What is the optimal medical management of infertility and minor endometriosis?

Analysis and future prospects

D.J. Cahill

Centre for Reproductive Medicine, University of Bristol, Division of Obstetrics and Gynaecology, St Michael's Hospital, Southwell Street, Bristol BS2 8EG, UK. E-mail: d.j.cahill{at}bris.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
By asking the question `What is the optimal medical management of infertility and minor endometriosis?', it is assumed that endometriosis has a detrimental effect on fertility. The published data suggest that oocyte dysfunction may contribute to infertility associated with endometriosis. This is expressed as a reduction in fertilization and implantation rates; implantation rates to a lesser extent, though still significant. Other evidence for oocyte dysfunction exists, not all of which is consistent. Suppression of ovulation and menstruation to treat endometriosis-associated infertility is not effective. However, ovulation induction, perhaps with intrauterine insemination, does result in pregnancy rates higher than in control cycles, while stimulated IVF success rates are equivalent to those of other diagnostic groups. For the future, angiogenesis is critical to the support of endometriotic deposits and targeted therapies are promised; their role in improving fertility has not yet been explored.

Key words: endometriosis/infertility/medical treatment


    Introduction
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
What is the optimal medical management of infertility when associated with endometriosis? Does endometriosis have any relevance to fertility? Does it affect it in any way? The evidence for a relationship between endometriosis and fertility and the benefits of medical treatment of endometriosis are discussed in this paper. Appropriate medical treatments for infertility related to endometriosis are proposed.

Moderate to severe (major) endometriosis is a destructive disease, and benign only in its classification as having no abnormal meiotic activity. In many other respects, it is a `malignant' disease that causes considerable anatomical destruction and symptomatology, particularly pain. Severe endometriosis also significantly impairs fertility, as demonstrated in studies looking at both natural (Olive and Lee, 1986Go) and assisted conception (Matson and Yovich, 1986; GoDlugi et al., 1989; GoPal et al., 1998; GoAzem et al., 1999; GoOlive and Pritts, 2001Go). Medical treatment has very little to offer infertility patients with major endometriosis. It is only of value to discuss the role of medical intervention in minimal and mild non-adhesive endometriosis [Stages I and II by the American Classification (American Fertility Society, 1985; GoAmerican Society for Reproductive Medicine, 1997Go)]. These have been grouped together as minor endometriosis to distinguish these degrees from moderate and severe (Stages III and IV).


    Evidence for a relationship between endometriosis and fertility
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
Evidence from population and prevalence studies, studies of fertilization and implantation rates and endocrine studies can be used to discuss and explore the relationship between endometriosis and fertility.

Prevalence studies of subfertility
When investigating infertility, endometriosis prevalence rates at laparoscopy exceed those in fertile controls (21–47 versus <5%) (Hassan, 1976; GoDrake and Grunert, 1980; GoStrathy et al., 1982Go). When re-laparoscoped >=2 years later, 20% of women with a previously normal pelvis and otherwise unexplained infertility had macroscopic endometriosis (Pepperell and McBain, 1985Go). Significantly lower 3 year cumulative conception rates were observed in women with endometriosis compared with controls (36 versus 54%) (Akande et al., 2001Go). When donor insemination is used to control for male and coital factors for subfertility, reduced conception rates are consistently demonstrated in women with endometriosis (Bordson et al., 1986; GoJansen, 1986; GoRodriquez-Escudero et al., 1988;GoBarratt et al., 1990Go).

