Abstract
Gonadotropin therapy is so central to infertility treatment that it is easy to overlook the considerable discovery and research that preceded production of the effective and safe products available today. The history underpinning this development spans over 300 years and provides a splendid example of how basic animal experimentation and technological advances have progressed to clinical application. Following the discovery of germ cells in 1677 and realizing, in 1870, that fertilization involved the merging of two cell nuclei, one from the egg and one from sperm, it took another 40 years to discover the interplay between hypothalamus, pituitary and gonads. The potential roles of gonadotropin regulation were discovered in 1927. Gonadotropin, such as pregnant mare serum gonadotropin (PMSG), was first introduced for ovarian stimulation in 1930. However, use of PMSG leads to antibody formation, and had to be withdrawn. Following withdrawal of PMSG, human pituitary gonadotropin (HPG) and urinary menopausal gonadotropin (hMG) appeared on the market, and 50 years ago the first child was delivered by our group in 1961 and opened the path to controlled ovarian stimulation. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt–Jakob disease (CJD). HMG preparations containing a high percentage of unknown urinary proteins, making quality control almost impossible, were then the only gonadotropins remaining on the market. With the availability of hMG, clomiphene citrate, ergot derivatives, GnRH agonists and antagonists, as well as metformin, algorithms were developed for their optimal utilization and were used for the next four decades. Following the first human IVF baby in 1978 and ICSI in 1991, such procedures became standard practice. The main agents for controlled ovarian stimulation for IVF were gonadotropins and GnRH analogues, with batch to batch consistent gonadotropic preparations; methods could be developed to predict and select the correct dose and the optimal protocol for each patient. We are now seeing the appearance of gonadotropin with sustained action and orally active GnRH analogues as well as orally active molecules capable to stimulate follicle growth and inducing ovulation. These new developments may one day remove the need for the classical gonadotropin in clinical work.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig4_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig5_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig6_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig7_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig8_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig9_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12522-011-0097-2/MediaObjects/12522_2011_97_Fig10_HTML.gif)
Similar content being viewed by others
References
Vesalius, A. De humani corporis fabrica libri septem . Basileae [Basel]: Ex officina Joannis Oporini; 1543.
Fallopius, G. Observationes anatomicae, Venise; 1561.
De Graaf, R. De Mullerium Organis. Paris; 1672.
Sims HM. Sterility and the value of microscope in its diagnosis and treatment, vol 13. Boston: Trans Am Gynecol Soc; 1888.
Soma K. Testosterone and aggression: berthold, birds and beyond. J Neuroendocrinol. 2006;19:543–51.
Gregory R. The gastrointestinal hormones: a review of recent advances. J Physiol. 1974;241:1–32.
Huhner M. The diagnosis and treatment of sexual disorders in the male and female. Philadelphia: Davis; 1937.
Rubin IC. Non-operative determination of the patency of Fallopian tubes in sterility. JAMA. 1920;74:1017.
Crowe SJ, Cushing H, Homans J. Experimental hypophysectomy. Bull Johns Hopkins Hosp. 1910;21:127–67.
Aschner B. Ueber die Beziehung zwischen Hypophysis und Genitale. Arch Gynäkol. 1912;97:200–27.
Smith PE. Hastening of development of female genital system by daily hemoplastic pituitary transplants. Proc Soc Exp Biol Med. 1926;24:1311–33.
Smith PE, Engle ET. Experimental evidence of the role of anterior pituitary in development and regulation of gonads. Am J Anat. 1927;40:159.
Zondek B. Ueber die Funktion des Ovariums. Zeitschr Geburtsh Gynäkol. 1926;90:327.
Smith PE. The disabilities caused by hypophysectomy and their repair. JAMA. 1927;88:158–61.
Smith PE. Hypophysectomy and replacement therapy in the rat. Am J Anat. 1930;45:205–74.
Zondek B. Weitere Untersuchungen zur Darstellung, Biologie und Klinik des Hypophysenvorderlappenhormones (Prolan). Zentralblatt für Gynäkologie. 1929;14:834–48.
Ascheim S, Zondek B. Hypophysenvorderlappenhormone und Ovarialhormone im Harn von Schwangeren. Klin Wochenschr. 1927;6:13–21.
Seegar-Jones GE, Gey GO, Ghisletta M. Hormone production by placental cells maintained in continuous culture. Bull Johns Hopkins Hosp. 1943;72:26–38.
