Regression Of Endometriosis Research Articles

Effect of Protoberberine-Rich Fraction of Chelidonium majus L. on Endometriosis Regression.

Endometriosis is a gynecological disease defined by the presence of endometrial tissue outside the uterus. To date, the effective treatment of this disease is still based on invasive surgery or laparoscopy. Chelidonium majus L. (Papaveraceae) belongs to medicinal, latex-bearing plants. Extracts from the plant are a rich source of pharmacologically active agents. Protoberberine compounds derived from C. majus possess anticancer and antiproliferative activities. In the present study of a rat model of endometriosis, we investigated the influence of the plant protoberberine-rich fraction (BBR) obtained from the medicinal plant C. majus on the development of endometriosis. To understand of BBR therapeutic potential for endometriosis, metabolomics has been applied to study. BBR was prepared from an ethanolic extract of dry plants C. majus. Rats (n = 16) with confirmed endometriosis were treated with BBR administered orally (1 g/kg) for 14 days. Blood serum samples were collected from all of the animals and metabolites were studied using the NMR method. The metabolomic pattern was compared before and after the protoberberine treatment. The performed analysis showed significant changes in the concentrations of metabolites that are involved in energy homeostasis, including glucose, glutamine, and lactate. Histopathological studies showed no recurrence of endometriosis loci after treatment with BBR. The results of the study found that BBR treatment prevents the recurrence of endometriosis in rats. Moreover, metabolomics profiling can be applied to better understand the mechanisms of action of these protoberberine secondary plant metabolites. Our findings provide new insights into the pharmaceutical activity of natural protoberberine plant compounds.

The regression of endometriosis with glycosylated flavonoids isolated from Melilotus officinalis (L.) Pall. in an endometriosis rat model

ObjectiveMelilotus officinalis (L.) Pall. is commonly used for treating bronchitis, painful menstruation, hemorrhoids, kidney stones, ulcers of the eyes, earache, and hardening and swelling of uterus. The European Medicines Agency reported the use of M. officinalis orally against stomach ache, gastric ulcer, and disorders of the liver and uterus in folk medicine. The present study aimed to appraise the activity of M. (L.) Pall. aerial parts in endometriosis rat model. Materials and methodsThe endometriosis rat model was used to evaluate the potential activity of M. officinalis aerial parts based on its folkloric usage. The aerial parts of M. officinalis were extracted with n-hexane, ethyl acetate (EtOAc), and methanol (MeOH), respectively. The adhesion scores, endometrial foci areas, and cytokine levels were measured in all treated groups. After the biological activity studies, phytochemical studies were performed on the active extract and the fractions obtained from the active extract. ResultsThe MeOH extract significantly decreased the endometrial foci areas and cytokine levels in rats with endometriosis. Fractionation was performed on the MeOH extract to achieve bioactive molecules. Following the fractionation, the fractions obtained from the MeOH extract were tested. Fraction C showed the highest activity in the rat endometriosis model. Phytochemical investigation of the active fraction (Fraction C) resulted in isolation and elucidation of some quercetin and kaempferol glucoside derivatives. ConclusionFraction C obtained from the MeOH extract of M. officinalis showed the highest activity, yielding four glycosylated flavonoids.

Activity of catalase in surgically induced endometrial-like lesions in rats

Hypothesis/aims of study. There is a link between the activities (and polymorphisms of genes) of antioxidant enzymes and endometriosis. It is also known that progesterone induces some antioxidant enzymes in the endometrium and that progesterone analogs are effective for reduction of endometrial lesions. In addition to morphometric and histological estimations of endometriosis regression, it could be useful to assess the activity of antioxidant enzymes within endometriotic foci. The present study is aimed at estimating the activity of catalase, a hydrogen peroxide-detoxifying enzyme, in surgically induced endometrial-like lesions with a variable degree of reduction.
 Study design, materials and methods. The study was carried out on 12 mature female rats of Wistar strain. Endometrial-like lesions were induced by autotransplantation of uterine tissue fragments on the abdominal wall. After 35-37 days, the endometrial foci were extracted. Catalase activity in the ectopic endometrium was determined by the Beers Sizer method modified as follows: recording hydrogen peroxide concentration decrease at 250 nm and using 3-amino-1,2,4-triazole (AT) to assess specificity. The correlation between the specific catalase activity and protein amount in the ectopic endometrium was estimated.
 Results. At the wavelength of 250 nm, a relatively weak interference of AT with other components of the reaction mixture was observed, which allows using the specific catalase inhibitor to indicate the enzyme activity. The activity is measured in a short period of incubation (less than 1 minute) and is proportional to amount of the endometrial tissue extract in the reaction mixture. As a rule, the most reduced endometriotic foci (with the lowest weight) possessed a higher catalase activity (the Spearmans rho was 0.66 with p 0.025).
 Conclusion. The method for determining catalase activity was adapted to work with endometriotic foci. With p 0.025, we can accept that a low weight of endometriotic foci is linked with a relatively high catalase activity within their tissue. The results allow suggesting the involvement of catalase in reduction of endometrial lesions.