Ability of oocytes to fertilize and implant
Fertilization and implantation rates have been studied in women with minor endometriosis and compared with controls, usually women with tubal damage. Studies with or without exogenous ovarian stimulation with gonadotrophins (FSH, HMG and/or HCG) have been presented separately in Table IGo. When taken in combination, the results suggest reduced fertilization and cleavage rates in women with endometriosis compared with controls. These differences were consistent and significant in cycles with exogenous stimulation (52 versus 69%) or without stimulation (49 versus 69%). In Table IGo, two studies conflict with the majority (Mahadevan et al., 1983; GoMatson and Yovich, 1986Go). This may be due to chance or differences in design. In some studies, the endometriosis had been previously treated (Mahadevan et al., 1983Go). In most, this was not clarified, though some explicitly excluded such previously treated patients (Wardle, 1985; GoMahmood, 1991a;GoCahill, 1997Go). Most included only women with minor endometriosis, but some included severe disease, reporting no differences in women with or without severe disease (Matson and Yovich, 1986Go). One study of women with severe disease reported fewer mature follicles, reduced fertilization rates and fewer oocytes (though not significantly so), suggesting that anatomical distortion may interfere with ovarian responsiveness to stimulation (Dlugi et al., 1989Go). Considerable heterogeneity in control groups was sometimes present, e.g. couples whose primary infertility cause was sperm disorder (Mahadevan et al., 1983Go).


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Table I. Summary of studies which provide data on fertilization rates (cleaving embryos as percentage of oocytes) in women with endometriosis (generally minor) compared with tubal infertility as controls
 
Implantation rates after standard IVF treatment in women with endometriosis compared with controls are summarized in Table IIGo. As in Table IGo, most patients with endometriosis had minor disease. Reduction of implantation rates was reported in three studies, though this was significant in only one. Overall the implantation rate of individual embryos was reduced (11 versus 13%, P < 0.05).


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Table II. Summary of studies which provide data on implantation rates (gestational sacs with fetal heart as percentage of embryos transferred) in women with endometriosis (generally minor) compared with controls (tubal and/or unexplained infertility)
 
When ICSI is used, oocyte factors (as well as sperm defects) may be overcome, partly by selection of metaphase II oocytes. Two recent studies using ICSI comparing patients with endometriosis with controls found no reduction in fertilization, cleavage (Minguez et al., 1997Go) or implantation rates (Bukulmez et al., 2001Go) in women with endometriosis. No reduction in implantation rates was noted when ICSI treatment was used in women with endometriosis compared with controls (15 versus 13%) (Minguez et al., 1997Go). In addition, to add to the evidence for an oocyte dysfunction, no reduction in implantation rates was found in recipients of donor oocytes according to whether the recipient had endometriosis or not (12 versus 13%) (Sung et al., 1997Go).

Evidence for a disorder of pituitary or ovarian function
Endocrine and ultrasound studies in women with minor endometriosis suggest that ovulatory dysfunction contributes to their infertility. Abnormalities observed include reduced follicular growth rate (Doody et al., 1988Go), reduced preovulatory follicle functional capacity (estradiol levels over the 4 days before ovulation) (Tummon et al., 1988; GoCahill et al., 1995Go), impaired LH surge pattern and amplitude (peak LH levels and sum LH levels during the surge) (Cheesman, 1982; GoBancroft, 1992; GoCahill, 1995Go), reduced oocyte fertilizing ability (Cahill et al., 1997Go) and disturbed early luteal function (Cheesman, 1982Go). Luteal phase abnormalities include indistinct early luteal phase rises in basal temperature and delayed return to the low temperature phase at menstruation (Swolin and Skogsberg, 1985Go). A slow rise in progestogen may explain the initial slow rise in temperature (Cheesman, 1982Go) while increased ovarian progesterone and reduced estradiol secretion during the follicular phase may explain the delayed fall in temperature (Ayers et al., 1987Go). Follicular maturation in subsequent cycles may be altered by impaired luteolysis.