Tausk M. Organon. De geschiedenis van een bijzondere Nederlandse onderneming. In: Nijmegen: Dekker, Van de Vegt; 1978.
Cole HH, Hart GH. The potency of blood serum of mares in progressive stages of pregnancy in affecting the sexual maturity of the immature rat. Am J Physiol. 1930;93:57.
Fevold HL. The gonadotropic hormones. Cold Spring Harbor Symp (Quantitative Biology). 1937;5:93.
Hamblen EC. Results of preoperative administration of extract of pregnancy urine: study of ovaries and endometria in hyperplasia of endometrium following such administration. Endocrinology. 1935;19:169–78.
Hamblen EC. Clinical evaluation of ovarian responses to gonadotropic therapy. Endocrinology. 1939;24:848–57.
Mazer C, Ravetz E. The effect of combined administration of chorionic gonadotropin and the pituitary synergist on the human ovary. Am J Obstet Gynaecol. 1941;41:474–588.
Hamblen EC, Davis CD, Durham NC. Treatment of hypo-ovarianism by the sequential and cyclic administration of equine and chorionic gonadotropins—socalled one–two cylic gonadotropic therapy. Summary of 5 years’ results. Am J Obstet Gynecol. 1945;50:137–46.
Ostergaard E. Antigonadotrophic substances. Copenhagen: Ejnar Munksgaard; 1942.
Zondek B, Sulman F. The antigonadotropic factor. Baltimore: Williams & Wilkins; 1942. p. 1–185.
Leathem JH, Rakoff A. Gonadotrophic hormone therapy in man complicated by antihormone formation. Am J Obstet Gynecol. 1948;56(3):521–6.
Borth R, Lunenfeld B, de Watteville H. Activité gonadotrope d’un extrait d’urines de femmes en menopause. Experientia. 1954;10:266–70.
Lunenfeld B, Menzi A, Volet B. Clinical effects of human post-menopausal gonadotropin. In: Fuchs F, editor. Advance abstracts of short communications, 1st International Congress of Endocrinology (Copenhagen 1960).
Lunenfeld B, Rabau E, Rumney G, Winkelsberg G. The responsiveness of the human ovary to gonadotropin (Hypophysis III). Proc Third World Cong Gynecol Obstet (Vienna). 1961;1:22.
Lunenfeld B, Sulimovici S, Rabau E. Les effets des gonadotrophins urinaires des femmes menopausees sur l’ovaire humain. CR Soc Franc Gynecol. 1962;32/5:291.
Lunenfeld B, Sulimovici S, Rabau E, Eshkol A. L’induction de l’ovulation dans les amenorrheas hypophysaires par un traitement combiné de gonadotropins urinaires menopausiques et de gonadotropins chorioniques. CR Soc Franc Gynecol. 1962;32/5:346.
Lunenfeld B. Treatment of anovulation by human gonadotropins. J Int Fed Gynecol Obstet. 1963;1:15.
Palmer R, Dorangeon P. Les gonadotropines dans les traitements de la stérilité féminine. CR Soc Franc Gynecol. 1962;32:407–15.
Salomon Y, Netter A. Traitement de l’anovulation par les gonadotrophines humaines. In: Gazette Medicale de France; 1965, t.72. p. 3.615–28.
Rosenberg E, Coleman J, Damani M, Garcia CR. Clinical effect of post menopausal gonadotropin. Clin Endocrinol Metab. 1962;23:181–9.
Taymor ML, Sturgis SH, Lieberman BL, Goldstein DP. Induction of ovulation with human postmenopausal gonadotropin. I. Case selection and results of therapy. Fertil Steril. 1966;17:731–5.
Tanaka Y. Combined effect of HMG and HCG on ovulaton. Sanfujinka No Jissai. 1969;18:314–9. (statistical reports in Japan).
WHO. Expert Committee on biological Standardization (Chair B. Lunenfeld), vol 565. Technical Report Series. Geneva: World Health Organization, 1972; p. 56–7.
WHO Expert Committee. Agents stimulating gonadal function in human (Chair B. Lunenfeld). Technical Report Series. Geneva: World Health Organization; 1973.
Eshkol A, Lunenfeld B. Purification and separation of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from human menopausal gonadotropin (HMG). Part III. Acta Endocrinol. 1967;54:919.
Lunenfeld B, Eshkol A. Immunology of follicle stimulating hormone and luteinizing hormone. Vitam Horm. 1970;27:131–59.
