Endometriosis
Diseases

Endometriosis and its hormonal therapy

Endometriosis is a disease of ectopic occurrence and growth of endometrium in the ovary, oviduct and pouch of Douglas. The disease causes inflammation at the site and development of severe menstrual and lower abdominal pain at times other than the menstrual period (Deep infil- trating endometriosis: Relation between severity of dysmen- orrhea and extent of disease*. 2003 ).
Endometriosis is estimated to affect 2-3% of the general female population, between the ages of 18-42, and may cause dysmenorrhea, dyspareunia, chronic pelvic pain, and primary or secondary infertility.
Because of its dependence on follicular hormones (*estrogens*), the disease increases gradually in menstruating women and decreases and disappears postmenopausally because of the reduced production of estrogens (2. Pellicer A, Navarro J, Bosch E, et al: Endometrial quality in infertile women with endometriosis. Ann N Y Acad Sci 2001; 943:122–130). Because of that endometriotic implants tend to regress in a hypoestrogenic enviroment. That has brought the development of several medical antigonadotropic and antiestrogenic treatments for endometriosis. Because of their anabolic and androgenic side effects, danazol and the progestogens have been replaced by the Gn-RH analogs. This treatment is conducted usually for 6 months, effectively alleviating or eliminating menstrual pain due to endometriosis and pain from other causes. However, symptoms of ovarian deficiency appear with high frequency during treatment, seriously impairing the quality of life. Moreover, the incidence of subsequent recurrence of endometriosis is extremely high after treatment. Because of the risks of these hormonal treatments, there is a need for effective treatment of endometriosis without long-lasting adverse effects.

Pycnogenol: French Pinus pinaster bark extract, charachteristics

Pycnogenol® (French Pinus pinaster bark extract) contains polyphenolic compounds (these compounds consist of catechin, taxifolin, procyanidins of various chain lengths formed by catechin and epicatechin units, and phenolic acids) capable of producing diverse potentially protective effects against chronic and degenerative diseases. Several in vitro studies have revealed that* PBE*(Pinus pinaster bark extract, Pycnogenol) has anti-inflammatory effects and inhibits the initiation of inflammation by preventing the release of pro-inflammatory mediators regulated by oxidative stress. PBE inhibits the pro-inflammatory mediators in keratinocytes (epidermal cells), leukocytes, and endothelial cells. Furthermore, an in vitro study has shown that*PBE* and its metabolites inhibit the release of tissue destroying enzymes (matrix metalloprotein-ases) collagenase, elastase, and gelatinase from inflammatory cells (3. Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Grimm T, Schäfer A, Högger P. Free Radic Biol Med. 2004 Mar 15; 36(6):811-22).
It has also reported that after oral intake of PBE, the enzymatic activity of Cyclo-oxygenase (COX-1 and COX-2) in serum samples of human volunteers was inhibited. Cyclo-oxygenase is responsible for formation of biological mediators, such as prostaglandins, prosta-cyclin, and thromboxane.

Pharmacological Inhibition of this enzyme can provide relief from the symptoms of inflammation and pain (4.* Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol)*. Schäfer A, Chovanová Z, Muchová J, Sumegová K, Liptáková A, Duracková Z, Högger P. Biomed Pharmacother. 2006 Jan; 60(1):5-9).
Moreover the effects of bioflavonoids extracted from the bark of Pinus maritima Pycnogenol on free radical formation, activation of redox sensitive transcription factors, as well as interleukin-1 beta (IL-1 beta) production were investigated in murine macrophage cell lines. PBE exerted strong scavenging activities against reactive oxygen species generated either by H(2)O(2) or PMA in RAW 264.7 and IC-21 cells, respectively. In situ ELISA, immunoblot analysis, and competitive RT-PCR demonstrated that PBE pretreatment of LPS-stimulated RAW 264.7 cells dose-dependently reduced both the production of IL-1 beta and its mRNA levels. Furthermore, in the same cells, PBE blocked the activation of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1), two major transcription factors centrally involved in IL-1 beta gene expression.
When RAW 264.7 cells were stimulated with LPS, the inhibitor protein I kappa B largely disappeared from cytosolic fractions. However, pretreatment of the cells with PBE abolished the LPS-induced I kappa B degradation. These results suggest that PBE can inhibit the expression of the proinflammatory cytokine IL-1 by regulating redox-sensitive transcription factors. This study may support the possibility that bioflavonoids including PBE can be used as antiinflammatory and immunosuppressive drugs based on their radical scavenging activities (5. Cho KJ, Yun CH, Yoon DY, et al: Effect of bioflavonoids ex- tracted from the bark of Pinus maritima on proinflammato- ry cytokine interleukin-1 production in lipopolysaccharide- stimulated RAW 264.7. Toxicol Appl Pharmacol 2000;168: 64–71).
Moreover treatment with Pycnogenol showed good efficacy in treating menstrual cramps and pain in clinical trials: in 1 investigation, women with severe menstrual pain and endometriosis showed a high response rate (71– 100%) after supplementation with Pycnogenol. In another clinical trial with patients complaining of dysmenorrhea, we could observe a significant alleviation of abdominal and lower back pain (p < 0.01). Patients reported fewer days of pain, and use of analgesics dropped (7. Kohama T, Suzuki N, Ohno S, et al: Analgesic efficacy of French maritime pine bark extract in dysmenorrhea: An open clinical trial. J Reprod Med 2004;49:828–832).