Follicular endocrinology
Preovulatory follicular function is estimated by steroid measurements in follicular fluid (FF) and by determining granulosa cells steroidogenic capacity when collected at oocyte recovery for IVF. Studies of unstimulated cycles are more relevant to natural fecundability but difficult to undertake. In such unstimulated cycles, two studies of FF sex steroid concentrations found no differences between women with endometriosis and controls (Mahmood et al., 1991a; GoCahill et al., 1995Go). In the latter paper (Cahill et al., 1995Go), endogenous gonadotrophin levels were also measured. No difference was found in FSH concentrations, but LH concentrations were significantly reduced in women with endometriosis. Reduced LH concentrations in FF were associated with impaired fertilization of oocytes in vitro, despite normal FF FSH and steroid levels (Verpoest et al., 2000Go). The inference might be drawn that lower LH levels were associated with the reduced fertilization associated with endometriosis. In both unstimulated and stimulated cycles, production of estradiol and progesterone is reported to be reduced (Harlow et al., 1996Go). Further evidence for an ovarian dysfunction comes from glucocorticoid abnormalities reported in the FF of women with minor endometriosis (Smith et al., 2002).

In contrast to the above studies, Pellicer and co-workers found significant, apparently favourable, increases in FF progesterone and decreases in testosterone concentrations in patients with endometriosis, together with increased granulosa cell steroidogenesis (Pellicer et al., 1998Go).

The nuclear state of granulosa cells undergoing mitotic division has been studied using flow cytometry. Women with moderate and severe endometriosis have abnormal cell cycles and a higher incidence of apoptotic cells in their granulosa cells compared with other infertile women (Toya et al., 2000Go). These data complement earlier findings of impaired granulosa cell viability in women with minor endometriosis (Cahill, 1998Go). These aberrant nuclear events may be responsible for poorer quality oocytes with impaired fertilizing ability.

In summary, studies of altered steroid concentrations within the preovulatory follicles of women with endometriosis are not consistent. Any dysfunctional steroidogenesis that does exist may be due to altered mitotic activity in granulosa cells, altered glucocorticoid exposure or gonadotrophin sensitivity or exposure.


    Does the evidence support a causal or casual relationship?
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
In Stage I (minimal) and Stage II (mild) endometriosis (American Fertility Society, 1985;GoAmerican Society for Reproductive Medicine, 1997Go), it is often stated that the evidence for the relationship between endometriosis and fertility is unclear. Can superficial endometriosis in the pelvis really affect fertility? A considerable body of evidence would suggest that these women have got some oocyte dysfunction that leads to reduced fertilization and implantation rates. The environment that the oocyte is subjected to may also be affected by altered glucocorticoid balance or sex steroidogenesis. That this is the case still does not confirm whether endometriosis is causal or casual in this relationship. One model to explain the oocyte dysfunction links this with the abnormalities of LH secretion seen during the LH surge and the lower fertilization rate observed in some studies. This may result from inadequate follicular phase drive, perhaps from FSH or some other intra-ovarian paracrine hormone. Stimulation of FSH secretion in the early follicular phase by clomiphene or by exogenous gonadotrophins may be beneficial in improving fertility.

The much debated Canadian study of laparoscopic surgical treatment suggested that altering the peritoneal environment had a beneficial effect on conception rates (Marcoux et al., 1997Go). A second similar study from Italy found no significant difference in 1 year pregnancy rates (Parazzini, 1999Go). When the results of these studies were combined (Olive and Pritts, 2001Go), there was still a higher chance of pregnancy following surgical treatment, though the effect was small [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.5]. Thus, the presence of endometriosis may be causative in itself, or may be additive to other factors leading to infertility. This provides an imperative to treat it, even though the `proven' treatments are surgical rather medical.


    Current state of knowledge on the medical treatment of endometriosis-associated infertility
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 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
Medical treatments for endometriosis alter the hormonal balance of the menstrual cycle and produce chronic anovulation, endometrial decidualization (a pseudo-pregnancy) or atrophy (a pseudo-menopause). The endometriotic implants will respond similarly to become ultimately atrophic.

The main categories of the medical treatments used for pain are the progestogens (usually medroxyprogesterone acetate or norethisterone), gestrinone, danazol and the GnRH agonists. These have been extensively studied in the treatment of pain associated with endometriosis. They all have similar levels of efficacy and for all these treatments, between 80–90% of women will have improvement in symptoms (Hughes et al., 2001; GoOlive and Pritts, 2001Go).

