Peritoneal Endometriotic Implants Research Articles

HYALURONIC ACID PATHWAY EXPRESSION IN ESTROGEN-PROGESTERONE TREATMENT AND PROGESTERONE ONLY TREATMENT OF ENDOMETRIOSIS

Cellular processes involved in the development of peritoneal endometriotic implants and endometriomas from refluxed endometrial cells are poorly understood. Progesterone (P) and estrogen influence the hyaluronic acid (HA) system which has been shown to be involved in the initial development of endometriotic lesions in vitro and in vivo (Knudtson, Dachaud). Both combined oral contraceptive pills (OCPs) and progestin-only methods are currently used for treatment of endometriosis. Changes in the HA system following medical therapy has not yet been studied.

HYALURONIC ACID PATHWAY EXPRESSION IN PAIRED EUTOPIC ENDOMETRIAL AND ENDOMETRIOMA CELLS

Cellular processes involved in the development of peritoneal endometriotic implants and endometriomas from refluxed endometrial cells (ECs) is poorly understood. Progesterone and estrogen influence the hyaluronic acid (HA) system which has been shown to be involved in the initial development of endometriotic lesions in vitro and in vivo (Knudtson, Dachaud). We previously showed that P4 inhibits attachment of ECs; however, the effect of P4 on the HA system within endometriomas has not yet been studied.

Comparison of the symptoms and localisation of endometriosis involvement according to fertility status of endometriosis patients

This cross-sectional study aimed to assess the prevalence of endometriosis in women who were referred for Diagnostic Laparoscopy Unit due to infertility or pelvic pain between January 2012 and January 2013 and compare the symptoms and laparoscopic signs among the three groups according to the fertility status. Four hundred and thirteen women were evaluated; of these, 383 patients for infertility and 30 patients for pelvic pain and/or cyst. Endometriosis symptoms were compared between fertile and infertile women with primary and secondary infertility. There was no statistically significant difference in the overall prevalence of endometriosis between the three study groups (52.9%, 45% and 40.7%, respectively, in primary, secondary infertile and fertile women). The endometriosis stage was categorised as early- (I and II) or late- (III and IV) stages and the extent of endometriosis was divided into peritoneal, ovarian and ovarian coexisting with peritoneal. There is no relationship between the frequency of dysmenorrhoea or non-cyclic pelvic pain and the disease stage; although these pain symptoms are significantly more prevalent in cases with both ovarian and peritoneal endometriotic implants. Infertility was more prevalent among the patients with peritoneal endometriosis in comparison to the ones with ovarian endometriosis. Further studies with a larger sample size are required to confirm these findings.Impact statementWhat is already known on this subject? Few studies have been done in this area and only one study compared the localisation of endometriosis lesions between fertile and infertile endometriosis cases; however, more study is needed to confirm their results.What the results of this study add? A possible relationship between localisation of endometriosis involvement and infertility was found in the present study in agreement to result of a previous study performance in this area. Although the present study includes a greater number of cases than that of the previous reported study, further studies with a larger sample size are required for the confirmation or refusal of this finding.What are the implications of these findings for clinical practice and/or further research? The results of this study could have clinical application in the consultation and decision-making in infertile women with an endometriosis diagnosis.

Laparoscopic repair of a symptomatic post–cesarean section isthmocele: a video case report