The study

Due to this background Kohama et al. have put forward a study comparing effects and efficency of french maritime pine bark extract and leuprolelin acetate in the endometriosis medical treatment (8. Effect of French maritime pine bark extract on endometriosis as compared with leuprorelin acetate. Kohama T, Herai K, Inoue M. J Reprod Med. 2007 Aug;52(8):703-8).

From 1999 to 2004, 58 women participated in this study, their ages ranging from 21 to 38 years (mean, 33.2 ± 4.0). They had undergone conservative operations for endometriosis within the previous 6 months. They were surgically diagnosed in accordance with Revised American Fertility Society (R- AFS) classification: stage II, 22 cases; stage III, 28 cases; and stage IV, 12 cases. The patients refused to undergo further surgery and were diagnosed having recurrent moderate to severe dysmenorrhea or other pelvic pain or disorders. Patients gave informed consent prior to the study and could leave the study at any time.

After confirming regular menstruation and ovulation with the basal body temperature (BBT) for 3 months before treatment, the patients were examined before and at 4, 12, 24 and 48 weeks after starting treatment to check for symptom control (pain score and urinary and bowel symptom scores), breakthrough bleeding and side effects of the medication. Pain was evaluated by patients’ self-assessment score of the severity of dysmenorrhea and pelvic pain since their previous visit. The investigator interviewed and performed a gynecologic examination on each patient. The smear test examination of the uterine cervix, ultrasonography, magnetic resonance imaging and serologic hormonal examinations of all patients, in- cluding CA-125 and estradiol in the middle of the proliferative phase, were performed before treatment.

Patients were randomized to 2 groups: Pycnogenol or Gn-RHa.
1. Patients in the Pycnogenol group took 30 mg Pycnogenol orally as capsules twice a day (total, 60 mg) for 48 weeks immediately after morning and evening meals. Treatment started on the eighth day of the menstrual cycle after reporting pain scores during a whole cycle before treatment. If a patient did not take the prescribed amount of capsules on a certain day, she was instructed to increase the dosage accordingly on the next day. The patients did not take psychotropic drugs, vitamins or Chinese kampo medicines during treatment with Pycnogenol. Also, physical therapy could not be introduced during the study period. Laxatives and medications necessary to continue with existing therapy were allowed. The use of analgesics was not re- stricted during the study; however, the dosage and type of analgesic had to be reported to a physician. The patients kept BBT charts during observation. If symptom control was unsatisfactory or side effects became significant, the patient could choose to terminate the medication or switch to another therapy.
2. The patients who received Gn-RHa therapy received injected leuprorelin acetate depot, 3.75 mg intracutaneously, 6 times every 4 weeks.10 Add- back therapy, hormonal replacement with Premarin (*Wyeth Medica Ireland, Newbridge, Co. Kil- dare, Ireland*), 1.25 mg/d, during Gn-RHa treatment was performed if necessary. After 6 treatments with Gn-RHa, patients did not receive other hormonal therapy. The patients were supposed to start checking their BBT at the onset of menstruation after the last treatment with Gn-RHa during observation.

The characteristics of the treatment groups showed no differences at the start of treatment:
In the Pycnogenol group, 32 patients were included (mean age, 33.6 ± 4.1 years; range, 24–39). Endometriosis was surgically diagnosed as stage II in 12 cases, stage III in 14 cases and stage IV in 6 cases according to the R-AFS.
In the Gn-RHa group 26 patients were included (mean age, 32.8 ± 3.8 years; range, 21–38). Endometriosis was diagnosed as stage II in 10 cases, stage III in 10 cases and stage IV in 6 cases.
In the Pycnogenol group, 3 patients stopped treatment after 8 weeks; after 16 weeks, 2 patients requested another treatment. Of the remaining 29 patients, 5 became pregnant (after 4–12 weeks, 2 cases; after 12–24 weeks, 3 cases). Their data before they left the study were used for statistical evaluation.
In the Gn-RHa group, 5 patients stopped therapy due to general malaise after 12 weeks of treatment and 1 patient stopped therapy because of pro- longed, massive uterine bleeding after 8 weeks of treatment.
Patients in both groups reported severe pain, pelvic tenderness and pelvic indurations at the start of treatment. Treatment with Pycnogenol slowly but steadily reduced all the symptom scores from severe to moderate. Treatment with Gn-RHa reduced the scores more efficiently; how- ever, 24 weeks after the end of treatment the scores demonstrated the recurrence of symptoms.
As expected, Gn-RHa suppressed menstruation during treatment, whereas in the Pycnogenol group no influence of treatment on menstrual cycles was observed. Gn-RHa lowered estrogen levels drastically;in contrast, the estradiol values of the Pycnogenol group showed no systematic changes over the observation period.
The values of serum marker CA-125 for endometriosis decreased in both treatment groups. Patients with smaller endometriomas responded better to treatment as compared to patients with large endometriomas. The lowering of CA-125 concentrations was by far more pronounced in the Gn-RHa group; however, a clear rebound effect was observable in the Gn-RHa group in contrast to the Pycnogenol group, where values remained at a lower level.
Side effects observed in the Pycnogenol group were mild and transient, none of the patients left the study because of side effects. In the Gn-RHa group, hot flushes, general malaise and lumbago were reported. Five patients reported general malaise stopped treat- ment because of its severity. Add-back therapies had to be prescribed in 8 cases of general malaise after the last treatment with Gn-RHa. The period from last treatment with Gn-RHa to onset of first menstruation was 13.2 ± 2 weeks and of first ovulaItion, 11.4 ± 2.2 weeks.