Because these drugs are effective for symptoms (principally pain), they have been used extensively in the management of infertility associated with endometriosis. A number of studies have investigated these drugs in comparison with other drugs, with a placebo or with no treatment. These have been summarized by meta-analysis in a Cochrane review (Hughes et al., 2001Go). There was no difference in efficacy as measured by the likelihood of clinical pregnancy whichever drug was used, or indeed if no treatment or a placebo was used.

It has taken some time for this message to be widely disseminated, but it is now clear that there is no role for these drugs in the management of endometriosis-associated infertility. Indeed, because many women have a delay in return to normal ovulatory function after such drugs, the lack of any positive effect is accentuated. Some have claimed a benefit in a small number of women with particular markers for uterine receptivity (Lessey, 2000Go). However, the weight of evidence is in favour of not treating these women.


    Appropriate medical treatments of endometriosisassociated infertility
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
Current therapies
From the evidence provided earlier, no medical suppressive treatment appears to be of any value, and suppression of endometriosis is unhelpful. Does this imply that non-adhesive, non-cystic endometriosis is of no consequence to fertility? Results from laparoscopic surgical treatments would seem to suggest that the removal of the endometriotic tissue, and whatever it is producing improves fertility (Marcoux et al., 1997; GoParazzini, 1999Go)

If part of endometriosis-associated infertility is due to follicular development, does ovulation induction make any difference in women with minor endometriosis? One small but well designed study of follicular development in spontaneous and clomiphene (with or without FSH) induced cycles in women with minor endometriosis addressed this question (Mahmood et al., 1991bGo). Clomiphene alone did not improve follicular development, though clomiphene and FSH did (P < 0.01).

In women with minor endometriosis, the use of clomiphene for ovulation stimulation results in a higher pregnancy rate than the use of danazol for ovarian suppression (OR = 2.9, 95% CI 1.2–7.1 versus 1.02, 0.5–2.3) (Simpson et al., 1992Go). A number of reports have examined the role of ovulation induction in the medical management of minor endometriosis (Deaton et al., 1990; GoFedele et al., 1992;GoTummon et al., 1997Go). These studies are heterogeneous in their protocols, in the drugs used for ovulation induction and whether intrauterine insemination was used. It is therefore difficult to combine their data with any degree of common analysis. Each study does show a consistent increase in cycle fecundity rate following the particular intervention. One non-randomized study examined pregnancy rates after expectant management, clomiphene or HMG following surgical treatment of endometriosis (Karabacak et al., 1999Go). In this, the cycle rates for fecundity for expectant management, clomiphene and HMG were 0.021, 0.066 and 0.174 respectively (expectant versus HMG, P = 0.005). In addition, the relative risk (RR) of pregnancy was higher if the duration of infertility was <5 years (RR = 1.42, 95% CI 1.02–2.05). The negative effect of increasing age is borne out by the findings of others (Snick et al., 1997Go).

These studies suggest some improvement in fertility from ovulation induction. In systematic reviews of the role of ovulation induction and/or intrauterine insemination in unexplained infertility, most trials reported in favour of the use of clomiphene (Hughes 1997; GoHughes et al., 2000Go). The common OR for pregnancy per patient for this intervention was 2.37 (95% CI 1.22–4.62), suggesting a significant treatment benefit. However, the presence of endometriosis in persistent infertility is associated with a significant reduction in the likelihood of pregnancy (OR = 0.45, 95% CI 0.27–0.76).

The additional operative element of assisted conception may exclude it from consideration as medical treatment. If not, then it forms an important arm of the treatment plan for couples with minor endometriosis. Success rates in IVF for women with minor endometriosis are generally comparable with other female diagnostic groups (Mills et al., 1992; GoHull et al., 1998Go), because although fertilization rates are reduced, sufficient embryos are obtained and implantation rates are at worst minimally affected. Therefore, early recourse to assisted conception is valid after failure of other methods of medical management or even as a primary treatment in older women.

