Relation Between Hysterectomy, Oophorectomy and the Risk of Incident Differentiated Thyroid Cancer
The E3N Cohort
Agathe Guenego; Sylvie Mesrine; Laureen Dartois; Laurence Leenhardt; Francoise Clavel-Chapelon; Marina Kvaskoff; Marie-Christine Boutron-Ruault; Fabrice Bonnet
DISCLOSURES Clin Endocrinol. 2019;90(2):360-368.

You can download the PDF and references here.

Abstract and Introduction

Abstract

Background: Thyroid cancers are threefold more frequent in women than in men. A role of reproductive or hormonal factors has been suggested but with contradictory results. We investigated potential associations between history of hysterectomy, with or without oophorectomy, and history of benign gynaecological disease (uterine fibroids, endometriosis) and the incidence of differentiated thyroid cancer, in a large French prospective cohort.

Methods: A total of 89 340 women from the E3N cohort were followed up between 1990 and 2012. Gynaecological diseases treated by surgery were self-reported. Thyroid cancers were validated by histological reports. Time-dependent covariates included smoking status, BMI and history of benign thyroid disease. Cox proportional hazard models with age as timescale were used to estimate Hazard Ratios (HR) and 95% confidence intervals (CI).

Results: A total of 412 cases of thyroid cancer were diagnosed during follow-up. A history of hysterectomy was associated with an increased risk of differentiated thyroid cancer (adjusted HR=2.05; 95%CI: 1.65-2.55). The association was not altered after further adjustment for reproductive factors. Endometriosis, uterine polyps, ovarian cysts and oophorectomy without hysterectomy were not associated with the risk of thyroid cancer. A history of fibroids was also significantly related to the risk of thyroid cancer over the follow-up period (adjusted HR=1.91; 95%CI: 1.50-2.44) and the increased risk persisted after adjustment for history of hysterectomy.

Conclusions: Women who had either a history of fibroids or hysterectomy had an increased risk of differentiated thyroid cancer. These findings suggest shared biological mechanisms between fibroids and thyroid cancer, which deserve to be further dissected.

Introduction

Incidence of thyroid cancer has increased worldwide over the recent decades. Some established risk factors for thyroid cancer are known, such as ionizing radiation, benign thyroid disease, genetic predisposal and high body mass index (BMI). Based on epidemiological data, it has long been proposed that hormonal factors may determine or modulate the risk of thyroid cancer. Indeed, thyroid cancers are threefold more frequent in women than in men after puberty and incidence decreases after menopause. A role of female hormones in the aetiology of thyroid cancer has been suggested with a direct action of oestrogens, via its receptors (ER), on proliferative and neoplastic disorders. However, the relationship between thyroid cancer risk and reproductive or hormonal factors is still debated, with contradictory and often inconclusive findings on the association between thyroid cancer and age at puberty, menopause, parity, breast-feeding or menopausal hormone therapy.

Hysterectomy is one of the most common surgical procedures in gynaecology worldwide and is mainly performed in case of a benign disease such as fibroma and endometriosis, conditions which are associated with lifetime sex steroid hormone exposure.

Several studies have attempted to determine hormonal and reproductive factors involved in the development of thyroid cancer in women, with conflicting results. A potential association between hysterectomy and thyroid cancer risk has already been described, but in studies with methodological heterogeneities and potential bias. Moreover, links between thyroid cancer risk and hysterectomy, oophorectomy or benign gynaecological disease histories have not been investigated simultaneously, despite common aetiological factors and frequent morbid associations. Thus, we aimed to prospectively explore the link between differentiated thyroid cancer (micro- or macro-carcinomas) and a history of hysterectomy, with or without oophorectomy, in a large cohort, according to age and time since gynaecological surgery. In addition, we investigated the relation between a history of benign gynaecological disease (uterine fibroids, endometriosis, ovarian cyst and uterine polyp) and the risk of incident thyroid cancer.

Materials and Methods

The E3N Cohort

The E3N cohort study (Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale) is a prospective cohort of 98 995 French women born between 1925 and 1950 and insured by a national health system primarily covering teachers.18Participants have received 11 follow-up questionnaires (mailed every 2-3 years) and responded to each at a rate of ~80%. The women were enrolled in 1990 after they returned a baseline self-administered questionnaire on their lifestyle and medical history. All women signed an informed consent, in compliance with the rules of the French National Commission for Data Protection and Individual Freedom from which approval was obtained.

Thyroid Disease Assessment

Each questionnaire inquired about cancer occurrence, and requested information and permission to contact participants’ physicians. Cases were confirmed by pathology reports. Here, we considered only histologically confirmed first incident primary differentiated thyroid cancer cases (ie, papillary (International Classification of Diseases for Oncology, ICD-O codes: 8050, 8052, 8130, 8260, 8263, 8340- 8344, 8350, 8450) and follicular (8290, 8330–8335, 8480, 8490)), excluding 21 cases of anaplastic or medullary thyroid cancer. Micro- and macro-carcinomas were defined as tumours sized <10 mm and 10 mm, respectively.

Each questionnaire also inquired about diagnoses of dysthyroidism (hyperthyroidism or hypothyroidism) and of benign morphological thyroid conditions.

Assessment of Hysterectomy and Benign Gynaecological Diseases

Hysterectomy and oophorectomy status (none, or uni- or bilateral), and age at surgery were recorded in each questionnaire. Benign gynaecological diseases considered in this analysis were endometriosis, ovarian cysts, fibroids and uterine polyps recorded in each questionnaire. Ovarian cysts reported by women diagnosed with endometriosis were not considered, to avoid potentially misdiagnosed ovarian endometrioid cyst cases. For all diseases, diagnostic procedures as laparoscopy, biopsy, hysterography, hysteroscopy or ultrasonography were recorded in the 1992, 1993 and 1994 questionnaires and surgical treatments were available in each questionnaire except the baseline questionnaire. For each gynaecological disease, we separately considered those confirmed by surgery or laparoscopy, confirmed by at least one treatment or diagnosis examination, and only self-reported gynaecological diseases.

