Can GnRH agonists act directly on the ovary and contribute to cyst formation?

R.H.Mehta1 and T.C.Anand Kumar cysts remains unclear. Three hypotheses have been proposed to explain this phenomenon: Hope Infertility Clinic, Reproductive Health Clinic And Research Centre, 12 Aga Abbas Ali Road, Bangalore 560 042, India Hypothesis I 1To whom correspondence should be addressed Commencement of GnRH agonist, either as a single dose of This debate was previously published on Webtrack 96, the long-acting form or as daily s.c. doses, results in an initial December 1, 1999 transient ‘flare-up effect’ on the pituitary leading to a surge of circulating gonadotrophins. It is postulated that this surge Pituitary desensitization with gonadotrophin-releasing hortriggers the growth of the primordial follicles. The absence of mone (GnRH) agonists prior to ovarian stimulation is now a a subsequent luteinizing hormone (LH) surge prevents the routine part of most in-vitro fertilization (IVF) and intracytorupture or luteinization of the follicles which then get converted plasmic sperm injection (ICSI) procedures. The two criteria into cystic structures. This hypothesis was first proposed to which are used to determine whether pituitary desensitization explain the presence of ovarian cysts after GnRH agonist has occurred are: (i) serum oestradiol concentrations of 50 administration (Feldberg et al., 1989) and then later by most pg/ml and (ii) the absence of any ovarian cysts with a diameter other investigators reporting on the presence of ovarian cysts 15–20 mm(Ron-El et al., 1989; Sampaio et al., 1991; Jenkins after administration of GnRH agonists ( Herman et al., 1990; et al., 1993; Tarlatzis et al., 1994; Keltz et al., 1995). It takes Ron-El et al., 1990; Stewart et al., 1992; Jenkins et al., 1993; ~10–15 days for this effect of GnRH agonist to manifest on Tarlatzis et al., 1994). the ovary, irrespective of the phase of the cycle (early follicular The incidence of ovarian cyst formation following GnRH phase or mid-luteal phase) in which the GnRH agonist is agonist treatment in IVF cycles is related to the serum started, the type of GnRH agonist used (long-acting triptorelin progesterone concentrations on the day of GnRH agonist or short-acting buserelin or leuprolide acetate) and the mode treatment initiation (Marqalioth et al., 1991) and is lower when of administration (nasal spray, i.m. administration of longprogesterone is administered prior to starting GnRH agonist acting preparations or s.c. administration) (Sampaio et al. treatment (Aston et al., 1995). This is attributed to the ability 1991; Parinaud et al., 1992; Jenkins et al., 1993). of progesterone to decrease gonadotrophin release in response There have been several reports on the presence of ovarian to GnRH agonist (Araki et al., 1985), therefore the initial cysts while the women are still undergoing treatment with transient ‘flare-up effect’ of GnRH agonist becomes subdued GnRH agonists (Feldberg et al., 1989; Ron-El et al., 1989; and subsequently the formation of cysts. This hypothesis Sampaio et al., 1991; Jenkins et al., 1992; Parinaud et al., explains the presence or formation of ovarian cysts after GnRH 1992; Stewart et al., 1992; Jenkins et al., 1993; Tarlatzis et al., agonist administration, but fails to explain how these ‘cysts’ 1994; Keltz et al., 1995; Weissman et al., 1998). The elevated continue growing and secreting oestradiol in the absence of concentrations of serum oestradiol and the high concentration any endogenous or exogenous gonadotrophin stimulation for of oestradiol in the fluids aspirated from these cysts indicate a prolonged period of time. that these cysts originate from the ovarian follicles and have Several authors (Ron-El et al., 1989; Herman et al., 1990) been termed as ‘functional follicular cysts’ (Jenkins et al., have clearly demonstrated that there is a sharp rise in the 1993). Some of these cysts may also be endometriomata serum FSH and LH concentrations within the first 48 h of (Yanushpolsky et al., 1998). GnRH agonist administration with a concomitant rise in The incidence of formation of such cysts is reported to be oestradiol concentrations. Daily administration of buserelin or 2–40% (Feldberg et al., 1989; Ron-El et al., 1989; Parinaud leuprolide acetate for 4 days after the administration of longet al., 1992; Jenkins et al., 1993; Tarlatzis et al., 1994). There acting GnRH agonist results in a decrease in both serum are some reports that the incidence is higher in older women gonadotrophin and oestradiol values. In cases where these (Keltz et al., 1995); in those in whom GnRH agonists have cysts have been observed, the gonadotrophin concentrations been started in the follicular phase, compared with those in decrease but the diameter of the cysts and circulating oestradiol whom it is started in the mid-luteal phase (Ben-Rafael et al., concentrations are maintained or increase (Herman et al., 1990). 1990); and in those having higher basal (day 2) values of According to this hypothesis, if it is the ‘flare-up’ effect of follicle stimulating hormone (FSH) in the pre-treatment cycle (Keltz et al., 1995). The reasons for the formation of such the GnRH agonist which triggers the rise in gonadotrophin