Imminent or future therapies
Is there any treatment likely to alter these management options in the near future? Possibly. The role of new vessel formation in endometriosis is critical to the progression of the disease. Angiogenesis is also important in many other aspects of medicine, not just in obstetrics and gynaecology where tumour development and pre-eclampsia are important areas of study. The controlling role of vascular endothelial growth factor (VEGF) in many aspects of medicine and particularly in endometriosis is recognized. The potential roles for therapeutic intervention have been reviewed elsewhere (McLaren, 2000Go), but in essence these focus on VEGF production, bioavailability and receptor binding. Some endocrine manipulations have shown interesting alterations in receptor numbers and VEGF immunoreactivity in normal endometrium (Macpherson et al., 1999; GoCharnock-Jones et al., 2000Go). Both etonorgestrel and a combined oral contraceptive (20 µg ethinyl estradiol and 150 µg desogestrel) pill reduced VEGF immunoreactivity, while etonorgestrel increased progesterone receptor numbers and the combined pill decreased it. The therapeutic application of these findings is not yet established. Nonetheless, agents such as those that can alter angiogenesis (antibodies, soluble receptors, tyrosine kinase inhibitors and inhibitors of matrix-metalloproteinase) may soon be available for use clinically to inhibit the progression of endometriosis (Smith, 2001aGo). However, their role in the management of minor endometriosis is likely to be limited (Smith, 2001bGo).


    Conclusion
 Top
 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
When endometriosis is associated with infertility, there is a reduction in fertility beyond that seen in women with unexplained infertility. There are consistent findings of oocyte dysfunction and reduced fertilizing ability in women with minor endometriosis and a number of studies suggest additional disorders of gonadotrophin release and exposure to the follicle. Although new medical treatments are under development, no currently available medical treatments for suppression of endometriosis have been shown to improve fertility, whereas there may be a role for surgical treatment. Ovulation induction with clomiphene, exogenous gonadotrophins and intrauterine insemination, and assisted conception are all effective treatments for the infertile woman with minor endometriosis. Probably in that order, they should be used for the medical management of infertility associated with minor endometriosis.


    References
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 Abstract
 Introduction
 Evidence for a relationship...
 Does the evidence support...
 Current state of knowledge...
 Appropriate medical treatments...
 Conclusion
 References
 
Akande, V.A., Hunt, L.P., Cahill, D.J. and Jenkins, J.M. (2001) Factors affecting the difference in time to conception between women with unexplained infertility and infertility women with superficial endometriosis. Hum. Fert., 4, 214–215.

American Fertility Society (1985) Revised American Fertility Society (RAFS) classification of endometriosis. Fertil. Steril., 43, 351–352.[Medline]

American Society for Reproductive Medicine (1997) Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil. Steril., 67, 817–821.[ISI][Medline]

Arici, A., Oral, E., Bukulmez, O., Duleba, A., Olive, D. and Jones, E. (1996) The effect of endometriosis on implantation: results from the Yale University in in vitro fertilization and embryo transfer program. Fertil. Steril., 65, 603–607.[ISI][Medline]

Ayers, J.W., Birenbaum, D.L. and Menon, K.M. (1987) Luteal phase dysfunction in endometriosis: elevated progesterone levels in peripheral and ovarian veins during the follicular phase. Fertil. Steril., 47, 925–929.[ISI][Medline]

Azem, F., Lessing, J.B., Geva, E., Shahar, A., Lerner-Geva, L., Yovel, I. and Amit, A. (1999) Patients with stages III and IV endometriosis have a poorer outcome of in vitro fertilization-embryo transfer than patients with tubal infertility. Fertil. Steril., 72, 1107–1109.[ISI][Medline]

Bancroft, K., Vaughan Williams, C.A. and Elstein, M. (1992) Pituitary-ovarian function in women with minimal or mild endometriosis and otherwise unexplained infertility. Clin. Endocrinol. (Oxf.), 36, 177–181.[ISI][Medline]

Barratt, C.L., Chauhan, M. and Cooke, I.D. (1990) Donor insemination—a look to the future. Fertil. Steril., 54, 375–387.[ISI][Medline]