Population for Analysis

Follow-up started at the date of return of the 1990 questionnaire. Participants contributed person-years of follow-up until the date of diagnosis of any cancer (except basal cell carcinoma and in situ colorectal cancer), the date of the last completed questionnaire, or December 2011 (date of mailing of the 10th questionnaire), whichever occurred first. Women studied were censored at the date of a first thyroid cancer and we did not consider a hysterectomy or other benign gynaecological diseases which occurred following a first thyroid cancer. Among the 98 995 women included in the study, we excluded those who reported a prevalent cancer at baseline other than a basal cell cancer or in situ colorectal cancer (n = 4844), and women with no follow-up data (n = 2073), with primary amenorrhoea or unknown age at menarche (n = 2209), with missing information on age at hysterectomy or oophorectomy (n = 418), or with unknown date of cancer diagnosis (n = 111), ending up with 89 340 women for analysis.

Statistical Analyses

Cox proportional hazard models with age as timescale were used to estimate Hazard ratios (HR) and 95% confidence intervals (CI) of first differentiated thyroid cancer associated with history of hysterectomy or benign gynaecological disease. Women diagnosed with non-differentiated thyroid cancer were censored at the date of diagnosis. Hysterectomy status or benign gynaecological disease variables were analyzed as time-dependent variables. When the variables were not available at a given questionnaire, the preceding value was considered until the next known value. The proportional hazard hypothesis was verified for all time-independent variables of interest using log-log survivor plots. Covariates included in the models used are listed in Table 2 and Table 3. Information on time-dependent variables was updated at each questionnaire. Missing values for all adjustment variables were replaced by the modal value, as they were missing for less than 5% of women.

We performed stratified analyses to explore associations according to tumour size (micro- (<10 mm) or macro- (10 mm) carcinoma) using competing-risk models. Cases with missing values on tumour size were excluded from these analyses, and analyses were performed in each strata by censoring the cases belonged to the other strata at date of diagnosis.

We used homogeneity tests to compare risk estimates across strata using the Wald chi-square statistic.

Smoking status and a history of dysthyroidism were evaluated as potential effect modifiers by adding an interaction term in the final model and testing statistical significance. All tests were two-sided, and statistical significance (P-value) was set at the 0.05 level. All analyses were performed using Statistical Analysis Systems (SAS) software, version 9.3 (SAS Institute, Inc, Cary, North Carolina).

Results

Among 89 340 women considered in the present analysis, 412 cases of first primary differentiated thyroid cancer (381 papillary and 31 follicular) were diagnosed during 1 603 264 person-years of observation (median follow-up duration of 9.9 years for cases and 21.4 years for non-cases). Of the 412 cases of thyroid cancer, the information on the micro- or macro-carcinoma status was missing for 9. A total of 166 (41%) were considered as micro-carcinoma (size <10 mm) and 237 were micro-carcinoma (size ≥10 mm).

As shown in Table 1, the frequency of goitre/thyroid nodules was similar between women with an history of hysterectomy and those who did not have hysterectomy. The prevalence of excessive weight or obesity was higher among the women with an history of hysterectomy as compared to those without hysterectomy.

Hysterectomy/Oophorectomy and Risk of Thyroid Cancer

Women with a history of hysterectomy had an increased risk of differentiated thyroid cancer (HR=2.05, 95%CI 1.65-2.55; model 2), as compared to women without hysterectomy (Figure 1, Table 2). When considering types of hysterectomy/oophorectomy, the highest risk was observed for women with hysterectomy and uni- or bilateral oophorectomy (HR=2.21, 95%CI 1.67–2.91). There was no association between oophorectomy alone and thyroid cancer risk. Risks were similar whatever the age at the hysterectomy or the time since hysterectomy. Associations were similar although slightly stronger after adjustment for reproductive factors (model 3) (Table 2). Results were similar for papillary and follicular cancers (HR=2.02, 95%CI 1.61-2.53 for papillary, HR=2.52, 95%CI 1.17-5.44 for follicular, P _homogeneity =0.59, model 2). Both micro- and macro-carcinomas ((HR=1.81, 95%CI 1.28-2.57 and HR=2.16, 95%CI 1.62-2.88 respectively, P _homogeneity =0.45, model 2) were associated with a history of hysterectomy.

Figure 1.

Risk of thyroid cancer according to the mode of diagnosis of fibroids and the absence of a history of hysterectomy. Hazard ratio and 95% CI are displayed from the multivariate model 2

The association between a history of hysterectomy and thyroid cancer risk was not modified by smoking status nor dysthyroidism history (P _interaction=0.09 and 0.23, respectively) and was observed in all corresponding strata.

Fibroids

Overall, a history of benign gynaecological disease confirmed by surgery or laparoscopy was associated with increased thyroid cancer risk (HR 1.67, 95%CI 1.32-2.11; model 2; Table 3). The increase was driven by the association with uterine fibroids history (HR 1.91; 95% CI 1.50-2.44, model 2; Table 3). This association was observed whatever the mode of diagnosis of fibroids and irrespective of a history of hysterectomy (Table 3). Women with a confirmed history of fibroids had an increased risk of both micro- (HR=1.54, 95%CI 1.03-2.30, model 2) and macro-carcinomas (HR=2.16, 95%CI 1.57-2.97, model 2). If we consider simultaneously history of hysterectomy and of fibroids in the same multivariate statistical model (model 2), each variable remains statistically associated with the risk of thyroid cancer [hysterectomy (yes/no): HR=1.70, 95% CI :1.27-2.28; history of fibroids (yes/no): HR=1.33, 95% CI :1.01-1.75].

Neither self-reported nor confirmed history of endometriosis, uterine polyps or ovarian cysts were associated with thyroid cancer risk (Table 3). Results were similar for papillary and follicular thyroid cancers (data not shown).

Finally, we performed sensitivity analyses by excluding women who had an early diagnosis of thyroid cancer (first 2 years of follow-up) and the results were unchanged: women with a history of hysterectomy had an increased risk of differentiated thyroid cancer (HR=2.01, 95%CI 1.60-2.52; model 2), as compared to women without hysterectomy. Similarly, those who had a history of uterine fibroma were at higher risk of thyroid cancer as well (HR 1.84; 95% CI 1.47-2.30, model 2).

