Maria Pina Frattaruolo

‘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.

Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis

STUDY QUESTION Is adenomyosis associated with IVF/ICSI outcome in terms of clinical pregnancy rate? SUMMARY ANSWER In a meta-analysis of published data, women with adenomyosis had a 28% reduction in the likelihood of clinical pregnancy at IVF/ICSI compared with women without adenomyosis. WHAT IS KNOWN ALREADY Estimates of the effect of adenomyosis on IVF/ICSI outcome are inconsistent. STUDY DESIGN, SIZE, DURATION A systematic literature review and meta-analysis were conducted. A Medline search was performed to identify all the comparative studies published from January 1998 to June 2013 in the English language literature on IVF/ICSI outcome in women with and without adenomyosis. Two authors independently performed the literature screening, scrutinized articles of potential interest, selected relevant studies and extracted data. Studies were categorized based on research design. PARTICIPANTS, SETTING, METHODS Of the 17 articles assessed in detail, 9 were finally selected based on diagnosis of adenomyosis at magnetic resonance imaging or transvaginal ultrasonography. The quality of studies was evaluated by means of the Newcastle-Ottawa scale. A total of 1865 women were enrolled in the 9 selected studies, 665 of whom in 4 prospective observational studies, and 1200 in 5 retrospective studies. The dichotomous data for clinical pregnancy and secondary outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CIs) and were combined in a meta-analysis using the random-effects model. The heterogeneity Cochranes Q and the I(2) statistics were calculated. Eggers approach to testing the significance of funnel plot asymmetry was also used. MAIN RESULTS AND THE ROLE OF CHANCE The clinical pregnancy rate achieved after IVF/ICSI was 123/304 (40.5%) women with adenomyosis versus 628/1262 (49.8%) in those without adenomyosis. The RR of clinical pregnancy ranged from 0.37 (95% CI, 0.15-0.92) to 1.20 (95% CI, 0.58-2.45), with a significant heterogeneity among studies (I(2) = 56.8%, P = 0.023). Pooling of the results yielded a common RR of 0.72 (95% CI, 0.55-0.95). A funnel plot showed no indication of asymmetry among studies (Eggers test, P = 0.696). In a meta-regression model, no association was observed between prevalence of endometriosis and the likelihood of clinical pregnancy. Three studies reported the pregnancy rate per cycle. The common RR was 0.71 (95% CI, 0.51-0.98; I(2) = 78.1%, P = 0.010). The RR observed in a study with donated oocytes was 0.90 (95% CI, 0.75-1.08). The number of miscarriages per clinical pregnancy was reported in seven studies. A miscarriage was observed in 77/241 women with adenomyosis (31.9%) and in 97/687 in those without adenomyosis (14.1%). The RR of miscarriage ranged from 0.57 (95% CI, 0.15-2.17) to 18.00 (95% CI, 4.08-79.47) (I(2) = 67.7%, P = 0.005). Pooling of the results yielded a common RR of 2.12 (95% CI, 1.20-3.75). LIMITATIONS, REASONS FOR CAUTION Qualitative and quantitative heterogeneity among studies was high. At sensitivity analysis, I(2) statistic regarding the main outcome was reduced under the 50% threshold removing one trial, but the resulting confidence interval crossed unity. Also the confidence interval of the common RR of the four studies reporting only one IVF/ICSI cycle included unity. Only part of the studies could be included in the assessment of secondary outcomes. WIDER IMPLICATIONS OF THE FINDINGS Adenomyosis appears to impact negatively on IVF/ICSI outcome owing to reduced likelihood of clinical pregnancy and implantation, and increased risk of early pregnancy loss. Screening for adenomyosis before embarking on medically assisted reproductive procedures should be encouraged. The potentially protective role of long down-regulation protocols needs further evaluation. In future studies on the association between adenomyosis and IVF/ICSI outcome, a matched case-control design should be adopted, live birth should be the default primary outcome and only the results regarding the first cycle should be considered. STUDY FUNDING/COMPETING INTEREST None.

Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis.

