De novo postmenopausal endometriosis during tibolone treatment: a case report and review of the literature

Endometriosis is uncommon before puberty and after menopause as it is an estrogen-dependent disease. A case is presented of postmenopausal endometriosis encountered in a patient who had received tibolone (Livial, Organon, Cambridge, UK) 1 year before the diagnosis of the adnexal mass for 3 months for relief from vasomotor symptoms and had the medication stopped because of fibrocystic disease of the breast. Transvaginal ultrasonography showed homogeneous cystic adnexal mass of 36 × 26 mm with no internal echoes in the right ovary. Laparoscopic right salpingooophorectomy was performed and the histopathological examination of the cyst showed an endometriotic cyst. Most of the cases with postmenopausal endometriosis are associated with the use of hormone replacement therapy (HRT). However, tibolone is recommended in hormone replacement therapy of postmenopausal symptomatic women who have a past history of hormone-dependent tumors such as endometriosis. There is restricted data in the literature about tibolone use and recurrence or de novo formation of endometriosis.     

Recurrent endometriosis following total hysterectomy with oophorectomy mimicking a malignant neoplastic lesion: a diagnostic and therapeutic challenge

Case report  A woman with a previous hysterectomy and bilateral salpingo-oophorectomy for endometriosis presented with painless vaginal bleeding. Imaging revealed a heterogeneous soft tissue pelvic mass suggestive of a malignant neoplastic lesion. Radical surgery was performed including excision of the pelvic mass and anterior resection of the sigmoid colon. Histopathology revealed endometriosis. Conclusion  The risk of malignant transformation and the difficulty in achieving a preoperative diagnosis make radical surgery inevitable in the management of recurrent endometriosis. The use of hormone replacement therapy after bilateral salpingo-oophorectomy for endometriosis remains controversial and requires careful counseling about recurrence and close follow-up.     

Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy

OBJECTIVE: To estimate the risk of recurrence after administration of hormone replacement therapy (HRT) among women who have had endometriosis and who underwent bilateral salpingo-oophorectomy (BSO). DESIGN: Prospective randomized trial (115 women receiving HRT and 57 not receiving HRT). SETTING; Public university hospital. PATIENT(S): Women with a histologic diagnosis of endometriosis in whom BSO was performed; 91.8% had a total hysterectomy. INTERVENTION(S): Periodical clinical examination, vaginal ultrasound, and CA-125 levels; surgical evaluation and histologic study. MAIN OUTCOME MEASURE(S): Recurrence rate, prognostic factors, and a mean follow-up time of 45 months. RESULT(S): There was no recurrence among women who did not receive HRT, versus a 3.5% rate (4 out of 115), or 0.9% per year, in women who received HRT. Two recurrences required abdominal surgery. There was one additional patient who required surgery, but the relationship to the endometriosis recurrence was controversial. Among women receiving HRT, the following risk factors were detected: peritoneal involvement > 3 cm (2.4% recurrence per year vs. 0.3%) and incomplete surgery (22.2% per patient vs. 1.9%). CONCLUSION(S): Patients with a history of endometriosis in whom total hysterectomy and bilateral salpingo-oophorectomy have been performed have a low risk of recurrence when HRT is administered. In those patients, HRT is a reasonable option. However, in cases with peritoneal involvement > 3 cm, the recurrence rate makes HRT a controversial option; if HRT is indicated, it should be monitored closely.     

Today's treatments: medical,surgical and in partnership

Objective: To provide an overview of the medical, surgical and combined therapy options for endometriosis. Results: Available medical options include danazol, progestogens, gestrinone, oral contraceptive agents, analgesics and gonadotropin-releasing hormone (GnRH) agonists. Used in the short-term, most of these agents relieve pain in a large proportion of patients and produce disease regression, however, they do not prevent recurrence, and are associated with side-effects. However, few data confirm any benefit of short-term medical therapy on fertility. One of the most promising medical approaches appears to be GnRH agonists with add-back hormone replacement therapy. Surgery may relieve pain, eradicate visible disease and improve fertility. A combined approach may facilitate surgery and relieve pain, although any fertility benefit is as yet unproven. Conclusion: Both short-term medical treatment and surgery relieve endometriosis-associated pain and decrease endometriotic implants. However, all approaches have side effects which must be balanced against the benefits when defining suitable treatment for a particular patient.     

Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence

Research questionHow effective is medical hormonal treatment in preventing endometriosis recurrence and in improving women's clinical symptoms and quality of life?DesignThis observational cross-sectional study evaluated the effects of hormonal medical treatment (progestins, gonadotrophin-releasing hormone analogues or continuous oral contraceptives) on endometriosis recurrence, current clinical symptoms and quality of life in three groups of patients: Group A (n = 34), no hormonal treatment either before or after the first endometriosis surgery; Group B (n = 76), on hormonal treatment after the first endometriosis surgery; and Group C (n = 75), on hormonal treatment both before and after the first endometriosis surgery.ResultsGroup C patients were characterized by a lower rate of endometriosis reoperation (P = 0.011) and a lower rate of dysmenorrhoea (P = 0.006). Women who experienced repetitive endometriosis surgery showed worse physical (P = 0.004) and mental (P = 0.012) status than those who received a single surgery, independent of the treatment.ConclusionHormonal treatments represent a valid cornerstone of endometriosis management and may be useful as an alternative to surgery, but also before surgery, to plan better, and after surgery in order to reduce the risk of recurrence. Medical counselling is very helpful in choosing the correct and individualized endometriosis treatment. In fact, the gold standard for modern endometriosis management is the individualized approach and surgery should be considered, depending on the clinical situation and a patient's symptoms.     

Bilateral Ureteric Obstruction Due to Recurrent Endometriosis Associated with Hormone Replacement Therapy

EDITORIAL COMMENT : We accepted this case report for publication since it addresses the important problem of whether hormone replacement therapy should be withheld after bilateral oophorectomy (usually associated with hysterectomy) in the premenopausal woman who had extensive endometriosis. Our endocrinologist reviewer withholds oestrogen for 6 months in such women and prescribes medroxyprogesterone acetate 10 mg BD continuously if they have flushes or associated symptoms; he is especially unwilling to prescribe oestrogen if removal of endometriotic deposits is deemed by the surgeon to be incomplete. Our editorial panel consensus is that it is cruel to withhold oral hormone replacement therapy from these women but that the regimen should include a progestogen as well as oestrogen as in women who still have a uterus. We agree with the authors that we need data telling us how often hormone replacement therapy is associated with return of symptoms due to endometriotic deposits - in the editor's experience the problem is uncommon. Our Senior Gynaecologist Chairman states that in the few patients he has managed in whom endometriosis has been reactivated by hormone replacement therapy after pelvic clearance, the problem has been controlled by low-dose X-ray therapy - in his experience this has not resulted in ureteric obstruction although he has seen 2 women present with unilateral ureteric obstruction from previously untreated endometriosis involving the lateral pelvic wall.     

Endometriosis and estroprogestins: the chicken or the egg causality dilemma

Dysmenorrhea as a reason to initiate estroprogestins is significantly more common in women with endometriosis than in women without the disease. This might explain the previously reported mild association between endometriosis and past use of oral contraceptives.     

Repetitive surgery for recurrent symptomatic endometriosis: What to do?

