Different aetiological mechanisms for unexplained and endometriosis-associated infertility cannot be inferred from unstimulated IVF cycles using HCG to induce ovulation

Stephen D. Keay1,3 and David J. Cahill2

1 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL 2 Division of Obstetrics and Gynaecology, University of Bristol, St Michael's Hospital, Bristol BS2 8EG, UK


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Dear Sir,

Omland and colleagues' paper examining the outcome of IVF in a ’natural cycle’ model to study aetiological differences between endometriosis and other infertility groups interested us (Omland et al., 2001Go).

Their findings differ from ours and we have tried to understand these differences. It is important to distinguish between this study, which used HCG as a surrogate for the endogenous LH surge when fixed arbitrary criteria were reached, and truly natural cycle programmes, such as ours, devoid of all drugs. Our own programme was designed as a model for studying the mechanisms underlying unexplained and minor endometriosis-associated infertility in completely natural cycles.

We found significantly longer follicular phase, significantly reduced LH surges, significantly lowered LH-Area under the curve (AUC) and reduced fertilization rates in women with minor endometriosis compared with prolonged unexplained or tubal infertility (Cahill et al., 1995Go, 1997Go). Omland and colleagues found no differences in AUC-LH or peak LH concentrations. There are however profound differences in the methodologies of the studies that we feel this largely explains their failure to find any difference. Our serum samples were undertaken every 4 hours; theirs was ‘daily or every other day’. We suggest that our determination of the AUC-LH and peak LH measurements was therefore more rigorous and sensitive in determining differences. In addition, the supraphysiological doses of HCG used for ovulation induction might mask these differences.

The truly undisturbed nature of our study allowed for detailed follicular fluid and granulosa cell studies that provided further information on the understanding of endometriosis-associated infertility. Subtle important differences in cortisol and activin levels exist in the preovulatory follicle of infertile women with endometriosis compared with controls, which appear important in final oocyte maturation and inhibiting follicular LH action respectively (Akande et al., 2000Go; Smith et al., 2002Go).

Initially, we were at a loss to understand the marked difference in the fertilization rates observed in Omland et al.'s study compared with our own (Cahill et al., 1997Go) and with the combined data in the literature (Cahill and Hull, 2000Go). We have some reservations and concerns regarding the results of the statistical analysis as reported. The pregnancy rate per successful oocyte retrieval (P = 0.12) and per embryo transfer (P = 0.14) are not statistically significant using the tests reported and the significantly higher pregnancy rate per initiated cycles reaches significance (P = 0.0497) only when a one-sided P-value is used. The higher fertilization rate in the endometriosis group is non-significant (P = 0.066 using the {chi}2-test), the proportion of cleaving embryos in each group is very similar (62.2 versus 68%, P = 0.571 using the {chi}2-test) and the higher cleavage failure with endometriosis is consistent with our observations in completely natural cycles when HCG was not used. Furthermore, endometriosis is associated with defective steroidogenesis in granulosa-lutein cells in both natural and gonadotrophin-stimulated IVF cycles (Harlow et al., 1996Go). Adding HCG in vitro enhanced progesterone production three-fold and may explain the similar findings in the three groups during the luteal phase.

We agree that unstimulated IVF with HCG supplementation may be an appropriate clinical treatment for minimal endometriosis by overcoming a fundamental defect in women with minor untreated endometriosis, namely reduced LH surge quality. HCG administration may indeed be therapeutically helpful but we disagree that it provides additional information about aetiology. Finally, it seems contradictory to propose adding GnRH antagonists to HCG and still call this ‘natural’ cycle. It could only be ‘unstimulated’ and would likely detract from the lesser expense of ‘natural’ cycle IVF.


    Notes
 
3 To whom correspondence should be addressed. E-mail: skeay{at}bio.warwick.ac.uk Back


    References
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 Introduction
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Akande, A.V., Asselin, J., Keay, S.D., Cahill, D.J., Muttukrishna, S., Groome, N.P. and Wardle, P.G. (2000) Inhibin A, inhibin B and activin A in follicular fluid of infertile women with tubal damage, unexplained infertility and endometriosis. Am. J. Reprod. Immunol., 43, 61–69.[ISI][Medline]

Cahill, D.J. and Hull, M.G.R. (2000) Pituitary–ovarian dysfunction and endometriosis. Hum. Reprod. Update, 6, 56–66.[Abstract/Free Full Text]

Cahill, D.J., Wardle, P.G., Maile, L.A., Harlow, C.R. and Hull, M.G.R. (1995) Pituitary-ovarian dysfunction as a cause for endometriosis-associated and unexplained infertility. Hum. Reprod., 10, 3142–3146.[Abstract]

Cahill, D.J., Wardle, P.G., Maile, L.A., Harlow, C.R. and Hull, M.G.R. (1997) Ovarian dysfunction in endometriosis-associated and unexplained infertility. J. Assist. Reprod. Gen., 14, 554–557.[ISI][Medline]

Harlow, C.R., Cahill, D.J., Maile, L.A., Talbot, W.M., Mears, J., Wardle, P.G. and Hull, M.G.R. (1996) Reduced preovulatory granulosa cell steroidogenesis in women with endometriosis. J.Clin. Endocrinol. Metab., 81, 426–429.[Abstract]

Omland, A.K., Fedorcsak, P., Storeng, R., Dale, P.O., Åbyholm, T. and Tanbo, T. (2001) Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility. Hum. Reprod., 16, 2587–2592.[Abstract/Free Full Text]

Smith, M.P., Keay, S.D., Margo, F.C., Harlow, C.R., Wood, P.J., Cahill, D.J. and Hull, M.G.R. (2002) Total cortisol levels are reduced in the periovulatory follicle of infertile women with minimal-mild endometriosis. Am. J. Reprod. Immunol., 47, 52–56.[ISI][Medline]





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