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Chapter 1 24 and subsequently induces growth of large numbers of dominant follicles. Recently, serious concerns have been expressed concerning the stimulation of large numbers of follicles for assisted reproduction (Edwards et al., 1996; Fauser et al., 1999). Considering the risks, side-effects and the high costs of ovarian hyperstimulation and multiple gestation, current approaches for ovarian stimulation regimens should be re-evaluated (Hughes et al., 1998; Macklon and Fauser, 2000; de Jong et al., 2000a). It has been shown that a moderate, but continued elevation of FSH concentration during the mid to late follicular phase is capable of disrupting single dominant follicle selection and induces ongoing growth of multiple follicles (Schipper et al., 1998b). Mild interference with decremental FSH by extending the FSH window may therefore be a more physiological approach to ovarian hyperstimulation. 1.5. Study objectives Figure 1.4 The threshold/window concept. Interference with decremental FSH concentrations by the administration of exogenous FSH causes multifollicular development. Ovarian response to stimulation, within the scope of ovulation induction or ovarian hyperstimulation, usually shows strong inter-individual variability. This may result in either an inadequate or a too strong response in a significant proportion of women. In case of an inadequate response, the treatment is ineffective with still potential iatrogenic damage. In case of a too strong response, serious health threads may occur, such as OHSS or (high order) multiple pregnancies. In order to develop and optimize (milder) hyperstimulation protocols for assisted reproduction, a more profound understanding of gonadotrophin dependent follicle development and interference with single dominant follicle growth is needed. Previous research from our own group regarding follicle growth (Pache et al., 1990) and the FSH threshold/window concept (van Santbrink et al., 1995b; Schipper et al., 1998b) has generated some novel concepts in this field.
Introduction and objectives 25 This thesis is focused on various aspects of mono- and multiple dominant follicle development, aiming to generate more insight into (patho)physiological mechanisms concerning dynamics of follicle growth in the human ovary and interference with single dominant follicle selection. The first objective was to gain additional insight in the significance of the timing of initiation of exogenous FSH on follicle recruitment and selection (influencing the closure of the FSH window). A randomized study in 40 normo-ovulatory women was carried out to address this issue (Chapter 2.1). A second study in normo-ovulatory volunteers undergoing cycle intervention with exogenous FSH was performed to gain more insight in ovarian-pituitary regulation mechanisms by studying the relationship between inhibins and follicle development. The hypothesis was that serum inhibin levels may be useful as a clinical marker for the number of follicles to develop after ovarian hyperstimulation (Chapter 2.2). After these experiments in normo-ovulatory volunteers, the gained knowledge of timing of initiation of exogenous FSH was tested in a clinical setting. The FSH threshold/window concept was used as a basis of a novel, milder approach to ovarian hyperstimulation in IVF. In a randomized controlled trial in normo-ovulatory IVF patients, this concept was compared to 2 other ovarian hyperstimulation protocols (Chapter 3.2). The current knowledge on mono- and multi-follicular development may also be useful for the treatment of anovulatory patients. The introduction of new compounds such as insulin sensitizing drugs in the treatment of WHO 2 anovulation, along with the availability of new drugs like GnRH antagonists offer possible new approaches to the treatment of WHO 2 anovulatory patients. To generate more understanding of the pathophysiology in disturbed folliculogenesis in PCOS patients with elevated LH levels, a randomized study was performed. The use of newly available GnRH antagonists may normalise elevated LH serum levels in these patients, which might increase ovarian responsiveness to FSH and even restore normal ovarian function in some women (Chapter 4.2). The last objective was to explore the potential additional effect of insulin sensitizing drugs on ovarian responsiveness during exogenous gonadotrophin induction of ovulation. A placebo controlled double blind randomized study was performed in insulin resistant normogonadotrophic anovulatory patients to test the hypothesis that metformin may improve ovarian sensitivity to stimulation by exogenous FSH (Chapter 4.3). All these objectives were studied using frequent transvaginal sonography (TVS) combined with hormone estimations in peripheral blood.
Page 1 and 2: Aspects of Mono- and Multiple Domin
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Page 5: Ter nagedachtenis aan mijn vader Vo
Page 8 and 9: 4.2.1. Introduction 69 4.2.2. Mater
Page 10 and 11: SRY sex-determining region of the Y
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4.2.4. Discussion Alternative appro
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FSH treatment duration (days) FSH r
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General discussion General discussi
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General discussion 93 the developin
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General discussion 95 study in term
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General discussion 97 ian response
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References
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References 102 Beckers NG, Macklon
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References 104 Dunaif A, Graf M, Ma
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References 106 Gerris J, De Neubour
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References 108 Hughes EG, Collins J
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References 110 Mannaerts B, de Leeu
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References 112 Olivennes F and Fryd
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References 114 Sullivan MW, Stewart
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References 116 Whiteford LM and Gon
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Summary Chapter 1 Summary 119 The i
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Summary 121 resulted in pregnancy r
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Samenvatting Hoofdstuk 1 Samenvatti
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Samenvatting 125 op cyclusdag 2 of
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Publications and presentations
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Publications and presentations 130
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Dankwoord Dankwoord 133 Mijn promot
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Dankwoord 135 Dank je voor het bijb
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Dankwoord 137 Zonder ondersteuning
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Dankwoord 139 Lieve Elly en Joost,
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Curriculum vitae auctoris Curriculu
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