• Treatment of ovarian endometriomas
• Hormônio anti-mulleriano (AMH): novo marcador de reserva ovariana
• Management of poor responders
• Two decades of experience with GnRH analogues in endometriosis and infertility

Dr. Juliano A. Brum Scheffer

Endometriosis is a common gynaecological disorder in which endometrial tissue (glandular epithelium and stroma) is found outside the uterine cavity. It affects 20–40% of women who complain of subfertility, although it can be found also in 5–10% of fertile women. Endometriosis mostly presents as superficial and deep pelvic peritoneal implants, adhesions and ovarian cysts. Characteristic symptoms include dyspareunia, severe dysmenorrhoea and chronic pelvic pain.

It has been believed for almost a century by the majority of academic opinion that endometriosis is a disease caused by shedding of menstrual endometrium and its dissemination throughout the pelvis. The origin of ovarian endometriomas, endometriotic deposits within the ovary, is unknown; however, most authors believe that they result initially from a deposit of endometrium passed through the Fallopian tube, causing adherence of the ovary to the pelvic peritoneum and progressive invagination (folding inwards) of the ovary. If this is true, an endometrioma would be a pseudocyst (false cyst), the wall of which is the inverted ovarian cortex (centre) and hence the removal of this cyst wall might involve removal of normal ovarian tissue, with possible adverse implications for future fertility. Transvaginal ultrasound is an increasingly accepted technique for the diagnosis of an ovarian endometrioma.
The primary indications for treatment of ovarian endometriomas are the symptoms of pelvic pain and dyspareunia (pain during or after sexual intercourse). The evidence suggests that, although medical treatment will result in a reduction in size of the endometrioma of up to 57%, the most effective approach to treatment is surgical, but it may impair the outcome of fertility treatment.

Several alternative laparoscopic techniques have been described for the treatment of ovarian endometriomas: cyst wall laser vaporization (destruction by burning) preceded or not by medical therapy, drainage and coagulation, and stripping. The procedure of drainage of the endometrioma alone is not recommended due to the risk of infection and a high rate of recurrence. However, the most effective method of laparoscopic surgery (excisional or ablative) remains controversial. Following ovarian endometrioma cystectomy, some studies have shown conflicting results on ovarian response, with some patients showing a detrimental effect and others showing no adverse effect.

There is a lack of randomized controlled studies to report definitively the impact of endometriomas and conservative surgery of ovarian prior to IVF/ICSI cycles.. In this regard, it is important to note that, at present, there are no definitive data to clarify whether the damage is related to the surgical procedure and/or to the previous presence of the cyst. Indeed, it cannot be excluded that the cyst per se may damage the surrounding ovarian tissue. Using pathological sections of the ovarian cortex surrounding ovarian endometriomas, Maneschi et al., found a reduced number of follicles antecedent to surgery, suggesting that the disease per se may be detrimental to the ovary. A major concern is that resection of endometriomas results in the loss of small follicles adjacent to the cyst wall and a reduced oocyte pool, which itself is associated with infertility. In fact, several retrospective studies have reported reduced responses to gonadotrophins after cystectomy for ovarian endometriomas in young women and ovarian endometrioma cystectomy before starting ovulation induction in assisted reproduction cycles does not seem to improve the cycle outcome in asymptomatic and uncomplicated patients with certain diameters.
However, failure to operatively address the endometrioma might result in continued discomfort and potential complications, such as cyst rupture (endometrioma>4cm) and the possibility of malignancy (rare).

In conclusion, it would seem that the age of the patient, the certainty of diagnosis, and the patient’s symptoms are important factors to consider when counseling whether to consider conservative ovarian surgery or proceed directly to controlled ovarian hyperstimulation (COH). Proceeding directly to COH in asymptomatic women with ovarian endometriomas might reduce the time to pregnancy, diminish patient costs, and avoid the potential complications of surgery. Conversely, symptomatic women with ovarian endometriomas or asymptomatic with endometrioma > 4cm might be advised to surgical treatment.

