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.     

Hormone Replacement Therapy at the Menopause A Double Blind Controlled Study of Women's Preferences

Summary: Forty-nine women who had previously undergone hysterectomy and bilateral oöphorectomy took part in a double blind cross-over trial of hormone replacement therapies. This consisted of 3 months each of ethinyl oestradiol 50 μ g per day, d norgestrel 250 μg per day, a combination of these 2 substances ('Nordiol'), and a placebo. All drugs were administered in a randomized sequence as identical tablets. The 36 women who completed the study concorded in their preference of the drug received. The order of preference was ethinyl oestradiol, the combination of ethinyl oestradiol and d norgestrel, d norgestrel and placebo. From a symptomatic viewpoint, this suggests the use of oestrogen alone as the preferred hormone replacement therapy in menopausal women. The combination of oestrogen and progestogen may provide a satisfactory alternative where the use of unopposed oestrogens is undesirable.     

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.     

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.     

Hormone therapy after endometrial cancer

Endometrial carcinoma is often listed in data sheets as an absolute contraindication to hormone replacement therapy. However, observational studies have not shown an increased rate of recurrence or mortality. Thus, it is often used after stage I or II disease. Alternatives such as progestogens, tibolone, raloxifene, venlafaxine and herbal preparations are examined. The use of progestogens is under discussion because of potential adverse effects on the breast. Generally after treatment for endometrial cancer, current preference should be for low-dose oestrogen monotherapy rather than continuous combined therapy with progestogen addition in view of the increased risk of breast cancer and cardiovascular disease found with the latter regimen. It is important to note that risk factors for endometrial cancer such as hypertension, obesity, polycystic ovary syndrome and diabetes mellitus also increase the risk of cardiovascular disease. However, women must be informed about potential risks and the use of alternatives.     

Malignancy arising in residual endometriosis following hysterectomy and hormone replacement therapy

Two women with adenocarcinoma of the endometrium and a past history of disseminated pelvic endometriosis presented with vaginal bleeding. One also had obstructive uropathy. The two patients had undergone total abdominal hysterectomy with removal of one or both ovaries three and 13 years previously and subsequently were treated with unopposed oestrogen replacement therapy. Adenocarcinoma of the endometrium following endometriosis is a rare condition and few cases are reported in the literature. A summary of the cases and related literature are presented.     

Why tibolone is different?

Tibolone is a synthetic steroid that is structurally related to the 19 norethisterone derivative, such as norethynodrel and norethisterone. It is taken in a dose of 2.5 mg daily orally and after ingestion is metabolised predominantly to three other steroid molecules. One of these is the δ-4 isomer, which predominates at the endometrium demonstrating progestogenic activity resulting in an atrophic endometrium. Continuous combined hormone replacement therapy is also a non-bleeding therapy, but tibolone is different because it is a synthetic molecule, it has different activities at different tissues, and it has androgenic activities.The commonest reason for prescribing tibolone is for hypo-oestrogenic symptoms, namely vasomotor symptoms and urogenital symptoms. Tibolone demonstrates an oestrogenic effect on both of these symptoms. Tibolone is also prescribed for the protection of the female skeleton and it appears to act as an oestrogen on bone.One of the major concerns of long-term HRT administration is the effect on the breast. In vivo and in vitro pre-clinical studies have suggested that tibolone may demonstrate a protective effect on the breast. There are no human studies to confirm this but looking at mammographic data tibolone does not appear to increase breast density, and clinically does not cause breast tenderness.Tibolone appears to be well tolerated, with break-through bleeding in the first 6 months being the main side-effect.Tibolone is used for women who have no ovarian activity, i.e. women who are at least 1 year since their last menstrual period. However, tibolone can also be used in conjunction with GnRH analogues to relieve hypo-oestrogenic symptoms and protect against bone loss. Tibolone would also be appropriate in women who have had a pelvic clearance for endometriosis as if they were given oestrogen replacement therapy they may experience stimulation of any remaining deposits.Tibolone, therefore, is a synthetic hormone replacement therapy used to relieve hypo-oestrogenic symptoms and protect against bone loss in post-menopausal women.     

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.     

Oestrogen-induced endometrial carcinoma in a patient with gonadal dysgenesis.

This case report describes the genesis of endometrial carcinoma after prolonged stilboestrol therapy in a patient with gonadal dysgenesis (Turner's syndrome). The varied histological appearance included the presence of cartilage-like material. A review of the literature reveals the need to treat these patients with combined oestrogen/progestogen preparations rather than with continuous unopposed oestrogens.     

Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis

OBJECTIVE: Endometriosis is extremely common in developed countries. Obesity is a major health concern and may cause hyperestrogenism. Hormonal replacement, particularly unopposed estrogens after hysterectomy, is becoming popular. Because endometriosis is ectopic endometrium, hyperestrogenism (either endogenous or exogenous) may cause hyperplasia or transformation into cancer. This study was conducted to describe the main clinical and pathologic features of malignancies in endometriosis and define the treatment and outcome and to compare patients who had cancer arising in endometriosis with patients who had endometriosis but no cancer. METHODS: Patients who had tumors from endometriosis diagnosed from 1986 to 1997 were analyzed retrospectively. Each patient was matched with two control patients (endometriosis without cancer) treated during the same study interval. Clinical and epidemiologic variables were compared to identify risk factors for the development of cancer. RESULT: We identified 31 patients with cancer developing from endometriosis. Fifteen women were obese, 9 had a history of endometriosis, and 9 were taking unopposed estrogen. Endometrioid adenocarcinoma was the most common histologic type (16 patients). When the patients with cancer were compared with controls, no significantly higher risk for the development of cancer was found with prolonged use of unopposed estrogens or with higher body mass index, but a trend was observed. When obesity and use of unopposed estrogens were considered together, the difference was statistically significant (P = 0.05). CONCLUSION: Hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis. The prevalences of endometriosis, obesity, and use of hormonal replacement therapy in women in developed countries are increasing, and this trend justifies the assumption that cancer developing in endometriosis might become more common in the future.     