Bergendal, A., Naffah, S., Nagy, C., Bergqvist, A., Sjoblom, P. and Hillensjo, T. (1998) Outcome of IVF in patients with endometriosis in comparison with tubal-factor infertility. J. Assist. Reprod. Genet., 15, 530–534.[ISI][Medline]

Bordson, B.L., Ricci, E., Dickey, R.P., Dunaway, H., Taylor, S.N. and Curole, D.N. (1986) Comparison of fecundability with fresh and frozen semen in therapeutic donor insemination. Fertil. Steril., 46, 466–469.[ISI][Medline]

Bukulmez, O., Yarali, H. and Gurgan, T. (2001) The presence and extent of endometriosis do not effect clinical pregnancy and implantation rates in patients undergoing intracytoplasmic sperm injection. Eur. J. Obstet. Gynecol. Reprod. Biol., 96, 102–107.[ISI][Medline]

Cahill, D.J. (1998) Effect of granulosa cell apoptosis on fecundity? [letter; comment]. Fertil. Steril., 70, 1186–1187.[Medline]

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

Charnock-Jones, D.S., Macpherson, A.M., Archer, D.F., Leslie, S., Makkink, W.K., Sharkey, A.M. and Smith, S.K. (2000) The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium. Hum. Reprod., 15 (Suppl. 3), 85–95.[Medline]

Cheesman, K.L., Ben-Nun, I. and Chatterton, R.T. (1982) Relationship of luteinizing hormone pregnanediol-3-glucurinide and estriol-16-glucurinide in urine in infertile women with endometriosis. Fertil. Steril., 38, 542–548.[ISI][Medline]

Deaton, J.L., Gibson, M., Blackmer, K.M., Nakajima, S.T., Badger, G.J. and Brumsted, J.R. (1990) A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil. Steril., 54, 1083–1088.[ISI][Medline]

Dlugi, A., Loy, R., Dieterle, S., Bayer, S. and Seibel, M. (1989) The effect of endometriosis on in vitro fertilization outcome. J. IVF Embryo Transf., 6, 338–341.

Doody, W.C., Gibbons, W.E. and Buttram, V.C. (1988) Linear regression analysis of ultrasound follicular growth series: evidence for an abnormality of follicular growth in endometriosis patients. Fertil. Steril., 49, 47–51.[ISI][Medline]

Drake, T.S. and Grunert, G.M. (1980) The unsuspected pelvic factor in the fertility investigation. Fertil. Steril., 34, 27–29.[ISI][Medline]

Fedele, L., Bianchi, S., Marchini, M., Villa, L., Brioschi, D. and Parazzini, F. (1992) Superovulation with human menopausal gonadotropins in the treatment of infertility associated with minimal or mild endometriosis: a controlled randomized study. Fertil. Steril., 58, 28–31.[ISI][Medline]

Geber, S., Paraschos, T., Atkinson, G., Margara, R. and Winston, R. (1995) Results of IVF in patients with endometriosis: the severity of the disease does not affect outcome, or the incidence of miscarriage. Hum. Reprod., 10, 1507–1511.[Abstract]

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

Hassan, H.M. (1976) Incidence of endometriosis in diagnostic laparoscopy. J. Reprod. Med., 16, 135–137.[ISI][Medline]

Hughes, E.G. (1997) The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum. Reprod., 12, 1865–1872.[Abstract]

Hughes, E., Collins, J. and Vandekerckhove, P. (2000) Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev., 3.

Hughes, E., Fedorkow, D., Collins, J. and Vandekerckhove, P. (2001) Ovulation Suppression for Endometriosis (Cochrane Review). The Cochrane Library, Update Software, Oxford.

