Edgardo Somigliana

Endometriosis: pathogenesis and treatment.

Endometriosis is defined as the presence of endometrial-type mucosa outside the uterine cavity. Of the proposed pathogenic theories (retrograde menstruation, coelomic metaplasia and Müllerian remnants), none explain all the different types of endometriosis. According to the most convincing model, the retrograde menstruation hypothesis, endometrial fragments reaching the pelvis via transtubal retrograde flow, implant onto the peritoneum and abdominal organs, proliferate and cause chronic inflammation with formation of adhesions. The number and amount of menstrual flows together with genetic and environmental factors determines the degree of phenotypic expression of the disease. Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility. Dysmenorrhoea, deep dyspareunia, dyschezia and dysuria are the most frequently reported symptoms. Standard diagnosis is carried out by direct visualization and histologic examination of lesions. Pain can be treated by excising peritoneal implants, deep nodules and ovarian cysts, or inducing lesion suppression by abolishing ovulation and menstruation through hormonal manipulation with progestins, oral contraceptives and gonadotropin-releasing hormone agonists. Medical therapy is symptomatic, not cytoreductive; surgery is associated with high recurrence rates. Although lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate. Assisted reproductive technologies constitute a valid alternative. Endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer, but preventive interventions are feasible.

Surgical excision of endometriomas and ovarian reserve: a systematic review on serum antimüllerian hormone level modifications

OBJECTIVE To evaluate serum antimüllerian hormone (AMH) level modification after surgical excision of ovarian endometriomas. DESIGN Systematic review. MEDLINE search from January 1990 to April 2012 using the combination of medical terms endometriosis, endometrioma, endometriotic cyst, and AMH or antimüllerian hormone, MIF or müllerian inhibiting factor. Reference lists of selected studies were checked for additional potential contributions. SETTING Not applicable. PATIENT(S) Women with ovarian endometriomas requiring surgery. INTERVENTION(S) Serum AMH level assessment. MAIN OUTCOME MEASURE(S) Serum AMH level modifications. RESULT(S) Eleven articles satisfied our selection criteria. Data pooling were deemed inopportune owing to the heterogeneity of the study designs and of the reported parameters. Nine of 11 studies documented a statistically significant reduction of serum AMH level after surgery. The two studies failing to document this decrease were published by the same study group and partly overlapped. The magnitude of the decline was more evident in women operated on for bilateral endometriomas. CONCLUSION(S) Evidence deriving from the evaluation of serum AMH level modifications after surgical excision of endometriomas supports a surgery-related damage to ovarian reserve.

Surgery for endometriosis-associated infertility: a pragmatic approach

Laparoscopic treatment for endometriosis-associated infertility is gaining widespread popularity supported mostly by uncontrolled studies, but the purported benefit of surgery may be overvalued. We have therefore analysed the best available evidence with the aim of defining an approximate estimate of the effect size of conservative surgery for infertile women with endometriosis in various clinical conditions. The overall increase in post-operative likelihood of conception over background pregnancy rate may be estimated to be between 10 and 25%. The effect of surgery for peritoneal lesions is limited, and an estimate of benefit should be decreased by the fact that preoperative identification of the subjects actually with the condition is unfeasible. The benefit of excision of ovarian endometriomas is difficult to define due to multiple confounding factors and methodological drawbacks in the considered studies. Excision of rectovaginal endometriosis is of doubtful value and associated with worrying morbidity. The role of surgery before, after or as an alternative to IVF needs clarification. In conclusion, the absolute benefit increase of surgery for endometriosis-associated infertility appears smaller than previously believed. Complete and detailed information on risks and benefits of treatment alternatives must be offered to infertile patients to allow unbiased choices between possible options.