Conclusions

CA-125 is a good predicting marker for the evaluation and treatment of advanced endometriosis in patients with an initially elevated CA-125 level. CA-125 is a glycoprotein with a molecular weight of approximately 200 kd expressed on the cell surface of some derivatives of celomic epithelium. Accord- ing to Barbieri et al (9. Barbieri RL, Niloff JM, Bast RC Jr, et al: Elevated serum con- centrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986;45:630–634).
Two mechanisms may be responsible for elevated blood levels of CA-125 in endometriosis.
First,to normal endometrium.
Second, the local inflammation associated with endometriosis may increase the rate at which CA-125 is shed from the membranes of endometriotic lesions into the circulation. Inflammation-induced leakage of capillary endothelium could also explain why serum CA-125 increases in patients with acute pelvic inflammatory disease.
The reduction of symptoms could be the result of the combined action of the constituents of Pycnogenol, which contains a number of phenolic acids. Two of them, ferulic and caffeic acid, have a spasmolytic effect on the isolated uteri of rats . Ferulic acid especially can inhibit uterine contractions in rodents in vivo. These constituents of Pycnogenol, perhaps together with other phenolic acids in Pycnogenol, could be responsible for the relief from cramping pain. Recently a close relationship was demonstrated between reactive oxygen species and endometriosis. Pycnogenol shows strong free radical–scavenging activity against reactive oxygen and nitrogen species such as inactivation of the superoxide and hydroxyl radical, inhibition of singlet oxygen formation and protective effects against lipid peroxidation, thiobarbituric acid reactive products generation, and oxidative hemolysis induced by peroxide hydrogen; that indicates that Pycnogenol’s antioxidant capacity could also cause an improvement in endometriosis, especially long-term treatment. During treatment with Gn-RHa, estradiol in all patients was extremely lowered by the reduction of ovarian function, the main mechanism to inactivate endometrial cells due to their estrogen dependency._The result is a reduction in inflammatory changes inside the tissues that cause several symptoms of endometriosis_. However, this deactivated ovarian function quite frequently causes adverse effects, such as hot flushes, general malaise or loss of bone mineral. The profound hypoestrogenism is an inherent disadvantage of treatment with Gn-RHa. Moreover, after the end of treatment with Gn-RHa, estradiol levels increase rapidly around 3 months after the end of the therapy, causing recurrence of endometriosis, as demonstrated in this study by the increase in scores of pelvic pain, tenderness and induration after the end of treatment. In contrast, Pycnogenol treatment did not reduce estradiol, so endometriosis patients never lost the normal hormonal milieu.

Marta Sestero
Elisabetta Segre

DEFINITION

The disease definition according to a specific consensus conference or to The Diseases Database based on the Unified Medical Language System (NLM)

Also the link to the corresponding Mesh term has to be created

EPIDEMIOLOGY

age, sex, seasonality, etc

SYMPTOMS

DIAGNOSIS

histopathology
radiology
NMR
laboratory tests

PATHOGENESIS

PATIENT RISK FACTORS

Vascular

Genetic

Acquired

Hormonal

Genetic

Acquired

TISSUE SPECIFIC RISK FACTORS

anatomical (due its structure)

vascular (due to the local circulation)

physiopathological (due to tissue function and activity)

Introduction
Endometriosis, the presence of endometriumlike glands and stroma outside the uterus, is a common, poorly understood, and extremely debilitating benign gynecological condition. The psychological impact of the severe pain experienced by the patient is compounded by the negative impact of the disease on fertility. The etiology and pathophysiology of endometriosis is not well understood because of the lack of a suitable animal model on which to study the anatomic correlates and natural history of disease.1 No cure exists for the disease, and treatment is directed toward medical suppression, surgical excision, and symptom alleviation.

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Adenomyosis is the invasion of the myometrium by endometrial tissue.

Frequency
United States
Endometriosis occurs in 7-10% of women in the general population.2 It is an estrogen-dependent disease and, thus, usually affects reproductive-aged women. Endometriosis has a prevalence rate of 20-50% in infertile women3,4,5 and as high as 80% in women with chronic pelvic pain6 . Evidence of endometriosis was found during laparoscopy in 20-50% of asymptomatic women.7 Approximately 4 per 1000 women are hospitalized with endometriosis each year. A familial association exists, with a 10-fold increased incidence in women with an affected first-degree relative.8 Monozygotic twins are markedly concordant for endometriosis.9

Clinical
History
A significant number of women with endometriosis remain asymptomatic.

