Postmenopausal endometriosis: An enigma revisited
by Duru Shah
J Midlife Health. 2014 Oct-Dec; 5(4): 163–164.
doi:  10.4103/0976-7800.145189
PMCID: PMC4264277

Endometriosis is a common gynecological disorder associated with infertility and chronic pelvic pain and traditionally been considered as a disease of the premenopausal years.[1] For pelvic disease alone, three clinical forms have been described: superficial implants on the pelvic peritoneum and ovaries, ovarian endometriotic cysts and rectovaginal nodules.[2] Besides pelvic disease, extra pelvic disease has also been reported.[3] Many theories have been proposed to explain the cause of endometriosis, but no single theory is capable of explaining the pathophysiology of endometriosis in its various forms. It has been suggested that the three different presentations of pelvic endometriosis may be caused by three different mechanisms.[4] As no single mechanism has been elucidated for premenopausal disease, it is highly unlikely that one single theory could account for postmenopausal disease.

There are no sensitive markers for the diagnosis of endometriosis, except for diagnostic laparoscopy, which is the gold standard for its diagnosis. It is possible that women in their premenopausal years may have had asymptomatic endometriosis or there could be women who had symptoms, but did not undergo a laparoscopy, and in both these groups, the disease progressed in their postmenopausal years. It is also known that discovery of a lesion in a premenopausal woman does not always guarantee progression of disease in the menopause. And 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 could have arisen in patients with a premenopausal history of the disease.

Laparoscopic evaluation of chronic pelvic pain in endometriosis has shown poor correlation with symptoms and extent of disease[5] Endometriosis has also been detected laparoscopically in 70% of fertile, asymptomatic, multiparous women in whom a previous diagnosis of endometriosis has not been made based on either symptoms or investigations.[6] Endometriosis once established can persist in the presence of low circulating levels of estrogen as seen in the postmenopausal period. Local estradiol production by the endometriotic lesions drives the disease through autocrine and paracrine effects. If endometriosis does occur in the postmenopausal period, it is less common, is present in smaller volumes and is less active. Yet it has the same immunochemical profile as the disease occurring in premenopausal women and has the potential to reactivate when given the appropriate stimulation.[7]

Postmenopausal disease could be enhanced in the presence of higher circulating levels of estrogen especially in the form of phytoestrogens and hormone therapy (HT). Phytoestrogens have been known to exert estrogenic effects on the uterus, breast and pituitary[8] and support growth of endometriotic deposits.[2] As these are over-the-counter drugs, their use is indiscriminate and could be responsible for perpetuating preexisting premenopausal endometriosis in the postmenopausal period, when used for menopausal symptom relief. This can occur as density of estrogen receptors in endometriotic tissue appears to be unchanged in older patients.

Limited data are available on the effect of type of HT in women with previous endometriosis. Tibolone has been proposed to be a safe treatment in such women. Unopposed estrogen therapy was found to reactivate symptoms of pelvic pain and deep dyspareunia[8,,9] after Total Hysterectomy with Bilateral Salpingo (TAH and BSO) for endometriosis.[10] HT immediately after TAH + BSO or 6 weeks after surgery did not change the risk of recurrent pain.

Endometriosis is in some ways similar to malignant disease. It can cause local and distant metastases, attach to, invade and damage adjacent tissues. In 1925, Sampson was the first to describe malignant transformation and reported an incidence of 1%.[11] The risk of malignant transformation of endometriosis deposits is higher in postmenopausal women,[7] especially in women with long-standing history of ovarian endometriosis.[12] Hence, clinicians should 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 2 risk factors, which have an additional effect for significantly increasing the risk of cancer in endometriosis,[3] hence combined HT is recommended. The risk of extra ovarian malignant transformation is low, the most common site being the vagina.[13]

The treatment of postmenopausal endometriosis that was first reported in 1950 is primarily surgical, but medical treatment may be a future option. Use of GnRh analogues, danazol and progesterone, appears to be ineffective in postmenopausal endometriosis.[14] AI’s [Aromatase Inhibitors] may be a new promising 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. Al’s could significantly impair bone mineral density and increase the rate of bone fractures, hence need to be supplemented with bis-phosphonate therapy. HT has more benefits than risks in women who are premenopausal at the time of radical operation.
Unopposed estrogen therapy (ET) following menopause might increase the risk of persistence or reoccurrence of endometriosis. Furthermore, ET may potentially increase the risk of neoplastic transformation of the residual tissue whilst HT may have a lower risk. More data are needed to confirm this. It is important to follow-up all patients operated for endometriosis who have been subsequently prescribed HT, on a long-term basis.