Management of endometriomas in women requiring IVF: to touch or not to touch

The classic, unproven dogma that ovarian endometrioma should be removed in all infertile women prior to IVF has been recently questioned. There is currently insufficient data to clarify whether the endometrioma-related damage to ovarian responsiveness precedes or follows surgery. Both endometrioma-related injury and surgery-mediated damage may be claimed to be involved and the relative importance of these two insults remains to be clarified. Convincing evidence has emerged showing that responsiveness to gonadotrophins after ovarian cystectomy is reduced. Conversely, the impact of surgery on pregnancy rates is unclear since no deleterious effect has been reported. Of relevance here is that surgery exposes women to risk related to a demanding procedure whereas risks associated with expectant management are mostly anecdotal or of doubtful clinical relevance. We recommend proceeding directly to IVF to reduce time to pregnancy, to avoid potential surgical complications and to limit patient costs. Surgery should be envisaged only in presence of large cysts (balancing the threshold to operate with the cyst location within the ovary), or to treat concomitant pain symptoms which are refractory to medical treatments, or when malignancy cannot reliably be ruled out.

‘Waiting for Godot': a commonsense approach to the medical treatment of endometriosis

Conservative surgical treatment for symptomatic endometriosis is frequently associated with only partial relief of pelvic pain or its recurrence. Therefore, medical therapy constitutes an important alternative or complement to surgery. However, no available compound is cytoreductive, and suppression instead of elimination of implants is the only realistic objective of pharmacological intervention. Because this implies prolonged periods of treatments, only medications with a favourable safety/tolerability/efficacy/cost profile should be chosen. In the past few years, innumerable new drugs for endometriosis, which would interfere with several hypothesized pathogenic mechanisms, have been studied and their use foreseen. However, robust evidence of in vivo safety and efficacy is lacking and, at the moment, the principal modality to interfere with endometriosis metabolism is still hormonal manipulation. Regrettably, in spite of consistent demonstration of a major effect on pain even in patients with deeply infiltrating lesions, progestins are underestimated and dismissed in favour of more scientifically fashionable and up-to-the-minute alternatives. Moreover, oral contraceptives (OCs) dramatically reduce the rate of post-operative endometrioma recurrence and should now be considered an essential part of long-term therapeutic strategies in order to limit further damage to future fertility. Finally, women who have used OC for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer. To avoid the several subtle modalities for distorting facts and orientating opinions in favour of specific compounds, progestins and monophasic OC used continuously are here proposed as the reference comparator in all future randomized controlled trials on medical treatment for endometriosis.

Postoperative oral contraceptive exposure and risk of endometrioma recurrence

OBJECTIVE The purpose of this study was to compare the postoperative risk of endometrioma recurrence in women using oral contraception and in those undergoing simple observation. STUDY DESIGN After laparoscopic excision of ovarian endometriotiomas, a cyclic, low-dose, monophasic oral contraceptive pill (OCP) was offered to women not seeking pregnancy. One month after surgery, and every 6 months afterward, the patients underwent clinical and ultrasonographic assessment. RESULTS Of the 277 patients who entered the study, 102 used OCP for the entire follow-up period (always users), 129 used OCP discontinuously (ever users), and 46 declined treatment (never users). The median follow-up was 28 months. Recurrent endometriotic cysts were detected in 74 subjects (27%). The 36-month cumulative proportion of subjects free from endometrioma recurrence was 94% in the always users compared with 51% in the never users (P < .001); adjusted incidence rate ratio (IRR) = 0.10 (95% CI, 0.04-0.24). CONCLUSION Regular postoperative use of OCP effectively prevents endometrioma recurrence.

IVF–ICSI outcome in women operated on for bilateral endometriomas

BACKGROUND The influence of previous conservative surgery for endometriomas on IVF-ICSI outcome is debated. Conflicting information emerging from the literature may be consequent to the fact that endometriomas are mostly monolateral. The contralateral intact ovary may adequately supply for the reduced function of the affected one. To clarify this point, we assess IVF-ICSI outcome in women operated on for bilateral endometriomas. METHODS Women selected for IVF-ICSI cycles who previously underwent bilateral endometriomas cystectomy were matched (1:2) for age and study period with patients who did not undergo prior ovarian surgery. RESULTS Sixty-eight cases and 136 controls were recruited. Women operated on for bilateral endometriotic ovarian cysts had a higher withdrawal rate for poor response (P < 0.001). In these patients, despite the use of higher doses of gonadotrophins, the number of follicles (P = 0.006), oocytes retrieved (P = 0.024) and embryos obtained (P = 0.024) were significantly lower. The clinical pregnancy rate per started cycle in cases and controls was 7% and 19% (P = 0.037) and the delivery rate per started cycle was 4% and 17%, respectively (P = 0.013). CONCLUSIONS IVF outcome is significantly impaired in women operated on for bilateral ovarian endometriomas.