To describe our technique for laparoscopic management of post-cesarean section isthmocele. Surgical video article. Local Institutional Review Board approval for the video reproduction has been obtained. University hospital. A 36-year-old patient with a history of two previous cesarean deliveries. She complained of persistent postmenstrual spotting and chronic pelvic pain. At transvaginal ultrasound examination, a cesarean scar defect of 20.0 × 15.6mm was identified, with a residual myometrial thickness over the defect of 2.6mm. Repair of isthmocele and relief of pain. Isthmocele excision and myometrial repair was performed laparoscopically. The first step of the procedure was the cautious mobilization of the bladder from its adhesions with the site of the previous cesarean scar. Subsequently, the isthmocele site was identified with the aid of intraoperative transrectal ultrasonography. Transrectal ultrasonographic assistance is particularly important when a bulge of the cesarean scar is not laparoscopically visible. Once identified, the isthmocele pouch was incised and its pitchy content drained. Then the cesarean scar was excised with cold scissors, avoiding cauterization to reduce the risk of tissue necrosis. This step is considered completed when the whitish scar tissue of the isthmocele site margins are no longer present and reddish healthy myometrium is visualized. Before suturing the defect, a Hegar dilator was placed into the cervix with the aim of maintaining the continuity between the cervical canal and the uterine cavity. Then, the myometrial repair was performed with the use of a single layer of interrupted 2-0 Vycril sutures. To limit tissue ischemia, we prefer not to add a second layer of sutures. Finally, the visceral peritoneum defect was closed, with the aim of restoring the physiologic uterine anatomy. In this case, multiple peritoneal endometriotic implants were also identified and excised. Operating time was 70minutes. The postoperative course was uneventful and the patient was discharged on postoperative day 2. At 40-day postoperative follow-up, transvaginal and transabdominal ultrasonography showed complete anatomic repair of the uterine defect. At 3-month follow-up, the patient reported resolution of postmenstrual spotting and chronic pelvic pain. Good reproductive outcomes have been reported after hysteroscopic treatment of uterine isthmocele. However, laparoscopy has the advantage over hysteroscopy of allowing thorough repair of the uterine defect, thus restoring a normal myometrial thickness. Therefore, as demonstrated in this case, a laparoscopic approach might be considered to be the procedure of choice for the repair of a large uterine isthmocele with extreme thinning of the residual myometrium.

Follicle-Stimulating Hormone Receptor Expression in Endometriotic Lesions and the Associated Vasculature: An Immunohistochemical Study.

Follicle-stimulating hormone receptor (FSHR) is present on endothelial cells of blood vessels and endometrial glands of the proliferative and secretory endometrium. So far, the expression of FSHR in endometriosis has not been studied. We evaluated FSHR expression in 194 tissue specimens representing 3 relevant types of endometriosis: rectovaginal endometriotic nodules, ovarian endometriotic cysts, and peritoneal endometriotic implants. Specimens of normal endometrium were used as controls. Archival formalin-fixed and paraffin-embedded material was analyzed immunohistochemically with a highly specific monoclonal antihuman FSHR antibody using the peroxidase method. A robust vascular FSHR expression was found in all 194 patients, irrespective of the endometriosis lesion location. Follicle-stimulating hormone receptor was not detected in normal host tissues located more than 5 mm from the lesions. The endometriotic lymphatic vessels do not express FSHR. The density of FSHR-positive vessels in patients with rectovaginal endometriotic nodules was 46.0 ± 5.7 vessels/mm(2) Similar values were obtained for ovarian endometriotic cysts and peritoneal endometriosis. The density of FSHR-positive vessels associated with the core of rectovaginal endometriotic nodules was 2-fold higher than that of the perilesional, adjacent normal host tissue (64.2 ± 8.2 vs 27.2 ± 3.2 vessels/mm(2), respectively). Expression of FSHR was also detected either in endometriotic glandular epithelial cells, endometriotic stromal cells, or in both cell types (23%, 25%, and 21% of patients, respectively). Normal endometrium expressed FSHR predominately in basalis, in a cellular distribution dependent on hormonal environment. In conclusion, our data suggest novel FSHR expression in endometriotic lesions, qualitatively and quantitatively different from that of normal endometrium.

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.

Diameter of dominant leiomyoma is a possible determinant to predict coexistent endometriosis

To identify the frequency and assess risk factors for unexpected discovery of peritoneal endometriotic implants in patients who underwent myomectomy or hysterectomy for symptomatic uterine leiomyomas. We retrospectively collected medical records of 829 patients with symptomatic leiomyomas in The University of Tokyo Hospital. All the patients underwent abdominal or laparoscopic surgeries between January 2001 and December 2010 and the presence or absence of endometriosis during surgery was analyzed. Possible determinant to predict coexistent endometriosis was statistically investigated. In total, 105 leiomyoma cases (12.7% in 829 patients) were diagnosed with endometriosis. Patients with small dominant leiomyomas were significantly complicated by peritoneal endometriotic implants (small leiomyomas were classified as < 8 cm). The patients with both diagnoses were more likely to be infertile and at age 39 years or younger than those with leiomyoma alone. Women undergoing myomectomy or hysterectomy with both endometriosis and leiomyomas have several different clinical features compared with women with only leiomyomas. The size of largest leiomyoma may provide an important clue for coexistent endometriosis. Women with substantial infertility despite a smaller leiomyomas burden may be more likely to have a surgical indication for concomitant endometriosis.