Discussion

In this large prospective study with more than 400 incident thyroid cancer cases occurring in women aged 40-65 at baseline, we found a positive relationship between the risk of differentiated thyroid cancer and a history of hysterectomy, but not with a history of oophorectomy. Results were similar whatever the age at hysterectomy or time since hysterectomy. We observed also an association between a history of fibroids and the risk of thyroid cancer, which appears to be independent of a history of hysterectomy.

Hysterectomy/Oophorectomy Status and Risk of Thyroid Cancer

A recent meta-analysis reported an association between a history of hysterectomy and the risk of thyroid cancer with a summary relative risk (SRR) of 1.43. However, the results were contrasting as only five out of 24 studies found that hysterectomy was associated with an increased risk of thyroid cancer. Other studies focusing specifically on the link between differentiated thyroid cancer risk and a history of hysterectomy were also conflicting. Methodological flaws may partly explain these discrepancies, due to case-control design and retrospective self-reported surgery history. Besides, studies concluding that there was a positive relationship between a history of hysterectomy and thyroid cancer risk did not perform adjustment on history of benign thyroid disease or family history of thyroid cancer, and thus could not discard the possibility of confounding.

In contrast to previous studies, we did not observe any change in the association between hysterectomy and the risk of thyroid cancer in relation to the time elapsed since hysterectomy or according to the age at hysterectomy. This finding is an argument against a potential detection bias associated with gynaecological surgery. However, we cannot exclude such a detection bias. It could be speculated that thyroid cancer may be more likely to be found among women with hysterectomy or fibroids, because of medical attention received, as compared to those without the conditions. However, the slightly stronger relation observed between hysterectomy or fibroids and macro-cancers compared with micro-cancers is not in favour of a potential screening bias, which involved the detection of a majority of micro-carcinoma.

Surgically induced menopause, often defined in studies as hysterectomy and/or bilateral oophorectomy has previously been associated with an increased risk of thyroid cancer. When we considered simultaneously hysterectomy and oophorectomy status, we found that a history of oophorectomy was not related to the risk of thyroid cancer and did not substantially affect the association between hysterectomy and thyroid cancer. This is consistent with the WHI cohort for which Kabat et al did not find any association between thyroid cancer risk and bilateral oophorectomy. Some authors found either a higher, a lower or a similar risk of thyroid cancer in women with hysterectomy and bilateral oophorectomy compared to women with hysterectomy alone or hysterectomy with partial oophorectomy.

Benign Gynaecological Diseases History and Risk of Thyroid Cancer

Our study revealed a positive association between a history of fibroids and the risk of differentiated thyroid cancer, which is consistent with the relationship between hysterectomy and thyroid cancer as uterine fibroids are the most common cause of hysterectomy. The twofold increased risk of thyroid cancer linked to surgically treated fibroids was similar to results reported in two American studies.

Studies on the relationship between endometriosis history and thyroid cancer risk are more conflicting, with HR/SIR varying between 0.85 and 3.09. Only two studies found an increased risk of thyroid cancer in women with an endometriosis evolving from more than 5 years and in parous women. It may reflect discrepancies in the definition of endometriosis cases, differences in the populations and the design of the studies: some used retrospective cohort of infertile women, other used data extracted from inpatient and cancer registers or self-reported endometriosis history.

As previous studies, we found no relationship between an ovarian cyst history and thyroid cancer risk, which is in line with the lack of link between oophorectomy and thyroid cancer in our study.

Our results seem not to be related to detection bias. Uterine fibroids are the most common pelvic tumours, occurring in nearly 70% of all reproductive-aged women. Hyper- or hypothyroidism both enhance the likelihood of their diagnosis or treatment by causing abnormal uterine bleeding and have been linked with an increased risk of differentiated thyroid cancer.  However, the fact that we found a similar thyroid cancer risk whatever the time elapsed since surgery argues against this. Moreover, the slightly stronger relation observed between hysterectomy or fibroids and macro-cancers compared with micro-cancers is not in favour of a potential screening bias.

Potential Mechanisms Linking Uterine Fibroids and Differentiated Cancer Thyroid

Uterine fibroids have been associated with thyroid nodules and hypothyroidism in transversal studies, suggesting shared mechanisms between fibroids and thyroid diseases. Both fibroids and thyroid cancers are thought to be sex steroid dependent.

If the link between hormonal factors and the risk of fibroids is well established, the relationship between sex hormones and thyroid cancer is much less characterized. Both oestrogen receptors α (ER α) with a proliferative and anti-apoptotic function, and oestrogen receptors β (ERβ) with a pro-apoptotic function, are expressed in normal and thyroid tumour cells. Thyroid cell proliferation and neoplastic development might depend on the imbalance between ER α and ERβ. Moreover, progesterone receptors have already been described in thyroid follicular cells, and progesterone has been shown to upregulate genes involved in thyroid function and growth on normal human thyroid cells in vitro. Besides, thyroid cancer cells and fibroids are both able to biosynthesize estradiol in situ through the action of aromatase.

However, the link between hormonal factors and thyroid cancer remain inconclusive in several studies suggesting that not only direct oestrogen action but also other pathways may be shared between fibroids and thyroid cancer, such as growth factors pathways and TSH/thyroid hormones induced pathways. Growth factors and non-genomic estradiol pathways converge towards the aberrant activation of Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signalling in both thyroid and fibroids cells. In addition, due to common nucleotide sequence in ER and thyroid hormone receptor, these receptors can interact and regulate several transcriptional responses to environmental stimuli. Moreover, thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH) and thyroid hormone receptors were shown to be present in monkey uterus. Another study described a smooth muscle cells proliferation after stimulation by TSH.

Somatic genetic mutations play a part in the molecular pathogenesis of both fibroids (MED12 mutations) and differentiated thyroid cancer (eg, BRAFmutations).^[1] Thus, a chronic reduction in DNA repair capacity might explain partly a common susceptibility to differentiated thyroid cancer and fibroids. The increased risk of both thyroid cancer and fibroids in atomic bomb survivors illustrates this hypothesis. Increased insulin resistance or related hyperinsulinemia might be a common underlying factor shared by women with uterine fibroids which may predispose to the development of thyroid cancer as recently suggested.