Icon immunoconjugate treatment results in regression of red lesions in a non-human primate (Papio anubis) model of endometriosis

Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature.

Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model.

Bazedoxifene (BZA), a selective estrogen receptor modulator (SERM), inhibits the action of estrogens on endometrial proliferation. Here, we evaluate the effect of a tissue-selective estrogen complex (TSEC) containing BZA and conjugated estrogens (CE) on ectopic endometrial lesions in a mouse model of endometriosis. Experimental endometriosis was created in 60 female CD-1 mice. The mice were randomly divided into 10 groups that received varying doses of either BZA (1, 2, 3, or 5 mg/kg/day), BZA (1, 2, 3, or 5 mg/kg/day) in combination with CE (3 mg/kg/day), CE treatment alone (3 mg/kg/day), or vehicle control for 8 wk. Treatment with BZA alone or the TSEC containing BZA/CE led to a decrease in endometriotic lesion size compared to controls. The mean surface area of the untreated lesions was 19.6 mm(2). Treatment with BZA or BZA/CE resulted in reduced lesion size (to 8.8 and 7.8 mm(2), respectively). No significant difference was found in lesion size between the BZA and BZA/CE treatment groups or between different doses of either treatment. Ovarian cyst formation was not evident in the treated groups. Treatment with the TSEC containing higher BZA dosages (3 and 5 mg/kg/day) led to significantly lower levels of estrogen receptor (Esr1) mRNA expression compared to the control treatment. No differences were observed in expression of progesterone receptor (Pgr). Immunohistochemical analysis also demonstrated a decrease in ESR protein. The combination of CE and BZA may prove to be a novel treatment option for endometriosis.

Effects of amifostine on endometriosis, comparison with N-acetyl cysteine, and leuprolide as a new treatment alternative: a randomized controlled trial

To assess the effects of amifostine, N-acetyl cysteine (NAC), and leuprolide as a scavenger in a rat endometriosis model. This is a prospective randomized animal study. Setting The Animal Laboratory of Medical University. Animals 40 rats were used for transplantation of an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. After allowing 3 weeks for growth, laparotomies were performed to check the implants. Then animals were randomized into four groups: Group I amifostine (200 mg/day loading dose after 20 mg/kg/day, p.o.); Group II NAC (200 mg/day, p.o.); Group III leuprolide acetate 1 mg/kg single dose, sc; and Group IV (controls) no medication. Three weeks later, implants were evaluated morphologically. Serum and peritoneal TNF-alpha levels were evaluated. The transmission electron microscopic examination of the peritoneal samples and ovaries was also performed. Leuprolide acetate, amifostine and NAC caused significant decreases in the mean implant areas and significant decreases in serum and peritoneal TNF-alpha levels. On comparing all groups, these reductions were higher in Group II. According to the transmission electron microscopic findings, leuprolide seems to be protecting normal structure of peritoneum best when compared to the other groups. Amifostine, NAC and leuprolide caused regression of endometriosis in this experimental rat model by a yet unsettled mechanism.