Endometriosis: Current Therapies and New Pharmacological Developments

Endometriosis is a chronic inflammatory condition that is responsive to management with steroids. The establishment of a steady hormonal environment and inhibition of ovulation can temporarily suppress ectopic implants and reduce inflammation as well as associated pain symptoms. In terms of pharmacological management, the currently available agents are not curative, and treatment often needs to be continued for years or until pregnancy is desired. Similar efficacy has been observed from the various therapies that have been investigated for endometriosis. Accordingly, combined oral contraceptives and progestins, based on their favourable safety profile, tolerability and cost, should be considered as first-line options, as an alternative to surgery and for post-operative adjuvant use. In situations where progestins and oral contraceptives prove ineffective, are poorly tolerated or are contraindicated, gonadotrophin-releasing hormone analogues, danazol or gestrinone may be used. Future therapeutic options for managing endometriosis must compare favourably against existing agents before they can be considered for inclusion into current practice. Finally, as reproductive prognosis is not ameliorated by medical treatment, it is not indicated for women seeking conception.

Rate of severe ovarian damage following surgery for endometriomas

BACKGROUND There is growing and consistent evidence showing that ovarian reserve is affected following surgical excision of ovarian endometriomas. Of particular concern is the risk of severe ovarian damage leading to unresponsiveness to ovarian hyperstimulation. In this study, we aimed to determine the rate of this complication. METHODS Ninety-three women underwent surgery for monolateral endometriomas were recruited. Patients who underwent IVF were selected and, in all cases, follicular growth was monitored by serial transvaginal ultrasonography. The main outcome measure was the rate of ovaries remaining silent when stimulated after surgery for endometriomas. RESULTS Absence of follicular growth was observed in 12 operated ovaries although this event never occurred in the contralateral gonad (P < 0.001). The frequency (95% confidence interval) of severe ovarian damage following surgery was 13% (7-21%). CONCLUSIONS Severe ovarian damage, occurring in gonads operated on for ovarian endometriomas, is not a rare event.

Medical treatment for rectovaginal endometriosis: what is the evidence?

BACKGROUND Rectovaginal endometriosis usually causes distressing pain. Surgical treatment may be effective but is associated with a high risk of morbidity and major complications. Information on the effect of medical alternatives for pain relief in this condition is scarce. METHODS A comprehensive literature search was conducted to identify all the English language published observational and randomized studies evaluating the efficacy of medical treatments on pain associated with rectovaginal endometriosis. A combination of keywords was used to identify relevant citations in PubMed, MEDLINE and EMBASE. RESULTS A total of 217 cases of medically treated rectovaginal endometriosis were found; 68 in five observational, non-comparative studies, 59 in one patient preference cohort study, and 90 in a randomized controlled trial. An aromatase inhibitor was used in two of the non-comparative studies, vaginal danazol in one, a GnRH agonist in one, and an intrauterine progestin in one. Two estrogen-progestin combinations used transvaginally or transdermally were evaluated in the patient preference study, whereas an oral progestin and an estrogen-progestin combination were compared in the randomized controlled trial. With the exception of an aromatase inhibitor used alone, the antalgic effect of the considered medical therapies was high for the entire treatment period (from 6 to 12 months), with 60-90% of patients reporting considerable reduction or complete relief from pain symptoms. CONCLUSIONS Despite problems in interpretation of data, the effect of medical treatment in terms of pain relief in women with rectovaginal endometriosis appear substantial.