Cyclic pain: Cyclic pain is pain that accompanies bleeding at the time of menstruation. This could involve the bladder (hematuria), bowel (hematochezia and painful defecation), or, rarely, bleeding at uncommon sites such as the umbilicus, abdominal wall, or perineum.
Chronic pain: The most important point to remember is that the degree of visible endometriosis has no correlation with the degree of pain or other symptomatic impairment.10 However, pain does correlate with the depth of tissue infiltration.11,12 Midline disease is generally believed to be more painful than lateral disease.
Acute exacerbations: These are believed to be caused by chemical peritonitis due to leakage of old blood from an endometriotic cyst. Recently, with conscious laparoscopic pain mapping, painful lesions were found to involve peripheral spinal nerves rather than autonomic nerves.10
Dysmenorrhea: Secondary dysmenorrhea occurs twice as often in women with endometriosis as in controls.7 Pain frequently commences prior to menses. Endometriosis should be considered in a patient presenting with significant dysmenorrhea, and the patient should be started on empiric therapy.
Dyspareunia: Deep dyspareunia may be due to scarring of the uterosacral ligaments, nodularity of the rectovaginal septum, cul-de-sac obliteration, and/or uterine retroversion. All of these may also lead to chronic backache. These symptoms are exaggerated during menses. Women with deep infiltration of the uterosacral ligaments were shown to have the most severe impairment of sexual function.13

Physical
Pelvic examination: Tenderness upon examination is best detected at the time of menses. Nodularity of the uterosacral ligaments and the cul-de-sac may be found. The uterus may be fixed in retroversion, owing to adhesions. Occasionally, a bluish nodule may be seen in the vagina due to infiltration from the posterior vaginal wall.

Causes
Theories of causation include the following:

Retrograde menstruation
Sampson described this theory in his classic paper published in 1927. Retrograde flow of endometrial tissue through the fallopian tubes into the peritoneal cavity is believed to cause endometriosis.
Various animal experiments and clinical observations support this theory.14,15,16,17
Lymphatic and vascular spread
These pathways may explain the occurrence of endometriosis at distant, noncontiguous sites.
Ovarian endometriosis is also believed to be caused by lymphatic spread18 , although superficial ovarian endometriosis may also be due to implantation via retrograde menstruation.
Coelomic metaplasia
Transformation of coelomic epithelium into endometrial-type glands in response to as yet unknown stimuli could explain endometriosis in unusual sites.19
Coelomic metaplasia is also believed to explain the occurrence of endometriosis in women who have undergone total hysterectomy and are not taking estrogen replacement.20
Endometriosis may also occur in men on high-dose estrogen therapy.21
Immunogenetic defects
These are believed to increase the susceptibility of a woman to endometriosis. Humoral antibodies to endometrial tissue have also been found in sera of women with endometriosis.22
Recent work has focused on studying the differences between eutopic endometrium and endometriosis. In endometriosis, an aberrantly expressed factor SF-1 activates the expression of the enzyme aromatase, which converts C19 steroids to estrogens. Consequently, estrogen increases the synthesis of prostaglandin E2, which exerts a positive feedback effect, resulting in increased aromatase activity. Additionally, endometriotic tissue is deficient in the enzyme 17-beta hydroxy steroid dehydrogenase type 2, which converts E2 in eutopic endometrium to the less potent E1 under the direction of progestins. A recent study found a higher number of endometriomas, more bilateral disease, and a higher incidence of significant pain in women with aromatase positive disease.23 However, recent studies have shown increased cyclooxygenase-2 (COX-2) expression in the stromal cells24 and aberrant aromatase expression25 in eutopic endometrium of women with endometriosis.
While successful treatment has been described with the aromatase inhibitor anastrozole in women with severe postmenopausal endometriosis26 , more recent studies have also shown it to be effective in cases of severe endometriosis in premenopausal women27,28 . Additional data are needed before recommending this as primary treatment. See related Medscape CME Activity Aromatase Inhibitors May Relieve Endometriosis-Associated Pain: Review.
Anatomic spread
The ovary is the most common site for endometriosis. Spread to the ovary is believed to be lymphatic18 , although superficial implants may be due to retrograde menstrual flow because the ovaries are in a dependent part of the pelvis. Lesions can vary in size from spots to large endometriomas. The classic lesion is a chocolate cyst of the ovary that contains old blood that has undergone hemolysis.

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Although uncommon, interference in the genitourinary tract by endometriosis can affect the bladder, ureters, and kidneys by invasion, compression, or scarring. Medical therapy has less than satisfactory results, and surgical intervention is often required.
Uncommon sites include incisional scars, the umbilicus, and the thoracic cavity. Catamenial or cyclic pneumothorax can cause hemoptysis. Remember that ectopic endometrial tissue theoretically can undergo malignant transformation; histologic evaluation may be necessary.
Postmenopausal endometriosis may be encountered in women who are on estrogen replacement therapy (ERT). Occasionally, if ERT is administered after total abdominal hysterectomy, endometriosis can be stimulated in an ovarian remnant. Extrapelvic endometriosis is believed to be hormone-resistant when it occurs after surgical castration.20 Transplantation of endometrial implants during the original surgery is believed to explain this occurrence. Another possible explanation is coelomic metaplasia.

Differential Diagnoses
Pelvic Inflammatory Disease

Workup
Laboratory Studies
Serum cancer antigen 125 test: Serial measurements have a low sensitivity in detecting endometriosis29 , but the results are useful as prognosticators of treatment outcome30 . However, normal posttreatment values do not mean that endometriosis is absent.
Imaging Studies
Ultrasonography: Transvaginal sonography is a useful method of identifying the classic chocolate cyst of the ovary. The typical appearance is that of a cyst containing low-level homogenous internal echoes consistent with old blood.
MRI: The cost-effectiveness of this imaging modality for endometriosis has yet to be justified for use as a routine tool. However, MRI is helpful in detecting rectal involvement31 and has been shown to accurately detect rectovaginal endometriosis and cul-de-sac obliteration in more than 90% of cases when sonographic gel was inserted in the vagina and rectum32 .
Other Tests
Conscious pain mapping: Recently, conscious pain mapping (ie, with the patient awake) has been used to locate the specific areas that cause pain.10 Subsequently, the patient is placed under anesthesia and the deposits are ablated.
Procedures
Laparoscopy: Laparoscopy is considered the primary diagnostic modality for endometriosis. Endometriosis has been described as protean in appearance. The classic lesions are blue-black or have a powder-burned appearance. However, the lesions can be red, white, or nonpigmented. Peritoneal defects and adhesions are also indicative. Bear in mind that microscopic evidence of endometriosis may be found in normal-appearing peritoneum.