In spite of the increasing number of operative laparoscopies performed for endometriosis associated pelvic pain, postoperative symptomatic recurrences are very common. Reoperation is often considered the best treatment option, but the extent and duration of the effect of second-line surgery is still unclear. The best available evidence has been reviewed in order to define the results of repetitive conservative surgery, the effects of pelvic denervating procedures and postoperative medical treatments, as well as the long-term outcome of definitive surgery. Because of the paucity of published data, estimating the real risk of symptomatic recurrence and need for reoperation after repetitive conservative surgery for endometriosis is very difficult. Based on the limited information available, the long-term outcome appears suboptimal, with a cumulative probability of pain recurrence between 20% and 40%, and of a further surgical procedure between 15% and 20%. These figures are probably an underestimate related to drawbacks in study design, exclusions of dropouts, and publication bias and should be considered with caution. Systematic complementary performance of denervating procedures in addition to reoperation cannot be recommended, as only a few symptomatic patients complain of predominantly midline, hypo-gastric pain. The outcome of hysterectomy for endometriosis-associated pain at medium-term follow-up seems quite satisfactory. Nevertheless, about 15% of patients had persistent symptoms, and 3–5% experienced worsening of pain. Concomitant bilateral oophorectomy reduced the risk of reoperation due to recurrent pelvic pain by six times. However, atleast one gonad should be preserved in young women, especially in those with objections to the use of oestrogen–progestogens. Medical treatment appears to have limited and inconsistent effects when used for only a few months after conservative procedures. Data on the benefit of prolonged drug regimens with oral contraceptives or progestogen are lacking. The risk of recurrence of endometriosis during hormone replacement therapy seems marginal if combined preparations or tibolone are used and oestrogen-only treatments are avoided. The opportune surgical solution in women with recurrent symptoms after previous conservative procedures for endometriosis should be based on the desire for conception as well as on psychological characteristics. Studies on surgical management of recurrent rectovaginal endometriosis are warranted, due to the peculiar technical difficulties as well as the high risk of complications associated with this challenging disease form.     

Extraovarian Endometrioid Carcinoma Associated with Unopposed Oestrogen Replacement Therapy

EDITORIAL COMMENT: We accepted this case report for publication because, apart from being interesting, it raises the question of the appropriate hormone replacement therapy after bilateral oophorectomy (usually with hysterectomy) has been performed when there is evidence of endometriosis. Menopausal symptoms in these women can be relieved by oestrogen therapy without return of pelvic pain or dyspareunia. The authors report a case of endometrial-like carcinoma in a woman with known endometriosis after a hysterectomy and prolonged unopposed oestrogen therapy. Although this is a solitary case report, the authors explain that there are 8 others in the literature where malignancy occurred in extraovarian endometriosis after bilateral oophorectomy associated with unopposed oestrogen. One of our reviewers commented that a combination of oestrogen and progestogen should always be considered when prescribing hormone replacement therapy in women with a known history of endometriosis, following total hysterectomy and bilateral oophorectomy.     

Extraovarian Endometrioid Carcinoma Associated with Unopposed Oestrogen Replacement Therapy

EDITORIAL COMMENT: We accepted this case report for publication because, apart from being interesting, it raises the question of the appropriate hormone replacement therapy after bilateral oophorectomy (usually with hysterectomy) has been performed when there is evidence of endometriosis. Menopausal symptoms in these women can be relieved by oestrogen therapy without return of pelvic pain or dyspareunia. The authors report a case of endometrial-like carcinoma in a woman with known endometriosis after a hysterectomy and prolonged unopposed oestrogen therapy. Although this is a solitary case report, the authors explain that there are 8 others in the literature where malignancy occurred in extraovarian endometriosis after bilateral oophorectomy associated with unopposed oestrogen. One of our reviewers commented that a combination of oestrogen and progestogen should always be considered when prescribing hormone replacement therapy in women with a known history of endometriosis, following total hysterectomy and bilateral oophorectomy.     