REFERENCES
1. Bendon CL, Becker CM. Potential mechanisms of postmenopausal endometriosis. Maturitas. 2012;72:214–9. [PubMed]
2. Cotroneo MS, Lamartiniere CA. Pharmacologic, but not dietary, genistein supports endometriosis in a rat model. Toxicol Sci. 2001;61:68–75. [PubMed]
3. 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. [PubMed]
4. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68:585–96. [PubMed]
5. Szendei G, Hernádi Z, Dévényi N, Csapó Z. Is there any correlation between stages of endometriosis and severity of chronic pelvic pain? Possibilities of treatment. Gynecol Endocrinol. 2005;21:93–100. [PubMed]
6. Bailey AP, Schutt AK, Modesitt SC. Florid endometriosis in a postmenopausal woman. (e1-4).Fertil Steril. 2010;94:2769. [PubMed]
7. 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. [PubMed]
8. Rattanachaiyanont M, Tanmahasamut P, Angsuwatthana S, Techatraisak K, Inthawiwat S, Leerasiri P. Hormonal replacement therapy in surgical menopause with underlying endometriosis. J Med Assoc Thai. 2003;86:702–7. [PubMed]
9. 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. [PubMed]
10. Hickman TN, Namnoum AB, Hinton EL, Zacur HA, Rock JA. Timing of estrogen replacement therapy following hysterectomy with oophorectomy for endometriosis. Obstet Gynecol. 1998;91:673–7. [PubMed]
11. Sampson JA. Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. Arch Surg. 1925;10:1–72.
12. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176:572–9. [PubMed]
13. Gücer F, Pieber D, Arikan MG. Malignancy arising in extraovarian endometriosis during estrogen stimulation. Eur J Gynaecol Oncol. 1998;19:39–41. [PubMed]
14. Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril. 1998;69:709–13. [PubMed]

Hysterectomy linked to cardiovascular disease
By Lynne Peeples
NEW YORK | Tue Jan 4, 2011 4:43pm EST

NEW YORK (Reuters Health) – Women who have their uterus removed for reasons other than cancer may be at a greater risk of suffering a heart attack or stroke, suggests a large new study.

The risk appears to rise even higher for women who also have both ovaries removed. However, the Swedish researchers stop short of saying that taking out either the uterus or the ovaries can actually cause cardiovascular disease.

“Hysterectomy itself is a really safe procedure,” senior researcher Dr. Daniel Altman of the Karolinska Institute told Reuters Health. “But some surgeries can be associated with risks that don’t immediately show up, rather raising risks in the long term.”

“That’s something to at least consider before doing something irreversible,” he added.

One in three women in the U.S. will undergo a hysterectomy, or the permanent removal of the uterus, at some point in their lives, for reasons ranging from fibroids or endometriosis to chronic pelvic pain. Cancer is rarely what prompts the surgery, although removal of the ovaries is commonly used for ovarian cancer prevention.

Meanwhile, cardiovascular disease — including heart attack, coronary heart disease and stroke — remains the number one killer of women.

To determine if there might be a link, Altman and his colleagues studied more than 800,000 women with and without hysterectomies over the course of three decades. On average, women were followed for about 10 years.

After accounting for several factors that might explain differences in risk — such as a woman’s financial situation and the age at which her hysterectomy was performed — the researchers found that a woman who underwent a hysterectomy before age 50 had a nearly 20 percent higher risk of developing cardiovascular disease compared to a similar woman who still had both her uterus and her ovaries.

In women who had hysterectomy and also had their ovaries removed, cardiovascular risk was more varied – it could equal that of a women without any surgeries or rise to more than double that of a woman with only a hysterectomy.

The timing of the two surgeries appeared to play a significant role, report the researchers in the European Heart Journal.

For example, of 100 women under the age of 50 who had their ovaries removed before or at the same time as a hysterectomy, about four went on to develop heart disease, a stroke or a heart attack over the course of 10 years. On the other hand, about two of every 100 women with hysterectomy who had their ovaries removed at a later time developed cardiovascular disease. This was a similar rate to women who had neither procedure.

Given the large size of the study, the team was also able to tease apart the effects of the surgeries on specific types of cardiovascular disease. “We found that the risk was there whether you looked at stroke or heart attack or heart failure,” noted Altman.

The researchers did not find the same relationships among women aged 50 or older when they had their hysterectomies, however.

Altman suggested that the hormonal changes that take place after the organs are removed might be to blame for the increased risks seen in the younger group. Prior research has shown that removal of the uterus can disrupt blood flow to the ovaries, which generate estrogen. Removal of the ovaries is known to trigger early menopause, which itself has been linked with an increased risk of cardiovascular disease.

“We’re adding risks here,” said Altman, noting that his team previously tied hysterectomy to other health problems including incontinence and kidney cancer.

“If we add all of these together,” he suggested, “I think we’re talking about a procedure that causes a great deal of morbidity, and even mortality.”

