Neal G. Mahutte

Uterine Chemokines in Reproductive Physiology and Pathology

PROBLEM: Chemokines are increasingly recognized as important regulators of uterine function.

Medical management of endometriosis-associated pain

In the coming years, basic science research into the mechanisms of endometriosis development and persistence almost certainly will open new avenues for treatment. A wide armamentarium of medical therapies already exists, however. The efficacy of most of these methods in reducing endometriosis-associated pain is well established. The choice of which to use depends largely on patient preference after an appropriate discussion of risks, side effects, and cost. Typically, oral contraceptives and NSAIDs are first-line therapy because of their low cost and mild side effects (Box 6). Because of its greater potential for suppressing endometrial development, consideration should be given to prescribing a low-dose monophasic oral contraceptive continuously. If adequate relief is not obtained or if side effects prove intolerable, consideration should be given to the use of progestins (oral, intramuscular, or IUD) or a GnRH agonist with immediate add-back therapy. Progestins are less expensive, but GnRH agonists with add-back may be better tolerated. If none of these medications proves beneficial or if side effects are too pronounced, then repeat surgery is warranted. The surgery may have analgesic value and serves to reconfirm the diagnosis. Finally, if endometriosis is identified at the time of surgery, then consideration should be given to prescribing medical therapy postoperatively.

NEW ADVANCES IN THE UNDERSTANDING OF ENDOMETRIOSIS RELATED INFERTILITY

The association between endometriosis and infertility is complex. Nevertheless, in the absence of tubal distortion considerable evidence suggests four principle factors likely to contribute to subfertility. These include impaired folliculogenesis, decreased fertilization, inflammatory factors in follicular, peritoneal and reproductive tract fluid, and implantation defects. The potential impact of each of these is critically examined. The role of endometriomas, prior surgeries and donor oocytes is also discussed.

Poor responders: does the protocol make a difference?

An inadequate response to gonadotropins during in-vitro fertilization treatment may result in cycle cancellation, fewer embryos available for transfer and decreased pregnancy rates. For these reasons, numerous strategies to improve ovarian stimulation in poor responders have been proposed. These include variations in the type, dose and timing of gonadotropins, gonadotropin-releasing hormone agonists and gonadotropin-releasing hormone antagonists. Unfortunately, despite optimism generated by studies using retrospective controls, epidemiologically sound trials have been scarce. Indeed, of the three prospective randomized trials performed in poor responders to date no compelling advantage for one stimulation protocol over another has been established. Although this lack of improvement may reflect inadequate sample sizes, an alternative explanation is simply that the protocol, after a certain point, does not make a difference. Aside from oocyte donation, greater hope for poor responders may rest in aneuploidy screening, in-vitro oocyte maturation and cytoplasm/nuclear transfer.

Impact of body mass index on IVF and ICSI outcome: a retrospective study

A group of 140 women with a body mass index (BMI) < or = 24 kg/m(2) undergoing 291 cycles was compared with a group of 138 women with a BMI >24 kg/m(2) in 291 cycles, with respect to duration of ovarian stimulation and dose of gonadotrophin, number of oocytes collected, cleavage and implantation rate, clinical pregnancy, miscarriage and delivery rates. Patients with a BMI > 24 kg/m(2) demonstrated a significant decrease in the number of follicles after stimulation (P = 0.01), a comparative increase in the number ampoules of gonadotrophin used (P = 0.03) and a lower number of eggs collected (P = 0.05). The mean number of embryos on days 1, 2 and 3 was significantly lower in the group with BMI > 24 kg/m(2) (P < 0.001). No significant difference was found in clinical pregnancy and miscarriage rates between the two groups. In spite of the lower response in women with BMI > 24 kg/m(2), the delivery rate per retrieval was not different (24.6 versus 24.8%). These results indicate a lower stimulation response in women with elevated BMI, but no adverse effect on IVF outcome. In relation to wellbeing, however, it is recommended that patients with a high BMI reduce their weight before IVF treatment.

Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis

OBJECTIVE Peritoneal fluid (PF) inflammatory factors may participate in the pathogenesis of endometriosis. The aim of this study was to investigate PF interleukin (IL)-18 levels in women with and without endometriosis. DESIGN Controlled clinical study. SETTING Women undergoing laparoscopy at a university hospital. PATIENT(S) Fifty women with previously untreated endometriosis, 8 women on GnRH agonists for endometriosis, and 18 control women with normal pelvic anatomy who were undergoing tubal ligation. INTERVENTION(S) Peritoneal fluid IL-18 levels as measured by ELISA. MAIN OUTCOME MEASURE(S) Peritoneal fluid IL-18 levels. RESULT(S) Peritoneal fluid IL-18 levels were significantly higher in women with previously untreated endometriosis (mean +/- SEM, 91.1 +/- 6.5 pg/mL) than in control women (59.4 +/- 2.0 pg/mL). Interestingly, women with superficial (100.0 +/- 10.2 pg/mL) and deep peritoneal implants (94.0 +/- 10.8 pg/mL) had significantly higher PF IL-18 levels than did women with endometriomas (57.8 +/- 1.8 pg/mL). Similarly, women with stage I-II endometriosis (97.3 +/- 8.0 pg/mL), but not women with stage III-IV endometriosis (74.9 +/- 9.9 pg/mL), had significantly higher PF IL-18 levels than did control women. Peritoneal fluid IL-18 levels were significantly higher in the luteal phase than in the follicular phase but did not discriminate between women with pelvic pain or infertility. CONCLUSION(S) Peritoneal fluid IL-18 is elevated in women with peritoneal, minimal- to mild-stage endometriosis.

