Arguments for a left lateral predisposition of endometrioma.

OBJECTIVE: To analyze a hypothesis regarding the pathogenesis of endometriosis. DESIGN: Retrospective study. SETTING: Two academic endometriosis referral centers. PATIENT(S): We evaluated operative and pathologic reports of 251 women who underwent laparoscopic or laparotomy treatment of endometrioma from August 1996 to February of 2002 at Yale University School of Medicine and at the University of Crete Department of Obstetrics and Gynecology. INTERVENTION(S): Laparascopic examination. MAIN OUTCOME MEASURE(S): Statistical methods included chi(2) and Mann-Whitney U tests measuring incidence of right- vs. left-sided endometria. RESULT(S): One hundred seventy patients from Yale University and 81 Greek patients participated in this study. Endometrioma was significantly more frequent in the left ovary (139 of 206 [67.4%]) than in the right ovary (67 of 206 [32.6%]; odds ratio [OR] = 4.3; 95% confidence interval [CI) 2.9-6.5; chi(2) = 48.9) and significantly different from the expected proportion of 50% (chi(2) = 25.2). When bilateral endometriomas were included, 62.1% (184 of 296) were left-sided and 37.15 (112 of 296) were right-sided (OR = 17.5; 95% CI 1.9-3.8; chi(2) = 34.1). Dilated ovarian veins in were found in 22 (68.7%) of 32 Greek cases with endometrioma. All 20 women with left endometrioma had left ovarian vein dilated. CONCLUSION(S): We suggest a new mechanical theory of implication, the female varicocele theory, which could play an important role in the development of ovarian endometriosis or endometriomas.

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.

Familial aggregation of endometriosis in the Yale Series.

OBJECTIVE: To investigate the familial aggregation and the risk of endometriosis among the female relatives of women with endometriosis. We also compared the epidemiologic characteristics of women with and without family history of endometriosis. PATIENT(S): A total of 485 women with endometriosis and 197 infertile women without endometriosis underwent surgical investigation between August 1996 and February 2002. MAIN OUTCOME MEASURE(S): The relative risk of endometriosis in a first-degree relative and the association between potential risk factors was estimated by chi2 and by crude adjusted odds ratios (95% CI). RESULTS: Endometriosis was identified in 9.5% of first-degree relatives of women with endometriosis versus only 1% of controls. The odds ratio for endometriosis in a first-degree relative was 10.21 (95% CI 2.45-42.5; P<0.001). In 3.9% of cases women with endometriosis reported that their mother had been diagnosed with endometriosis and 5.6% of cases that at least one sister had been diagnosed. Compared to the control group the odds ratio for the mother having endometriosis (7.99, 95% CI 1.06-60.1) or at least one sister having (11.55, 95% CI 1.56-85.59) were significantly elevated. Among women with endometriosis who reported a family history of endometriosis, and women with endometriosis who did not report a family history of endometriosis, there were no differences in demographic characteristics, body habitus, or menstrual parameters. CONCLUSION(S): Women with endometriosis have a tenfold increased risk of endometriosis in their first-degree relatives.

Epidemiological characteristics in women with and without endometriosis in the Yale series.

OBJECTIVE: The association between demographic factors, menstrual and reproductive characteristics, and clinical profile for women with endometriosis was analyzed in a retrospective case-control study. METHODS: Over a 6-year period, 535 women with endometriosis and 200 infertile women without endometriosis, studied by laparoscopy or laparotomy, were evaluated. Information was then collected in a uniform manner from the patients' medical records. Statistical methods included chi(2) and Mann-Whitney U test. RESULTS: The factors associated with an increased risk for endometriosis include lower body weight, alcohol use (chi(2) = 8.8; P < 0.003), early menarche (chi(2) = 5.08; P < 0.024), shorter cycle length (chi(2) = 13.06; P < 0.001), and heavier menstrual cycles. Pelvic pain was present in 79.1% of women with endometriosis, dysmenorrhea in 70.2%, and dyspareunia in 49.5%. These symptoms were statistically significantly higher in comparison with the infertile women without endometriosis (P < 0.001). Moreover, we found that women with endometriosis had fewer prior pregnancies, elective abortions and ectopic pregnancies compared to women seeking care for infertility, who did not have endometriosis. Interestingly, women with endometriosis were significantly more likely to report a family history of cancer compared to women in control group (chi(2) = 78.2; P < 0.001). CONCLUSIONS: Body habitus, personal habits and menstrual characteristics are all strongly associated with the development of endometriosis. There may also be an association between family history of cancer and the development of endometriosis.

p16, retinoblastoma (pRb), and cyclin D1 protein expression in human endometriotic and adenomyotic lesions.