Ovulation seems crucial in the pathogenesis of ovarian endometriomas. Therefore, suppression of ovulation should be protective against cyst relapse after excision. The objective of this systematic review was to assess the effect of long‐term postoperative medical treatment on the risk of endometrioma recurrence. A MEDLINE search was conducted to identify all the comparative studies published in the last 12 years in the English language literature on the relation between long‐term postoperative adjuvant therapy and risk of endometrioma recurrence. Of the 12 articles assessed in detail, four were finally selected based on surgery for endometriotic cysts, postoperative medical treatment use for ≥12 months vs. expectant management, and ultrasonographic and/or histological diagnosis of endometrioma recurrence. A total of 965 women were enrolled, 726 of whom were in three cohort studies and 239 in one randomized controlled trial. Oral contraceptives (OCs) were always used as postoperative adjuvant treatment. The absolute effect of postoperative OC use was assessed by comparing “always” and “never” users. A recurrent endometrioma was identified in 33 of 423 (8%) “always” OC users and in 117 of 341 (34%) women who underwent expectant management (pooled odds ratio 0.12; 95% confidence interval 0.05–0.29). To define the effect of duration of use, “always” users were compared with “ever” users, and “ever” with “never” users, with a pooled odds ratio of, respectively, 0.21 (95% confidence interval 0.11–0.40) and 0.39 (95% confidence interval 0.23–0.66). Postoperative OC use dramatically decreased the risk of ovarian endometrioma recurrence, especially in women who used OCs regularly and for prolonged periods.

Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study

Please cite this paper as: Vercellini P, Parazzini F, Pietropaolo G, Cipriani S, Frattaruolo M, Fedele L. Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study. BJOG 2012;119:1538–1543.

Surgical versus low-dose progestin treatment for endometriosis-associated severe deep dyspareunia II: Effect on sexual functioning, psychological status and health-related quality of life

STUDY QUESTION Does surgical and low-dose progestin treatment differentially affect endometriosis-associated severe deep dyspareunia in terms of sexual functioning, psychological status and health-related quality of life? SUMMARY ANSWER Surgery and progestin treatment achieved essentially similar benefits at 12-month follow-up, but with different temporal trends. WHAT IS ALREADY KNOWN Conservative surgery and hormonal therapies have been used independently for endometriosis-associated deep dyspareunia with inconsistent results. STUDY DESIGN, SIZE, DURATION Patient preference, parallel cohort study with 12-month follow-up. The effect of conservative surgery at laparoscopy versus treatment with a low dose of norethisterone acetate per os (2.5 mg/day) in women with persistent/recurrent severe deep dyspareunia after first-line surgery was compared. PARTICIPANTS/MATERIALS AND SETTING, METHODS A total of 51 patients chose repeat surgery and 103 progestin treatment. Variations in sexual function, psychological well-being and quality of life were measured by means of the Female Sexual Function Index (FSFI), the Hospital Anxiety and Depression Scale (HADS) and the Endometriosis Health Profile-30 (EHP-30). MAIN RESULTS AND THE ROLE OF CHANCE Four women in the surgery group and 21 women in the progestin group withdrew from the study for various reasons. Total FSFI scores, anxiety and depression scores and EHP-30 scores improved immediately after surgery, but worsened with time, whereas the effect during progestin use increased more gradually, but progressively, without overall significant between-group differences at 12-month follow-up. A tendency was observed towards a slightly better total FSFI score after surgery at the end of the study period. LIMITATIONS, REASONS FOR CAUTION Treatments were not randomly allocated, and distribution of participants as well as of dropouts between study arms was unbalanced. However, the possibility of choosing the treatment allowed assessment of the maximum potential effect size of the interventions. WIDER IMPLICATIONS OF THE FINDINGS Both surgery and medical treatment with progestins are valuable options for improving the detrimental impact of endometriosis-associated dyspareunia on sexual functioning and quality of life. Women should be aware of the pros and cons of both options to decide which one best suits their needs. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a research grant from the University of Milan School of Medicine (PUR number 2009-ATE-0570). None of the authors have a conflict of interest.