Apoptosis and Differential Expression of Apoptosis-Related Proteins in Endometriotic Glandular and Stromal Cells

Objective: Apoptosis is an important regulator of eutopic endometrial function. Endometriosis, the growth of endometrial tissue outside the uterus, could result from increased cellular proliferation or decreased apoptosis in response to appropriate stimuli. The objective of this study was to evaluate the rate of apoptosis and the expression of apoptosis-related Bcl-2 and Bax proteins in endometriotic tissues within the glandular and stromal compartments, according to the phase of the menstrual cycle and the stage of disease. Methods: Ovarian endometriosis samples were evaluated in 75 women who had surgery at a university hospital. Apoptotic cells were detected with the use of the dUTP nick-end labeling (TUNEL) assay. Bcl-2 and Bax expression were assessed by immunohistochemical techniques. Results: The percentage of apoptotic cells was significantly higher in endometriotic stormal cells (73.3%) compared with glandular cells (48%; P = .002). In contrast, the expression of the apoptosis-related proteins Bcl-2 and Bax was significantly lower in the endometriotic stroma (17.3% for both) than in the glandular epithelium (38.6% and 41.3%, respectively; P < .004). No significant menstrual cycle phase-dependent changes or endometriosis stage-related changes were observed in TUNEL, Bcl-2, or Bax positivity within ovarian endometriotic tissues. Conclusion: Apoptosis occurs in ovarian endometriots lesions at significantly higher levels in the stroma than the glandular epithelium. However, Bcl-2 and Bax proteins are distributed preferentially in glandular epithelial cells. the apoptotic rate as well as Bcl-2 and Bax expression in ovarian endometriotic cells were not affected by the stage of endometriosis or the phase of thhe menstrual cycle.

Endometriosis and assisted reproductive technologies: are outcomes affected?

The preponderance of recent data suggests that endometriosis does not adversely affect in-vitro fertilization pregnancy rates. However, many studies demonstrate impaired oocyte quality, decreased fertilization, and compromised implantation rates. Such findings give insight into the mechanisms by which endometriosis may impact on fertility, and provide clues as how to focus assisted reproductive technologies in order to overcome these deficiencies. Specifically, extended downregulation protocols, ample use of gonadotropins for ovarian stimulation, and conservative management of endometriomas have all been suggested as means to optimize in-vitro fertilization outcomes for women with endometriosis.

The familial risk of breast cancer in women with endometriosis from Yale series

OBJECTIVE Few studies examining the association of endometriosis with the risk of breast cancer. Our goal was to investigate the familial risk of breast cancer in women with endometriosis. DESIGN Retrospective study. SETTING University-based endometriosis referral center. PATIENTS Three hundred fifty-two women with endometriosis and 180 infertile women without endometriosis were studied using laparoscopy between August 1996 and February 2002. The endometriosis group was further subdivided into a group of women with 94 positive and 268 negative family histories of breast cancer. MAIN OUTCOME MEASURE(S) The overall risk of familial breast cancer among first- and second-degree relatives in patients with endometriosis and the association between potential risk factors was estimated by chi(2) and by crude adjusted odds ratios (95% CI). RESULTS Positive family history of breast cancer was detected in (26.7%) 94/352 of endometriosis group and in (5%) 9/180 of controls. The relative risk of women with endometriosis and positive family history of breast cancer was (OR=6.9 (95% CI, 3.4-14.1), chi(2)=34.6, P<0.001). Endometriosis was associated with the risk of first-degree relatives of breast cancer (OR=5.69 (95% CI, 2.4-13.3), P<0.001). Moreover, endometriosis was significantly associated with the risk of breast cancer in mothers (OR=6.3 (95% CI, 2.2-17.8), P<0.001) and in maternal aunts (OR=5.9 (95% CI, 1.3-72.9), P<0.001). The two groups are similar in age, race height, main complaints, age of menarche, cycle length, days of flow, estimated blood loss, stage of endometriosis and the presence of endometrioma. CONCLUSION(S) This study found an elevated risk associated with family history of breast cancer among women with endometriosis. A familial clustering interaction with a familial history of breast cancer in women with endometriosis is possible, but should be investigated further.

Increased pregnancy-associated plasma protein-A (PAPP-A) concentrations in peritoneal fluid of women with endometriosis.

PROBLEM:  Pregnancy‐associated plasma protein‐A (PAPP‐A) belongs to a group of glycoproteins isolated from extracts of human placenta. Healthy ovarian and uterine tissues are also known to express PAPP‐A. We hypothesized that PAPP‐A levels might also be elevated in the peritoneal fluid (PF) of women with endometriosis, and examined variations in PF PAPP‐A during the menstrual cycle and with the severity of the disease.