Juliano Augusto Brum Scheffer, MD
* Diretor Científico do Instituto Brasileiro de Reprodução Assistida - IBRRA
* Membro do Corpo Clínico e de Pesquisa do Centro de Reprodução Humana do Hôpital Antoine Béclère – Paris/ França

References

1. Yazbeck C, Madelenat P, Sifer C, Hazout A, Poncelet C. Ovarian endometriomas: Effect of laparoscopic cystectomy on ovarian response in IVF-ET cycles Gynecol Obstet Fertil. 2006;34(9):808-12.
2. Yanushpolsky EH, Best CL, Jackson KV, Clarke RN, Barbieri RL and Hornstein MD Effects of endometriomas on oocyte quality, embryo quality and pregnancy rates in in vitro fertilization cycles: a prospective, case-controlled study. J Assist Reprod Genet 1998;15,193–197.
3. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril. 2002 Jul;78(1):206-7.
4. Audebert A Ovarian endometrioma and infertility: when not to treat? Gynecol Obstet Fertil 2005;33(6):416-22.
5. Tinkanen H, Kujansuu E. In vitro fertilization in patients with ovarian endometriomas.
6. Acta Obstet Gynecol Scand. 2000;79(2):119-22.
7. Ho HY, Lee RK, Hwu YM, Lin MH, Su JT, Tsai YC. Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet. 2002;19(11):507-11.
8. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of >3 cm in diameter. Hum Reprod. 2001;16(12):2583-6.
9. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, Pellicer A. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril. 2004 May;81(5):1194-7. S
10. Somigliana E, Infantino M, Benedetti F, Arnoldi M, Calanna G, Ragni G The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins. Fertil Steril. 2006 Jul;86 (1):192-6.
11. Maneschi F, Marasa L, Incandela S, Mazzarese M, Zupi E. Ovarian cortex surrounding benign neoplasms: a histologic study. Am J Obstet Gynecol. 1993;169(2Pt 1):388-93.

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Dr. Juliano A. Brum Scheffer

A razão da dosagem do hormônio folículo estimulante (FSH), inibina B (InbB) e estradiol (E) no terceiro dia do ciclo menstrual é essencialmente baseada na habilidade do folículo antral precoce de produzir InbB e E em resposta ao FSH. O valor da dosagem desses marcadores varia de acordo com a fase de crescimento folicular e varia com o tamanho dos folículos antrais durante a fase folicular precoce. Essas limitações podem explicar em parte a notável variabilidade dos resultados desses hormônios de um ciclo menstrual ao outro.

O hormônio anti-mulleriano é uma glicoproteína que pertence à superfamília dos fatores ß de crescimento. Esta molécula é principalmente expressada pelas células de Sertoli no testículo fetal, onde está envolvido na diferenciação do trato reprodutor dos mamíferos e pelas células da granulosa dos folículos ovarianos. Estudos em roedores e em humanos têm sugerido que o AMH esteja envolvido na inibição do crescimento folicular primordial a primário (fase inicial do crescimento dos folículos ovarianos) e na resposta folicular ao FSH.

A concentração sérica do AMH no terceiro dia do ciclo diminui progressivamente ao longo da idade e torna-se não detectável depois da menopausa. A alteração da concentração do AMH ocorre mais precocemente que a dos outros hormônios em relação ao avanço da idade da mulher e a alteração substancial do FSH sérica ocorre somente depois dos ciclos menstruais já terem tornados irregulares. Isto sugere que a dosagem periférica do AMH é um parâmetro valioso para monitorar a exaustão folicular (insuficiência ovariana).

A relação entre a quantidade de folículo antral e a concentração sérica do AMH no terceiro dia é significativa e melhor quando comparado com o FSH, InbB e E, além da pequena variação entre ciclos menstruais do AMH. A concentração sérica do AMH durante a fase folicular precoce do ciclo menstrual reflete o número de oócitos em cada ovário, o número de oócitos recrutados após ciclos estimulados, o número de oócitos obtidos na punção folicular e relaciona positivamente com a taxa de gravidez em ciclos estimulados.