OBJECTIVE: To investigate the expression of p16, retinoblastoma (pRb), and cyclin D1 oncoproteins in endometriomas and adenomyosis. DESIGN: Immunohistochemical study for p16, pRb, and cyclin D1 proteins in formalin-fixed paraffin-embedded endometriotic and adenomyotic tissues. SETTING: University hospital. PATIENT(S): Tissues from 25 women with endometriomas and 31 women with adenomyosis were evaluated. INTERVENTION(S): Tissue samples were collected during gynecologic surgery and confirmed by histology to have endometriosis or adenomyosis. Nuclear expression of p16, pRb, and cyclin D1 proteins was examined by immunohistochemistry. MAIN OUTCOME MEASURE(S): Distribution and intensity of immunostaining. RESULT(S): In the proliferative phase of the cycle, p16 was detected in 77% of adenomyosis tissues but in only 15% of endometriosis tissues. Moreover, in adenomyosis samples positive for p16, 100% of the adenomyotic cells expressed p16, whereas only 10%-20% of endometriosis cells from positive cases expressed p16. In contrast, pRb was detected in 28% of endometriosis cases but not in any adenomyotic tissues. Cyclin D1 was absent in both endometriotic and adenomyotic tissue samples. CONCLUSION(S): Differences in oncoprotein expression between endometriotic and adenomyotic tissues provide further evidence that the pathogenesis of endometriosis is different from that of adenomyosis.

High concentrations of the CA-125, CA 19-9 and CA 15-3 in the peritoneal fluid between patients with and without endometriosis.

OBJECTIVE: In the present study we compared the levels of CA-125, CA 19-9, and CA 15-3 in the peritoneal fluid (PF) of patients with and without endometriosis, then assessed the possibility of a correlation among these tumor markers. STUDY DESIGN: Our study was a controlled clinical study of patients undergoing laparoscopy for infertility or other benign gynecology conditions. Peritoneal fluid samples were collected from 65 women with endometriosis and 43 women without pelvic disease. Levels of CA-125, CA 19-9 and CA 15-3 in the peritoneal fluid were determined by immunoradiometric assay. RESULTS: The concentration of CA-125 in PF from patients with endometriosis was significantly higher than that in the control group (p<0.001); for CA 19-9 and CA 15-3, PF concentrations were not statistically different between these two groups. Women with endometriosis had significantly higher levels of CA-125 in proliferative and secretory phases than the control group (p<0.001 and p<0.002 respectively); furthermore, in patients with endometriosis the CA 19-9 levels were significantly lower in secretory phase than the proliferative (p<0.004). The levels of CA-125 were significantly lower in women with tubal ligation, in comparison with infertility or pelvic pain in the control group (p<0.001). No significant difference was seen in women with infertility or pelvic pain in endometriosis group and the levels of CA-125, CA 19-9, and CA 15-3. We did not find any correlation between the stages of endometriosis and the concentration of CA-125, CA 19-9 and CA 15-3. A significant correlation between the CA 19-9 levels and CA 15-3 in patients with endometriosis was found (r=0.72, p=0.001). CONCLUSIONS: We found high concentrations of CA-125, CA 19-9, and CA 15-3 in the peritoneal fluid of women with and without endometriosis in the Yale series. However, the levels only of CA-125 were higher in women with endometriosis, but without diagnostic value. The role of simultaneously high concentrations of CA 19-9 and CA 15-3 in women with endometriosis needs to be explored further.

Elevations in peritoneal fluid macrophage migration inhibitory factor are independent of the depth of invasion or stage of endometriosis.