Treatment with Bazedoxifene, a Selective Estrogen Receptor Modulator, Causes Regression of Endometriosis in a Mouse Model

Endometriosis is a common estrogen-dependent disorder. Medical treatments currently consist of progestins or GnRH agonists; however, neither is fully effective and both entail significant side effects. Selective estrogen receptor (ER) modulators (SERM) have tissue-selective actions, acting as an ER agonist in some tissues and ER antagonist in others. The SERM bazedoxifene (BZA) effectively antagonizes estrogen-induced uterine endometrial stimulation without countering estrogenic effects in bone or central nervous system. These properties make it an attractive candidate for use in the treatment of endometriosis. Experimental endometriosis was created in reproductive-age CD-1 mice. After 8 wk, 10 animals received i.p. injections of BZA (3 mg/kg·d) for 8 wk, whereas 10 received vehicle control. Mice were killed, and implant size was assessed. The mean size of the implants after treatment was 60 mm(2) in the control group and 21 mm(2) in the BZA treatment group (P = 0.03). Quantitative PCR and immunohistochemical analysis were used to determine the effect on endometrial gene expression. PCNA, ERα, and LIF mRNA and protein expression were significantly decreased in endometrium of the treated group. Caspase 3 mRNA expression was increased. Expression of PR and Hoxa10 were not significantly altered by treatment. There was no evidence of ovarian enlargement or cyst formation. Decreased PCNA and ER expression demonstrated that the regression of endometriosis likely involved decreased estrogen-mediated cell proliferation. BZA may be an effective novel agent for the treatment of endometriosis due to greater endometrial-specific estrogen antagonism compared with other SERM.

Effect of resveratrol on the induction of endometriosis in a rat model

OBJECTIVE: Resveratrol is a natural polyphenol which has anti-angiogenic, anti-oxidant and anti-inflammatory effects.We aimed to assess the effect of resveratrol in a rat endometriosis model. DESIGN: Prospective randomized animal study. MATERIALS AND METHODS: Endometriosis was induced surgically in 24 rats.3 weeks after the initial surgery, the rats underwent laparotomy to determine the size of endometrial implants. Two rats died during the procedures. The remaining rats were randomized into three groups. Group I (Resveratrol group, seven rats) was given 60 mg/kg/d resveratrol via orogastric tube. Group II (GnRH agonist group, eight rats) was given a single dose of 1 mg/kg s.c. leuprolide acetate. Group III served as control group (seven rats). All rats received the treatment for 21 days. After treatments, the rats were euthanized and a third laparotomy was performed and the surface areas of the implants were calculated. Also before and after medications, peritoneal fluids were collected to measure VEGF and MCP-1 levels. The implants were then excised and examined histopathologically. RESULTS: All rats developed similar areas of implants at the second laparotomy. After treatment, the mean areas of implants were smaller in the resveratrol and leuprolide acetate groups than those in the control group. The mean areas of implants decreased from 44.1 ± 5 to 7.1 ± 2.9 mm2 in the resveratrol group (P <.05). The mean histopathological score of the implants at the end of the treatment was lower in the resveratrol group when compared with the control group (1.2 ± 1.2 vs. 2.5 ± 0.5, P <.05). Peritoneal level of VEGF decreased significantly in resveratrol group after treatment (from 80.9 ± 15.9 to 31.3 ± 30.4, P <.05).MCP-1 peritoneal level decreased significantly in resveratrol group after treatment (from 2.6 ± 1.8 to 2 ± 2, P <.05). CONCLUSION: Resveratrol caused regression of endometriosis in a rat model. Resveratrol may represent a novel therapeutic strategy for treatment of endometriosis in the future.

The Immunoconjugate “Icon” Targets Aberrantly Expressed Endothelial Tissue Factor Causing Regression of Endometriosis

Endometriosis is a major cause of chronic pain, infertility, medical and surgical interventions, and health care expenditures. Tissue factor (TF), the primary initiator of coagulation and a modulator of angiogenesis, is not normally expressed by the endothelium; however, prior studies have demonstrated that both blood vessels in solid tumors and choroidal tissue in macular degeneration express endothelial TF. The present study describes the anomalous expression of TF by endothelial cells in endometriotic lesions. The immunoconjugate molecule (Icon), which binds with high affinity and specificity to this aberrant endothelial TF, has been shown to induce a cytolytic immune response that eradicates tumor and choroidal blood vessels. Using an athymic mouse model of endometriosis, we now report that Icon largely destroys endometriotic implants by vascular disruption without apparent toxicity, reduced fertility, or subsequent teratogenic effects. Unlike antiangiogenic treatments that can only target developing angiogenesis, Icon eliminates pre-existing pathological vessels. Thus, Icon could serve as a novel, nontoxic, fertility-preserving, and effective treatment for endometriosis.

