Abstract
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) have been used in diagnostics and therapeutics from biologically purified sources. Though both hormones function via the same receptor (LHCGR), mostly hCG has been used due to its widespread availability. Hence, in the mind of the practising physician, both molecules have been considered equal. The recent availability of recombinant LH has led us to reconsider the specificities of both hormones in terms of actions on the body.
LH and hCG play essential roles in the reproductive cycle. LH plays a key role in follicular maturation and the ovulation process, and hCG is the “pregnancy hormone.”
LH and hCG are different in terms of structure, expression, regulation, and function. LH and hCG fundamentally differ in their expression patterns and have complex and unique aspects. LH and hCG should be considered as hormone mixtures, the composition of which fluctuates during the course of the ovarian cycle and pregnancy and throughout the lifespan of men and women. Diverse isoforms have distinct functions, reflected by their relative abundance in normal and aberrant physiologic processes. Quantitative and qualitative distinctions in signaling cascades, activated by LH and hCG have been recently discovered; furthermore, the extragonadal activities are currently under exploration. Availability of recombinant LH and hCG as new therapeutic tools for use in specific clinical pro-fertility conditions could lead us to reconsider the specific indications for each of both molecular entities. The first part of this chapter reviews the current knowledge on both parent molecules, emphasizing their specificities and the consequences at the receptor level.
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References
Fritz MA, Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.
Rahman NA, Rao CV. Recent progress in luteinizing hormone/human chorionic gonadotrophin hormone research. Mol Hum Reprod. 2009;15:703–11.
Rao CV. Differential properties of human chorionic gonadotrophin and human luteinizing hormone binding to plasma membranes of bovine corpora lutea. Acta Endocrinol (Copenh). 1979;90:696–710.
Liu JH, Yen SS. Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical evaluation. J Clin Endocrinol Metab. 1983;57:797–802.
Van de Wiele RL, Bogumil J, Dyrenfurth I, Ferin M, Jewelewicz R, Warren M, et al. Mechanisms regulating the menstrual cycle in women. Recent Prog Horm Res. 1970;26:63–103.
Reader SC, Robertson WR, Diczfalusy E. Microheterogeneity of luteinizing hormone in pituitary glands from women of pre- and postmenopausal age. Clin Endocrinol (Oxf). 1983;19:355–63.
Wide L. Median charge and charge heterogeneity of human pituitary FSH, LH and TSH. II. Relationship to sex and age. Acta Endocrinol (Copenh). 1985;109:190–7.
Ding YQ, Huhtaniemi I. Preponderance of basic isoforms of serum luteinizing hormone (LH) is associated with the high bio/immune ratio of LH in healthy women and in women with polycystic ovarian disease. Hum Reprod. 1991;6:346–50.
Ropelato MG, Garcia-Rudaz MC, Castro-Fernandez C, Ulloa-Aguirre A, Escobar ME, Barontini M, et al. A preponderance of basic luteinizing hormone (LH) isoforms accompanies inappropriate hypersecretion of both basal and pulsatile LH in adolescents with polycystic ovarian syndrome. J Clin Endocrinol Metab. 1999;84:4629–36.
Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8:102.
Cole LA. New discoveries on the biology and detection of human chorionic gonadotropin. Reprod Biol Endocrinol. 2009;7:8.
Shi QJ, Lei ZM, Rao CV, Lin J. Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinology. 1993;132:1387–95.
Rao CV, Alsip NL. Use of the rat model to study hCG/LH effects on uterine blood flow. Semin Reprod Med. 2001;19:75–85.
Zygmunt M, Herr F, Keller-Schoenwetter S, Kunzi-Rapp K, Munstedt K, Rao CV, et al. Characterization of human chorionic gonadotropin as a novel angiogenic factor. J Clin Endocrinol Metab. 2002;87:5290–6.
Kovalevskaya G, Birken S, Kakuma T, Ozaki N, Sauer M, Lindheim S, et al. Differential expression of human chorionic gonadotropin (hCG) glycosylation isoforms in failing and continuing pregnancies: preliminary characterization of the hyperglycosylated hCG epitope. J Endocrinol. 2002;172:497–506.