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Staging
The American Society for Reproductive Medicine classification is currently the most widely used staging system.33 Point scores are assigned based on the number of lesions and their bilaterality. Lesion size is also a scoring factor. This classification is a fairly accurate method of recording laparoscopic findings. However, high intraobserver and interobserver variability precludes its use in comparing the outcomes of therapeutic studies.34 Further, this staging system does not correlate well with pain and dyspareunia35 and fecundity rates cannot be predicted accurately.

Treatment

Medical Care
Endometriosis and subfertility
Peritubal and periovarian adhesions can interfere mechanically with ovum transport and contribute to subfertility. Peritoneal endometriosis has been postulated to contribute to subfertility by interfering with tubal motility, folliculogenesis, and corpus luteum function. Aromatase is believed to increase the prostaglandin E levels via increase in the COX-2 expression. Endometriosis may also cause subfertility by causing more sperm binding to the ampullary epithelium thereby affecting sperm-endosalpingeal interactions.36
Medical treatment of minimal or mild endometriosis has not been shown to increase pregnancy rates.37 Moderate-to-severe endometriosis should be treated surgically.38
Other options for achieving pregnancy include intrauterine insemination, superovulation, and in vitro fertilization. In a case-controlled study, pregnancy rates with intracytoplasmic sperm injection were not affected by the presence or extent of endometriosis.39 Further, other analyses have shown improvement in in vitro fertilization pregnancy rates with pretreatment of stage 3 and 4 endometriosis with gonadotropin-releasing hormone (GnRH) agonists.
Interval treatment
Some authorities believe that endometriosis should be suppressed prophylactically by continuous combined oral contraceptives, GnRH analogs, medroxyprogesterone, or danazol in order to cause regression of asymptomatic disease and enhance subsequent fertility.
Surgical ablation of asymptomatic endometriosis has also been shown to improve fecundity rates on a 3-year follow-up.38
Recurrent pregnancy loss: Based on results from controlled prospective studies, no evidence indicates that endometriosis is associated with recurrent pregnancy loss and no evidence indicates that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate.40
Medical therapy: Combination oral contraceptive pills (COCPs), danazol, progestational agents, and GnRH analogs form the mainstay of medical therapy. All these therapies have similar clinical efficacy in terms of reduction in pain-related symptoms and duration of relief.
COCPs act by ovarian suppression and continuous progestin administration.
Initially, a trial of continuous or cyclic COCPs should be administered for 3 months. If pain is relieved, this treatment is continued for 6-12 months. Subsequent pregnancy rates upon discontinuation of the pill are 40-50%. This applies to a population unselected for stage and fertility status of the disease.
Although few choices are available among individual formulations, note that the long-term efficacy of multiphasic preparations remains unproven.
Continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.
Women with endometriosis are at increased risk of epithelial ovarian cancer, and COCPs are believed to protect against this.41
All progestational agents act by decidualization and atrophy of the endometrium.
Medroxyprogesterone acetate has proven efficacy in pain suppression in both the oral and injectable depot preparations.42,43 Oral doses of 10-20 mg/d can be administered continuously. The time to resumption of ovulation is longer and variable with depot preparations. Adverse effects include weight gain, fluid retention, depression, and breakthrough bleeding.
Megestrol acetate has been used in doses of 40 mg with similarly good results.44
The levonorgestrel intrauterine system (LNG-IUS) has been shown to reduce endometriosis-associated pain.45
GnRH analogs produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.
Once again, efficacy is limited to pain suppression and fertility rates may show no improvement.46 Winkel et al claim that GnRH therapy may lead to improvement in pain associated with endometriosis in 85-100% of women.47 Further, the pain relief is believed to persist for 6-12 months after cessation of treatment.
Treatment is usually restricted to monthly injections for 6 months.
Loss of trabecular bone density caused by GnRH is restored by 2 years after cessation of therapy.48 Other prominent adverse effects include hot flashes and vaginal dryness.
Much interest has been shown in whether add-back therapy should be instituted to prevent osteoporosis and hypoestrogenic symptoms. Hormone replacement therapy preparations, progestins, tibolone maleate, and bisphosphonates have all been shown to be effective.49,50,51,52 Add-back therapy has been shown to prevent loss in bone density and to relieve vasomotor symptoms without reducing the efficacy of GnRH regimens. GnRH agonists have been used for 12 months with norethindrone add-back therapy with good results.53
A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic algorithm without definitive laparoscopic diagnosis, is efficacious.54 However, long-term effects of GnRH analogs on bone density in this population remain unproven. Therefore, add-back therapy remains the standard of care while the patient is on GnRH treatment. Also, empiric treatment without a firm diagnosis could result in unnecessary treatment in patients with chronic pelvic pain, whose condition could be due to other causes. In Ling's study, 13% of subjects were shown to not have endometriosis.
GnRH therapy has also been proven to relieve the pain and bleeding associated with extrapelvic distant endometriosis.55
Danazol acts by inhibiting the midcycle follicle-stimulating hormone (FSH) and luteinizing hormone (LH) surges and preventing steroidogenesis in the corpus luteum. It is the most extensively studied agent for endometriosis.
Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects.
Its androgenic manifestations include oily skin, acne, weight gain, deepening of the voice, and facial hirsutism. Hypoestrogenic features due to danazol include emotional lability, hot flashes, vaginal dryness, and reversible breast atrophy.
The recommended dose is 600-800 mg/d. However, smaller doses have been used with success.56,57 In a recently reported small study of 21 patients, vaginal danazol (200 mg/d) was successful in relieving endometriosis-associated pain.58
Because of the possibility of virilizing changes in a female fetus, additional barrier contraception must be used while on danazol therapy.
Surgical Care
Surgical care can be broadly classified as conservative when reproductive potential is retained, semiconservative when reproductive ability is eliminated but ovarian function is retained, and radical when the uterus and ovaries are removed. Age, desire for future childbearing, and deterioration of quality of life are the main considerations when deciding on the extent of surgery.