Strengths and Limits

Strengths of our study include its prospective design, large sample size, histological confirmation of all thyroid cancer cases and availability of data for most differentiated risk factors including a history of benign thyroid conditions. Exposure data were collected before diagnosis of thyroid cancer, avoiding potential recall biases. To our knowledge, it is the first study that investigated an association between hysterectomy, uterine fibroids and micro- and macro-thyroid cancer risk.

This cohort is not representative of the French population and our results cannot be extrapolated to the entire French population. As in all observational studies, residual confounding may subsist. Misclassification of exposure status is a potential limitation because of the self-reported assessment of surgery, benign gynaecological and thyroid diseases. Moreover, when we restricted the analysis to the treated cases, the associations remain consistent. Women included in our study, although younger than in the WHI and PLCO studies, were mostly postmenopausal, and our results may not be generalizable to young premenopausal women.

Conclusion

Our findings showed that hysterectomy or a history of fibroids were associated with a twofold increased risk of differentiated thyroid cancer (micro- and macro-carcinomas) in mostly postmenopausal women. This relation might be explained by common signalling pathways regulated by oestrogen, progesterone or TSH/thyroid hormones. Further studies are needed to delineate the underlying molecular mechanisms or pathways.

You can download the PDF and references here.

I am sharing the article below because women with endometriosis have a higher chance of developing cancer of the ovaries, uterus, breast, brain and endocrine system, as well as Non-Hodgkin’s Lymphoma.

It Looked Like a Familiar Case of Depression, but Could It Be Something Else?
By LISA SANDERS, M.D. JAN. 18, 2018

“Have you been to see your doctor?” the woman asked her 72-year-old mother anxiously. Her mother had come from Miami to visit her in New York. They hadn’t seen each other for a couple of months, and her daughter hardly recognized her. Her mother had been slender; now, she looked emaciated. Her usually bright eyes peered dully above her newly prominent cheekbones.

But it was more than that – the unrelentingly cheerful, energetic, outgoing woman she had known her entire life had disappeared. Now her mother spoke of nothing but how awful she felt and spent most of her day in bed.

A Vacation Gone Wrong
It started a couple of months earlier when the mother and her partner were traveling in Italy for a month. While there, she began to feel irritable. She had fallen in love with this man eight years earlier – two years after the sudden death of her husband. And their years together had been happy ones. But on this trip, everything about him, about their relationship, began to grate on her. Suddenly she didn’t want to travel with him; she didn’t even want to see him. Indeed, she didn’t want to see anyone.

When she got home, she felt no better. She was a psychologist and recognized the symptoms of anxiety. She had never felt this before, but she had seen it in her patients. She went back to the psychiatrist she saw a few times after her husband died. Yes, the therapist agreed, she did seem anxious. She was also depressed. The woman accepted the psychiatric diagnoses, but told her therapist that it wasn’t just her mind; her body felt like it was too fatigued to do the work of living. But of course, the therapist told her, your mind is part of your body. People, especially older people, often feel symptoms of depression in their bodies – feeling sick and tired rather than sad.

The Medications Begin
The woman started taking an antidepressant and saw the psychiatrist once a week. When that didn’t help, the psychiatrist tried another drug. When she was still no better, she saw another psychiatrist, who added an antipsychotic. By the time the mother went to visit her daughter, she was on four medications: one for anxiety, two for depression and one for her insomnia. Yet she remained anxious, depressed and unable to sleep.

Her daughter worried. Why wasn’t she getting better? ‘Go see Cindy,’ her daughter said.” Dr. Cindy Mitch-Gomez, her mother’s longtime physician.

Upon returning home to Miami, she went to her doctor. When Dr. Mitch-Gomez saw her patient, she, too, was alarmed. She had lost weight. And she seemed to have lost so much more; she slouched in her chair as if it were too much work to sit up straight. During her routine physical five months earlier, the woman was her normal, lively self. Now she was a skinny, sullen shadow.

A Battery of Tests
The patient explained to Dr. Mitch-Gomez that she had suddenly developed anxiety and depression. She was taking four medications and meeting with a therapist, and still she felt terrible. She gave up her daily morning exercise class because she didn’t want to see anyone. She wasn’t suicidal, but she couldn’t bear feeling like this for the rest of her life.

She was one of the last patients of the day, so Dr. Mitch-Gomez settled in for a full investigation. The patient had a few vague complaints – she felt nauseated sometimes and occasionally awoke covered in sweat, as if she were going through menopause again. To Dr. Mitch-Gomez, it seemed clear that something beyond depression had to be going on. Although the patient was focused on the psychiatric symptoms, her doctor was worried about the fatigue, nausea, weight loss and sweat. The patient was treated for breast cancer nearly 15 years earlier. Could it have come back and invaded her liver, lungs or brain? It would be unusual after so many years, but not impossible.

Finally, a Clue
If not cancer, what? Hypothyroidism is common in older adults. So is Vitamin B12 deficiency. Each can cause depression. She frequently visited the Northeast; could this be some form of advanced Lyme disease? She sent the patient to the lab for blood tests and ordered a chest X-ray, a scan of her brain and another of her abdomen and pelvis.

The blood tests came back quickly. Her thyroid was normal; so was her vitamin B12. It wasn’t Lyme. The chest X-ray showed nothing. The head CT was completely normal. But the scan of the pelvis was not. There was an abnormality around the left ovary and uterus. A transvaginal ultrasound revealed a small mass on the ovary. After some testing, a gynecologist recommended removing the ovary and uterus.

The patient’s partner heard the news before she was even out of the O.R.: It was ovarian cancer, which had spread to a fallopian tube. But the surgeon assured him that they had gotten it all.

The patient no longer had cancer, but, she was still depressed. Dr. Mitch-Gomez referred her to a psychiatrist who specialized in cancer and depression. She wasn’t sure how the two were related – but it would be an odd coincidence, she thought, if they weren’t.