SOURCE: Hysterectomy and risk of cardiovascular disease: a population based cohort study – European Heart Journal, online December 24, 2010 (PDF saved here)

See also:

• Alternative procedures to hysterectomies not being advertised
• Fact or Myth? Hysterectomy cures endometriosis
• In The News – Pharmaceuticals (Hormone Replacement Therapy) Can Be Dangerous

GWEN IFILL: “The Journal of the American Medical Association” released a new study today that finds women on hormone replacement therapy are at greater risk for contracting more aggressive cancers. The study followed nearly 13,000 women between the ages of 50 and 79 for 11 years.

It found the women who took a combination of estrogen plus progestin had an increased risk of death compared to women not on the drugs. The use of hormone replacement therapy to relieve post-menopausal discomfort such as hot flashes has long been the subject of debate.

Dr. Rowan Chlebowski, the study’s lead author, is a medical oncologist at the Los Angeles Biomedical Research Institute. And Dr. Julie Gralow is director of breast medical oncology at the Seattle Cancer Care Alliance and the University of Washington School of Medicine.

Welcome to you both, Doctors. Dr. Chlebowski, you authored this report. At least you were one of the authors. Tell us a little bit about what you found about the increased cancer risk.

DR. ROWAN CHLEBOWSKI, Medical Oncologist, Los Angeles Biomedical Research Institute: Sure. We expanded our observations of the women’s health initiative trial, as you mentioned, of estrogen plus progestin vs. placebo.

Previously, we had reported that the breast cancers were increased and that they were at higher stage. Now we extend that to show that not only good-prognosis cancers, but also aggressive cancers, were increased. And for the first time, we report that deaths from breast cancer are statistically increased as well.

So, this means that cancers that originate on estrogen plus progestin are a real concern.

GWEN IFILL: Does that mean that they’re not diagnosed as soon or that they’re just more virulent in the first place?

DR. ROWAN CHLEBOWSKI: Well, it seems like a little bit of both. The stage is related to the delay in diagnosis. Estrogen plus progestin increases breast density. It acts like a veil over the breast, so it’s harder to see the tumors, yet they’re still growing. So, that’s one factor.

We also think that estrogen plus progestin may have direct effects on the biology of the cancer, making them grow more aggressively.

GWEN IFILL: Dr. Gralow, what is your thought about this after you read this report?

DR. JULIE GRALOW, Seattle Cancer Care Alliance: Well, I think it’s really important that we’re now showing a death.

I think no women should be going on hormone replacement therapy indefinitely after they go through menopause. But I also think it’s important to point out that a companion study that just showed estrogen alone, without the same progestin, really didn’t show an increase in breast cancer. So, there are some other options.

GWEN IFILL: Well, let me ask you about that a little bit. Are we talking about the duration, the amount of time that women are on these drugs, or which drugs they’re on?

DR. JULIE GRALOW: I think it’s probably part of both.

GWEN IFILL: No, go ahead, Dr. Gralow. I will ask you that as question, Dr. Chlebowski.

DR. ROWAN CHLEBOWSKI: Sure.

DR. JULIE GRALOW: I think it’s part of both. The women in this study, on average, were about 62 at the time that they started their hormone replacement therapy. They weren’t women in their late 40s, early 50s who were just starting to get menopausal symptoms. So, it doesn’t really address the age at which they started.

These women were a bit older than most women thinking about going on hormone therapy. Also, I will let Dr. Chlebowski answer the question about the duration. Probably shorter is better if you have to go on these drugs.

GWEN IFILL: Let me ask Dr. Chlebowski to respond to that.

DR. ROWAN CHLEBOWSKI: Sure. One thing is that, for heart disease, it may make a difference to start estrogen plus progestin closer to menopause. But, actually, in this study, we had 5,000 women in their 50s. And the women who started estrogen plus progestin within five years of menopause actually had a somewhat higher risk of breast cancer incidence. Their increase was 41 percent, which was higher than women who entered later.

But it’s true that the estrogen only, which can really be given practically to women who don’t have a uterus, didn’t show this effect. Now, in terms of duration, because the estrogen plus progestin hinders breast cancer diagnosis, it’s really not possible to define a safe interval for at least breast cancer risk. But women should really heed the short-duration FDA labeling indication.

And I think if they have been on it for a year or so, they should talk to their doctor about potentially stopping to see if they still have climacteric symptoms, hot flashes, night sweats that would require them to continue on therapy.

GWEN IFILL: Before I ask Dr. Gralow to respond to that, I want to ask you a little bit about this report, because the study, which began in 1993 — and periodically we get new results from it — have the drugs changed, have the treatments changed in the period of time since this study began?

DR. ROWAN CHLEBOWSKI: Well, of course we evaluate only one dose and schedule.