Hormontherapie bei gynäkologischen, nichtmalignen Erkrankungen

About one third of all postmenopausal women need hormone replacement therapy (HRT) and hypoestrogenism affects most organ systems. The therapeutic benefit of HRT is well proven and in postmenopausal women with endometriosis and/or uterine myoma represents a special challenge. Both benign diseases are estrogen-dependent and can be negatively influenced by HRT. Cases of endometriosis/uterine myoma in postmenopausal women are rare but can severely influence the quality of life of those women affected. A HRT is still feasible as long as the advantages and disadvantages are taken into account but should be reserved for patients with severe hypoestrogenism. In cases of active endometriosis and symptomatic myoma surgical therapy should be preferentially performed. As estrogen replacement can be associated with a higher risk of recurrence or malignant transformation, combined preparations should be chosen instead of estrogen monotherapy. Although there is no firm evidence tibolone and aromatase inhibitors appear to be the optimal choice.     

Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density

OBJECTIVE: Our purpose was to compare the effects of tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. STUDY DESIGN: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E(2)/NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. RESULTS: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving tibolone (2%-6%) and placebo (0%) treatment. The difference between E(2)/NETA and placebo was highly significant (P <.001). Treatment with tibolone did not differ from that with placebo. The relative risk of an increase in breast density for E(2)/NETA versus tibolone was found to be 8.3 (95% CI 2.7-25.0). CONCLUSION: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, tibolone seems to exert little stimulation of breast tissue.     

Continuous combined hormone replacement therapy and risk of endometrial cancer

OBJECTIVE: Postmenopausal women who receive sequential hormone replacement therapy with estrogen combined with progestogen for 10 to 24 d/mo for a prolonged period may have an elevated endometrial cancer risk relative to those who have never received hormone replacement therapy. We investigated whether daily use of estrogen and progestogen (continuous combined hormone replacement therapy) could diminish any excess endometrial cancer risk.Study Design: A population-based study in Washington State obtained interview data from 969 women aged 45 to 74 years with endometrial cancer diagnosed during 1985 through 1991 or 1994 through 1995 and from 1325 age-matched control subjects selected primarily by random digit dialing. Women who had received only continuous combined hormone replacement therapy were compared with women who had only received another hormone replacement therapy regimen or who had never received hormone replacement therapy. RESULTS: The risk of endometrial cancer among users of continuous combined hormone replacement therapy (n = 9 case patients, n = 33 control subjects) relative to women who had never received hormone replacement therapy was 0.6 (95% confidence interval, 0.3-1.3); the risk relative to women who received hormone replacement that included progestogen for 10 to 24 d/mo was 0.4 (95% confidence interval, 0.2-1.1). Most continuous combined hormone replacement therapy use was short-term (<72 months) or recent (in the previous 24 months). CONCLUSION: Women who had received continuous combined hormone replacement therapy for several years did not appear to be at any increased risk for endometrial cancer relative to women who had never received hormone replacement therapy and may in fact be at decreased risk for endometrial cancer.     

Endometrial adenocarcinoma arising from endometriosis of the rectosigmoid colon

BACKGROUND: Only 21.3% of cases of malignant transformation of endometriosis occur at extragonadal pelvic sites. Forty cases of endometriosis-associated intestinal tumors are reported in the literature. Of these, 17 cases are primary adenocarcinomas arising in the rectosigmoid colon. In 8 of the 17 case reports the patients were using unopposed estrogen replacement therapy. CASE: The patient had previously undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for deeply infiltrating rectovaginal endometriosis, and was using estrogen replacement therapy. She presented with rectal bleeding 12 years later, and a polyp was detected arising from the sigmoid colon. A biopsy detected malignant transformation of endometriosis to adenocarcinoma. CONCLUSION: This is the ninth case of a patient with this condition reported in the literature.     

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.     

Hormone replacement therapy with estradiol and drospirenone: an overview of the clinical data

A new form of continuous combined hormone replacement therapy has become available that contains estradiol and drospirenone as the progestogen component. Drospirenone is a synthetic progestogen, the only one in hormone replacement therapy in the UK that possesses clinically relevant anti-mineralocorticoid activity. The combination of estradiol and drospirenone has been shown to provide relief from estrogen-deficiency symptoms of the menopause. It also helps to prevent osteoporosis in postmenopausal women by increasing bone density. Further, it has been shown to provide protection against endometrial hyperplasia associated with unopposed estrogen therapy.     

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.     

Cancer and the use of estrogens

Although unopposed estrogen therapy, as well as persistent or increased endogenous estrogens, increases the risk for endometrial hyperplasia and cancer, added progestogen decreases the risk for adenocarcinoma of the endometrium to less than that observed in untreated women. The progestogen challenge test should be administered to all postmenopausal women with an intact uterus--including estrogen-treated postmenopausal women and those with sufficient endogenous estrogens to remain asymptomatic--and the progestogen continued for 13 days each month for as long as withdrawal bleeding results. Estrogen replacement therapy should not be withheld from postmenopausal women who are estrogen deficient, since there is no evidence that estrogens increase the risk for breast cancer. Progestogen added to estrogen replacement significantly reduces the risk for mammary malignancy; therefore, progestogens should be given, even to women who have had a hysterectomy, for 10 to 13 days each month whenever they are prescribed estrogen therapy.