Conservative surgery
With conservative surgery, the aim is to destroy visible endometriotic implants and lyse peritubal and periovarian adhesions that are a source of pain and may interfere with ovum transport. The laparoscopic approach is the method of choice for treating endometriosis conservatively.59,60 Ablation can be performed with laser or electrodiathermy. Overall, the recurrence rate is 19% and is similar for all techniques.61 Laparoscopic ablative surgery with bipolar diathermy or laser for endometriomas was shown to be effective for relieving pelvic pain in 87% of patients.62 Ovarian endometriomas can be treated by drainage or cystectomy. Laparoscopic cystectomy was found to yield better pain relief and pregnancy rates than drainage.63,64 Medical therapy with GnRH agonists reduces the size of the cyst but does not influence pain relief.65
Tubal flushing with oil-soluble media has been shown to improve pregnancy rates in women with endometriosis-associated infertility.66
Presacral neurectomy is used to relieve severe dysmenorrhea. The nerve bundles are transected at the level of the third sacral vertebra, and the distal ends are ligated. Vascular injury to the middle sacral artery and vein is a potential complication, and some authors advocate prophylactic ligation. Also, constipation is a long-term adverse effect (94%) of this procedure and should be considered while deciding whether to perform this procedure.
Nodularity of the uterosacral ligaments may contribute to dyspareunia and low back pain. The transmission of neural pathways is via the Lee-Frankenhãuser plexus. Laparoscopic uterine nerve ablation (LUNA) is performed to interrupt the pain fibers. Potential complications of this procedure include uterine prolapse and pelvic denervation. A systematic review of trials of LUNA found no advantage in terms of pain relief when compared to placebo.67 However, when combined with laparoscopic ablation, LUNA significantly reduced pain attributed to endometriosis.68 In patients with subfertility, tissue ablation significantly increased the cumulative pregnancy rate.38 A recent Cochrane review failed to show any benefit from either LUNA or presacral neurectomy.69
For patients with mild disease, postoperative adjunctive hormonal treatment has been shown effective in reducing pain but has no impact on fertility. GnRH analogs, danazol, and medroxyprogesterone have all been found to be useful for this indication.70,71,72,73 However, for severe endometriosis, the efficacy of preoperative or postoperative hormonal treatment has not yet been established.
Semiconservative surgery
The indication for this type of surgery is mainly in women who have completed their childbearing, are too young to undergo surgical menopause, and are debilitated by the symptoms. Such surgery involves hysterectomy and cytoreduction of pelvic endometriosis. Ovarian endometriosis can be removed surgically because one tenth of functioning ovarian tissue is all that is needed for hormone production. Patients who undergo hysterectomy with ovarian conservation have a 6-fold higher rate of recurrence compared to women who undergo oophorectomy.74
Medical therapy in women who have completed childbearing is equally efficacious for symptom suppression.75,76,77
Radical surgery
This involves total hysterectomy with bilateral oophorectomy and cytoreduction of visible endometriosis. Adhesiolysis is performed to restore mobility and normal intrapelvic organ relationships.
Ureteric obstruction may warrant surgical release or excision of a damaged segment. Bowel obstruction may require a resection anastomosis or a wedge resection if the obstruction is confined to the anterior rectosigmoid.
Endometriosis may recur in 15% of women after extirpative surgery, irrespective of whether ERT is given postoperatively.78 ERT can be instituted safely immediately after surgery, especially in younger women who face the prospect of accelerated bone loss and vasomotor symptoms.78,79 No trials have reported the use of estrogen plus progestin therapy compared to estrogen therapy alone postoperatively. However, theoretically, the addition of a continuous progestin could decrease the regrowth of endometriosis.
Comparison of medical and surgical therapy: In women who wish to preserve their reproductive potential, the rates of recurrent pain symptoms are 44% with surgical management and 53% with medical management.68,76

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Oral contraceptives
COCPs act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be given for 3 mo. If pain is relieved, this treatment is continued for 6-12 mo. Subsequent pregnancy rates are 40-50% upon discontinuation of the contraceptive pill. Although individual formulations offer few variations, note that the long-term efficacy of multiphasic preparations remains unproven. In addition, continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.