GWEN IFILL: That’s true.

DR. ROWAN CHLEBOWSKI: And that was the dose and schedule that was being used by 95 percent of U.S. women when the study started.

GWEN IFILL: Which is Prempro, right?

DR. ROWAN CHLEBOWSKI: Which is Prempro. Conjugated equine estrogen and medroxyprogesterone acetate is one pill.

Now the dosage is about half that’s commonly used. Other preparations are being used. But, of course, we don’t have safety information on lower dose or different schedules or different drugs. You would have to do a repeat safety study, which would again take years and years to complete.

GWEN IFILL: Dr. Gralow, how — how — what should people make of this? What should women make of this? What kinds of risks vs. benefits should they be applying to this kind of information?

DR. JULIE GRALOW: I think, if we’re talking estrogen plus progestin, we really no longer can feel that it’s safe to stay on it for a long period of time.

The main reason to use that combination is to help get through those hot flashes, the insomnia, the mood swings that go along with the period that we call perimenopause, as we’re kind of getting into menopause.

I do think serious considerations should be given to other ways of giving progestin. I agree with Dr. Chlebowski that we don’t have big, huge 10,000-, 20,000-patient studies with different forms of progestin.

But in a study without any progestin alone, we didn’t see increased breast cancer. Perhaps progestin can be used just a few times a year to help protect our uterus, or maybe different forms of progestin, such as an IUD giving progesterone, might be another alternative, if you have a uterus.

If you don’t have a uterus, don’t take progestin. That’s a clear answer.

GWEN IFILL: Dr. Chlebowski, I’m curious whether this is just indicated — the negative indications here are only about breast cancer, or about other cancers as well.

DR. ROWAN CHLEBOWSKI: Yes. I think, in the last October, we reported from the WHI in the same study that lung cancer mortality was increased by 71 percent. That was statistically significant. And so these two taken together really are really quite a tandem, when you say that estrogen plus progestin taken for about five years significantly increases the risk of deaths in the two most common causes of cancer death in women.

So that I think raises the bar for women to think how serious their symptoms or limiting their symptoms should be before they should consider starting this therapy.

GWEN IFILL: Is it raising the bar for doctors as well when it comes to prescribing it?

DR. ROWAN CHLEBOWSKI: I think so. I have been looking at the news reports coming out this afternoon. And I think there’s been a number of people who, surprisingly, are saying now that they have more reservations than they did before these last two reports.

GWEN IFILL: Dr. Gralow, do you have more reservations?

DR. JULIE GRALOW: Well, I’m a breast cancer physician. Most of my patients have breast cancer. And I’m not recommending estrogen for them. So, it doesn’t really change my standard practice.

As for what I will be discussing with patients at increased risk for breast cancer, if you really need, for symptoms — and symptoms only — to go on some estrogen, do it at the lowest dose for the shortest amount of time. For osteoporosis, for cholesterol, for other issues, or vaginal, urogenital health, we have other options. And we should be using those first.

GWEN IFILL: Dr. Chlebowski, is there an immediate action that the medical industry or the pharmaceutical industry can take, say, put warning labels on these kinds of drugs?

DR. ROWAN CHLEBOWSKI: Well, I guess the FDA, you know, is responsible for the labeling.

And I, for one, would like to see a little bit more emphasis on the cancer risk on the label. There is a — there is a label warning for breast cancer risk, not for lung cancer risk. Again, that’s a Federal Drug Administration decision as to what the labeling should be.

GWEN IFILL: Is that something which is at all useful, Dr. Gralow?

DR. JULIE GRALOW: Well, I think that, you know, it’s helpful. It will make physicians and make patients think a little bit harder about it. It really doesn’t help you make the decision.

GWEN IFILL: And that’s a decision that still has to be up to the woman, rather than just the doctors or the FDA, I gather?

Dr. Julie Gralow…

DR. JULIE GRALOW: Well, it’s a complicated…

GWEN IFILL: Oh, go ahead.

DR. JULIE GRALOW: It’s a complicated discussion…

GWEN IFILL: Yes.

DR. JULIE GRALOW: … you know, between the patient and the physician. And there are risks and there are benefits. And it’s a very individualized decision.

GWEN IFILL: It’s finding that balance. Dr. Julie Gralow and Dr. Rowan Chlebowski, thank you both very much.

DR. ROWAN CHLEBOWSKI: You’re welcome.

DR. JULIE GRALOW: Thanks.

 
See also In The News – Pharmaceuticals Can Be Dangerous.

See also the MSNBC video report, “Study: Hormone Therapy Increases Health Risk”. Hopefully you won’t have to sit through the political commercial before the news report. But if you do, sorry. :/

Many thanks to Jeanne for posting about this on Facebook!