Menopause Live (30 July, 2012) From IMS

Endometriosis is a chronic gynecological disorder that has been widely viewed as a disease of the premenopausal years. Estrogen dependence is considered central to the development and progression of this disease which normally regresses during the menopause, yet has been thought to affect 2–4% of postmenopausal women. In a review of postmenopausal endometriosis, Bendon and Becker [1] have proposed mechanisms for postmenopausal disease which are compatible with our current understanding of this disease. The authors have suggested that it could persist from the premenopausal period into a woman’s postmenopausal years, due to the progressive nature of premenopausal disease or it could arise de novo in the absence of menstruation. 

The authors have presented new evidence which suggests that locally produced estrogen plays a significant role in the pathophysiology of endometriosis. It is possible that endometriosis is a self-perpetuating condition, with the lesions themselves driving local estrogen production. Local PGE2 production further enhances local estradiol production which occurs due to high levels of aromatase and StAR (steroidogenic acute regulatory protein) expression and enzyme activity expressed in stromal cells from endometriotic lesions. Estrogen produced within lesions further promotes disease proliferation and progression through autocrine and paracrine effects, resulting in further inflammation and further PGE2 production, enhancing estrogen synthesis. This theory can explain those cases of postmenopausal endometriosis where a source of excessive circulating estrogen cannot be identified. In such a situation, aromatase inhibitors have been found to be useful in treating postmenopausal disease. 

Postmenopausal endometriosis is morphologically similar to premenopausal disease, based on similar distributions of estrogen and progesterone receptors irrespective of age. Thus, endometriotic lesions might have the potential to reactivate when given the appropriate hormonal stimulus. The authors have suggested that excessive obesity, use of phytoestrogens and hormone therapy (HT) can aggravate existing premenopausal disease and also enhance its malignant potential.

Comment
It is known that the discovery of an endometriotic lesion in a premenopausal woman does not always guarantee progression of disease in the menopause. On the other hand, a previous negative laparoscopy does not always mean that there would be no later development of the disease just prior to the menopause. Evidence suggests that postmenopausal endometriosis can arise in patients with a premenopausal history of the disease. Once established, endometriosis can persist in the presence of low circulating levels of estrogen, as seen in the postmenopausal period. 

Postmenopausal disease could be enhanced in the presence of higher circulating levels of estrogen, especially in the form of phytoestrogens and HT. Phytoestrogens have been known to exert estrogenic effects on the uterus, breast and pituitary [2] and support growth of endometriotic deposits [3]. As these are over-the-counter drugs, their use is indiscriminate and could be responsible for perpetuating pre-existing premenopausal endometriosis in the postmenopausal period, when used for relief of menopausal symptoms. Tibolone has been proposed to be a safe treatment in such women, whilst unopposed estrogen therapy was found to reactivate symptoms of pelvic pain and deep dyspareunia [2,4].

Endometriosis is in some ways similar to malignant disease. It can cause local and distant metastases and attach to, invade and damage adjacent tissues. The risk of malignant transformation of endometriosis deposits is higher in postmenopausal women [5], especially in women with a long-standing history of ovarian endometriosis [6]. Hence we need to be alert to the possibility of endometriosis in any postmenopausal patient with symptoms of the disease. If endometriosis is confirmed on investigation, a careful follow-up of such women on a long-term basis is necessary for future adverse outcomes. Obesity and unopposed estrogen are two risk factors which have an additional effect for significantly increasing the risk of cancer in endometriosis [7]; hence, combined HT is recommended. HT has more benefits than risks in women who are premenopausal at the time of bilateral oophorectomy. Hence it is important to follow up all patients operated for endometriosis who have been subsequently prescribed HT, on a long-term basis. 

The treatment of postmenopausal endometriosis is primarily surgical, but medical treatment may be a future option. GnRH analogues, danazol and progesterone are ineffective in postmenopausal endometriosis as the source of estrogen is not the ovary [8]. Aromatase inhibitors may be a promising new method which could potentially improve symptoms and treat these patients, either as first-line treatment when surgery is contraindicated or as a second-line treatment for recurrences following surgical treatment [9]. Aromatase inhibitors could significantly impair bone mineral density and increase the rate of bone fractures, and hence they need to be supplemented with bisphosphonates.

Duru Shah
Director Gynaecworld, The Center for Women’s Health and Fertility, Mumbai, India

References
1. Bendon CL, Becker CM. Potential mechanisms of postmenopausal endometriosis. Maturitas 2012;72:214-19.
http://www.ncbi.nlm.nih.gov/pubmed/22607814
2. Rattanachaiyanont M, Tanmahasamut P, Angsuwatthana S, et al. Hormonal replacement therapy in surgical menopause with underlying endometriosis. J Med Assoc Thai 2003;86:702-7.
http://www.ncbi.nlm.nih.gov/pubmed/12948267
3. Cotroneo MS, Lamartiniere CA. Pharmacologic, but not dietary, genistein supports endometriosis in a rat model. Toxicol Sci 2001;61:68-75.
http://www.ncbi.nlm.nih.gov/pubmed/11294976
4. Fedele L, Bianchi S, Raffaelli R, Zanconato G. Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis. Maturitas 1999;32:189-93.
http://www.ncbi.nlm.nih.gov/pubmed/10515676
5. Cumiskey J, Whyte P, Kelehan P, Gibbons D. A detailed morphologic and immunohistochemical comparison of pre and postmenopausal endometriosis. J Clin Pathol 2008;61:455-9.
http://www.ncbi.nlm.nih.gov/pubmed/17908802
6. Brinton LA, Gridley G, Persson I, et al. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 1997;176:572-9.
http://www.ncbi.nlm.nih.gov/pubmed/9077609
7. Zanetta GM, Webb MJ, Li H, Keeney GL. Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 2000;79:18-22.
http://www.ncbi.nlm.nih.gov/pubmed/11006024
8. Takayama K, Zeitoun K, Gunby RT, et al. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril 1998;69:709-13.
http://www.ncbi.nlm.nih.gov/pubmed/9548162
9. Polyzos NP, Fatemi HM, Zavos A, et al. Aromatase inhibitors in post-menopausal endometriosis. Reprod Biol Endocrinol 2011:9:90.
http://www.ncbi.nlm.nih.gov/pubmed/21693039