Combined Surgical and Hormone Therapy for Endometriosis is the Most Effective Treatment: Prospective,Randomized, Controlled Trial

Study ObjectiveTo evaluate 3 therapy strategies: hormone therapy, surgery, and combined treatment.DesignProspective, randomized, controlled study (Canadian Task Force classification I).SettingUniversity-based teaching hospital.PatientsFour hundred fifty patients with genital endometriosis, aged 18 to 44 years, before first laparoscopy.InterventionsPatients were randomly assigned to 1 of 3 treatment groups: hormone therapy, surgery, or combined treatment. Patients were reevaluated at second-look laparoscopy, at 2 to 2 months after 3-month hormone therapy in groups 1 and 3 and at 5 to 6 months in group 2 (surgical treatment alone). Outcome data were focussed on the endometriosis stage, recurrence of symptoms, and pregnancy rate.Measurements and Main ResultsAll treatment options, independent of the initial Endoscopic Endometriosis Classification stage, achieved an overall cure rate of ≥50%. A cure rate of 60% was achieved with the combined treatment, 55% with exclusively hormone therapy, and 50% with exclusively surgical treatment. Recurrence of symptoms was lowest in patients who received combined treatment. Significant benefit was achieved for dysmenorrhea and dyspareunia. An overall pregnancy rate of 55% to 65% was achieved, with no significant difference between the therapeutic options.ConclusionIn the quest to find the most effective treatment of genital endometriosis, this clinical randomized study shows the lowest incidence of recurrence with combined surgical and medical treatment and improved pregnancy rate in any medically treated patients with or without surgery. The highest cure rate (Endoscopic Endometriosis Classification stage 0) for endometriosis was also achieved in the combined treatment group.     

Hormone replacement therapy in women with past history of endometriosis.

Endometriosis is a common clinical condition and its treatment will often lead to an estrogen deficiency status. As most of these patients are young, they will need to consider hormone replacement therapy. Endometriosis is a hormone-dependent disease and estrogen replacement can be associated with a risk of recurrence or malignant transformation. Only a few studies have addressed this problem. With the use of hormone replacement therapy (HRT), there is an increased, although undefined, risk of recurrence of endometriosis, especially in known severe cases and in obese patients. Unopposed estrogen appears to carry a higher risk than combined preparations. Delay in starting HRT after pelvic clearance is not of any benefit. After radical surgery for severe endometriosis, women often have much to gain from HRT, particularly in the early years. Benefits of HRT in terms of control of menopausal symptoms, prevention of urogenital atrophy and loss of libido and bone protection are of particular importance. HRT may still have a role in prevention of cardiovascular disease in early menopause, but this remains unproven. Although there is no firm evidence, continuous combined preparations or tibolone would appear to be the optimum choice.     

复发性子宫内膜异位症根治术时自体卵巢组织移植的价值

目的 探讨保守手术后复发的重症子宫内膜异位症(内异症)根治术时自体卵巢组织移植的应用价值。方法 1997年2月-2000年3月,对17例40岁以下,内异症保守手术后出现复发性疼痛和盆腔包块,药物治疗无效的Ⅳ期内异症患者,施行根治术时将自体卵巢组织片移植于大网膜之中。术后雌激素替代治疗3个月。停药后1个月后每月测定卵泡刺激素(FSH)、黄体生成素(LH)和雌激素(E2),直至卵巢功能恢复。E2水平上升后,测定基础体温,每周做阴道脱落细胞检查,计算成熟指数(MI)。每4次为1个周期。结果17例患者中,8例术后4个月血清E2水平上升,7例术后6个月E2水平上升,2例术后12个月E2维持在低水平,FSH、LH上升被列为卵巢组织失活。卵巢组织移植成活率为88.2％。卵巢功能恢复后,基础体温呈双相型,阴道脱落细胞涂片呈现周期性变化片型。随访17例患者均无复发性疼痛和盆腔包块。结论 对卵巢组织破坏严重的复发性重症内异症患者,根治术时实施卵巢组织移植是避免内异症复发,重建卵巢功能的有效方法。     

Complications of unopposed oestrogen following radical surgery for endometriosis.

