Contemporary pharmacological manipulation in assisted reproduction

Follicle-stimulating hormone (FSH) treatment to induce follicular development in anovulating women and multiple follicular development for assisted conception has been incorporated in almost all reproductive treatment cycles in the form of either urinary, purified urinary or recombinant preparations. Besides improved tolerance and theoretically lower chances of infection by prions, the latter may be more effective in terms of clinical pregnancy rates, FSH requirement and cost effectiveness. The low-dose, step-up protocol to induce monofollicular development, which is applied worldwide, has to compete with the equally effective but health economically beneficial step-down protocol. The long protocol using recombinant FSH 150 IU/day is advocated when using gonadotropin-releasing hormone (GnRH) agonists in in vitro fertilisation (IVF) or intracytoplasmatic sperm injection treatment. However, the current paradigmatic hyperstimulation came under scrutiny after the introduction of the GnRH antagonists, which allow milder and more convenient approaches with acceptable cancellation and pregnancy rates but lower requirements for FSH. Risk of ovarian hyperstimulation syndrome (OHSS) can be further eliminated if recombinant luteinising hormone (rLH) or GnRH agonists are used to trigger oocyte maturation and ovulation; the latter require pituitary responsiveness and are therefore excluded in agonist protocols. FSH and LH are both required for appropriate folliculo- and steroidogenesis. In hypogonadotropic women, the addition of LH (human menopausal gonadotropin, human chorionic gonadotropin or rLH) is therefore obligate to achieve appropriate follicular growth and pregnancy. The role of LH in ovulation induction is still a matter of debate, although in GnRH agonistic protocols there seems to be a 'therapeutic window'; levels that are too high or too low have detrimental effects on IVF outcome. To broaden the pharmaceutical armoury, recent efforts have been directed towards the development of novel GnRH antagonists and FSH preparations with optimal pharmacokinetic, pharmacodynamic and safety profiles. Alternative strategies with fewer adverse effects and higher benefit/cost ratios are under development. However, before the GnRH agonist is abandoned for the antagonist as standard therapy, the cause of the observed possible lower pregnancy rates with the latter need to be clarified. In addition, prospective studies investigating possible direct effects of GnRH analogues, optimal dose-finding studies and treatment regimens under different conditions, with or without pharmacological coadministration and for different indications, should be performed to optimise the efficacy and tailor treatment strategies to individual needs.