Hull, M.G., Williams, J.A., Ray, B., McLaughlin, E.A., Akande, V.A. and Ford, W.C. (1998) The contribution of subtle oocyte or sperm dysfunction affecting fertilization in endometriosis-associated or unexplained infertility: a controlled comparison with tubal infertility and use of donor spermatozoa. Hum. Reprod., 13, 1825–1830.[Abstract]

Jansen, R. (1986) Minimal endometriosis and reduced fecundability: prospective evidence from an artificial insemination by donor program. Fertil. Steril., 46, 141–143.[ISI][Medline]

Karabacak, O., Kambic, R., Gursoy, R. and Ozeren, S. (1999) Does ovulation induction affect the pregnancy rate after laparoscopic treatment of endometriosis? Int. J. Fertil. Women's Med., 44, 38–42.[ISI][Medline]

Lelaider, C., Caetano, J.A.J. and Frydman, R. (1993) In vitro fertilization and endometriosis. Current status of endometriosis—research and management. Proceedings of the 3rd World Congress on Endometriosis. Parthenon, Camforth, UK, pp. 419–424.

Lessey, B.A. (2000) Medical management of endometriosis and infertility. Fertil. Steril., 73, 1089–1096.[ISI][Medline]

Macpherson, A.M., Archer, D.F., Leslie, S., Charnock-Jones, D.S., Makkink, W.K. and Smith, S.K. (1999) The effect of etonogestrel on VEGF, oestrogen and progesterone receptor immunoreactivity and endothelial cell number in human endometrium. Hum. Reprod., 14, 3080–3087.[Abstract/Free Full Text]

Mahadevan, M., Trounson, A. and Leeton, J. (1983) The relationship of tubal blockage, infertility of unknown cause, suspected male infertility and endometriosis to success of in vitro fertilization and embryo transfer. Fertil. Steril., 40, 755–762.[ISI][Medline]

Mahmood, T., Arumugam, K. and Templeton, A. (1991a) Oocyte and follicular fluid characteristics in women with mild endometriosis. Br. J. Obstet. Gynaecol., 98, 573–577.[ISI][Medline]

Mahmood, T.A., Messinis, I.E. and Templeton, A. (1991b) Follicular development in spontaneous and stimulated cycles in women with minimal–mild endometriosis. Br. J. Obstet. Gynaecol., 98, 783–788.[ISI][Medline]

Marcoux, S., Maheux, R. and Berube, S. (1997) laparoscopic surgery in infertile women with minimal or mild endometriosis. N. Engl. J. Med., 337, 217–222.[Abstract/Free Full Text]

Matson, P. and Yovich, J. (1986) The treatment of infertility associated with endometriosis by in vitro fertilization. Fertil. Steril., 46, 432–434.[ISI][Medline]

McLaren, J. (2000) Vascular endothelial growth factor and endometriotic angiogenesis. Hum. Reprod. Update, 6, 45–55.[Abstract/Free Full Text]

Mills, M.S., Eddowes, H.A., Cahill, D.J., Fahy, U.M., Abuzeid, M.I., McDermott, A. and Hull, M.G. (1992) A prospective controlled study of in-vitro fertilization, gamete intra-Fallopian transfer and intrauterine insemination combined with superovulation. Hum. Reprod., 7, 490–494.[Abstract]

Minguez, Y., Rubio, C., Bernal, A., Gaitan, P., Remohi, J., Simon, C. and Pellicer, A. (1997) The impact of endometriosis in couples undergoing intracytoplasmic sperm injection because of male infertility. Hum. Reprod., 12, 2282–2285.[Abstract]

Olive, D.L. and Lee, K.L. (1986) Analysis of sequential treatment protocols for endometriosis-associated infertility. Am. J. Obstet. Gynecol., 154, 613–619.[ISI][Medline]

Olive, D.L. and Pritts, E.A. (2001) Treatment of endometriosis. N. Engl. J. Med., 345, 266–275.[Free Full Text]

Pal, L., Shifren, J.L., Isaacson, K.B., Chang, Y., Leykin, L. and Toth, T.L. (1998) Impact of varying stages of endometriosis on the outcome of in vitro fertilization–embryo transfer. J. Assist. Reprod. Genet., 15, 27–31.[ISI][Medline]