Follow-up

Prognosis
Endometriosis was found to resolve spontaneously in one third of women who were not actively treated.80
Patient Education
For current information on endometriosis, visit the National Institutes of Health (NIH) Web site at Endometriosis Research at NIH.
For excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center and Women's Health Center. Also, see eMedicine's patient education articles Birth Control Overview, Birth Control FAQs, Female Sexual Problems, and Endometriosis.

Lavoro eseguito da NIKA LULASH.

Endometriosis and oxidative stress.

Endometriosis is a gynecological disorder characterized by the presence and growth of endometrial tissue outside the uterine cavity. (1. Farquhar CM. Endometriosis. Extarcts form the “clinical evidence”. BMJ. 2000;320:1449-1452.) The prevalence of endometriosis among asymptomatics women ranges from 2-22%, while in women with infertility the incidence is 35% to 50%. (2. Dckitt K. Infertility and subfertility. Clin Evid. 2003;9:2044-2073.) This pathology is one of the most common disease during women’s reproductive age. We still don’t know the real cause of this gynecological disorder, but one of the most approved theory says that the presence of endometrial tissue outside of the endometrial layer could be caused by a retrograde menstruation, which consist of the reflux of menstrual fluid through the Fallopian tubes to the abdominal cavity. (3. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422-469).

Data reported in the literature have suggested that oxidative stress might play a role in the development and progression of endometriosis. (4. Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D. Oxidative stress and endometriosis. Hum Reprod. 2005;20:2014-2020.) Evidence shows a higher concentration of lipid peroxidation markers in the peripheral blood and peritoneal fluid of women with endometriosis. (5. Van Landendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002;77:861-870). The higher lipid peroxidation markers observed in women with endometriosis have been related to a pro-inflammatory milieu, a consequence of the activation of peritoneal macrophages due to the presence of apoptotic and undigested endometrial ectopic cells and red blood cells. (6. Murphy AA, Santanam N, Parthasarathy S. Endometriosis: a disease of oxidative stress? Semin Reprod Endocrinol. 1998;16:263-73) Upon activation peritoneal macrophages release reactive oxygen and nitrogen species (RONS), also known as free radicals. Analyzing the peritoneal fluid the confirm came that an higher number, concentration and activation of macrophages was present in women with this disorder, in comparison with women without endometriosis. (7. Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM. Potential involvment of the immune system in the development of endometriosis. Reprod Biol Endocrinol. 2033;1:123. D’Hooghe TM, Hill JA. Immunobiology of endometriosis. In: Bronston R, Anderson DJ, editor. Immunology of reproduction. Cambridge: Blackwell Scientific; 1996. pp. 322-356. Zeller JM, Henig I, Radwanska E, Dmowski WP. Enhancement of human monocyte and peritoneal macrophage chemilluminescence activities in women with endometriosis. Am J Reprod Immunol MIcrobiol. 1987;13:78-82).

Role of the oxidative stress.

Abnormally high concentrations of free radicals could disrupt the balance between oxidants and antioxidants, promoting oxidative stress conditions. This condition is settled if the production of RONS is increased and/or the level of antioxidants is decreased. (8. Agarwal A, Gupta S, Sharma A. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:1-28) Our defenses against RONS damage are the antioxidants synthetized in the body and taken up in the diet. These defense systems are enzymatic and non-enzymatic, and allow scavenging of RONS. The former include proteins, such as catalase, gluthathione peroxidase and superoxide dismutase, that need a small concentration of minerals to get to their optimal enzymatic activity. Ascorbate, alfa-tocopherol, beta-carotene and minerals need to be eaten regularly because they generally do not accumulate in the body. (9. Cadenas E, Packer L. Handbook of antioxidant. New York: Marcel Dekker; Inc;2001) Until now there is little information about the consumption of antioxidants (vitamins and minerals that may counter oxidative stress) in women with endometriosis and on the condition’s possible relationship with oxidative stress. (10. Parazzini F, Chiaffarino F, Surace M, Chatenoud L, Cipriani S, Chiantera V, Benzi G, Fedele L. Selected food intake and risk of endometriosis. Human Reprod. 2004;19:1755-1759. Mier-Cabrera J, Genera-Garcia M, De La Jara-Dìaz J, Perichart-Perera O, Vadillo-Ortega F, Hernàndez-Guerrero C. Effects of vitamins C and E supplementation on peripheral oxidative stress markers and pregnancy rate in women with endometriosis. Int J Gynaecol Obstet. 2008;100:252-256)

The study

The objective of this work was to compare antioxidant intake among women with and without endometriosis and the design and application of a high-antioxidant diet (vitamins A, C and E) to evaluate its capacity to abrogate oxidative stress markers and improve antioxidant markers in the plasma of women with endometriosis.

Method

The first part of the study consisted in the recruitment of two groups of women, thanks to their medical record, without (n = 80) and with endometriosis (n = 86) in a population of Mexican mestizo women. Their record was checked the day before surgery, to be sure that they were fitting the inclusion criteria. The day after surgery the women who elected to participate gave their informed and written consent and where asked for demographic, socioeconomic and educational status. The group of WWE (women without endometriosis) included fertile women who had a tubal ligation as a permanent contraceptive method. The WEN’s group (women with endometriosis) was composed by women infertile, in which the laparoscopy confirmed the presence of I or II stage of endometriosis. (11. American Society for Reproductive Medicine Revised American Society for Reproductive Medicine classification for endometriosis. Fertil Steril. 1997;67:817-821).
The exclusion criteria for both groups were: presence and diagnosis of inflammatory pelvic disease, a previous history of autoimmune or endocrine/metabolic diseases, tobacco and alchol consumption, and/or use of multivitamine supplements.