Findings of Pelvic Endometriosis at Transvaginal US, MR Imaging, and Laparoscopy

Endometriosis is a common multifocal gynecologic disease that manifests during the reproductive years, often causing chronic pelvic pain and infertility. It may occur as invasive peritoneal fibrotic nodules and adhesions or as ovarian cysts with hemorrhagic content. Although findings at physical examination may be suggestive, imaging is necessary for definitive diagnosis, patient counseling, and treatment planning. The imaging techniques that are most useful for preoperative disease mapping are transvaginal ultrasonography (US) after bowel preparation, and magnetic resonance (MR) imaging. Initial transvaginal US is a reliable technique for detecting rectosigmoid endometriotic lesions. MR imaging is indicated as a complementary examination in complex cases of endometriosis with extensive adhesions and ureteral involvement. Peritoneal endometriotic implants are typically hypoechoic on transvaginal US images and demonstrate low signal intensity on T2-weighted MR images. Endometriotic implants most commonly are found in retrocervical and rectosigmoid sites, followed by the vagina, bladder, and ureters. Cysts with low-level internal echoes and echogenic peripheral foci at transvaginal US are suggestive of endometriomas. MR imaging has high specificity for identifying endometriomas, which are characterized by high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Correlation of the radiologic imaging features of endometriotic lesions with their laparoscopic appearances may help improve individual proficiency in the radiologic diagnosis of endometriosis.

Cadherin expression in gastrointestinal tract endometriosis: possible role in deep tissue invasion and development of malignancy

Cadherins are cell surface proteins crucial for cell adhesion and tissue integrity. The mechanism of deep tissue invasion in gastrointestinal endometriosis is unknown and may be related to the altered expression of these cell surface proteins. The goal of this study was to evaluate the expression of N-cadherin, E-cadherin, and β-catenin in peritoneal endometriotic implants, gastrointestinal endometriosis, and carcinoma arising in gastrointestinal endometriosis. Cases of peritoneal endometriosis, gastrointestinal endometriosis, and carcinoma arising in gastrointestinal endometriosis were identified from our pathology database. Immunohistochemistry was performed using antibodies against N-cadherin, E-cadherin, and β-catenin on representative tissue sections. Cases of normal proliferative and secretory endometrium and adenomyosis were included in the study for comparison. The intensity and extent of staining for each marker was scored semiquantitatively. Appropriate positive and negative controls were used. A total of 38 cases (peritoneal endometriosis (n=14), gastrointestinal endometriosis (n=21: 11 colon, 8 appendix, 2 small bowel), and 3 cases of endometrioid carcinoma arising in colonic endometriosis (n=3)) were included in the study. Compared with normal proliferative endometrium, N-cadherin expression was decreased in intensity and extent in secretory endometrium. Peritoneal and gastrointestinal endometriosis also showed markedly decreased expression of N-cadherin compared with proliferative endometrium. All three cases of carcinoma arising in colonic endometriosis showed a total loss of N-cadherin in the tumor, but preserved E-cadherin and β-catenin expression. In these cases, areas of benign endometriotic glands near the tumor showed weak and focal N-cadherin expression that was gradually lost. Moderate-to-strong membranous staining for β-catenin expression and variable intensity of E-cadherin expression was seen diffusely in normal endometrium and all study cases. These results strongly suggest that alterations of N-cadherin expression in gastrointestinal endometriosis may have an important role in the mechanism that underlies deep tissue invasion, and possibly also in the development of malignancy.