Doxycycline causes regression of endometriotic implants: a rat model

Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase (MMP) activity. The aim of this study was to assess the effects of Dox in a rat endometriosis model. Endometriosis was surgically induced in 40 rats by transplanting of endometrial tissue. After 3 weeks, repeat laparotomies were performed to check the implants and the animals were randomized into four groups: Group I, low-dose Dox (5 mg/kg/day); Group II, high-dose Dox (40 mg/kg/day); Group III, leuprolide acetate 1 mg/kg single dose, s.c.; and Group VI (controls), no medication. The treatment, initiated on the day of surgery and continuing for 3 weeks, was administered to the study groups. Three weeks later, the rats were euthanized and the implants were evaluated morphologically and histologically for immunoreactivity of MMP-2 and -9, and interleukin-6 (IL-6) concentration in the peritoneal fluid was assayed. Treatment with leuprolide acetate, or high-dose or low-dose Dox caused significant decreases in the implant areas compared with the controls (P = 0.03, P = 0.006, and P = 0.001, respectively). IL-6 levels in peritoneal fluid decreased in Group I (P = 0.02) and Group III (P < 0.05). MMP H scores were significantly lower in the group that received low-dose Dox in both epithelial and stromal MMP-2 and -9 immunostaining when compared with the control group [P = 0.048, P = 0.002, P = 0.007 and P = 0.002, respectively, MMP-2 (epithelia), MMP-2 (stroma), MMP-9 (epithelia) and MMP-9 (stroma)]. Low-dose Dox caused regression of endometriosis in this experimental rat model.

JNK Inhibitor AS-01 Causes Regression of Endometriosis and Suppression of Inflammatory Cytokines and Tissue Remodeling Enzymes.

JNK Inhibitor AS-01 Causes Regression of Endometriosis and Suppression of Inflammatory Cytokines and Tissue Remodeling Enzymes.

Leitlinien für den Einsatz der GnRH-Agonisten zur Behandlung der Endometriose

Today GnRH-Analogues are the most effective substances for the regression of endometriosis and endometriosis related complaints. In combination with add-back medication the treatment is effective with only few tolerable side effects. The different types of GnRH-Analogues are equally effective, but depot preparation have the best compliance. The tailored application of GnRH-Analogues preoperatively, postoperatively or instead of surgery is dependent on the individual situation of the patient and dependent on the proliferative activity, localisation, type and stage of the disease.

O6.2 A new therapy for endometriosis: regression of endometriosis in a rat model following local application of danazol-loaded hyaluronic acid hydrogel

O6.2 A new therapy for endometriosis: regression of endometriosis in a rat model following local application of danazol-loaded hyaluronic acid hydrogel

The Selective Estrogen Receptor Modulator, Raloxifene: An Overview of Nonclinical Pharmacology and Reproductive and Developmental Testing

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. In the ovariectomized (OVX) rat, raloxifene prevents the loss of bone at the distal metaphysis of the femur, proximal tibia, and vertebrae; reduces cancellous bone resorption; and reduces serum cholesterol, but does not cause any significant changes in stromal eosinophilia or uterine epithelium. In estrogen-stimulated OVX rats, raloxifene prevents the morning lowering of serum luteinizing hormone levels, produces a reduction in afternoon serum prolactin levels, antagonizes pituitary weight increase, and antagonizes stimulation of mammary gland development. Raloxifene also has been shown to exhibit antiestrogenic activity in several in vivo and in vitro mammary tumor models. Raloxifene treatment results in regression of endometriosis in both a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure. Also, uterine leiomyomas in estrogen-stimulated OVX guinea pigs regress after the onset of raloxifene treatment. Raloxifene antagonizes testosterone-induced increases in prostate weight of castrated rats, but does not bind to androgen receptors or affect prostatic 5-α-reductase or testicular steroid 17-α-hydroxylase activity. A series of preclinical toxicology studies was designed to characterize reproductive and developmental outcomes following various schedules of raloxifene treatment in rats or rabbits. Studies of female reproduction and developmental outcome were conducted primarily at pharmacologic doses (0.1, 1, or 10 mg/kg/d); male reproductive studies used higher doses (10, 30, or 100 mg/kg/d). In this series of studies, male reproductive end points were not affected, whereas embryo implantation, fetal rabbit morphology, and several aspects of offspring development were disrupted by the lowest dose of maternal raloxifene treatment, a profile consistent with estrogen antagonist activity.