Adenomyosis and reproductive performance after surgery for rectovaginal and colorectal endometriosis: a systematic review and meta-analysis

The relationship between rectovaginal-bowel endometriosis and fertility is unclear. Nevertheless, extirpative surgery, including colorectal resection, is being fostered as a fertility-enhancing procedure. Adenomyosis and deep endometriosis often coexist. As the uterine condition may further impact on reproductive outcome, this work performed a systematic literature review with the objective of identifying all English-language reports on surgical treatment for rectovaginal and colorectal endometriosis, including bowel resection, in which participants were screened preoperatively for uterine adenomyosis. Risk ratios (RR) were then combined in a meta-analysis. In the five selected observational studies, in women seeking pregnancy, 7/59 (11.9%) with concomitant adenomyosis conceived, compared with 74/172 (43.0%) in those without adenomyosis. Adenomyosis was never excised. One in 10 women experienced a major surgical complication. The RR of clinical pregnancy ranged from 0.23 to 0.46, with absence of heterogeneity among studies (I(2)=0.0%). Pooling of the results yielded a common RR of 0.32 (95% confidence interval 0.16 to 0.66). No small-study effect was detected (Eggers test). Screening for adenomyosis before suggesting difficult and risky procedures may allow identification of a subgroup of patients at particularly worse prognosis for which surgery would have a marginal effect on the likelihood of conception. Deep endometriosis may infiltrate the rectum, vagina and sigmoid colon. These severe forms are usually associated with pain, but their relationship with fertility is unclear. Despite lack of convincing evidence, extirpative surgery, including colorectal resection, is being fostered as a fertility-enhancing procedure, although these procedures may cause major complications. Adenomyosis (i.e. the infiltration of the uterine wall by endometrial glands) often coexists with deep endometriosis, and several investigators believe that the former condition may have a detrimental effect on fertility more than the latter. If this is true, screening for adenomyosis may allow preoperative identification of a subgroup of patients at particularly worse prognosis for whom difficult and risky surgery would have a marginal or no effect on the likelihood of conception. To disentangle this issue, we performed a systematic literature review with the objective of identifying all English-language reports on surgical treatment for rectovaginal and colorectal endometriosis, including bowel resection, in which participants were also investigated preoperatively for uterine adenomyosis. Risk ratios (RR) were then combined in a meta-analysis. In the five selected observational studies, in women seeking pregnancy, 7/59 (11.9%) women with concomitant adenomyosis conceived, compared with 74/172 (43.0%) in those without adenomyosis. One in 10 women experienced a major surgical complication. The RR of clinical pregnancy consistently ranged from 0.23 to 0.46. Pooling of the results yielded a common RR of 0.32 (95% CI 0.16-0.66). Adenomyosis was associated with a 68% reduction in the likelihood of pregnancy in women seeking conception after surgery for rectovaginal and colorectal endometriosis.

Role of surgery in endometriosis-associated subfertility.

Analysis of published series reveals that no more than a fourth of subfertile patients undergoing surgery for peritoneal endometriotic implants, rectovaginal endometriotic lesions, or recurrent endometriomas achieved conception spontaneously. First-line surgery for ovarian endometriotic cysts appears associated with a better reproductive performance, that is, a mean postoperative pregnancy rate of ∼50%. At the same time, excision of endometriomas paradoxically seems to induce gonadal damage. With the exception of peritoneal disease, no randomized trials are available to assess the effect of surgery in subfertile women with endometriosis. Therefore, it is not possible to define the absolute benefit increase of the treatment of ovarian and rectovaginal lesions. The decision to undergo surgery for endometriosis-associated subfertility must be shared with the woman after detailed information and taking into account several additional conditions, such as presence of pain, large or complex adnexal masses, bowel or ureteral stenosis, and coexisting infertility factors. When considering surgery, a therapeutic equipoise should be reached that includes demonstrated benefits, potential morbidity, and costs of treatment alternatives. Particularly in case of recurrent endometriosis, in vitro fertilization should generally be preferred to surgery. The role of surgery in endometriosis-associated subfertility includes temporary pain relief in symptomatic women desiring a spontaneous conception.

