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Treatment of WHO 2: Gonadotropins and the Role of GnRH Agonists and Antagonists
Introduction
Polycystic ovary syndrome (PCOS) is the most common form of WHO 2 anovulation, characterized by a normo-gonadotrophic and normo-estrogenic hormonal pattern. In women who failed to ovulate following clomiphene citrate (CC resistant) or to conceive following CC treatment (CC failure), gonadotropins are usually the next line of treatment. As polycystic ovaries are extremely sensitive to gonadotropins, ovulation induction with exogenous gonadotropins carries a high risk for multiple follicle recruitment, ovarian hyper-stimulation syndrome (OHSS) and multiple pregnancies.
The issue of how to prescribe gonadotropins was addressed many years ago. Although induction of ovulation using gonadotropin was first initiated in 1961, no guidelines of prescription were provided at that time. A major advance was the report by Brown of his clinical experience. Indeed, Brown proposed in 1978 the concept of a FSH threshold, emphasizing that the ovarian requirement for FSH operates in a very narrow range (1). The principle was to determine the individual dose of FSH leading to the development of the most sensitive follicle. As this threshold dose may hugely differ between individuals, he suggested a stepwise FSH increment by no more than 30% in agreement with the elevation of serum FSH during the early follicular phase. This observation allowed the development of the so-called “step-up protocols,” which are now the gold standard in many centers. It was a major breakthrough to reduce the risk of overstimulation often associated with ovarian stimulation in patients with WHO 2 anovulation.
Overview of Existing Evidence
Step-Up Regimens
Step-up protocols are the most commonly used, at least for the first stimulation cycle. Indeed, it allows the assessment of the individual ovarian responsiveness to FSH by determining the dose required to induce the development of the most sensitive follicle of the cohort.
In the early 1980s, the use of conventional dose (150 IU/d) in conjunction with a rapid dose increment in absence of follicular growth was associated with high rates of cycle cancellation or multiple pregnancies due to multi-follicular development. Therefore, a subtle adjustment of both the starting dose and the dose increment was recommended in order to carefully achieve the FSH threshold for follicular growth. As soon as a selected follicle has emerged, the same dose is maintained up to the time of hCG administration. This principle of step-up administration of gonadotropins was applied with the low-dose and chronic low-dose protocols that proved to be safer than the conventional one. In nonobese patients, the recommended starting daily dose of FSH is 37.5 to 50 UI. A strict adhesion to a first step of 14 days was associated with a reduction in the risk of multi-follicular development. Adjustment in the dose every 5–7 days was justified because, due to the long FSH half-life, it took about 5 days to get a steady state of serum FSH. The increment at any stage of the stimulation should not exceed 50% in order to reduce the risk of over-response. In absence of pregnancy, treatment of the subsequent cycle generally begins at the threshold of response previously determined. Due to the possible cycle-to-cycle variability of the individual ovarian response, a close monitoring of each cycle is recommended. In absence of ovarian response to a daily dose of 225 IU or after 35–42 days of treatment, ovarian stimulation is usually cancelled.
Step-Down Regimen
An alternative was proposed to mimic physiology more closely. The step-down protocol aimed at administering an initial loading dose of gonadotropin to surpass the FSH threshold (2). Subsequently, when a follicle emerges from the cohort, the daily dose is reduced in order to close the FSH window. This regimen allowed a decrease in the duration of FSH administration but needs more experience and skill to avoid an ovarian hyper-response or a drop in follicular growth.
Efficacy and Safety of Different Regimens
There is no doubt that application of the low-dose and the chronic low-dose step-up regimens was associated with higher efficacy and safety than the conventional use of FSH. Using the chronic low-dose regimen (CLD), reported results showed a remarkably consistent rate of mono-ovulatory cycles of around 70% and an acceptable pregnancy rate of 20% per cycle. In addition, the risk of ovarian hyper-stimulation syndrome was significantly reduced and the rate of multiple pregnancies was <6% (3). Fair cumulative conception rates were reported (60% at 6 months).
Few studies have compared the efficacy and the safety of CLD step-up and step-down protocols in the first stimulation cycle. Even if the clinical characteristics of patients included in these studies were not comparable, the risk of over-response appeared to be high with the step-down regimen as a first-line therapy because the FSH threshold dose was not previously assessed. Therefore, it seemed safer to offer first a “dose-finding” CLD step-up induction cycle. In the next cycle, a step-down regimen can be applied with a starting dose 37.5 IU above the effective response dose individually determined. Using this approach, both protocols showed comparable ovulation and pregnancy rates with a low risk of multiple pregnancy and OHSS. Nevertheless, the small number of patients included in these studies and the heterogeneity between PCOS women limit the conclusion of these trials.
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