A nutritionist, who did not know the fertility status of the patients, assessed the dietary intake of WWE and WEN using a Food Frequency Questionnaire for Mexican women.

The second part of the study consisted in the application of an high anti-oxidant diet (HAD) to a random chosen group of women fitting in the WEN group. The follow up included 5 visits for each patient. Each time we manage to make anthropometric measurements: height (only at the beginning), weight and BMI. Patient were eliminated if they missed a control or if they became pregnant during the diet study. The HAD was tailored according to each patient’s energy requirements. The follow up lasted for 4 month, with a visit every 30 days and the filling of a multiple-step 24-hours record to evaluate the antioxidant vitamin intake. The evaluation was made with a vein puncture, taking a blood sample and analyzing the total plasma lipid hydroperoxides, the malondialdehyde (for the oxidative stress level), plasma and leukocyte ascorbate, ascorbic acid, serum retinol, serum alfa-tocopherol, carotenoids and tocopherols (vitamins), the superoxide dismutase and glutathione peroxidase activity (enzyme activity).

Design of the antioxidant diet (HAD)

Three food groups were created in order to guarantee 150% of the intake of the Suggested Daily Intake (SDI) of vitamin A (1050µg retinol equivalent), 660% of the Recommended Daily Intake (RDI) of vitamin C (500mg) and 133% of the RDI of vitamin E (20mg).

WWE vs. WEN: antioxidant intake

With this study the previous data regarding a lower antioxidant intake in WEN compared with women without the disease was confirmed. (12. Hernandez Guerrero CA, Bujalil Montenegro L, de la Jara Diaz J, Mier Cabrera J, Bouchan Valencia P. Endometriosis and deficient intake of antioxidants molecules related to peripheral and peritoneal oxidative stress. Ginecol Obstet Mex. 2006;74:20-28). Vitamin C, copper and zinc were above the RDI in both groups. Nevertheless WEN showed a 30% lower intake of these antioxidants in comparison to WWE. Vitamin E selenium and zinc intake, in the women with endometriosis showed a statistical difference when compared with the control group.
The body’s complex antioxidant system is influenced by dietary intake of non-enzymatic antioxidants, such as manganese, copper, selenium and zinc, beta-carotenes, vitamin C, vitamin E, taurine, hypotaurine and B vitamins. (9.) On the other hand the body produces several antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase and molecules like glutathione and NADH. Both enzymatic and non-enzymatic antioxidant systems scavenge and deactivate excessive free radicals, helping to prevent cell damage.

Control diet vs. HAD

With the development of the HAD this study designed a high antioxidant diet and evaluated the effect in WEN to improve peripheral antioxidant markers. Although they were not all reached (vitamin A: 95%, vitamin E 66%, vitamin C 79%) the evidence showed that this diet had a positive effect by diminishing the oxidative stress markers and improving the antioxidant enzyme activity and the vitamin concentrations in peripheral blood. The supplemented intakes were enough to observe a decrease in the oxidative stress markers from the third month of intervention. A decrease of 20% of MDA and LPH after three months following the HAD was found.
Vitamin E is the most effective lipid-soluble, chain-breaking antioxidant, singlet oxigen quenchers against lipid peroxidation. A change of 29% and 34% was observed in the third and fourth month after taking 20mg of alfa-tocopherol from seeds. It’s documented that natural vitamin E is twice as effective as synthetics, since the former stays for longer in tissues. (13. Lodge J. Vitamin E bioavailability in humans. J Plant Physiol. 2005;162:790-796)
For vitamin A it was possible to observe an increase of 12% in plasmatic concentration at the end of the study.
Plasmatic vitamin C reflects the vitamin C intake of a previous day. On the other hand leukocyte ascorbate concentration gives us information about the vitamin C pool, which is a consequence of the vitamin C intake of 20 days before. A change of 40% was observed for the plasma ascorbate from the second month and a leukocyte ascorbate change of 28% from the third month to the end of the study. That confirmed the positive effect of the HAD on such vitamins in the body.
It’s however known that inorganic nutrients are essential for the optimal functioning of antioxidant enzymes. Women with endometriosis showed a glutathione peroxidase activity increase of 25% from the third month of study, while superoxide dismutase activity increased by 40% after two months of study. Nevertheless inorganic nutrients were not quantified in the study; the activity of the enzymes that were evaluated is associated with the increase of inorganic nutrients, such as selenium, zinc, magnesium and iron.

Conclusions

Women with endometriosis had lower vitamin A, C, E, zinc, and copper intake in comparison to women without endometriosis.
The application of the HAD in women with endometriosis increased in the peripheral concentration of vitamins A, C and E after 3 months of intervention in comparison to the control diet group.
The application of the HAD in women with endometriosis increased the peripheral enzymatic superoxide dismutase and glutathione peroxidase activity after 3 months of intervention in comparison to the control diet group.
The application of the HAD in women with endometriosis decreased the peripheral concentration of malondialdehyde and lipid hydroperoxides after 3 months of intervention in comparison to the control diet group.

Zerbinati Chiara