Chronic pelvic pain: oral contraceptives and non-steroidal anti-inflammatory compounds.

A correct classification of female pelvic pain originating from gynaecological disorders is essential if the most appropriate therapy is to be chosen. Certain types of non-steroidal anti-inflammatory drugs and oral contraceptives reduce the production of prostaglandins, which are responsible in large part for primary dysmenorrhoea. Oestroprogestin formulations become the drugs of choice if the patient also requests contraception. Secondary dysmenorrhoea and chronic pelvic pain may require combined medical and surgical treatment. Oral contraceptives can also be used as post-treatment agents in endometriosis, one of the most common causes of pelvic pain, whereas more specific compounds (GnRH-analogues and Danazol) are used to produce anatomical regression of endometriosis.

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

To evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis. An open, prospective clinical trial. The clinical practice of an academic faculty. Nine women with endometriosis were studied. RU486 (50 mg/d) was administered for 6 months. Daily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment. Pelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged. RU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

Using drugs with immunomodulatory properties for the treatment of adenomyosis

Based on the statement that immune system disorders play an important role in the pathogenesis of endometriosis, we evaluated a new method of treatment. This approach permitted subsequent administration of noretisteron acetate and myelopid (polypeptide compound from the bone marrow of mammals) for the treatment of 63 women with adenomyosis and endometrial hyperplasia. In total, 30 women were given noretisteron only; 28, noretisteron and myelopid; and 5 myelopid only. All patients were managed by HSG, hysteroscopy, laparoscopy, and the study of their hormonal and immune systems. A follow-up between 6 and 9 months after treatment revealed total pain relief in 29 patients, and partial relief in 4, who received myelopid. In this group, normal endometrium appeared in 21 (63.6%) cases with regression of endometriosis in 19 (57.5%). This therapeutic strategy significantly improved the results in comparison to the results of treatment with noretisteron acetate only.

Time-related effects of RU486 treatment in experimentally induced endometriosis in the rat

To evaluate the time-dependent effect of the progesterone antagonist RU486 on experimentally induced endometriosis in the rat. Endometriosis was induced by implanting endometrium onto the peritoneal side wall. Size of the implants was measured before and after treatment. Fifty-two adult female Sprague-Dawley female rats weighing 200 to 225 g. Departmental research laboratory of university hospital. Animals treated with RU486 or vehicle only for 2, 4, 6, or 8 weeks. Size of the implant was measured before and after treatment; relative change in size of the implants was calculated. There was not a statistically significant difference between the treatment groups and the control groups. There was no regression of endometriosis in any of the treatment groups. RU486 administered for 8 weeks in the rat model was not effective therapy for endometriosis.

Antigestogens

Antigestogens are compounds which inhibit the synthesis of progesterone or antagonise its biological action. The progesterone antagonist mifepristone (RU 486) binds with high affinity to progesterone receptors throughout the body, blocking the action of endogenous progesterone. In the last 10 years it has been demonstrated that mifepristone, in combination with a suitable prostaglandin, is a safe, effective alternative to vacuum aspiration for termination of pregnancy in the first two months. Preliminary trials suggest that antigestogens may be useful true contraceptives by inhibiting ovulation or by preventing implantation as once a month pills and postcoital agents. In late pregnancy, by sensitising the uterus to prostaglandins and by promoting cervical dilatation, they may induce labour and facilitate lactation. In non-pregnant women mifepristone may have application in the treatment of hormone-dependent conditions such as endometriosis, fibromyomata, meningioma and breast cancer. The availability of hormone antagonists to oestrogens, androgens and progesterone offers the possibility of new methods of regulating reproductive function in health and disease.