OBJECTIVE: To quantify levels of macrophage migration inhibitory factor (MIF) in the peritoneal fluid (PF) of women with endometriosis, and to correlate these levels with the extent of disease. DESIGN: Controlled clinical study. SETTING: Academic medical center. PATIENT(S): Peritoneal fluid samples were collected during laparoscopic surgery in 60 women with endometriosis and 16 controls undergoing tubal ligation; 52 of the women with endometriosis had received no hormonal treatment in the 6 months prior to surgery, while 8 were using gonadotropin-releasing hormone (GnRH) agonists. MAIN OUTCOME MEASURE(S): Peritoneal fluid migration inhibitory factor (PF MIF) levels. RESULT(S): Women with endometriosis had significantly higher PF MIF levels (10.8 +/- 0.9 ng/mL) than controls (3.0 +/- 0.7 ng/mL). However, no correlation existed between MIF levels and the stage of disease (r = 0.05) or the depth of endometriotic invasion (r = 0.08). Moreover, treatment with a GnRH agonist did not suppress PF MIF levels. Peritoneal fluid MIF levels did not vary significantly between the proliferative and secretory phases of the cycle, and did not distinguish women with endometriosis-associated infertility from women with endometriosis-associated pain. CONCLUSION(S): Peritoneal fluid migration inhibitory factor levels are markedly elevated in women with endometriosis but are independent of the extent of disease.

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 stromal 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 endometriotic 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 the menstrual cycle.

Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis.

OBJECTIVE: To investigate the effects of danazol and leuprorelin acetate on CA-125 levels during treatment for endometriosis. PATIENTS AND METHODS: Fifty women with laparoscopically diagnosed and treated endometriosis, and 50 women without pelvic disease as a control group. Following surgical treatment, 35 women with endometriosis were divided into two groups. The first group (20 women) received 200 mg danazol three times daily for 6 months; the second group (15 women) received 3.75 mg leuprorelin acetate depot every 28 days for 6 months. Serum CA-125 levels were measured before medical treatment, during the last 15 days of the 6-month treatment course, and 3 months after treatment. RESULTS: Serum CA-125 levels were significantly higher in women with endometriosis than in women in the control group. Before treatment, CA-125 levels in patients with stage III/IV endometriosis were significantly higher than those in stage I/II endometriosis. Six months of danazol or leuprorelin acetate depot treatment decreased serum CA-125 levels. Three months after stopping danazol, CA-125 levels remained significantly lower than pretreatment levels. On the other hand, 3 months after stopping leuprorelin acetate, CA-125 levels returned to pretreatment levels. CONCLUSIONS: (a) Danazol and leuprorelin acetate are equally effective in the treatment of endometriosis. (b) Moreover, the results support the view that the determination of CA-125 levels may assist in evaluating progress of endometriosis treatment.

Endometriosis arising during estrogen and testosterone treatment 17 years after abdominal hysterectomy: a case report.

OBJECTIVE: To report the possible association between the use of oestrogen replacement therapy and endometriosis in a postmenopausal woman. METHODS: We present a case of a postmenopausal, previously hysterectomised, woman who received hormonal replacement therapy and developed a large broad ligament cyst. Two years prior to her presentation she had been complaining of pelvic pain and deep dyspareunia. RESULTS: Pelvic ultrasound showed an adnexal cyst that was increasing in size. CA-125 was normal. Laparoscopy revealed multiple endometriotic deposits and a broad ligament cyst. Cystectomy and oophorectomy were done. Histology confirmed a diagnosis of endometriosis including the broad ligament cyst. CONCLUSIONS: Hormonal replacement therapy can be associated with de novo endometriosis including at sites, which are unusual.

Inverse correlation between peritoneal fluid leptin concentrations and the extent of endometriosis.

BACKGROUND: The role of leptin in reproductive processes has received increasing attention. Because leptin has intrinsic angiogenic properties, may be induced by inflammatory cytokines and induces matrix metalloproteinases, we examined peritoneal fluid (PF) leptin concentrations in women with endometriosis. METHODS: PF samples were collected from 60 women undergoing laparoscopy for endometriosis, and 18 controls undergoing tubal sterilization. Fifty of the women with endometriosis had received no prior hormonal treatment, while 10 with moderate- severe endometriosis were using GnRH agonists. RESULTS: Women with untreated endometriosis had significantly higher (mean +/- SD) PF leptin levels (34.9 +/- 7.9 ng/ml) than controls (17.9 +/- 4.1 ng/ml; P < 0.001). However, PF leptin levels were inversely correlated with the stage of disease (r = -0.62; P < 0.001). Nevertheless, women with stage III-IV endometriosis maintained significantly higher PF leptin levels (26.3 +/- 4.8 ng/ml; P < 0.001) than controls. Although PF leptin levels were significantly higher in the secretory versus proliferative phase of the menstrual cycle, they remained higher in both phases in women with untreated endometriosis. PF leptin levels in women on GnRH agonists were similar to controls. CONCLUSIONS: PF leptin levels are elevated in women with endometriosis, but inversely correlated with extent of disease. These findings suggest a potential role for leptin in the pathogenesis of peritoneal endometriosis.