The Depression-Cancer Link
The patient went to see Dr. M. Beatriz Currier, an expert in the biochemical connection between cancer and depression. Patients with cancer are up to three times as likely to have depression as those without cancer, Dr. Currier told her new patient. It’s not simply that having cancer is depressing. It is that some cancers – perhaps most of them – can trigger the body to release chemicals that signal the brain to develop depressive symptoms. It’s a phenomenon first reported in 1931, when Dr. Joseph Yaskin, a neurologist at the University of Pennsylvania, published a case series on four otherwise-healthy middle-aged patients who were initially thought to have a late-onset depression and anxiety and who within months were found to have pancreatic cancer. The depression, Yaskin hypothesized, was a reaction – the part of the central nervous system to the toxic or metabolic changes produced by the progressive visceral condition – the cancer.

More recent research suggests that the body’s response to an injury like that caused by a tumor or an infection is to release messenger chemicals known as cytokines. These messengers communicate with other parts of the body – the immune system, the brain, the gut – to trigger a response to that injury. Different messengers elicit different responses, and the cytokines triggered by certain cancers have been found to set off not only a robust immune inflammatory response but also the neurological changes that cause depression. Some researchers hypothesize that the behavioral changes caused by depression and anxiety – lethargy and avoiding contact with others – might have provided a survival benefit in the face of infection or injury.

Your body released a flood of cytokines in response to the invasion of abnormal cells, Dr. Currier told her, and these chemicals triggered your brain to become depressed. For the first time in months, the patient felt a flicker of hope.

Hearing that she was depressed for a reason somehow made the depression a little easier to bear. With the cancer gone, she asked Dr. Currier, would her depression subside? That’s the theory, Dr. Currier agreed.

And it did, slowly, over months. During the last year Dr. Currier has weaned the patient off the psychiatric medications she was taking. She gained back her lost weight. She started going to her exercise class again. “I’m back,” she told me triumphantly – and it’s all thanks to her doctor, who suspected that what looked like a familiar depression could be something more.

Lisa Sanders, M.D., is a contributing writer for The New York Times Magazine and the author of “Every Patient Tells a Story: Medical Mysteries and the Art of Diagnosis.” If you have a solved case to share with Dr. Sanders, write her at Lisa.Sandersmd@gmail.com.

Variations in Gene May Be Connection Between Endometriosis and Ovarian Cancer, Study Reports
MARCH 6, 2017 BY JOANA FERNANDES, PHD IN NEWS

Variations in the HNF1B gene may be the link between endometriosis and the development of ovarian cancer, according to results of a new study.

The study “Genetic Risk Factors For Ovarian Cancer And Their Role For Endometriosis Risk,” was published in the journal Gynecologic Oncology.

Endometriosis occurs when the lining of the uterus grows outside the uterus. Previous studies have suggested the condition is a risk factor for ovarian cancer.
Ovarian cancer may be caused by mutations in several genes, but whether the mutations are also involved in endometriosis or they mediate the link between the two diseases is unknown.

“Identifying overlapping genetic risk factors for endometriosis and ovarian cancer might be able to provide evidence of which molecular pathways are involved not only in the [origin], but also in the pathogenetic [or gene-caused disease] pathway leading from endometriosis to ovarian cancer,” researchers wrote.

The study included 385 endometriosis patients and 484 healthy participants who provided blood samples for genetic analysis. Researchers investigated 12 genetic variations, or polymorphisms, associated with ovarian cancer — all validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project.

The analysis showed that a variation in the HNF1B gene (rs11651755) was associated with endometriosis, providing a link between this disease and ovarian cancer. None of the other variations tested were associated with a risk of endometriosis.

“The validated ovarian cancer risk [variation] rs11651755 in HNF1B was identified as a susceptibility [factor] for endometriosis,” researchers wrote. “This could be an indication that HNF1B plays a role in the pathogenesis (the way the disease develops) and possibly in the progression of endometriosis to ovarian cancer.”

The HNF1B gene has been previously linked to other diseases, such as liver dysfunction, endometrial cancer and prostate cancer. It encodes a transcription factor, or type of protein that controls and regulates gene expression in cells. Gene expression involves the production of other proteins.

“It can be hypothesized that HNF1B is involved in the very early pathogenesis of ovarian cancer including endometriosis as part of this pathway,” researchers added. “Further studies are needed in order to confirm these results and to try to identify drivers and inhibitors of this multistep [cancer pathway] through endometriosis. HNF1B represents a reasonably well known gene that can help promote this research in the field of endometriosis and ovarian cancer.”

With special thanks to endo sister Lindsay Parks for finding this story and posting it to the endo forums. Please see the additional commentary at the bottom.

Endometriosis linked to 3 types of ovarian cancer
CTVNews.ca Staff
Date: Tue. Feb. 21 2012 7:19 PM ET
Women who suffer from endometriosis may have a higher risk of developing three types of ovarian cancer, a new study says.

Endometriosis is a gynaecological disorder that affects an estimated 10 per cent of women of reproductive age.

The research, published in the online edition of The Lancet Oncology, calculated the association between endometriosis and the risk of the five major types of ovarian cancer: high-grade serous, low-grade serous, clear cell, endometrioid and mucinous carcinomas.

The researchers looked at data from 13 studies that included more than 23,000 women.

Based on their analysis, the researchers estimate that endometriosis is associated with a threefold chance of developing clear-cell cancer, and more than double the risk of developing endometrioid tumours.

The researchers also said that their study is the first to establish a link between endometriosis and low-grade serous cancers, with the researchers finding a twofold risk.

In their study, the researchers caution that despite their findings, “most women with endometriosis do not develop ovarian cancer.” However, doctors should be aware of the potential increase in risk among their patients with a history of endometriosis.

In women with the condition, cells that line the uterus grow in other parts of the body, including the ovaries, bowel, bladder or around the pelvis.

Endometriosis can be very painful and cause severe cramping during menstruation, as well as abdominal pain or back pain before and after a woman gets her period. Pain can also occur during sex or a bowel movement, and lead to fertility problems.

Experts believe the cells travel outside the uterus during menstruation, via the fallopian tubes.