The influence of peritoneal endometriotic lesions on the generation of endometriosis-related pain and pain reduction after surgical excision

To investigate the influence of different kinds of endometriotic lesions, especially peritoneal endometriotic implants in pain generation and the pain reduction after surgical excision in a prospective study. Fifty-one pre-menopausal patients underwent surgical laparoscopy due to chronic pelvic pain, dysmenorrhoea and/or for ovarian cysts. In 44 patients, endometriosis was diagnosed. The pre- and post-operative pain score was determined using a standardized questionnaire with a visual analogue scale. Patients with peritoneal endometriosis were divided into two different groups depending on their pre-operative pain score: group A had a pain score of 3 or more, while group B a pain score of 2 or less. Patients without peritoneal endometriosis were classified as group C, and patients without endometriosis were classified as group D. The pre- and post-operative pelvic pain and/or dysmenorrhoea was analysed according to the different types of endometriotic lesions. In groups A and C, the post-operative pain score decreased by at least 2 grades or more (p < 0.0). In group D, the post-operative pain score showed no significant reduction. The present study suggests that the surgical excision of endometriotic lesions -- including peritoneal implants -- is an effective treatment of endometriosis-associated pelvic pain and/or dysmenorrhoea.

Effect of BCG vaccine on peritoneal endometriotic implants in a rat model of endometriosis

To investigate the effect of Bacillus Calmette-Guerin (BCG) vaccine on peritoneal implantation of endometrial tissue in rats. Forty sexually mature virgin Wistar albino rats weighing 190-200 g were randomly assigned (double blind) to two groups. The rats in the first group were vaccinated with 0.1 mL BCG and those in the second group were injected with 0.1 mL saline into the tail, intracutaneously. All the rats underwent median laparotomy after 4 weeks of vaccination or injection. The right uterine horn was excised, and the two samples of endometrial tissue dissected from myometrium were implanted on each side of peritoneum at the 2 cm lateral line of the median laparotomy incision. The implanted peritoneal segments were excised after 8 weeks of laparotomy. The tissue samples were accepted, histologically, as endometriosis when both glands and stroma of endometrial tissue were seen in sections. Thirty-six implants from the study group and 34 implants from the control group were obtained. Ten and 23 implants were accepted as endometriosis in the study and control group, respectively. The number of endometriotic foci were significantly lower in the study group than in the control group (P = 0.01). Stimulation of the cellular immune response with BCG vaccine could exert an inhibitory effect on ectopic endometriotic implants.

Expression of Inhibitory‐Motif Killer Immunoglobulin‐Like Receptor, KIR2DL1, is Increased in Natural Killer Cells from Women with Pelvic Endometriosis

We investigated inhibitory and activation motif expression of killer immunoglobulin-like receptor (KIR) by natural killer (NK) cells, which may be pathogenetically involved in endometriosis. We compared cells from 24 Japanese women laparoscopically diagnosed with endometriosis, to cells from 25 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood (PB) and peritoneal fluid (PF) by flow cytometry. Intracellular immunoreceptor tyrosine-based (IT) inhibitory and activation motifs (ITIM and ITAM) of KIR in PB was assessed by Western blotting. ITIM-KIR expression by PB NK cells was significantly and similarly greater than ITAM-KIR expression in women with and without endometriosis. Percentages of CD56(+) NK cells in PB and PF did not differ significantly between women with and without endometriosis; however, the percentage of CD158a(+) cells among CD56(+) NK cells in PB and PF was significantly higher in women with than without endometriosis. ITIM-KIR expressing NK cells might confer tolerance to peritoneal endometriotic implants.