Twenty-year history of endometriosis-associated pelvic pain: too much surgery or not enough?

A 36-year-old woman with a 20-year history of endometriosis-associated pelvic pain was a unique case from a total of 700 patients with endometriosis recently evaluated at Yale University. Her previous treatments included 11 surgical procedures related to pelvic pain or endometriosis. Multiple recurrences of endometriosis were documented. Although clearly an unusual case, our patient highlights the importance of using even the most advanced surgical techniques judiciously.

CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis.

OBJECTIVE: To investigate the possibility of genetic contribution of CYP1A1, CYP19, GSTM1, and GSTT1 polymorphisms to endometriosis. DESIGN: Genetic polymorphism analysis. SETTING: Case-control study. PATIENT(S): A group of 275 women with sporadic endometriosis was compared with a group of 346 fertile, endometriosis-free women. INTERVENTION(S): Surgical, laparoscopic, and histological examination. MAIN OUTCOME MEASURE(S): Blood specimens were obtained from endometriosis cases and controls. Polymerase chain reaction-based assays were performed for the determination of individual's genotype. RESULT(S): The CYP19 VNTR, located in intron 4 (TTTA)(10) allele increases the risk for endometriosis development (odds ratio [OR], 4.99; 95% confidence interval [95% CI], 1.351 to 18.436). The combined genotype CYP1A1 wt/m1 or m1/m1 and GSTM1 null deletion adds to this risk (OR, 1.95; 95% CI, 1.266 to 2.995 and OR, 2.23; 95% CI, 0.631 to 7.906, respectively). In contrast, the CYP1A1 wt/wt genotype exhibits a protective effect, with a 38% reduction in the odds for endometriosis development (OR, 0.62; 95% CI, 0.440 to 0.883). CONCLUSION(S): Our data suggest that CYP19 VNTR (TTTA)(10) allele as well as the combined genotype CYP1A1 m1 polymorphism and GSTM1 null deletion associate with the endometriosis phenotype, whereas the GSTT1 null deletion does not.

Expression of serum human leukocyte antigen and growth factor levels in a Greek family with familial endometriosis.

OBJECTIVE: An increased incidence of endometriosis in the first-degree relatives of patients with endometriosis has been reported, suggesting a familial predisposition and possible genetic influence. In this study, we present a family with four members who have histologically proven endometriosis (mother and three daughters) in two generations and one member with suspected endometriosis in the third generation. The aim of this study was to investigate the presence of serum-soluble class I and class II human leukocyte antigen (sHLA) levels, because they have been shown to be reduced in women with endometriosis. We also studied the levels of vascular endothelial growth factor (VEGF) and epidermal growth factor-receptor (EGF-Rc) whose function in angiogenesis implies an active role in endometriosis. METHODS: Apart from the family members under study, the control groups consisted of 38 women with endometriosis and 30 without any pelvic disease. All the soluble factors under investigation were measured by an enzyme-linked immunosorbent assay technique using a specific immunoassay. RESULTS: All the affected family members and the 38 women with endometriosis had very low levels of serum-soluble class I and class II HLA levels compared with healthy subjects. The circulating levels of VEGF were higher in the endometriosis group than the healthy control group, a pattern in accordance with the family members. On the contrary, EGF-Rc was negative in controls and women with endometriosis, with the exception of certain family members in specific stages of endometriosis. CONCLUSION: We studied the association of endometriosis with circulating levels of human leukocyte antigens and VEGF in two generations of a single family (mother and three daughters). These markers were expressed distinctly in women with familial endometriosis.

Mutation analysis of BrCA1, BrCA2, and p53 versus soluble HLA class I and class II in a case of familial endometriosis.