Dr. Steven Narod of the Women’s College Research Institute said the study “shows beyond any doubt women with endometriosis are at risk of ovarian cancer.”

He told CTV News that the risk is still low, and so the findings “should not cause panic.”

But it does raise the question for doctors about whether to classify women with endometriosis “to be at high risk of ovarian cancer.”

“And,” he added, if so, “what should we do?”

In a comment accompanying the study, Charlie Gourley of the University of Edinburgh Cancer Research UK Centre, writes that although the risk demonstrated by the study “is perhaps not in itself sufficient to justify targeted ovarian-cancer screening of patients with a history of endometriosis, the fact that some of the associated histological subtypes (eg, clear-cell) predominantly present at an early stage…makes this a consideration.”

Study co-author Dr. Celeste Leigh Pearce, of the University of Southern California Los Angeles, agrees, saying that the findings may help doctors better identify their patients who are at greater risk of developing ovarian cancer, which could lead to more individualized prevention and detection strategies.

Ovarian cancer is difficult to detect in its early stages and, according to Pearce, scientists have yet to develop adequate screening programs for the disease.

Pearce told CTV News that research that is still ongoing is investigating whether increased screening offers any kind of benefit, and those results are expected later this year.

While they aren’t sure why endometriosis may lead to cancer, the researchers hope to figure that out with further study.

Pearce said women who have an increased risk for disease can talk to their doctor about preventive strategies, which range from taking oral contraceptives — which have been proven to offer some protective benefit against ovarian cancer — to surgery to remove the fallopian tubes and ovaries.

“If you look at the complete body of research on endometriosis and ovarian cancer it does definitely look like endometriosis is a precursor lesion for ovarian cancer,” Pearce told CTV.

“And with that knowledge now we can do work in the laboratory to understand how it goes from a benign gynaecological condition into a cancer, and with that info we can develop new treatments and new approaches to screening.”

The study was conducted by a team from the Ovarian Cancer Association Consortium (OCAC), which is comprised of more than 40 groups of researchers from around the world who are looking at ovarian cancer and the factors that affect a woman’s risk of developing the disease.

With a report from CTV’s medical specialist Avis Favaro and producer Elizabeth St. Philip

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Marya Zilberberg broke down the study on her blog, with a post entitled Endometriosis and cancer: When a “breakthrough” may not be all that. Also, endometriosis.org broke down the story in their article, entitled Is there an increased risk of ovarian cancers with endometriosis?

You should check these articles out – highly recommended.

Many thanks to endo sister Dawn Singleton for sharing this news on the endo forums:

Gene mutation discovery sparks hope for effective endometriosis screening
By Karen N. Peart February 6, 2012

Researchers at Yale School of Medicine have, for the first time, described the genetic basis of endometriosis, a condition affecting millions of women that is marked by chronic pelvic pain and infertility. The researchers’ discovery of a new gene mutation provides hope for new screening methods.

Published in the Feb. 3 early online issue of EMBO Molecular Medicine, the study explored an inherited mutation located in part of the KRAS gene, which leads to abnormal endometrial growth and endometrial risk. In endometriosis, uterine tissue grows in other parts of the body, such as the abdominal cavity, ovaries, vagina, and cervix. The condition is often hereditary and is found in 5%-15% of women of reproductive age, affecting over 70 million women worldwide.

Although the disorder has been studied for many years, its exact cause and how it develops remained unclear. It was previously shown that activating the KRAS gene caused mice to develop endometriosis. However, no mutations in this gene have been identified in women with endometriosis.

Led by senior author Dr. Hugh S. Taylor, professor and chief of the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics, Gynecology & Reproductive Sciences, the authors studied 132 women with endometriosis and evaluated them for a newly identified mutation in the region of the KRAS gene responsible for regulation. This mutation was previously linked to an increased risk of lung and ovarian cancer by study co-author Joanne Weidhaas, M.D., assistant professor of therapeutic radiology.

“We found that 31% of the women with endometriosis in the study carried this mutation, compared to only 5.8% of the general population,” said Taylor. “The presence of this mutation was also linked to higher KRAS protein levels and associated with an increased capacity for these cells to spread. It also may explain the higher risk of ovarian cancer in women who have had endometriosis.”

The Yale team is the first to identify a cause of this common and previously little understood disease. “This mutation potentially represents a new therapeutic target for endometriosis as well as a basis of potential screening methods to determine who is at risk for developing endometriosis,” said Taylor.

Other authors on the study include Olga Grechukhina, Rafaella Petracco, Shota Popkhadze, Trupti Paranjape, Elcie Chan, Idhaliz Flores, and Joanne Weidhaas.

The National Institutes of Health supported the study.

Citation: EMBO Molecular Medicine DOI: 10.1002/emmm.201100200

 

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See related: Genetic variants on chromosome 1 and 7 more likely to induce endometriosis.

For further education, please see the Genetics Home Reference guide.

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!

Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada
Published on: 2010-01-19

Objectives: Endometriosis has been believed to increase the risk of developing ovarian cancer, but recent data supporting this hypothesis are lacking. The aim of this study was to verify whether the incidence of endometriosis, ovarian cancer and the both increased during the last 10 years among women living in the Estrie region of Quebec.

Methods: We collected data of women diagnosed with endometriosis, ovarian cancer or both, between 1997 and 2006, from a population living in the Estrie region of Quebec.

We performed this retrospective cross-sectional study from the CIRESSS (Centre Informatise de Recherche Evaluative en Services et Soins de Sante) system, the database of the CHUS (Centre Hospitalier Universitaire of Sherbrooke), Sherbrooke, Canada.

Results: Among the 2854 identified patients, 2521 had endometriosis, 292 patients had ovarian cancer and 41 patients had both ovarian cancer and endometriosis. We showed a constant increase in the number of ovarian cancer (OC) between 1997 and 2006 (r2 = 0.557, P = 0.013), which is not the case for endometriosis (ENDO) or endometriosis-associated ovarian cancer (EAOC).