Sasaki Y, Ladner DG, Cole LA. Hyperglycosylated human chorionic gonadotropin and the source of pregnancy failures. Fertil Steril. 2008;89:1781–6.
Birken S, Maydelman Y, Gawinowicz MA, Pound A, Liu Y, Hartree AS. Isolation and characterization of human pituitary chorionic gonadotropin. Endocrinology. 1996;137:1402–11.
Braunstein GD. Endocrine changes in pregnancy. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams textbook of endocrinology. Philadelphia: Elsevier Saunders; 2011. p. 581–660.
O’Connor JF, Kovalevskaya G, Birken S, Schlatterer JP, Schechter D, McMahon DJ, et al. The expression of the urinary forms of human luteinizing hormone beta fragment in various populations as assessed by a specific immunoradiometric assay. Hum Reprod. 1998;13:826–35.
Lambert A, Talbot JA, Anobile CJ, Robertson WR. Gonadotrophin heterogeneity and biopotency: implications for assisted reproduction. Mol Hum Reprod. 1998;4:619–29.
Burgon PG, Stanton PG, Robertson DM. In vivo bioactivities and clearance patterns of highly purified human luteinizing hormone isoforms. Endocrinology. 1996;137:4827–36.
Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev. 2002;23:141–74.
Puett D, Li Y, DeMars G, Angelova K, Fanelli F. A functional transmembrane complex: the luteinizing hormone receptor with bound ligand and G protein. Mol Cell Endocrinol. 2007;260–262:126–36.
Menon KM, Menon B. Structure, function and regulation of gonadotropin receptors – a perspective. Mol Cell Endocrinol. 2012;356:88–97.
Anobile CJ, Talbot JA, McCann SJ, Padmanabhan V, Robertson WR. Glycoform composition of serum gonadotrophins through the normal menstrual cycle and in the post-menopausal state. Mol Hum Reprod. 1998;4:631–9.
Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Li Z, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011;43:55–9.
Eriksen MB, Brusgaard K, Andersen M, Tan Q, Altinok ML, Gaster M, et al. Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis. Eur J Obstet Gynecol Reprod Biol. 2012;163:39–42.
Mutharasan P, Galdones E, Penalver Bernabe B, Garcia OA, Jafari N, Shea LD, et al. Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. J Clin Endocrinol Metab. 2013;98:E185–90.
Cole LA, Kardana A, Andrade-Gordon P, Gawinowicz MA, Morris JC, Bergert ER, et al. The heterogeneity of human chorionic gonadotropin (hCG). III The occurrence and biological and immunological activities of nicked hCG. Endocrinology. 1991;129:1559–67.
Gilchrist RL, Ryu KS, Ji I, Ji TH. The luteinizing hormone/chorionic gonadotropin receptor has distinct transmembrane conductors for cAMP and inositol phosphate signals. J Biol Chem. 1996;271:19283–7.
Donadeu FX, Esteves CL, Doyle LK, Walker CA, Schauer SN, Diaz CA. Phospholipase Cbeta3 mediates LH-induced granulosa cell differentiation. Endocrinology. 2011;152:2857–69.
Ben-Ami I, Armon L, Freimann S, Strassburger D, Ron-El R, Amsterdam A. EGF-like growth factors as LH mediators in the human corpus luteum. Hum Reprod. 2009;24:176–84.
Palaniappan M, Menon KM. Human chorionic gonadotropin stimulates theca-interstitial cell proliferation and cell cycle regulatory proteins by a cAMP-dependent activation of AKT/mTORC1 signaling pathway. Mol Endocrinol. 2010;24:1782–93.
Brown C, LaRocca J, Pietruska J, Ota M, Anderson L, Smith SD, et al. Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKB alpha/Akt1. Biol Reprod. 2010;82:246–56.
Reizel Y, Elbaz J, Dekel N. Sustained activity of the EGF receptor is an absolute requisite for LH-induced oocyte maturation and cumulus expansion. Mol Endocrinol. 2010;24:402–11.
