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Nick S. Macklon Department of Reproductive Medicine and Gynecology, University Medical Center, Utrecht, The Netherlands.; Richard L. Stouffer Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Oregon, USA.; Linda C. Giudice Department of Obstetrics and Gynecology, Stanford University School of Medicine, California, USA; Bart C.J.M. Fauser Department of Reproductive Medicine and Gynecology, University Medical Center, Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: n.s.macklon{at}umcutrecht.nl.
To allow selection of embryos for transfer following in vitro fertilization, ovarian stimulation is usually carried out with exogenous gonadotropins. To compensate for changes induced by stimulation, GnRH analog co-treatment, oral contraceptive pre-treatment, late follicular phase hCG and luteal phase progesterone supplementation are usually added. These approaches render ovarian stimulation complex and costly. The stimulation of multiple follicular development disrupts the physiology of follicular development, with consequences for the oocyte, embryo and endometrium. In recent years, recombinant gonadotropin preparations have become available, and novel stimulation protocols with less detrimental effects have been developed. In this article, the scientific background to current approaches to ovarian stimulation for IVF is reviewed. Following a brief discussion of relevant aspect of ovarian physiology, the development, application and consequences of ovarian stimulation strategies are reviewed in detail.
Contents
I. Introduction
II. Physiology of ovarian function relevant to ovarian stimulation
A. Endocrine control of follicular development
B. Intra-ovarian modulators of steroidogenesis
C. Control of corpus luteum function
D. Control of endometrial function
E. Ovarian aging
III. The development of ovarian stimulation agents
A. Background
B. The discovery of Clomiphene Citrate
C. Gonadotropins
D. GnRH agonists
E. GnRH antagonists
IV. Ovarian stimulation regimens
A. Clomiphene Citrate
B. Gonadotropins
C. The role of LH
D. GnRH agonists
E. GnRH antagonists
V. Adjuvant therapies
A. Oral contraceptive pre-treatment
B. Insulin sensitizing agents
C. Aromatase Inhibitors
D. Growth Hormone
E. Androgens
VI. Sequelae of ovarian stimulation
A. Effects on corpus luteum function
B. Effects on endometrial receptivity
C. Effects on embryo quality
D. Side effects and complications
VII. Contemporary issues in ovarian stimulation
A. Poor response to ovarian stimulation
B. Minimal vs. maximal ovarian stimulation
C. HCG substitutes for inducing final oocyte maturation
D. Chromosomal competence of embryos
VIII. Conclusions and future perspectives
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