The mean age +/- SD was 40.0 +/- 9.9 and 53.9 +/- 11.4 for patients having ENDO and OC, respectively. Mean age of women with EAOC was 48.3 +/- 10.8, suggesting an early onset of ovarian cancer in women having endometriosis of about 5.5 years average, P = 0.003.

Women with ENDO were at increased risk for developing OC (Rate Ratio [RR] = 1.6; 95% Confidence Interval [CI] = 1.12-2.09). Pathological analyses showed the predominance of endometrioid type (24.4%) and clear-cell type (21.9%) types in EAOC compared to OC, P = 0.0070 and 0.0029, respectively.

However, the serous type is the most widespread in OC (44.5%) in comparison to EAOC (19.51%), P = 0.0023.

Conclusion: Our findings highlight that the number of cases of ovarian cancer is constantly increasing in the last ten years and that endometriosis represents a serious risk factor which accelerates its apparition by about 5.5 years.

Author: Aziz Aris
Credits/Source: Journal of Ovarian Research 2010, 3:2

Expression of interleukin-1 (IL-1) ligands system in the most common endometriosis-associated ovarian cancer subtypes
Published on: 2010-01-28

Objectives: Endometrioid carcinoma of the ovary is one of the most types of epithelial ovarian cancer associated to endometrioisis. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of both, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors.

Pro-inflammatory cytokines, including interleukin-1 (IL-1) have been reported to be involved in both endometriosis and ovarian carcinogenesis. The major objective of this study was to determine the level expression of IL-1 ligands system (IL-1alpha, IL-1beta and IL-1RA) in the most common subtypes of ovarian cancer cells compared to endometrial cells.

Methods: We used primary endometrial cells, endometrial cell line RL-952 and different subtypes of epithelial ovarian cancer cell lines including TOV-112D (endometrioid), TOV-21G (clear cell) and OV-90 (serous).

Immunofluorescence and real-time PCR analysis were used respectively for detecting IL-1 ligands at the levels of cell-associated protein and mRNA. Soluble IL-1 ligands were analyzed by ELISA.

Results: We demonstrated that IL-1 ligands were expressed by all endometriosis-associated ovarian cancer subtypes and endometrial cells.

In contrast to other cancer ovarian cells, endometrioid cells exhibit a specific decrease of cell-associated IL-1RA expression and its soluble secretion.

Conclusion: Endometrioid ovarian cancer exhibits an alteration in the expression of IL-1RA, a key protector against tumorogenic effects of IL-1. This alteration evokes the same alteration observed in endometriotic cells in previous studies.

This suggests a possible link between the endometrium, the tissue ectopic endometriosis and endometrioid ovarian cancer.

Author: Mamadou KeitaPaul BessetteManuella PelmusYoussef AinmelkAziz Aris
Credits/Source: Journal of Ovarian Research 2010, 3:3

Harvard Study Examines Endometriosis Cases After Menopause
Original story at vitabeat.com. Original press release at Harvard Health Publications.
January 31, 2006

Endometriosis, a gynecological disorder that affects as many as 1 in 10 women. With symptoms being the most severe during the reproductive years don’t necessarily disappear once a woman stops menstruating, according to a Harvard Study.

Endometriosis with symptoms including menstrual cramps, gastrointestinal problems, and pain during sex occurs when tissue similar to the lining of the uterus shows up on the walls of the abdominal cavity and the outer surfaces of the uterus, ovaries, fallopian tubes, bowel, bladder, and nearby organs.

But rather than exiting through the vagina, the way menstrual fluid does, it remains trapped, triggering inflammation and scar tissue.

But even after periods have ceased, the ovaries continue to produce small amounts of the hormone, so endometriosis may continue to cause trouble.

Dr. Martha K. Richardson says, “I think of endometriosis as a chronic disease that often — but not always — improves after natural or surgical menopause.”

Women with endometriosis also have a higher-than-average risk of autoimmune disorders and related problems, such as chronic fatigue syndrome, hypothyroidism, and fibromyalgia. They’re also more likely to develop ovarian cancer.

Endometriosis at Menopause
I originally found this article at Canadian Women’s Health Network, but I can no longer find the article there. A search of the web has led me to its potential duplication at findarticles.com.
Friend Indeed, A, Nov/Dec 2003

In the late 1970s and early 1980s, many of you may remember reading about endometriosis as the Career Woman’s Disease. It was so called because it supposedly only affected childless women in their 30s. Today, we know so much more. Endometriosis is now classified as a hormonal and immune-system disease that can affect females from childhood well into old age. In endometriosis, tissue that lines the uterus (endometrium) is found outside the uterus in other areas of the body such as the ovaries, bladder, rectum and intestines. Every month this tissue builds up and sheds during the menstrual cycle, developing into growths or implants that can cause pain. Many women diagnosed with endo may be looking forward to menopause as a time of relief from the pain. Many do experience a reprieve, but new studies show that symptoms may also reappear. In fact, some women may be diagnosed with endo for the first time at menopause or later.

To fill you in on the latest information about endometriosis at menopause, we’ve excerpted parts of a chapter from the recently released Endometriosis: The Complete Reference for Taking Charge of Your Health, by Mary Lou Ballweg, founder, president and executive director of the U. S.-based Endometriosis Association.

Introduction

Will your endo symptoms resolve with menopause? Should you use hormone replacement therapy, or will it reactivate the endo? Even if the endo implants don’t recur, what other health problems should you be aware of? There are no easy answers to these questions and few guideposts for the generation of endoknowledgeable Baby Boomer women now entering menopause.

As you enter your postmenopausal years, you may find that endo no longer plays a central part in your health and life (although that’s not the experience for all women with endo; read on). But it’s critical that you not stop thinking of yourself as a woman with healthcare needs and health risks. Endo pain may be gone, and fertility may no longer be an issue, but you may face other health problems related to immune system dysfunction-allergies, autoimmune diseases, cancers.