Gemzell CA, Diczfalusy E, Tillinger G. Clinical effect of human pituitary follicle stimulating hormone (FSH). J Clin Endocrinol Metab. 1958;18:1333.
Dumble LD, Klein RD. Creutzfeld–Jakob disease legacy for Australian women treated with human pituitary gonadotropins. Lancet. 1992;330:848.
Cochius JI, Mack K, Burns RJ. Creutzfeld–Jakob disease in a recipient human pituitary derived gonadotropin. Aust NZ J Med. 1990;20:592.
Pincus G, Enzmann EV. Can mammalian eggs undergo normal development in vitro? Proc Natl Acad Sci USA. 1934;20(2):121–2.
Rock J, Menkin MF. In vitro fertilization and cleavage of human ovarian eggs. Science. 1944;100(2588):105–7.
Dauzier L, Thibault C, Wintenberger S. Fecundation in vitro of rabbit egg. C R Hebd Seances Acad Sci. 1954;238(7):844–5.
Chang Mc. Fertilization of rabbit ova in vitro. Nature. 1959; 184(Suppl 7):466–7.
Shettles LB. Human blastocyst grown in vitro in ovulation cervical mucus. Nature. 1971;229(5283):343.
de Kretzer D, Dennis P, Hudson B, Leeton J, Lopata A, Outch K, Talbot J, Wood C. Transfer of a human zygote. Lancet. 1973;2(7831):728–9.
Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2(8085):366.
Jones GS, Andrews MC, Acosta A, et al. The program for in vitro fertilization at Norfolk. Fertil Steril. 1982;38(1):14–21. Jul.
Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science. 1981;212(4495):681–2. May 8.
Fleming R, Jamieson ME, Hamilton MP, Black WP, Macnaughton MC, Coutts JR. The use of GnRH analogues in combination with exogenous gonadotropins in infertile women. Acta Endocrinol Suppl (Copenh). 1988;288:77–84.
Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340(8810):17–8.
Massone R Urine collection and processing, a 40 year experience 2011 10th International symposium on GnRH. http://www.kenes.com/gnrh.
Shaked GM, Shaked Y, Jaruv-Inbal A, et al. A proteaseresistant prion protein isoform is present in urine of animals and humans affected with prion diseases. J of Biol Chem. 2001;276:1479–82.
Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, McNair DS, Krewski D, Cashman NR. Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach. PLoS One. 2011;6(3):17815.
Rathnam P, Saxena B. Primary amino acid sequence of folliclestimulating hormone from human pituitary glands I alpha subunit. J Biol Chem. 1975;250:6735–46.
Saxena BB, Rathnam P. Amino acid sequence of the beta subunit of follicle-stimulating hormone from human pituitary glands. J Biol Chem. 1976;251:993–1005.
Howles CM. Genetic engineering of human FSH (Gonal-F). Hum Reprod Update. 1996;2(2):172–91.
Olijve W, de Boer W, Mulders JW, van Wezenbeek PM. Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Puregon). Mol Hum Reprod. 1996;2(5):371–82.
Olijve W, de Boer W, Mulders JW, van Wezenbeek PM. Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Puregon). Mol Hum Reprod. 1996;2(5):371–82.
Driebergen R, Baer G. Quantification of follicle stimulating hormone (follitropin alfa): is in vivo bioassay still relevant in the recombinant age? Curr Med Res Opin. 2003;19(1):41–6.
Hugues J-N, Barlow DH, Rosenwaks Z, et al. Improvement in consistency of response to ovarian stimulation with recombinant human follicle stimulating hormone resulting from a new method for calibrating the therapeutic preparation. Reprod Biomed Online. 2003;6:185–90.
Devroey P, Van Steirteghem A, Van Mannaerts A, Coelingh Bennink H. Successful in vitro fertilization and embryo transfer after treatment with recombinant human FSH. Lancet. 1992;339:1170–1.
Germond M, Dessole S, Senn A, et al. Successful in vitro fertilization and embryo transfer after treatment with recombinant human FSH. Lancet. 1992;339:1170.
Out HJ, Mannaerts BMJL, Driessen SGAJ, et al. A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle-stimulating hormone (Puregon versus Metrodin) in in vitro fertilization. Hum Reprod. 1995;10:2534–40.
Agrawal R, West C, Conway GS, Page ML, Jacobs HS. Pregnancy after treatment with three recombinant gonadotropins. Lancet. 1997;349:29–30.