Parazzini, F. (1999) Ablation of lesions or no treatment in minimal–mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi. Hum. Reprod., 14, 1332–1334.[Abstract/Free Full Text]

Pellicer, A., Valbuena, D., Bauset, C., Albert, C., Bonilla-Musoles, F., Remohi, J. and Simon, C. (1998) The follicular endocrine environment in stimulated cycles of women with endometriosis: steroid levels and embryo quality. Fertil. Steril., 69, 1135–1141.[ISI][Medline]

Pepperell, R.J. and McBain, J.C. (1985) Unexplained infertility: a review. Br. J. Obstet. Gynaecol., 92, 569–580.[ISI][Medline]

Rodriquez-Escudero, F., Neyro, J., Corcostegui, B. and Benito, J. (1988) Does minimal endometriosis reduce fecundity? Fertil. Steril., 50, 522–524.[ISI][Medline]

Simon, C., Gutierrez, A., Vidal, A., de los Santos, M.J., Tarin, J., Remohi, J. and Pellicer, A. (1994) Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum. Reprod., 9, 725–729.[Abstract]

Simpson, C.W., Taylor, P.J. and Collins, J.A. (1992) A comparison of ovulation suppression and ovulation stimulation in the treatment of endometriosis-associated infertility. Int. J. Gynaecol. Obstet., 38, 207–213.[ISI][Medline]

Smith, S.K. (2001a) Regulation of angiogenesis in the endometrium. Trends Endocrinol. Metab., 12, 147–151.[ISI][Medline]

Smith, S.K. (2001b) Angiogenesis and reproduction. Br. J. Obstet. Gynaecol., 108, 777–783.[ISI]

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 minor endometriosis. Am. J. Reprod. Immunol., 47, 52–56.[ISI][Medline]

Snick, H.K., Snick, T.S., Evers, J.L. and Collins, J.A. (1997) The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum. Reprod., 12, 1582–1588.[Abstract]

Strathy, J.H., Molgaard, C.A. and Coulam, C.A. (1982) Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertil. Steril., 38, 667–672.[ISI][Medline]

Sung, L., Mukherjee, T., Takeshige, T., Bustillo, M. and Cooperman, A. (1997) endometriosis is not detrimental to embryo implantation in oocyte recipients. J. Assist. Reprod. Gen., 14, 152–156.[ISI][Medline]

Swolin, K. and Skogsberg, K. (1985) Endometriosis and basal body temperature. A new and simple diagnostic method. Preliminary report. Acta Obstet. Gynecol. Scand., 64, 617.[ISI][Medline]

Toya, M., Saito, H., Ohta, N., Saito, T., Kanedo, T. and Hiroi, M. (2000) Moderate and severe endometriosis is associated with alterations in the cell cycle of granulosa cells in patients undergoing in vitro fertilization and embryo transfer. Fertil. Steril., 73, 344–350.[ISI][Medline]

Tummon, I.S., Asher, L.J., Martin, J.S. and Tulandi, T. (1997) Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil. Steril., 68, 8–12.[ISI][Medline]

Tummon, I.S., Maclin, V.M., Radwanska, E., Binor, Z. and Dmowski, W.P. (1988) Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility. Fertil. Steril., 50, 716–720.[ISI][Medline]

Verpoest, W.M., Cahill, D.J., Harlow, C.R. and Hull, M.G. (2000) Relationship between midcycle luteinizing hormone surge quality and oocyte fertilization. Fertil. Steril., 73, 75–77.[ISI][Medline]

Wardle, P., McLaughlin, E., McDermott, A., Mitchell, J.D., Ray, B.D. and Hull, M.G.R. (1985) Endometriosis and ovulatory disorder: reduced fertilisation in vitro compared with tubal and unexplained infertility. Lancet, ii, 236–239.

Yovich, J., Matson, P., Richardson, P. and Hilliard, C. (1988) Hormonal profiles and embryo quality in women with severe endometriosis treated by in vitro fertilization and embryo transfer. Fertil. Steril., 50, 308–313.[ISI][Medline]