Pyoderma gangrenosum at the incision site following gynecologic surgery

Pyoderma gangrenosum is an uncommon necrotizing skin disorder and the diagnosis is made clinically because no specific histopathologic pattern is present [1]. Peak incidence is at age 30–50 years with a slight female preponderance. In 50–75% cases an underlying condition is identified. The cause of pyoderma gangrenosum remains obscure; this condition was initially called pyoderma because it was thought to be a bacterial infection caused by streptococci. The cause is now recognized to be non-infectious although secondary bacterial colonization may occur. Recent investigations emphasize an altered immune system with impaired cellular immunity and defective function of polymorphonuclear leukocytes. A 27-old-year woman presented with a 6-month history of left lower quadrant pain. Her gynecologic and ultrasonographic examination revealed a large endometrioma of 10 cm and laparotomy was planned. Immediately before surgery povidone-iodine solution was applied to the abdominal skin. The abdomen was entered by a Pfannenstiel’s incision and the cut edges of the subcutaneous tissue were protected by placement of moist towels at the incision edges. A self-retaining retractor with lateral blades was put in place. Cystectomy was performed for the endometrioma within the left ovary and peritoneal endometriotic implants were coagulated. Meticulous layer-by-layer anatomical closure was performed. The parietal peritoneum fascia and skin were closed continuously with plain catgut delayed absorbable polyglactin (Vicrly; Ethicon USA) and subcuticular polypropilene (Prolene; Ethicon USA) respectively. No suture was placed in the muscular and subcutaneous adipose tissue layers. The patient received prophylactic antibiotic therapy (Cefazolin 1 gr IV) and was discharged on day 3 postoperatively. At this stage no peculiarity was noted at the incision site and the patient was called for follow-up 2 days later. (excerpt)

Differential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions compared with endometrium.

In vivo levels of mRNA and the specificity of the extrauterine environment on matrix metalloproteinase (MMP)-3, MMP-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were evaluated in eutopic and ectopic endometrial tissue during the establishment of endometriosis in a rat model. Uteri and endometriotic implants were collected and frozen at 36 h, 2 wk, and 4 wk postsurgery to study in vivo mRNA levels. Intact uteri, uterine tissues implanted in the peritoneum or under the skin, and peritoneal adipose implants were collected at 2 wk, halved, and either frozen or cultured. Gene-specific reverse transcriptase-polymerase chain reaction was performed to detect and quantify MMP-2, MMP-3, and TIMP-1 mRNA levels. The peritoneal endometriotic implants progressed from avascularized implants, to vascularized red lesions, to well-established encapsulated cysts. In vivo, MMP-3 mRNA was detectable at all times in ectopic tissues but not in eutopic uterine tissues, whereas MMP-2 and TIMP-1 were ubiquitously expressed at all times in both tissues. In vitro, only MMP-3 mRNA levels were elevated in endometrial tissues collected from the intact uterine and from under the skin, at levels similar to in vivo endometriotic implant MMP-3. In conclusion, ectopic endometrial MMP-3 may participate in the process of invasion and tissue remodeling that is hypothesized to occur in the pathogenesis of endometriosis.

Peritoneal endometriosis and “endometriotic” nodules of the rectovaginal septum are two different entities

To compare histologically and stereologically the endometriotic nodule of the rectovaginal septum to peritoneal endometriosis. Morphometric investigation, cytokeratin and vimentin content, and steroid receptor evaluation were performed on endometriotic tissue from the peritoneum (n = 52) and rectovaginal nodules (n = 68). An academic teaching hospital. Biopsies were taken from 120 patients undergoing a laparoscopy for infertility and/ or pelvic pain (52 from typical black peritoneal endometriotic implants and 68 from endometriotic nodule of the rectovaginal septum). None of the patients were treated. Mitotic activity was found to be significantly different in peritoneal and rectovaginal endometriosis. The evaluation suggested that the stroma is not mandatory for the invasion of glandular epithelium in the rectovaginal nodule, which is, like a adenomyoma, a circumscribed nodular aggregate of smooth muscle and glandular elements. Cytokeratin and vimentin content as well as the estrogen receptor (ER) and P receptor (PR) content were significantly lower in both types of lesion when compared with eutopic endometrium. But vimentin immunoreactivity in epithelium, as well as the ER and PR content, were significantly lower in nodules when compared with black peritoneal lesions. It is suggested that the rectovaginal endometriotic nodule is a different disease from peritoneal endometriosis and must be called rectovaginal adenomyosis or rectovaginal adenomyoma. Its histopathogenesis probably is not related to the implantation of regurgitated endometrial cells but to the metaplasia of Müllerian rests.

Aromatase expression in endometriosis.

