Centre for Reproductive Biology, University of Edinburgh, 37 Chalmers Street, Edinburgh, EH3 9ET, UK. Email: dtbaird{at}ed.ac.uk
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Abstract |
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Key words: anovulatory infertility in women/clinical medicine/FSH isoforms/hypogonadotrophic men
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Introduction |
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Before considering individual preparations and their potential application, it is worthwhile reviewing the physiological role of FSH and LH in men and women. In primates, including man, it is likely that spermatogenesis is initiated by both FSH and testosterone (Weinbauer and Nieschlag, 1998). Although there is some evidence that spermatogenesis, once initiated, can be maintained by LH-stimulated testosterone alone, it is likely that even in the adult man, FSH stimulates spermatogenesis by interacting with receptors on Sertoli cells. In women, antral follicles are totally dependent on FSH, the concentration of which fluctuates throughout the cycle (Baird, 1999
). These variations in the concentration of FSH play a crucial role in the final stages of folliculogenesis and ensure that only a single follicle is selected for ovulation. This concentration of FSH is carefully controlled at each stage of the follicular phase by the feedback of oestradiol and inhibin from the dominant follicle (McGee and Hsueh, 2000
). By limiting the time during which the concentration of FSH is elevated in the early follicular phase of the cycle, the number of follicles selected for ovulation is restricted. It is clear, therefore, that the feedback system must be sufficiently sensitive to signals from the dominant follicle that the concentrations of FSH fall promptly before additional follicles are recruited. The change in the secretion of isoforms of FSH from the pituitary prior to ovulation in response to increasing concentrations of oestradiol, may facilitate the more rapid clearance of FSH from the blood (Wide and Wide, 1984
).
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Clinical application |
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Women
Gonadotrophins are used in women for (i) ovulation induction and (ii) stimulation of multiple follicular development in association with assisted reproduction techniques.
Ovulation induction
One of the major problems associated with the standard methods of ovulation induction with gonadotrophins is the high incidence of multiple ovulation and high order births (Baird, 1993). New regimens such as `step down' or `low dose' are designed to reproduce the changes in concentration of FSH which occur in the normal cycle when there is a single ovulatory follicle (Glasier et al., 1988
; Fauser et al., 1993
; Franks et al., 1994
). Because of variations in responsiveness to FSH, it is necessary to tailor the dose to individual women by monitoring their response and adjusting the dose accordingly (Brown, 1978
). Because of the long half-life of present preparations of FSH, there may be a considerable lag time between altering the dose of FSH and the concentration in blood falling. A shorter acting preparation of FSH would facilitate achieving the optimum concentration particularly after the threshold concentration of FSH has been reached. At least three preparations with differing half-lives e.g. 6, 12 and 24 h, would be necessary to provide the optimum flexibility (Figure 1
) (Baird, 1999
). A small constant amount of LH could be given throughout (~75 IU/day) to maintain adequate oestrogen secretion. At the initial stage of follicle recruitment a preparation of FSH with a longer half-life (~24 h) could be used until the threshold concentration required to activate one or two follicles had been reached. This preparation would then be replaced by FSH with shorter half-lives so that as soon as a dominant follicle had emerged (1012 mm diameter) the dose could be lower to reduce the concentration of FSH below the threshold necessary to recruit or activate further follicles. By more closely reproducing the changes in FSH concentration which occur in the natural cycle with this `step down' regimen, it should be possible to achieve ovulation of a single follicle more easily.
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In conclusion, it is unlikely that isoforms of FSH with half-lives longer than present preparations would have much clinical application except for stimulation of spermatogenesis. For induction of ovulation, a range of products with relatively short half-lives would permit more sensitive manipulation of the therapeutic dose and facilitate achieving mono-ovulation. The current preparations of FSH are likely to continue to dominate clinical use for ovarian stimulation prior to IVF.
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References |
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