Laura Buggio

The ‘incessant menstruation’ hypothesis: a mechanistic ovarian cancer model with implications for prevention

Serous, endometrioid, clear cell and mucinous histotypes are the most common epithelial ovarian cancer. Most serous cancers appear to originate from precursor lesions at the fimbriated tubal end, whereas most endometrioid and clear cell cancers seem to derive from atypical endometriosis. Data regarding hormonal factors and associated gynaecologic conditions were critically analysed with the objective of defining a carcinogenic model for sporadic epithelial ovarian cancer complying with epidemiologic and pathologic findings. Oral contraceptives and tubal ligation substantially reduce the risk of serous, endometrioid and clear cell subgroups, but have no significant effect on mucinous tumours, which probably follow a different oncogenic pathway. We hypothesize that serous, endometrioid and clear cell cancers share a common pathogenic mechanism, i.e. iron-induced oxidative stress derived from retrograde menstruation. Fimbriae floating in bloody peritoneal fluid are exposed to the action of catalytic iron and to the genotoxic effect of reactive oxygen species, generated from haemolysis of erythrocytes by pelvic macrophages. This would explain the distal site of tubal intraepithelial neoplasia. Collection of blood inside endometriomas would lead to the same type of genotoxic insult on gonadal endometrial implants. This would explain why endometriosis-associated cancers develop much more frequently in the ovary than at extragonadal sites. In women not seeking conception, bilateral salpingectomy could be advised whenever planning surgery for independent indications, thus possibly reducing cancer risk, while preserving ovarian function. The use of oral contraceptives should be favoured for prolonged periods of time, especially in women with endometriosis, a population at doubled risk of gonadal malignancy.

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.

Estrogen-progestins and progestins for the management of endometriosis

Endometriosis is characterized by frequent recurrences of symptoms and lesions even after extirpative surgery. Because medical therapies control but do not cure the disease, long periods of pharmacologic management may be needed until pregnancy desire or, sometimes, physiologic menopause. Hormonal drugs suppress ovulation and menstruation and have similar beneficial effects against pain. However, only estrogen-progestins and progestins have safety/tolerability/cost profiles that allow long-term use. These compounds induce atrophy of eutopic and ectopic endometrium, have antiinflammatory and proapoptotic properties, and can be delivered via different modalities, including oral, transdermal, subcutaneous, intramuscular, vaginal, and intrauterine routes. At least two-thirds of symptomatic women are relieved from pain and achieve appreciable improvements in health-related quality of life. Progesterone resistance may cause nonresponse in the remaining one-third. When using estrogen-progestins continuously, individualized, tailored cycling should be explained to improve compliance. All combinations demonstrated a similar effect on dysmenorrhea, independently from progestin type. Estrogen-progestins with the lowest possible estrogen dose should be chosen to combine optimal lesion suppression and thrombotic risk limitation. Progestins should be suggested in women who do not respond or manifest intolerance to estrogen-progestins and in those with dyspareunia and/or deep lesions. Progestins do not increase significantly the thrombotic risk and generally may be used when estrogens are contraindicated. Estrogen-progestins and progestins reduce the incidence of postoperative endometrioma recurrence and show a protective effect against endometriosis-associated epithelial ovarian cancer risk.

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.

Endometriosis and ovarian cancer

In 556 patients undergoing surgery for ovarian cancers the frequency of endometriosis ranged from 3.6% to 5.6% in serous, mucinous, and miscellaneous neoplasms versus 26.3%, 21.1 %, and 22.2%, respectively, in endometrioid, clear cell, and mixed subtypes; the differences were statistically significant (x heterogeneity 50.0, p < 0.001) and consistent in strata of age, parity, menopausal status, and disease stage. (AM J OSSTET GVNECOL 1993;169:181-2.)

‘Behind blue eyes’: the association between eye colour and deep infiltrating endometriosis

STUDY QUESTION Is the prevalence of blue eye colour higher in women with deep endometriosis? SUMMARY ANSWER Blue eye colour is more common in women with deep endometriosis when compared with both women with ovarian endometriomas and women without a history of endometriosis. WHAT IS KNOWN ALREADY Recent and intriguing evidence suggests that women with deep endometriosis may have particular phenotypic characteristics including a higher prevalence of a light-colour iris. Available epidemiological evidence is however weak. STUDY DESIGN, SIZE, DURATION Case-control study performed in a large academic department specializing in the study and treatment of endometriosis. Individual iris colour was evaluated in daylight and categorized in three grades, namely blue-grey (blue), hazel-green (green) and brown. One observer assessed iris colour. In addition, the women themselves were invited to indicate the colour of their eyes according to the same classification system. Cases with discordant eye colour determinations between the observer and the woman were excluded from the final analysis. PARTICIPANTS MATERIALS, SETTINGS, METHODS Two hundred and twenty-three women with deep endometriosis (cases), 247 with ovarian endometriomas and 301 without a history of endometriosis were enrolled. MAIN RESULTS AND THE ROLE OF CHANCE After exclusion of 52 discordant cases, the proportions of brown, blue and green eye colours were, respectively, 61, 30 and 9% in the deep endometriosis group, 74, 16 and 10% in the endometrioma group and 75, 15 and 10% in the non-endometriosis group. Women in the deep endometriosis group had a statistically significant excess of blue eyes and a reduced proportion of brown eyes compared with the two control groups (P = 0.002 and P < 0.001, respectively). The proportion of blue eyes was almost identical in the ovarian endometrioma group and the non-endometriosis group, and that of green eyes was substantially similar in all study groups. The OR (95% CI) of having blue eyes in women with deep endometriosis compared with women with ovarian endometriosis and with those without endometriosis was, respectively, 2.2 (1.4-3.6) and 2.5 (1.6-3.9). LIMITATIONS, REASON FOR CAUTION We cannot exclude that some women without a previous diagnosis of endometriosis indeed had the disease. However, this would have led to a reduction of the observed difference in proportion of blue eyes, thus to a potential underestimation of the real strength of the association. Moreover, under-ascertainment is possible with regard to peritoneal disease, but unlikely with deep endometriotic lesions and ovarian endometriomas. WIDER IMPLICATIONS OF THE FINDINGS There are two possible explanations for our findings. Both may have intriguing implications for future research on endometriosis. Firstly, genes involved in the control of iris colour transmission may lie in a region with a strong pattern of linkage disequilibrium with genes involved in the invasiveness of endometriosis. Alternatively, blue eye colour could be considered an indicator of a photo-sensitive phenotype resulting in limited exposure to sunlight and UVB radiation. Limited sunlight exposure is associated with reduced circulating 25-hydroxyvitamin D3, an element that has recently been linked to endometriosis development.