O AMH apresenta três peculiaridades que a diferem dos outros marcadores hormonais de reserva ovariana (E, FSH, Inb B). Primeiro, o AMH é expressa pelas células da granulosa de todos os folículos “precoces” (estágio primário à antral precoce). Segundo, os folículos após o estágio antral precoce perdem progressivamente a capacidade de expressar o AMH. Terceiro, a produção do AMH pelos folículos ovarianos é independente do FSH.

Logo a dosagem periférica do AMH é um marcador importante e interessante da reserva ovariana e do prognóstico do tratamento de infertilidade.

1. Baerwald AR, Adams GP, Pierson RA 2003 A new model for ovarian follicular development during the human menstrual cycle. Fertility and Sterility 80, 116–22.
2. de Vet A, Laven JS, de Jong FH et al. 2002 Antimullerian hormone serum concentrations: a putative marker for ovarian aging. Fertility and Sterility 77, 357–362.
3. Ebner T, Sommergruber M, Moser M et al. 2006 Basal level of anti-Müllerian hormone is associated with oocyte quality in stimulated cycles. Hum Reprod. 21: 2022 - 2026.
4. Fanchin R, Taieb J, Lozano DH et al. 2005a High reproducibility of serum anti-Mullerian hormone measurements suggests a multi-staged follicular secretion and strengthens its role in the assessment of ovarian follicular status. Human Reproduction 20, 923–927.
5. Fanchin R, Mendez Lozano DH, Louafi N et al. 2005b Dynamics of serum anti-Mullerian hormone concentrations during the luteal phase of controlled ovarian hyperstimulation. Human Reproduction 20, 747–751.
6. Fanchin R, Louafi N, Mendez Lozano DH et al. 2005c Per-follicle measurements indicate that anti-mullerian hormone secretion is modulated by the extent of follicular development and luteinization and may reflect qualitatively the ovarian follicular status. Fertility and Sterility 84, 167–173.
7. Fanchin R, Schonauer LM, Righini C et al. 2003 Serum anti- Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Human Reproduction 18, 323–327.
8. Fanchin R, Schonauer LM, Righini C et al. 2003 Serum anti- Mullerian hormone dynamics during controlled ovarian hyperstimulation. Human Reproduction 18, 328–332.
9. Fiçicioglu C Kutlu T, Baglam E et al. 2006. Early follicular antimüllerian hormone as an indicator of ovarian reserve. Fertility and Sterility 85, 592–596

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Dr Daniel H. MENDEZ LOZANO

Ovarian ageing is one of the most difficult challenges on assisted reproduction therapy (ART). Lack of response to traditional ovarian stimulation converts it in an expensive, heavy, not tolerated and inadequate treatment. However, even when the incidence of poor response is of 9 to 24%, the importance of a homogeneous consensus to define it has been delayed with the consequent multi therapy proposed and their difficulty to be compared.

During reproductive life, follicle depletion occurs principally by the mechanisms of atresia in younger women or predominantly by their entrance on growing follicular phase in older women. Moreover, this depletion rate has an important increment after the age of 37 years or when the follicular pool disappearance has reached less than 25000 follicles. These weakening on oocyte quantity and its wide variation are determinant on the outcome of assisted reproduction therapy (ART).

Conversely, in order to optimize the reproductive capacity of growing antral follicular waves, one of the most important contributions to increase the outcome on IVF has been the controlled ovarian hyperstimulation (COH). The COH offers a multiple oocyte retrieval that allows a selective embryo transfer, the key to improve the pregnancy rates. Even though the COH remains an expensive and complex therapy, the augmented pregnancy rates justify its application. However, the embryo selection is not possible when only a few oocytes are collected and the embryo transfer is often performed with only the viable embryos with the consequent lower result. For this population with a reduced response to COH, a different approach seems to be necessary to obtain a better outcome or the same results with a simplified protocol.

Natural cycle IVF with controlled LH surge ovulation
An alternative that remains simple, efficient, inexpensive and to short term on treatment of poor responders is the in vitro fertilization on natural cycle (IVF Nat). However, the efficacy of IVF Nat varies from 0% to 23% on clinical pregnancy rate per ovarian punction (OPU). These irreproducible results are explained by the lack of standardization on the practice of IVF on natural cycle from a center to another.
One of the factors limiting the success on IVF Nat is the OPU failure. In this sense the semi natural cycle, based most of all on the utilization of GnRH antagonists, seems to improve the recovering rate by preventing the premature LH pick. Thus, follicular flushing seems to be an adequate method on semi natural cycle IVF and even it can duplicate the pregnancy rate/OPU (Mendez D. , Scheffer J. et al. in press).