The conversion of C19 steroids to estrogens occurs in a number of tissues, such as the ovary and placenta, and is catalyzed by aromatase P450 (P450arom; the product of the CYP19 gene). P450arom expression has also been detected in a number of uterine tumors, such as leiomyomas and endometrial cancer. On the other hand, P450arom expression was undetectable in normal endometrial and myometrial tissues. The present study was conducted to determine the presence or absence of aromatase expression in peritoneal endometriotic implants and in the eutopic endometrium of women with endometriosis. Endometriotic implants in pelvic peritoneum (n = 17; e.g. posterior culdesac, bladder, and anterior culdesac) and eutopic endometrial curettings (n = 11) of 14 patients with histologically documented pelvic endometriosis were obtained at the time of laparoscopy or laparotomy. Pelvic peritoneal biopsies distal to endometriotic implants as well as normal endometrial tissues (n = 7) from disease-free women were used as negative controls. We used competitive RT-PCR technology employing an internal standard to amplify P450arom transcripts in total ribonucleic acid (RNA) isolated from these tissues. P450arom transcripts were detected in all endometriotic implants and in all eutopic endometrial tissues from patients with endometriosis. P450arom messenger RNA species were not detectable in endometrial tissues from disease-free women or in endometriosis-free peritoneal tissues. The highest levels of transcripts were detected in an endometriotic implant that involved the full thickness of the anterior abdominal wall. The P450arom transcript level within the core of this endometriotic mass was 4-fold higher than that in the surrounding adipose tissue. It has been shown recently that aromatase expression in various human tissues is regulated by the use of tissue-specific promoters via alternative splicing. To analyze promoter usage, we amplified by RT-PCR the most likely promoter-specific untranslated 5'-termini of P450arom transcripts in 2 endometriotic implants. It appears that these endometriotic implants use both the adipose-type promoter I.4 and gonadal-type promoter II for aromatase expression. The use of promoter I.4 for aromatase expression in adipose tissue has been recently observed to be regulated by members of the interleukin-6 (IL-6) cytokine family. Based on these findings, we examined by RT-PCR, IL-6 and IL-11 messenger RNA expression in 5 endometriotic tissues and 1 eutopic endometrial sample from a patient with endometriosis. We detected IL-6 and IL-11 transcripts in all endometriotic tissues and in the eutopic endometrial tissue sample studied. Our findings indicate that both eutopic endometrial tissues and endometriotic implants from patients with endometriosis are biochemically different from normal endometrial tissues of disease-free women. The presence of aromatase expression in eutopic endometrial tissues from patients with endometriosis may be related to the capability of implantation of these tissues on peritoneal surfaces. Furthermore, the possibility of estrogen production in these implants may serve to promote their growth. Increased IL-6 and IL-11 expression in these tissues suggests that P450arom expression in endometriosis may be regulated in part by these cytokines.

Circulating lipid and lipoprotein concentrations during danazol and high-dose medroxyprogesterone acetate therapy of endometriosis

In a study on endometriosis, ten patients were treated with danazol (200 mg three times a day) and ten patients with high-dose medroxyprogesterone acetate (MPA) (100 mg a day) for 6 months. The circulating high-density lipoprotein-cholesterol concentration decreased significantly in the danazol (53%) and in the MPA groups (26%); the change in the danazol group was significantly higher than that in the MPA group. Danazol also significantly increased the low-density lipoprotein-cholesterol levels (37%), whereas MPA had no significant effect. Danazol (29%) and MPA (12%) decreased the apolipoprotein A-1 levels significantly. The decrease caused by danazol was significantly greater. Danazol also significantly decreased the apolipoprotein A-2 levels (12%) and significantly increased the apolipoprotein B levels (17%), whereas MPA had no significant effects on them. Three months after the end of medication, all values were at the pretreatment levels. The circulating cholesterol, triglyceride, and very low-density lipoprotein concentrations remained unchanged during both treatments. Danazol and high-dose MPA induced a similar significant regression of peritoneal endometriotic implants in relation to placebo. Our present results, showing that danazol, to a greater extent than high-dose MPA, is associated with changes in lipoprotein metabolism that expose the individual to an increased risk of cardiovascular diseases, suggest that high-dose MPA is preferable to danazol in the long-term treatment of endometriosis.