for gametogenesis and for the maintenance of sexual libido and secondary sexual characteristics. The biological action of LH is mediated by its interaction with specific cell surface receptors expressed primarily on the cell membranes of reproductive organs such as testis and ovary.
Lutropin/Choriogonadotropin Receptor (LHR) - The LHR is a single polypeptide chain with an overall structure and topology belonging to the rhodopsin/beta2-adrenergic receptor subfamily A of G-protein-coupled receptors (GPCR) family that differs by the presence of a large extracellular domain. It is composed of two subunits that can each bind rhCG. Occupancy of only one of the receptor subunits may favor dimerization, leading to the initiation of signal transduction by the hormone. Steroidogenesis in the Leydig cell depends on the action of gonadotropin [LH/human CG (hCG)] exerted through its homologous receptor, to induce coupling functions and activation predominantly of the adenylate cyclase/ cyclic AMP/ protein kinase pathway.
Binding of LH/hCG to the LHR - The binding of LH and CG occurs with similar high affinity, and both hormones have similar potencies and efficacies in stimulating gonadal cells. Regulation of the LHR - In the adult testis, gonadotropin induces a dual control of Leydig cell function. Low doses of LH/hCG maintain LH/hCG receptor and steroidogenic enzymes, whereas higher doses of the hormones cause receptor downregulation and desensitization of the steroid biosynthetic pathway with marked reduction of testosterone production.
Transcriptional regulation - The receptor gene expression is related to agonist exposure at a low level of hCG, the receptor expression is increased. The exposure of testicular cells expressing the endogenous LHR to a high concentration of hCG or LH down-regulates the levels of cell-surface receptor. At the same time down-regulation of cell-surface LHR is observed a decrease is also seen in the amount of LHR mRNA transcripts. Posttranscriptional regulation - Desensitization is a word that is used to describe the ability of target cells to turn off an agonist response in the face of continuous agonist exposure. Desensitization is an important component of the regulation of hormone actions and it can occur at multiple levels.
A model developed allowed the simulation of arbitrary dosing schemes. This process provided a mechanism to obtain a maximum response while using the minimum amount of drug. The simulated testosterone levels demonstrated reaching a target testosterone concentration of 25nmol/ liter (720ng/dL), a dose of 1000 IU of rhCG every other 4 days would be sufficient. A higher 2500IU dose produces a slightly higher response. At 5000 IU or greater the dose produced a lesser response. The down-regulation model performed well when compared to actual physiological values obtained.
Assumptions of the model were (1) the pharmacokinetics of hCG for the repeated s.c. administration are assumed to be linear in respect to the dose; (2) testosterone is released at a rate dependent on hCG concentration and is eliminated at a constant rate independent of hCG concentration; and (3) the relationship of hCG versus the production rate of testosterone is by means of a complex binding model consistent with a two-site binding receptor with an effect proportional to one-site bound concentration.
Interpretations for the down regulation could be the receptor is deactivated (stimulation of production rate decreases) or internalized (stimulation of production rate ends) when more than one molecule binds to it. The study design did not allow separation of a concentration effect at the receptor level or receptor internalization or a combination of the two.
Only a small fraction of the approximately 20,000 cellular receptors need to be occupied to obtain the maximum rate of testosterone synthesis. The time course of the LH/CG receptor activity after stimulation is complex and is a function of the duration of the stimulation. At a high concentration of agonist, this time course can be split into three parts. (1) During the first minutes, the receptor exhibits agonist-induced changes in functional properties without diminution of the total number of receptors. (2) The next phase or step may last from a few minutes up to 4 hours during which a slow decrease in the number of receptors is observed. The decrease is caused by the recycling of the receptor. Almost 50% of the internalized receptors are degraded at each cycle, leading to the decrease in the total number of receptors. (3) After 4 hours the receptor gene transcription is decreased by the diminution of 50% of the receptor mRNA. Combined with the reduction in receptor due to recycling (2) leads to a 95% total receptor reduction. At lower concentration of agonist, only some of these steps are involved.
Conversion of cholesterol to biologically active steroids is a multi-step enzymatic process. Along with some important enzymes, like cholesterol side-chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD), several proteins play key role in steroidogenesis. A key enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). In the testicle, cholesterol required for steroidogenesis and other cellular functions is acquired through de novo synthesis and through receptor-mediated uptake from LDL and HDL. The receptors for LDL and HDL as well as HMGR in testicles have been shown to be induced by LH/hCG.
LH/hCG up-regulates the expression of cholesterol biosynthesis enzymes and lipoprotein receptors to replenish cellular cholesterol. The up regulation produces a protein producing a complex with LHR mRNA that accelerates LHR mRNA decay. The decrease of LHR mRNA level culminates in the loss of cell surface LHR and produces a transient abolishment of the signal cascade.
Peace
Mike
(I am back)