Casarini L, Lispi M, Longobardi S, Milosa F, La Marca A, Tagliasacchi D, et al. LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS One. 2012;7, e46682.
Pakarainen T, Ahtiainen P, Zhang FP, Rulli S, Poutanen M, Huhtaniemi I. Extragonadal LH/hCG action–not yet time to rewrite textbooks. Mol Cell Endocrinol. 2007;269:9–16.
Rao CV. Human adrenal LH/hCG receptors and what they could mean for adrenal physiology and pathology. Mol Cell Endocrinol. 2010;329:33–6.
Strauss III JE, Barbieri RL. Yen & Jaffe’s reproductive endocrinology: physiology, pathophysiology, and clinical management. 6th ed. Philadelphia: Saunders Elsevier; 2009.
Park SJ, Goldsmith LT, Weiss G. Age-related changes in the regulation of luteinizing hormone secretion by estrogen in women. Exp Biol Med (Maywood). 2002;227:455–64.
Garcia-Rudaz MC, Ropelato MG, Escobar ME, Veldhuis JD, Barontini M. Augmented frequency and mass of LH discharged per burst are accompanied by marked disorderliness of LH secretion in adolescents with polycystic ovary syndrome. Eur J Endocrinol. 1998;139:621–30.
Silfen ME, Denburg MR, Manibo AM, Lobo RA, Ferin M, Levine LS, et al. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab. 2003;88(10):4682–8.
Carmina E, Campagna AM, Lobo RA. A 20-year follow-up of young women with polycystic ovary syndrome. Obstet Gynecol. 2012;119:263–9.
Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams textbook of endocrinology. 12th ed. Philadelphia: Elsevier Saunders; 2011.
Crochet JR, Shah AA, Schomberg DW, Price TM. Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells. J Clin Endocrinol Metab. 2012;97:E1741–4.
Odell WD, Griffin J. Pulsatile secretion of human chorionic gonadotropin in normal adults. N Engl J Med. 1987;317:1688–91.
Lei ZM, Toth P, Rao CV, Pridham D. Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes. J Clin Endocrinol Metab. 1993;77:863–72.
Eblen A, Bao S, Lei ZM, Nakajima ST, Rao CV. The presence of functional luteinizing hormone/chorionic gonadotropin receptors in human sperm. J Clin Endocrinol Metab. 2001;86:2643–8.
Licht P, Fluhr H, Neuwinger J, Wallwiener D, Wildt L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol. 2007;269:85–92.
Perrier d’Hauterive S, Berndt S, Tsampalas M, Charlet-Renard C, Dubois M, Bourgain C, et al. Dialogue between blastocyst hCG and endometrial LH/hCG receptor: which role in implantation? Gynecol Obstet Invest. 2007;64(3):156–60.
Zimmermann G, Ackermann W, Alexander H. Expression and production of human chorionic gonadotropin (hCG) in the normal secretory endometrium: evidence of CGB7 and/or CGB6 beta hCG subunit gene expression. Biol Reprod. 2012;86:87.
Lofrano-Porto A, Barra GB, Giacomini LA, Nascimento PP, Latronico AC, Casulari LA, et al. Luteinizing hormone beta mutation and hypogonadism in men and women. N Engl J Med. 2007;357(9):897–904.
Achard C, Courtillot C, Lahuna O, Méduri G, Soufir JC, Lière P, et al. Normal spermatogenesis in a man with mutant luteinizing hormone. N Engl J Med. 2009;36:1856–63.
Nagirnaja L, Venclovas C, Rull K, Jonas KC, Peltoketo H, Christiansen OB, et al. Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin beta-subunit. Mol Hum Reprod. 2012;18(8):379–90.
Arnhold IJ, Lofrano-Porto A, Latronico AC. Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. Horm Res. 2009;71:75–82.
Yariz KO, Walsh T, Uzak A, Spiliopoulos M, Duman D, Onalan G, et al. Inherited mutation of the luteinizing hormone/choriogonadotropin receptor (LHCGR) in empty follicle syndrome. Fertil Steril. 2011;96:e125–30.
