The influence, development and management of functional ovarian cysts during IVF cycles.

Jenkins JM. The influence, development and management of functional ovarian cysts during IVF cycles. Journal of the British Fertility Society, Vol 1(2) Hum. Reprod, 11, Natl Suppl 132-136. 1996

Introduction

Since the widespread use of Gonadotrophin Releasing hormone (GnRH) agonists functional ovarian cysts are not infrequently encountered during IVF cycles (see table 1). This review will consider the clinical significance and aetiopathogenesis of such cysts with the aim of establishing appropriate clinical management. The incidence of ovarian cysts during IVF cycles reported in the literature varies from 2% to 40% because of differences in the definition of cyst used, differing case mix of patients studied, differing treatment protocols and imprecise estimations of incidence due to inadequate sample size. By excluding certain patient groups more likely to develop cysts, such as patients with ovulatory dysfunction a lower incidence will be reported (Lockwood G.L. et al., 1995) than if unselected patients are studied (Lockwood G.L. 1995). Reviewing the larger series of ovarian cysts during IVF cycles using GnRH agonists reveals an incidence of at least 5%, and the incidence is higher if the GnRH agonist is commenced in the follicular phase compared to the luteal phase of the menstrual cycle (see table 1).

Influence of Functional Ovarian Cysts during IVF Cycles.

Conflicting evidence and opinion regarding the influence of ovarian cysts present during IVF cycles has led to recommendations as extreme as abandoning the IVF cycle (Thatcher et al., 1989) to others who suggested cysts were of no consequence (Karande et al., 1990). Although Thatcher (1989) and Goldberg (1991) found a higher cancellation rate in IVF cycles with ovarian cysts than IVF cycles without cysts, no such difference was seen in several other studies (Hornstein et al., 1989, Ron-El et al., 1989, Sampaio et al., 1991). Similarly some (Thatcher et al., 1989, Goldberg et al., 1991, Karande et al., 1990, Ron-El et al., 1989) but not all (Hornstein et al., 1989, Sampaio et al., 1991) studies found significantly lower peak serum oestradiol levels in the patients with ovarian cysts than in the patients without ovarian cysts. Ron-El (1989) found there were significantly fewer oocytes collected in IVF cycles with cysts than IVF cycles without cysts, although this was not supported by other studies (Hornstein et al,. 1989, Karande et al,. 1990, Sampaio et al., 1991). Whereas Thatcher (1989) found only 1 pregnancy from 40 IVF cycles with ovarian cysts, compared to 11 pregnancies from 86 IVF cycles without ovarian cysts, several other studies have shown no decrease in pregnancy rates in IVF cycles with ovarian cysts (Hornstein et al., 1989, Ron-El et al., 1989, Karande et al., 1990, Grazi et al., 1988).

The apparent conflict in the literature should be considered with regard to the possible mechanism of influence as this could explain the differences noted between the above studies (Jenkins J.M. 1993). The suggestion that ovarian cysts may exert a mechanical effect with the cysts possibly disrupting the blood supply to the developing follicles (Rizk et al., 1990) could not explain the observed influence in the contralateral ovary to the cyst (Thatcher et al 1989, Goldberg et al., 1991) nor the studies where ovarian cysts have no influence (Feldberg D. et al., 1989, Sampaio M. et al., 1991, Penzias A.S. et al., 1992). Alternatively ovarian cysts might exert a detrimental influence as a consequence of their functional activity (Jenkins J.M. et al., 1992a), which could influence the contralateral ovary and differ between cysts explaining the confusion in the literature.

Thatcher (1989) suggested that if cysts produced steroids this may alter the endocrine milieu leading to disturbance of normal follicular development. Differences in the influence of ovarian cysts during IVF cycles could thus relate to differences in the steroid production of the ovarian cysts. Sampaio (1991) found that there was no difference in the outcome of the IVF cycles with cysts compared to cycles without cysts if buserelin was continued until oestradiol levels were suppressed. In comparison to IVF cycles without ovarian cysts Karande (1990) found IVF cycles with ovarian cysts had a higher basal serum oestradiol level with a lower peak oestradiol, and more ampoules of human menopausal gonadotrophin (HMG) were required for stimulation. Thatcher (1989) found IVF cycles with ovarian cysts 16-30 mm diameter were associated with elevated basal oestradiol levels and a higher cancellation rate than IVF cycles without cysts. Thatcher's group has published a more recent study on baseline ovarian cysts during IVF cycles, which concluded that if the baseline serum oestradiol level was low then cysts do not affect the response to controlled ovarian hyperstimulation (Penzias et al., 1992). In a review of 780 IVF cycles with 53 cases of cysts were it was shown that only cysts associated with elevation of baseline serum oestradiol levels had a detrimental influence on IVF cycles (Jenkins J.M. et al., 1992a).

If steroid production by ovarian cysts was related to their influence on follicular development then one might expect more of an influence in the ipsilateral ovary to the cyst than in the contralateral ovary to the cyst. Karande (1990) studied 19 patients with unilateral ovarian cysts, and compared the number of follicles and oocytes between the ipsilateral and contralateral ovary to the ovarian cyst finding significantly (P<0.005) fewer follicles in the ipsilateral ovary to the ovarian cyst. Rizk (1990) studied 14 patients with unilateral ovarian cysts on day 2 menses. In 6 patients the cysts were aspirated before stimulation with clomiphene and HMG, and the ipsilateral ovary to the cyst of these patients produced significantly more oocytes than the ipsilateral ovary of the 8 cycles where the cyst was not aspirated, although there was no significant difference in the number of oocytes collected from the contralateral ovaries (Rizk et al., 1990).