A critical point in favor of the semi natural cycles is the lower cost by clinical pregnancy as it was previously described by Ubaldi et al.; in their analyze the cost of a clinical pregnancy obtained by classical ovarian stimulation was 72,050 euros versus 12,300 with semi natural cycles IVF. Even when the lower cost of the IVF Nat has been observed by several studies as well as the needless of anesthesia, until recently, the efficacy of semi natural cycles over classical ovarian stimulation has been established for poor responders patients. In this well conducted study, 129 patients with a previous response defined as 3 or less matured follicles on ovarian hyperstimulation where randomized to be treated with another ovarian stimulation (n=70) or with semi natural cycle IVF (n=59). A similar pregnancy rates/cycle was observed between both of groups (15% and 14.3%, respectively, for patients aged of less than 36 years). Conversely, an elevated implantation rate was observed in patients treated with semi natural cycle IVF (33.3% versus 12.5%), as it was observed previously by others.

However, optimal treatment for poor responder patients depends of age and the number of cycles offered. Others studies have shown a reduction on the implantation rate with female ageing possibly lied to an aneuploidy increment. Like this, seminatural cycle IVF should not be proposed on patients aged of more than 36-38 years old and the total number of attempts must be restricted to 3 because their very low results on this sub population. In fact, these studies confirm that for poor responder patients, more than the deficit on ovarian reserve, age is the most important predictive factor.

In base of this evidence, semi natural cycle IVF seems to be the most appropriate therapy to patients with a previous poor response, as it is cheaper, more simple and at least as effective as the traditional complex protocols. However, it should not be indicated in older women and their practice must include the use of antagonists and follicular flushing.

Dr Daniel H. MENDEZ LOZANO
Department of Obstetrics & Gynecology and Reproductive Medicine
Hôpital Antoine Béclère, Clamart, France
Reproductive Medicine CREASIS
ITESM School of Medicine, Monterrey, México

References

1. Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod. 50(3), 653-663 (1994).
2. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod. 7(10), 1342-1346 (1992).
3. Morgia F, Sbracia M, Schimberni M et al. A controlled trial of natural cycle versus microdose gonadotropin-releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization. Fertil Steril. 81(6), 1542-1547 (2004).
4. Bassil S, Godin PA, Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders. Hum Reprod. 14(5), 1262-1265 (1999).
5. Ubaldi FM, Rienzi L, Ferrero S et al. Management of poor responders in IVF. Reprod Biomed Online. 10(2), 235-246 (2005).
6. Castelo Branco A, Achour-Frydman N, Kadoch J, Fanchin R, Tachdjian G, Frydman R. In vitro fertilization and embryo transfer in seminatural cycles for patients with ovarian aging. Fertil Steril. 84(4), 875-880 (2005).
7. Olivenne F, Ayoubi JM, Fanchin R et al. GnRH antagonist in single-dose applications. Hum Reprod Update. 6(4), 313-317 (2000).
8. Castelo-Branco A, Frydman N, Kadoch J et al. The role of the semi natural cycle as option of treatment of patients with a poor prognosis for successful in vitro fertilization. J Gynecol Obstet Biol Reprod (6 Pt 1), 518-524 (2004).
9. Frydman R. GnRH antagonists in natural cycles. J Gynecol Obstet Biol Reprod. (6 Pt 2), 3S46-49 (2004).

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Juan A Garcia-Velasco

Endometriosis, a disease that occurs in about one woman in 10, and about which little accurate information is available, has been linked to infertility. A great variety of treatments have been assayed in infertile women suffering from endometriosis. The disease was first described in 1860 by Czech pathologist Von Rokitansky working in Vienna, but there is still a lack of understanding of the association between endometriosis and infertility. It has been estimated that 2% to 5% of the general population has endometriosis, and this prevalence increases up to 25% to 40% among infertile patients.

