Granulosa–luteal cell function <i>in vitro</i> and ovarian stimulation protocols

Dear Sir, We read the editorial of Fauser et al. (1999) on the benefits and drawbacks of minimal ovarian stimulation for IVF with interest. IVF uses hyperstimulation with the gonadotrophic hormones, FSH and LH during the first half of the menstrual cycle to stimulate the development of multiple Graafian follicles. This allows more oocytes to be retrieved for fertilization, providing more healthy embryos for implantation, thus increasing the chances of a pregnancy. Although the success rate in these hyperstimulated cycles is modest, it is better than that in untreated or natural cycle IVF. Natural cycles, with just one follicle developing, can at best lead to the recovery of only one oocyte, and this can often be missed during retrieval attempts. Natural cycle IVF is therefore rarely attempted anymore. While it is generally assumed that superovulation generates more oocytes without perturbing the system, this notion has not been seriously questioned. After the mid-cycle ovulatory stimulus, the granulosa cells of the ovulatory follicle differentiate further (luteinization) and switch from synthesizing predominantly oestrogens to progestins. The increased progesterone secreted from the resulting corpus luteum is critical in preparing the uterus for implantation. Women undergoing IVF and showing a poor progesterone response have an associated lower conception rate (Prien et al., 1995). In their editorial, Fauser et al. (1999) cite studies that clearly showed that corpus luteum support is necessary in IVF stimulation cycles that are combined with gonadotrophin-releasing hormone (GnRH) agonists. They proposed that this may occur because of alterations in pituitary function, the administration of large doses of human chorionic gonadotrophin (HCG), follicular puncture and the loss of granulosa cells, or it may reside within the ovary per se. We present evidence below that supports their latter proposal, i.e. that there is a change within the developing granulosa cells themselves as a result of IVF stimulation. This also raises the question as to whether the corpora lutea formed in IVF cycles are functionally similar to their `normal' counterpart. Granulosa–luteal cells were obtained from 21 spontaneously ovulating women. For those women undergoing IVF stimulation, leuprolide acetate was used for hypothalamic-pituitary axis down regulation. Seven underwent controlled ovarian hyperstimulation with human menopausal gonadotrophins (HMG) a mixture of FSH and LH (Pergonal®), eight with a more highly purified FSH (Metrodin®) and six were allowed to cycle naturally. Processing of cells from these patients was the same as previously described (Lobb et al., 1998). As shown in the figure, granulosa–luteal cells from natural cycles were much more robust in their progesterone production than were those from the stimulated cycles. Granulosa–luteal cells that developed under the influence of HMG had progesterone synthesis reduced approximately five-fold compared with those from the untreated or natural cycles whereas cells from Metrodin-treated cycles produced about two-fold less progesterone. The use of controlled ovarian hyperstimulation is essential for reasonably successful IVF. Perhaps because of this necessity it has come to be viewed as having minimal detrimental effects. However, subtle perturbations of the reproductive system have already been observed in response to IVF treatments. Granulosa–luteal cells from natural cycles were found to be morphologically larger and have more HCG staining than those from treated cycles (Gersak and Tomazevic, 1996). Endometrial cell projections (pinopodes) that indicate the narrow window of uterine receptivity for blastocyst implantation have been shown to develop earlier in IVF treated cycles (Nikas et al., 1999). Our data now suggests that IVF stimulation has a modulating effect on granulosa–luteal cell development, inhibiting their full steroidogenic potential. However, impaired progesterone synthesis by granulosa–luteal cells in vitro does not necessarily mean diminished progesterone production by the corpus luteum in vivo. Often early luteal phase serum progesterones are elevated in IVF, the major differences then seeming to be early luteolysis and a subsequent short luteal phase. Whether these striking differences in progesterone production represent a compensatory mechanism correcting for the more numerous corpora lutea in IVF or a true developmental impairment caused by excessive exogenous gonadotrophins or GnRH agonists, remains to be determined. It does, however, indicate that not so subtle changes are induced with fertility treatment and further refinements in addition to corpus luteum support will likely be needed to improve pregnancy rates. In-vitro progesterone production (48 h) of granulosa–luteal cells from hyperstimulated or natural menstrual cycles. (mean ± SD of triplicate culture wells, n = number of patients, all different at P < 0.001).

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