Four cases are presented here of patients who had total abdominal hysterectomy and bilateral salpingooophorectomy for severe endometriosis. All were eventually placed on unopposed oestrogen replacement therapy, two immediately and the other two after a few months. All subsequently developed recurrence of their endometriosis whilst on oestrogen therapy, one developing an endometroid carcinoma. All required surgery and three were placed on continuous oestrogen/progestogen preparation or alternatively tibolone (which has oestrogenic, progestogenic and androgenic properties) postoperatively. No further recurrence of their disease occurred. The literature was reviewed regarding oestrogen therapy for women who have had bilateral oophorectomy. There were various suggestions as to management but no report on using continuous oestrogen/ progestogen or tibolone. We suggest this as a logical form of replacement therapy for patients who have bilateraloophorectomy for severe endometriosis, as unopposed oestrogen therapy can cause recurrence.     

Gonadotropin-releasing hormone agonists and estrogen-progestogen replacement therapy

Gonadotropin-releasing hormone agonists are effective in the treatment of endometriosis and myomas, both of which are estrogen-dependent processes, but there is a high clinical recurrence rate after therapy is discontinued. Long-term continuous therapy (2 years or more) has a cumulative effect on bone loss and causes other uncomfortable or harmful side effects. Noninvasive assessments of disease response in patients with myomas have shown that bone changes might be prevented and other side effects of long-term therapy can be alleviated by adding back small amounts of estrogen or progestin. No comparable data are available for patients with endometriosis because the need for repeated laparoscopy has made long-term studies impractical. Nevertheless, a short-term study of patients with endometriosis showed that adding small amounts of progestin during treatment with a gonadotropin-releasing hormone agonist may help prevent bone changes.     

Dienogest and the Risk of Endometriosis Recurrence Following Surgery: A Systematic Review and Meta-analysis

Study ObjectiveTo determine whether dienogest therapy after endometriosis surgery reduces the risk of endometriosis recurrence compared with expectant management.Data SourcesOvid MEDLINE, Ovid EMBASE, PubMed, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, clinicaltrials.gov, and International Standard Randomized Controlled Trial Number Registry were searched from inception to March 2019 for observational and randomized controlled trials.Methods of Study SelectionThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Medical Subject Heading terms and keywords such as “dienogest,” “endometriosis,” and “recurrence” were used to identify relevant studies.Tabulation, Integration, and ResultsThe search yielded 328 studies, 10 of which were eligible for inclusion, representing 1184 patients treated with dienogest and 846 expectantly managed controls. Among these studies, 9 looked exclusively at endometrioma recurrence, whereas 1 used reappearance of symptoms as evidence of disease recurrence. Data on both incidence of and time to recurrence of endometriosis were extracted.The incidence rate of endometriosis recurrence in patients treated with dienogest was 2 per 100 women over a mean follow-up of 29 months (95% confidence interval [CI], 1.43–3.11) versus 29 per 100 women managed expectantly over a mean follow-up of 36 months (95% CI, 25.66–31.74). The likelihood of recurrence was significantly reduced with postoperative dienogest (log odds −1.96, CI, −2.53 to −1.38, p <.001).ConclusionPatients receiving dienogest after conservative surgery for endometriosis had significantly lower risk of postoperative disease recurrence than those who were expectantly managed.     

Short-term postoperative GnRH analogue or danazol treatment after conservative surgery for stage III or IV endometriosis before ovarian stimulation: a prospective, randomized study

OBJECTIVE: To assess the effect of short-term use of a gonadotropin releasing hormone (GnRH) analogue for 3 months before ovarian stimulation in patients with stage III and IV endometriosis after conservative surgery. STUDY DESIGN: Eleven patients were randomly selected to receive intramuscular injections of GnRH analogue, leuprolide acetate (3.75 mg), every 28 days, or 400 mg danazol orally 2 times per day for 3 months before ovarian stimulation after conservative laparoscopic or laparotomy surgeryfor stage III and IV symptomatic endometriosis (group 1), as compared with 30 patients who had received no postoperative treatment with GnRH analogue or danazol but underwent ovarian stimulation immediately after thefirst menses within 3 months postoperatively (group 2). RESULTS: Although the number of oocytes retrieved and number of embryos per cycle were significantly higher in group 1, the pregnancy rate per cycle in group 1 was not significantly different from that in group 2 (18% vs. 20%). The cumulative pregnancy rate at 12 months was 54.5% and 56.7% in group 1 and group 2, respectively. With regard to recurrence of disease after 24 months of follow-up, group 2 had a statistically significantly higher recurrence rate (13.3%) than did group 1 (0%). CONCLUSION: Short-term use of GnRH analogue before ovarian stimulation in women with stage III or IV endometriosis confers no definite benefits on pregnancy rates per cycle when compared with patients who received ovarian stimulation within 3 months after conservative surgery.     