Medical management of endometriosis-associated pelvic pain is common today. However, when we try to extrapolate medical therapies that have proved to be useful for pain in women with endometriosis-associated infertility it raises very high expectations that to date are completely unfulfilled.

Endometriosis may be affecting oocyte quality, ovulation, corpus luteum formation, egg transport into the fallopian tube, sperm motility inside the uterus, fertilization, embryo cleavage and embryo quality. Some of the treatments that have been assayed are pseudopregnacy with medroxiprogesterone acetate – based on the observation that pregnancy induces a favourable effect on the disease, continuously given oral contraceptive pills to avoid the monthly menstrual bleeding, antiprogestins more recently, and obviously a sustained hypoestrogenic state, either with danazol or GnRH analogues (GnRHa).

There are several decapeptides and nonapeptides known as GnRHa approved for treating endometriosis-associated pain with proven efficacy. Due to the hypogonadal state induced, vasomotor instability and reduction in bone mineral density may occur with prolonged treatments (>six months) unless add-back therapy with small addition of estrogens or progestins is instituted.

Considering GnRHa treatment of endometriosis-associated infertility, no prospective, randomized, double-blind, controlled clinical trial has provided evidence that this therapy improves their reproductive outcome. A recent metaanalysis published by the Cochrane Library has shown no benefit of GnRHa vs placebo, or GnRHa vs danazol, in terms of pregnancy rate in women with endometriosis-associated infertility.

The experience with GnRH antagonists in this subject is very limited, and small descriptive series have shown good results with weekly administration of 3mg of the antagonist. New venues are being explored, such as chronic low dose GnRH antagonist administration or even new orally active molecules.

Trying to show that medical therapy is effective in these women has some intrinsic difficulties. First, we have to remember that 50% of women with stage I-II endometriosis will conceive spontaneously. Second, patient heterogeneity makes comparison quite complicated. Treating patients with a GnRHa makes them infertile for the time period that they are being treated, so in order to compare their outcome with non-treated patients, we should start the observation period at the end of the treatment with the analogues and probably extend this observation period; otherwise, control patients will conceive while treated patients are unable to do so due to the treatment, making the effect of the treatment invisible. Ideally, we should have one or a combination of biomarkers that could select those 50% patients who will conceive spontaneously, so we could focus on the really infertile ones. And third, most studies compare patients classified according to the revised American Society for Reproductive Medicine (r-ASRM) classification. While being an interesting classification in terms of morphology and description of the lesions, it is absolutely useless in terms of fertility prognosis. There are studies showing a complete lack of correlation between r-ASRM classification and either pain or infertility.

Although hormonal treatment does not improve fertility in infertile women with endometriosis, it has a role in ART. Observational data from the early 1990s showed that IVF cycle outcome was improved if the patient received GnRHa. Considering the patients with endometriosis have a poorer outcome according to recent metaanalysis, we might hypothesize that treating the patient with GnRHa right before the cycle could improve the outcome. Two recent randomized trials have proved this hypothesis, although sample size was limited. The rationale behind this effect might be a reduction in natural killer (NK) cell activity.

To conclude, medical therapy is ineffective for endometriosis-associated infertility but a combination of therapy with ART might be beneficial. Future research should focus in the area of biomarkers and in well designed, properly controlled clinical trials.

Juan A Garcia-Velasco, MD
IVI-Madrid, Rey Juan Carlos University, Madrid, Spain

References

1. Lessey BA. ‘Medical management of endometriosis and infertility’. Fertil Steril 2000; 73: 1089-96.
2. Evers JL. ‘Endometriosis does not exist; all women have endometriosis’. Hum Reprod 1994; 9: 2206-9
3. Rickes D, Nickel I, Kropf S, Kleinstein J. ‘Increased pregnancy rates after ultralong postoperative therapy than gonadotropin-releasing hormone analogs in patients with endometriosis’. Fertil Steril 2002; 78: 757-762
4. Surrey E, Silverberg KM, Surrey MW, Schoolcraft WB. ‘Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis’. Fertil Steril 2002; 78: 699-704

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