Natural menopause

Endo implants, if they have not been removed surgically, may still exist, but the symptoms may no longer be a problem. There are only a few studies in the medical literature about recurrence of endo lesions in menopause (or about appearance of new endo lesions-it may be hard to tell the difference). We now understand mat the lesions of endo depend on estrogen for their growth. It seems reasonable, therefore, to conclude that the lesions would no longer be stimulated when the ovaries produce less estrogen in menopause and monthly bleeding stops. However, smaller amounts of estrogen are still being produced. We don’t yet know how large a factor this might be in women who experience continued endo growth and symptoms. Nor do we know what role the immune system, exposure to environmental toxins, diet, lifestyle choices, weight, and other factors play in endo after menopause.

So what do we know about the incidence of endo symptoms in natural menopause? According to some studies, it is estimated that two to five percent of postmenopausal women have endo, including women up to age 76. Another source shows that an estimated two to four percent of postmenopausal women treated at one institution were diagnosed with endo for the first time during surgery for other problems-42 percent had not been using hormone replacement therapy (HRT). This could contradict the belief that endo needs premenopausal levels of estrogen or added estrogens, such as HRT, to thrive.

Surgical menopause

Women who have had their ovaries removed may find that, in spite of the challenges of being thrown suddenly into menopause, they have finally seen the end of excruciating pelvic pain and other symptoms of endo. We know differently. The Association’s data show that endo symptoms continued in 35.7 percent of 731 women who had undergone surgical menopause. In another study of postmenopausal women with chronic pelvic pain, endo was found during laparoscopy in 37 percent of 65 women whose uterus and ovaries had been removed. As well, new endo was found in 13 percent (three cases), but these may represent endo undiagnosed at the first surgery. The incidence of endo was more common in women who had used estrogen replacement therapy (ERT) after their initial surgery.

If you experience endo symptoms in menopause

Be stubborn if you are worried! Try to find a gynecologist who has experience in treating endo. If you see a general surgeon for bowel pain, be aware that she may not consider endo (or the gastrointestinal problems of those with endo) as a possibility. Make sure the surgeon or gynecologist knows about your history with endo. Insist on a rectovaginal bimanual exam; not all doctors do this routinely. If there is tenderness, you may have endo; if not, the pain may be caused by adhesions from previous surgeries and old endo.

Treatment options for peri- and postmenopausal endo

Medical therapy is even less understood in postmenopausal women with endo than in those with perimenopausal endo. Side effects of danazol [a drug that diminishes luteinizing hormone, halting ovulation] increase the risk of problems in women with severe high blood pressure, congestive heart failure or impaired kidney function. We might be dealing not only with endo in menopause, but also with age-related medical problems [e.g. heart disease] that must be considered as well.

Unless there are medical or other reasons not to do this, some endo experts suggest that the procedure of choice in postmenopausal women is “definitive” surgery. This means the complete removal of all visible endo, the uterus, tubes, ovaries and adhesions (when possible). This is a contentious issue. While a number of endo experts emphasized the importance of cutting out all visible endo, not all agreed that the ovaries must also be removed, even in menopause.

In women who have already been castrated and continue to experience endo symptoms, surgery can be done to confirm that endo tissue is still present, to rule out cancer, and to remove all visible endo.

Hormone replacement therapy

The question of whether or not hormone replacement therapy is a safe and helpful option for women with endo is of great concern to many women. Unfortunately, we cannot simply look to the medical literature for guidance. Studies on HRT are usually not specific to women with endo.

Many women are concerned HRT might reactivate their endo. When speaking with your doctor about HRT, be sure to ask how it can help reduce bothersome menopausal symptoms, but also discuss the risks. Of specific concern to women with endo are breast and ovarian cancer, non-Hodgkin’s lymphoma, melanoma, and transformation of endo into cancer. [The book has a chapter explaining the strong association of endo with these cancers.]

Bio-identical hormones

Unlike the synthetic and animal-derived hormones [such as Premarin and Provera], bio-identical hormones have exactly the same chemical structure as the hormones that women’s bodies produce. They include the three estrogens (estradiol, estriol, and estrone in products such as Estrace, Vivelle, Climara, and Estraderm patches) and micronized progesterone (such as Prometrium and Crinone vaginal gel). According to pharmacist Maria Ahlgrimm, R.Ph., an Association Advisor and co-author of The HRT Solution, bio-identical hormones have a different biological effect than synthetic or animal-derived hormones. They fit like a key in a lock, into the hormone receptors, making the hormones readily available within the body and better able to be broken down and eliminated. [No long-term clinical trials comparable to the Women’s Health Initiative have been conducted on bioidentical hormones. Risks are unknown.]

Endo and osteoporosis

A number of risk factors for osteoporosis are particularly relevant for women with endo:

* Hormonal treatments (such as GnRH agonist therapy) that purposely reduce estrogen levels

* Hormone imbalances, including problems with progesterone (a bone-stimulating hormone)

* Gastrointestinal problems that could lead to poor absorption of bone-building minerals and other nutrients

* Severe allergic disease, which increases body acidity, resulting in minerals being pulled from the bones to balance blood pH

Hormone therapy is now commonly used as addback therapy in premenopausal women who use GnRH agonists (the agonists put them into a “pseudomenopause”). Because women using the agonists can lose up to six percent of bone mineral density in the first six months of use, estrogen is added (usually with progestin or progesterone) to reduce this bone loss and allow the use of the therapy for longer than six months. We don’t know at thus time if repeated use of GnRH agonists will result in women entering menopause with below-average bone density. We also don’t know if add-back therapy successfully prevents bone loss; some studies show that it doesn’t completely.

One author suggests a baseline bone density test before starting GnRH therapy to determine wherner you have high or low bone density to start. A urine test (NTx) can also determine the rate of bone breakdown, which can help you and your doctor adjust your dose and type of HRT, or lead you to consider it, to prevent further bone loss.

From ENDOMETRIOSIS by Mary Lou Ballweg and the Endometriosis Association. Copyright @ 2004 by the Endometriosis Association. Reprinted by permission of the McGraw-Hill Companies, www.books.mcgraw-hill.com (ISBN 0-07-141248-4) All rights reserved. US$17.95 CDN$25.95, pp. 494, including 36 pages of footnotes.
Copyright Initiatives for Women’s Health, Inc. Nov/Dec 2003
Provided by ProQuest Information and Learning Company. All rights Reserved