Endometriosis: preoperative and postoperative medical treatment

The quality of the evidence that supports the use of medical treatment before conservative surgery for endometriosis is manifestly poor, and no recommendations can be made based on the results of the published studies. There are practical advantages inherent to this schedule, but whether this translates into better conception rates and reduced pain recurrence rates is unproven. The effect of drug therapy after surgery can be assessed better as data from seven true randomized, controlled trials are available. The results of the current review do not support the notion that suppressing ovarian activity postoperatively increases the long-term pregnancy rate. As far as pelvic pain is concerned, more data are needed to verify the reduced symptoms recurrence rate found in four trials in women who were allocated to postoperative medical therapy, particularly in view of the different results obtained in some of the considered studies. The observed differences among various drugs used before or after surgery are limited in clinical terms and, in the absence of formal randomized comparisons, are difficult to interpret. Because of their tolerable side effects and limited cost, progestins with or without estrogens should be considered strongly as first-line postoperative medical treatment if and when suppression of ovulation after conservative surgery is deemed opportune.     

High rate of endometriosis recurrence in young women

Objective

To evaluate rate and determinants of long-term recurrence of endometriosis in a population of young women.

Design

Retrospective cohort study.

Setting

University tertiary care referral center for women with benign gynecologic diseases.

Participants

Young women undergoing first-line conservative surgery for endometriosis were eligible for the study. Data on age at surgery, disease stage, anatomical characteristics of endometriotic lesions, and endometriosis-related symptoms were collected. After diagnosis, patients were treated according to the standard care of the center. The protocol required all women to be followed up 1 month after surgery, and every 6 months afterward, with an interview to investigate persistence of symptoms, a clinical examination, and an ultrasound pelvic assessment.

Results

Fifty-seven women aged ≤ 21 (mean age at diagnosis ± SD: 19.0 ± 1.1 years) entered the study. During a 5-year follow-up, 32 (56%, 95% confidence interval [CI]: 43%-68%) recurrences of endometriosis were diagnosed. A second laparoscopy to treat the recurrence was performed in 11 (34%) cases and confirmed the presence of the disease in all of them. In the remaining 21 (66%) cases, the recurrence was based on the reappearance of the symptoms or clinical or sonographic findings. The recurrence rate increased constantly with time from first surgery. No association emerged between recurrence rate and endometriosis-related symptoms, site/stage of the disease, type of surgery, and post-surgical medical treatment.

Conclusions

The recurrence rate of endometriosis in young women appears higher than in older women. Since no determinants for recurrence have been detected among the factors examined, a profile of women at increased risk cannot be drawn.     

Hormonal contraceptives and endometriosis/adenomyosis

Over the past 50 years hormonal contraceptives have gradually developed to be cost-effective medical treatment modalities for primary and secondary therapy of endometriosis/adenomyosis. This is particularly true for the various estrogen/progestogen combinations as monophasic – particularly progestogen-dominant – preparations in cyclic, long-cyclic and continuous treatment forms. An alternative is the progestogen-only therapy used continuously. Therapeutic effects have been shown for peritoneal, ovarian and deep-infiltrating endometriosis as well as for adenomyosis. An individualized, medical long-term treatment concept to control endometriosis/adenomyosis-related symptoms, endometriosis/adenomyosis development and minimizing the recurrence rate needs to be further studied in women, who do not desire to become pregnant.