It is important to consider that raised serum oestradiol may be no more than a marker of activity of functional ovarian cysts and that other factors produced by the cysts might explain the detrimental influence of the cyst during an IVF cycle (Giudice L.C et al., 1993). In this context it was interesting to note that the concentration of insulin-like growth factor binding protein 1 is related to oestradiol concentrations within functional ovarian cysts (Jenkins J.M. et al., 1993b).

Development of Functional Ovarian Cysts during IVF Cycles

Three possible mechanisms for cyst formation during pituitary downregulation have been suggested. Feldberg (1989) suggested that the transient stimulatory phase induced by GnRH agonists may cause small foci of ovarian endometriosis to develop into endometriomata that appear identical to ovarian cysts. Hodgen (1988) has suggested that ovarian cysts may develop because of the presence on ovarian receptors of physiologically inactive heterogonadotropins secreted by the hypophysis depressed by a GnRH agonist. Ron-El (1989) hypothesised that the transient stimulatory phase caused by GnRH agonists stimulates primordial follicles to grow, but because of rapid pituitary downregulation follicular development is impaired, ovulation does not occur and follicular cysts are formed.

A prospective study of 280 IVF cycles identified 16 patients who developed functional ovarian cysts during pituitary downregulation with buserelin prior to IVF (Jenkins J.M. et al., 1993a). In 10 of the 16 patients with cysts serum oestradiol levels remained elevated despite prolonged use of buserelin, and the cysts were aspirated. The serum progesterone was <5.7 nmol/l in all 16 patients with cysts on day 4 of the IVF cycle, and in 8 of these patients the serum progesterone was <5.7 nmol/l on the day buserelin was commenced. The aspirate in all cases was clear without any suggestion of endometriosis. The cyst aspirates had significantly lower progesterone, higher androstenedione and similar oestradiol concentrations to 10 follicular fluid samples collected at the time of oocyte retrieval. These results supports Ron-El's (1989) suggestion that the cysts which develop during pituitary downregulation are follicular cysts and not persistent corpora lutea nor endometriomata.

Management of Functional Ovarian Cysts during IVF Cycles.

The first stage in the management of functional ovarian cysts during IVF cycles is to consider both the differential diagnosis (including ovarian neoplasia, hydrosalpinx, and endometrioma) and the possibility of an acute cyst complication. The management of endometrioma and hydrosalpinges is beyond the context of this review, but it is important to consider the small possibility of malignancy whenever an ovarian cyst is encountered in an infertile patient (Greenbaum et al 1992). Although IVF cycles may be cancelled when an ovarian cyst is present because of concern that the cyst may grow further, rupture, or undergo torsion during controlled ovarian stimulation, this appears to be an uncommon event (Goldberg, 1991). Moreover Goldberg (1991) found that in only 8 of 62 IVF cycles with ovarian cysts studied was there a slight increase in the size of the cyst, whereas in the remainder an equal proportion were either unchanged or decreased in size during ovarian stimulation.

From the evidence presented above it would appear that the physical presence of cysts is less important than their functional activity when considering management. Although oestradiol feedback from a functional ovarian cyst could delay the time to desensitise the pituitary (Araki S. et al., 1985), GnRH stimulation tests have confirmed that pituitary desensitisation may be achieved despite persistent elevated serum oestradiol levels (Jenkins J.M. et al., 1994). A conservative approach has been shown to be effective where GnRH agonists are continued until serum oestradiol levels fall, although occasionally this may take several weeks (Ron-El et al., 1989, Sampaio et al., 1991). An alternative effective, quick and simple method of dealing with persistent functional ovarian cysts is cyst aspiration (Jenkins et al., 1992b, Rizk at al., 1990, Silverberg et al., 1990). If a functional ovarian cyst developing during pituitary desensitisation with GnRH agonists is a dysfunctional ovarian follicle then a single human chorionic gonadotrophin (HCG) injection should rupture the follicle. In 7 cases of persistent functional ovarian cysts this approach was successfully adopted (unpublished personal data), although a prospective controlled study would be required to confirm this observation.

Prevention of cysts

It had been found that the incidence of functional ovarian cysts developing during pituitary downregulation is related to the serum progesterone level at the time of commencing the GnRH agonist, with a high serum progesterone having a low incidence (Marqalioth E.J. et al., 1991, Jenkins J.M. et al., 1993a). It is known that progesterone reduces the pituitary release of follicle stimulating hormone (FSH) in response to GnRH (Araki et al., 1985), and it has been suggested that the initial surge of FSH when GnRH agonist is commenced might be the trigger factor to initiate cyst development (Jenkins J.M. et al., 1993a). A prospective double blind placebo control trial further suggested that a 7 day course of medroxyprogesterone acetate 10 mg daily (Provera, Upjohn Limited, UK) commenced 3 days before starting GnRH agonist might reduce the incidence of cyst development (Aston K. et al., 1995).

Conclusions

In conclusion ovarian cysts only appear to have a detrimental influence on IVF cycles if functionally active as shown by elevated serum oestradiol levels. Functionally active follicular ovarian cysts occur in at least 5 % of IVF cycles with GnRH agonists; more frequently if the serum progesterone is low at the time GnRH agonist is commenced as in the follicular phase of the menstrual cycle. The simple addition of oral progestogen therapy at the time of commencing GnRH agonist may reduce or prevent cyst formation. If a cyst develops the treatment alternatives to consider are: to wait until the cyst regresses functionally, to aspirate the cyst or possibly to administer HCG. The mechanism by which cysts influence the ovarian response to a gonadotrophin excess is unclear, but stimulates further study into the control of ovarian function.

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Table 1. Relationship between incidence of ovarian cysts noted during IVF cycles and the use of GnRH agonists.

† Number of IVF cycles with cyst present / number of IVF cycles studied - percentage in parenthesis