Donderwinkel PFJ, Schoot DC, Coelingh I, Bennink HJT, Fauser CJM. Pregnancy after induction of ovulation with recombinant human FSH in polycystic ovary syndrome. Lancet. 2002;340:983.
Lehert P, Schertz JC, Ezcurra D. Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis. Reprod Biol Endocrinol. 2010;16(8):112.
Kaufmann R, Dunn R, Vaughn T, Hughes G, O’Brien F, Hemsey G, Thomson B, O’Dea LS. Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women. Clin Endocrinol (Oxf). 2007;67:563–9.
O’Dea L, O’Brien F, Currie K, Hemsey G. Follicular development induced by recombinant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anovulatory women with LH and FSH deficiency: evidence of a threshold effect. Curr Med Res Opin. 2008;24:2785–93.
Bühler K, Naether O. A 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice: a large, multicentre, observational study. Gynecol Endocrinol. 2010 (Epub ahead of print). PMID: 20849209.
Boime I, Keene J, Galway AB, Fares FM. Expression of recombinant human FSH LH and CG in mammalian cells, a structure-function model for therapeutic drug design. Semin Reprod Endocrinol. 1990;10:45–50.
Devroey P, Koper N, Mannaerts B. A randomized, dose-finding trial to establish the ovarian response to a single injection of Org 36286 for sustained follicular stimulation. Abstracts of the 22nd Annual Meeting of the ESHRE, Prague, Czech Republic, 18–21 June 2006. Free Communication. Session 45—ART—Ovarian stimulation. O-172; 2006.
Beckers NGM, Macklon NS, Devroey P, Platteau P, Boerrigter PJ, Fauser BCJM. First live birth after ovarian stimulation using a chimeric long-acting human recombinant follicle-stimulating hormone (FSH) agonist (recFSH-CTP) for in vitro fertilization. Fertil Steril. 2003;79:621–3.
The Corifollitropin Alfa Dose-finding Study Group. A randomized dose–response 482 trial of a single injection of corifollitropin alfa to sustain multifollicular growth 483 during controlled ovarian stimulation. Hum Reprod. 2008;23:2484–92.
de Greef R, Zandvliet AS, de Haan AF, Ijzerman-Boon PC, Marintcheva-Petrova M, Mannaerts BM. Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation. Clin Pharmacol Ther. 2010;88(1):79–87.
Devroey P, Boostanfar R, Koper N, Mannaerts B, IJzerman-Boon P, Fauser B. ENGAGE investigators. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2009;24(12):3063–72.
Mannaerts B. The corifollitropin alpha ENSURE study group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reproductive Biomed Online. 2010;21(1):66–76.
Fatemi HM, Oberyé J, Popovic-Todorovic B, Witjes H, Mannaerts B, Devroey P. Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial. Fertil Steril. 2010;94(5):1922–4.
Arey BJ, Deecher DC, Shen ES, Stevis PE, Meade EH, Wrobel J, Frail DE, Lopez FJ. Identification and characterization of a selective, nonpeptide follicle-stimulating hormone receptor antagonist. Endocrinology. 2002;143:3822–9.
Guo T, Adang AE, Dolle RE, Dong G, Fitzpatrick D, Geng P, Ho KK, Kultgen SG, Liu R, McDonald E, et al. Small molecule biaryl FSH receptor agonists. Part 2. Lead optimization via parallel synthesis. Bioorg Med Chem Lett. 2004;14:1717–20.
Maclean D, Holden F, Davis AM, Scheuerman RA, Yanofsky S, Holmes CP, Fitch WL, Tsutsui K, Barrett RW, Gallop MA. Agonists of the follicle stimulating hormone receptor from an encoded thiazolidinone library. J Comb Chem. 2004;6:196–206.
Yanofsky SD, Shen ES, Holden F, Whitehorn E, Aguilar B, Tate E, Holmes CP, Scheuerman R, MacLean D, Wu MM, et al. Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists. J Biol Chem. 2006;281:13226–33.
van de Lagemaat R, Timmers CM, Kelder J, van Koppen C, Mosselman S, Hanssen RGJM. Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. Hum Reprod. 2009;24:640–8.
Conflict of interest
None to declare.
Author information
Authors and Affiliations
Corresponding author
Additional information
Tables 1, 2 and 3 are taken from an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Lunenfeld, B. Gonadotropin stimulation: past, present and future. Reprod Med Biol 11, 11–25 (2012). https://doi.org/10.1007/s12522-011-0097-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12522-011-0097-2