OBJECTIVE: To investigate possible correlation(s) between mutations of BrCA1, BrCA2, and p53 genes versus soluble HLA expression in familial endometriosis. DESIGN: Mutation analysis. SETTING: University teaching departments and hospital. PATIENT(S): A family with seven women in two generations with familial endometriosis. INTERVENTION(S): Mutation analysis of BrCA1, BrCA2, and p53 genes. MAIN OUTCOME MEASURE(S): A point mutation of the BrCA1 gene appears to inhibit soluble HLA secretion. RESULT(S): Among the three genes examined, only the BrCA1 gene showed a T to A mutation at position 3232 that correlates with total abolishment of both class I and class II antigen release. CONCLUSION(S): A possible correlation between a BrCA1 mutation and soluble HLA expression appears to exist. The mutation is not stage dependent and seemingly influences the secretion of both class I and class II antigens that are totally absent from the serum of only one family member.

The role of leptin in fertility.

The relationship between metabolism and reproduction remains a mystery in female endocrinology. Such substances as insulin, amino acids and IGFBP-I have been proposed as signals of body mass fat on the genital axis. Today this role is claimed by leptin, a protein hormone decoded from the obesity gene and is secreted exclusively from adipose tissue. This hormone acts on the central nervous system (CNS) to result in the suppression of food intake and increase in energy consumption. What is more, it also influences the capacity for reproduction. This paper reports findings with regard to the factors influencing the secretion of leptin and identification of the leptin's hormonal receptors. Particular emphasis was placed on the relationship between secretion of leptin and disturbances in menstruation, the anticipated role of this hormone in the pathogenesis of the polycystic ovarian syndrome (PCOS) and its effects on the reproductive capacity.

Diagnostic role of inhibin B in resistant ovary syndrome associated with secondary amenorrhea.

To report two rare cases of gonadotropin-resistant ovary syndrome associated with secondary amenorrhea and normal levels of inhibin B. Case report. Two university teaching hospitals. Two women presenting with secondary amenorrhea and infertility. The control group for the inhibin B levels consisted of 30 cycling women of reproductive age. Medical history, physical examination, laboratory data, histologic findings, and IVF results. Diagnosis and treatment of resistant ovary syndrome. Case 1 was a 25-year-old woman with secondary amenorrhea and primary infertility. She had high serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (62 pg/mL). Karyotype was 46,XX, and ovarian biopsy showed primordial follicles with oocytes. Administration of GnRH analogue with hMG for 15 days did not affect E(2) levels. She had a successful pregnancy with IVF using donor oocytes. Case 2 was a 24-year-old woman with secondary amenorrhea. She had elevated serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (57 pg/mL). Karyotype was 46,XX and ovarian biopsy showed primordial follicles. Administration of GnRH analogue with hMG for 12 days did not affect E(2) levels. Both women were given estrogen-progestin replacement therapy. Inhibin B has a diagnostic role in women with gonadotropin-resistant ovary syndrome associated with secondary amenorrhea. A review of the literature confirms the uniqueness of the diagnostic role of inhibin B in these cases.

Pulmonary endometriosis in a patient with unicornuate uterus and noncommunicating rudimentary horn.

OBJECTIVE: To report a rare case of a patient with catamenial hemoptysis, secondary infertility, and endometriosis associated with a unicornuate uterus and noncommunicating rudimentary horn. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 29-year-old woman who developed progressive catamenial hemoptysis and secondary infertility was evaluated at the University Hospital of Crete. INTERVENTION(S): The complete history, laboratory data, laparoscopic findings, and chest magnetic resonance image of this patient were analyzed. A GnRH agonist, leuprolide acetate, was successfully administered. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate treatment of pulmonary endometriosis in a patient with rudimentary uterine horn. RESULT(S): Treatment with a GnRH agonist achieved suppression of both menstruation and hemoptysis. After 6 months of normal menstrual activity, the symptoms reappeared. The patient was again treated with leuprolide acetate (3.75 mg/mo IM) for 6 months and remained asymptomatic. In fact, the patient became pregnant after cessation of therapy. Finally, the patient was treated successfully with removal of the rudimentary uterine horn during cesarean section. Three-year follow-up showed disappearance of the chest symptoms. CONCLUSION(S): Pulmonary endometriosis and unicornuate uteri are rare. To our knowledge, this is the first case of catamenial hemoptysis with a congenital müllerian anomaly. We describe successful management using a combination of GnRH agonist and surgical resection of the rudimentary uterine horn.