“I Can't Get No Satisfaction”∗: deep dyspareunia and sexual functioning in women with rectovaginal endometriosis

OBJECTIVE To assess the impact of rectovaginal endometriosis on pain at intercourse and sexual functioning. DESIGN Case-control study. SETTING Academic department. PATIENT(S) Case subjects were women with rectovaginal endometriosis (n = 100), and control subjects were women with a surgical diagnosis of peritoneal and/or ovarian endometriosis (n = 100) or without endometriosis (n = 100). INTERVENTION(S) Questionnaires (visual analogue scale [VAS] and revised Sabbatsberg Sexual Self-Rating Scale [SRS]). MAIN OUTCOME MEASURE(S) Frequency and severity of deep dyspareunia and sexual functioning. RESULT(S) Deep dyspareunia was reported by 67/100 (67%) women in the rectovaginal endometriosis group, 52/99 (53%) in the peritoneal and/or ovarian endometriosis group, and 24/93 (26%) in the nonendometriosis group. Mean ± SD dyspareunia VAS scores were, respectively, 44 ± 34, 30 ± 32, and 13 ± 26. Women in both endometriosis groups performed significantly worse than those in the nonendometriosis group in several SRS subdomains. No significant difference in overall SRS score was detected between women in the two endometriosis groups. CONCLUSION(S) Women with endometriosis experienced more frequent and severe deep dyspareunia and worse sexual functioning compared with women without endometriosis, whereas differences between women with diverse endometriosis forms were marginal.

“You are so beautiful”*: Behind women’s attractiveness towards the biology of reproduction: a narrative review

Female beauty has always attracted human beings. In particular, beauty has been interpreted in terms of reproductive potential and advantage in selection of mates. We have reviewed the recent literature on female facial and physical beauty with the objective of defining which parameters could influence female attractiveness. Symmetry, averageness, and sexual dimorphism with regards to facial beauty, as well as waist-to-hip ratio (WHR), breast size, and body mass index (BMI) for physical beauty, have been assessed. In current societies, it appears that facial attractiveness results from a mixture of symmetry and averageness of traits, high forehead and cheekbones, small nose and chin, full lips, thin eyebrows, and thick hair. A low WHR reliably characterized physical attractiveness, whereas inconsistencies have been observed in the evaluation of breast size and BMI. The importance of breast size appears to vary with time and sex of evaluators, whereas the impact of BMI is related to socio-economic conditions. The various hypotheses behind beauty and the role of attractiveness in mate choice and sexual selection are here described in terms of continuation of human species. Intriguing associations are emerging between features of attractiveness and some reproductive disorders, as both are substantially influenced by sex steroid hormones.

Surgery versus hormonal therapy for deep endometriosis: is it a choice of the physician?

Deep endometriosis, occurring approximately in 1% of women of reproductive age, represents the most severe form of endometriosis. It causes severe pain in the vast majority of affected women and it can affect the bowel and the urinary tract. Hormonal treatment of deep endometriosis with progestins, such as norethindrone acetate or dienogest, or estroprogestins is effective in relieving pain in more than 90% of women at one year follow up. Progestins and estroprogestins can be safely administered in the long-term, may be not expensive and are usually well tolerated. Therefore, they should represent the first-line treatment of deep endometriosis associated pain in women not seeking natural conception. However, hormonal treatment is ineffective or not tolerated in about 30% of women, the most common side effects being erratic bleeding, weight gain, decreased libido and headache. Surgical excision of deep endometriosis is mandatory in presence of symptomatic bowel stenosis, ureteral stenosis with secondary hydronephrosis, and when hormonal treatments fail. Surgical treatment is similarly effective as compared to hormonal treatment in relieving dismenorhea, dyspareunia and dyschezia at one year follow up in more than 90% of women with deep endometriosis. Surgical removal of the nodules may require resection of the bowel, ureter or bladder, with possible severe complications such as rectovaginal or ureterovaginal fistula and anastomotic leakage. A thorough counsel with the patient is necessary in order to pursue a therapeutic plan centered not on the endometriotic lesions, but on the patients symptoms, priorities and expectations.