Hillier SG. Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis. Hum Reprod. 1994;9:188–91.
Mannaerts B, Uilenbroek J, Schot P, De Leeuw R. Folliculogenesis in hypophysectomized rats after treatment with recombinant human follicle-stimulating hormone. Biol Reprod. 1994;51:72–81.
Devroey P, Mannaerts B, Smitz J, Coelingh Bennink H, Van Steirteghem A. Clinical outcome of a pilot efficacy study on recombinant human follicle-stimulating hormone (Org 32489) combined with various gonadotrophin-releasing hormone agonist regimens. Hum Reprod. 1994;9:1064–9.
Hillier SG. Controlled ovarian stimulation in women. J Reprod Fertil. 2000;120:201–10.
Shoham Z. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Fertil Steril. 2002;77:1170–7.
Hugues JN, Theron-Gerard L, Coussieu C, Pasquier M, Dewailly D, Cedrin-Durnerin I. Assessment of theca cell function prior to controlled ovarian stimulation: the predictive value of serum basal/stimulated steroid levels. Hum Reprod. 2010;25:228–34.
Thuesen LL, Smitz J, Loft A, Nyboe Andersen A. Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose response study. Clin Endocrinol. 2013;79:708–15.
Shima K, Kitayama S, Nakano R. Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle. Obstet Gynecol. 1987;69:800–6.
Rajaniemi HJ, Rönnberg L, Kauppila A, Ylöstalo P, Jalkanen M, Saastamoinen J, et al. Luteinizing hormone receptors in human ovarian follicles and corpora lutea during menstrual cycle and pregnancy. J Clin Endocrinol Metab. 1981;52:307–13.
Calder MD, Caveney AN, Smith LC, Watson AJ. Responsiveness of bovine cumulus-oocyte-complexes (COC) to porcine and recombinant human FSH, and the effect of COC quality on gonadotropin receptor and Cx43 marker gene mRNAs during maturation in vitro. Reprod Biol Endocrinol. 2003;1:14.
Jeppesen JV, Kristensen SG, Nielsen ME, Humaidan P, Dal Canto M, Fadini R, et al. LH-receptor gene expression in human granulosa and cumulus cells from antral and preovulatory follicles. J Clin Endocrinol Metab. 2012;97:E1524–31.
Guzman L, Adriaenssens T, Ortega-Hrepich C, Albuz FK, Mateizel I, Devroey P, et al. Human antral follicles <6mm: a comparison between in vivo maturation and in vitro maturation in non-hCG primed cycles using cumulus cell gene expression. Mol Hum Reprod. 2013;19:7–16.
Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science. 2004;303:682–4.
Zamah AM, Hsieh M, Chen J, Vigne JL, Rosen MP, Cedars MI, et al. Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin. Hum Reprod. 2010;25:2569–78.
Rizos D, Ward F, Duffy P, Boland MP, Lonergan P. Consequences of bovine oocyte maturation, fertilization or early embryo development in vitro versus in vivo: implications for blastocyst yield and blastocyst quality. Mol Reprod Dev. 2002;61:234–48.
Weston AM, Zelinski-Wooten MB, Hutchison JS, Stouffer RL, Wolf DP. Developmental potential of embryos produced by in-vitro fertilization from gonadotrophin-releasing hormone antagonist-treated macaques stimulated with recombinant human follicle stimulating hormone alone or in combination with luteinizing hormone. Hum Reprod. 1996;11:608–13.
Oussaid B, Mariana JC, Poulin N, Fontaine J, Lonergan P, Beckers JF, et al. Reduction of the developmental competence of sheep oocytes by inhibition of LH pulses during the follicular phase with a GnRH antagonist. J Reprod Fertil. 1999;117:71–7.
Westergaard LG, Erb K, Laursen SB, Rasmussen PE, Rex S, Westergaard CG, et al. Concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid and serum in relation to stimulation protocol and outcome of assisted reproduction treatment. Reprod Biomed Online. 2004;8:516–23.
Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod. 2006;21:3217–27.
Thuesen LL, Loft A, Egeberg AN, Smitz J, Petersen JH, Andersen AN. A randomized controlled dose–response pilot study of addition of hCG to recombinant FSH during controlled ovarian stimulation for in vitro fertilization. Hum Reprod. 2012;27:3074–84.
Platteau P, Andersen AN, Balen A, Devroey P, Sorensen P, Helmgaard L, et al. Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study. Hum Reprod. 2006;21:1798–804.
Loumaye E, Coen G, Pampfer S, Vankrieken L, Thomas K. Use of a gonadotropin-releasing hormone agonist during ovarian stimulation leads to significant concentrations of peptide in follicular fluids. Fertil Steril. 1989;52:256–63.
Balasch J, Penarrubia J, Fabregues F, Vidal E, Casamitiana R, Manau D, et al. Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH-agonist for assisted reproduction. Reprod Biomed Online. 2003;7:35–42.
Bider D, Ben-Rafael Z, Shalev J, Goldenberg M, Mashiach S, Blankstein J. Pituitary and ovarian suppression rate after high dosage of gonadotropin-releasing hormone agonist. Fertil Steril. 1989;51:578–81.
Meldrum DR, Wisot A, Hamilton F, Gutlay AL, Huynh D, Kempton W. Timing of initiation and dose schedule of leuprolide influence the time course of ovarian suppression. Fertil Steril. 1988;50:400–2.
Albano C, Smitz J, Camus M, Riethmüller-Winzen H, Siebert-Weigel M, Diedrich K, et al. Hormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix). Hum Reprod. 1996;11:2114–8.
Fowler PA, Sorsa-Leslie T, Harris W, Mason H. Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research? Reproduction. 2003;126:689–99.
Andersen CY, Ziebe S. Serum levels of free androstenedione, testosterone and oestradiol are lower in the follicular phase of conceptional than of non-conceptional cycles after ovarian stimulation with a gonadotrophin-releasing hormone agonist protocol. Hum Reprod. 1992;7:1365–70.
Hugues JN, Soussis J, Calderon I, Balasch J, Anderson RA, Romeu A, et al. Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study. Hum Reprod. 2005;20:629–35.
Filicori M, Cognigni GE, Pocognoli P, Tabarelli C, Spettoli D, Taraborrelli S, et al. Modulation of folliculogenesis and steroidogenesis in women by graded menotrophin administration. Hum Reprod. 2002;17:2009–15.
Filicori M, Cognigni GE, Tabarelli C, Pocognoli P, Taraborrelli S, Spettoli D, et al. Stimulation and growth of antral ovarian follicles by selective LH activity administration in women. J Clin Endocrinol Metab. 2002;87:1156–61.
Hofmann GE, Bergh PA, Guzman I, Masuku S, Navot D. Premature luteinization is not eliminated by pituitary desensitisation with leuprolide acetate in women undergoing gonadotrophin stimulation who demonstrated premature luteinization in a prior gonadotrophin-only cycle. Hum Reprod. 1993;8:695–8.
Ubaldi F, Camus M, Smitz J, Bennink HC, Van Steirteghem A, Devroey P. Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH) and GnRH-a and urinary FSH. Fertil Steril. 1996;66:275–80.
Chappel SC, Howles C. Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Hum Reprod. 1991;6:1206–12.
Roy SK, Kurz SG, Carlson AM, DeJonge CJ, Ramey JW, Maclin VM. Transforming growth factor beta receptor expression in hyperstimulated human granulosa cells and cleavage potential of the zygotes. Biol Reprod. 1998;59:1311–6.
Acknowledgments
The author thanks Dr. Lea Thuesen, Prof. A.N. Andersen, Dr. J.-C. Arce for fruitful discussions over the last years regarding the pharmacological use of hCG for ovarian stimulation.
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J.S. has nothing to disclose.
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Smitz, J. (2016). LH and hCG: Their Distinct Physiological Roles and Use in Ovarian Stimulation Protocols. In: Allahbadia, G., Morimoto, Y. (eds) Ovarian Stimulation Protocols. Springer, New Delhi. https://doi.org/10.1007/978-81-322-1121-1_3
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