Unopposed Estrogen Use Research Articles

Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium.

Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI:1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI:0.81-1.78, pinteraction = 0.4). For White women, the associations between long-term unopposed estrogen or estrogen plus progesterone use and ovarian cancer risk were similar; the increased risk associated with long-term MHT use was confined to high-grade serous and endometroid tumors. Based on smaller numbers for Black women, the increased ovarian cancer risk associated with long-term MHT use was apparent for unopposed estrogen use and was predominately confined to other epithelial histotypes. The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study.

Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (Phomogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies.

Postmenopausal Bleeding: An Update

The clinical approach to postmenopausal bleeding requires prompt and efficient evaluation to exclude or diagnose endometrial carcinoma and endometrial intraepithelial neoplasia and to find out the real source. Postmenopausal bleeding is ‘endometrial cancer until proven otherwise’, although only 1-14% of such patients will actually have cancer. Clinical risk factors of endometrial carcinoma such as obesity, unopposed estrogen use, polycystic ovary syndrome, diabetes mellitus and family history of gynaecologic malignancy also should be considered during evaluation. Postmenopausal bleeding usually attributed to an intrauterine source, but it may arise from the cervix, vagina, vulva or fallopian tubes & ovaries. The origin of bleeding can also involve non-gynaecologic sites, such as the urethra, bladder, anus/rectum/bowel, or perineum.
 Meticulous history and thorough physical examination are must. Initial evaluation is by TVS, if endometrial thickness (ET) is <4mm no further evaluation is required but follow up consultation must. If ET is> 4mm, hysteroscopic evaluation and endometrial sampling is recommended
 Blind endometrial sampling is not accurate as only reveals when endometrial cancer exceeds more than 50% of the endometrial surface area so may be done if hysteroscopic evaluation is not possible. Higher dose of progesterone may be required for endometrial protection when higher doses of estradiol as hormone replacement therapy are used, or in women with high BMI. Unopposed estrogen therapy is associated with a duration and dose-related increase in risk of endometrial hyperplasia and cancer. Endometrial protection requires an adequate dose and duration of progestogen. Endometrial hyperplasia with atypia has much malignant potential but endometrial hyperplasia without atypia may be managed medically with 3 monthly endometrial sampling, if no regression or further progression hysterectomy is the choice of treatment. Finally, patient counseling with discussion of risks /benefits of different options of treatment modalities is the cornerstone of success of addressing postmenopausal bleeding.

Endocrine Risk Factors of Endometrial Cancer: Polycystic Ovary Syndrome, Oral Contraceptives, Infertility, Tamoxifen.

Endometrial cancer is the most common gynecologic cancer and is predominantly endocrine-related. The role of unopposed estrogen in the development of endometrial cancer has been investigated in numerous studies. Different reproductive factors such as younger age at menarche, late age at menopause, infertility, nulliparity, age of birth of the first child, and long-term use of unopposed estrogens during hormone replacement therapy have been associated with an increased risk of endometrial cancer. In contrast, there is a growing body of evidence for a protective role of oral contraceptives. Most of the published data on the association between infertility and polycystic ovary syndrome are inconclusive, whereas the effect of tamoxifen on the risk of endometrial cancer has been well established. With this review, we aim to summarize the evidence on the association between infertility, polycystic ovary syndrome, oral contraceptives, and tamoxifen and the development of endometrial cancer.

Menopausal Hormone Therapy and Risk of Melanoma: A Nationwide Register-Based Study in Finland.

The association between use of menopausal hormone therapy and risk of cutaneous melanoma is highly debated. We investigated the issue in a Finnish nationwide cohort of women ages 50 years or older. All women who had purchased hormone therapy between 1994 and 2007 were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. We calculated standardized incidence ratios (SIR) to compare incidence of cutaneous melanoma among hormone therapy users with that of the general population. During a mean follow-up of 15.6 years, 1,695 incident cutaneous melanoma cases were identified among 293,570 women who had used hormone therapy for at least 6 months. The SIRs for women who used unopposed estrogen therapy and combined estrogen-progestin therapy (EPT) for 6 to 59 months were 1.20 [95% confidence interval (CI), 1.06-1.35] and 1.00 (95% CI, 0.87-1.14; P heterogeneity = 0.04). The SIRs for women who used estrogen therapy and EPT for at least 60 months were 1.37 (95% CI, 1.22-1.52) and 1.23 (95% CI, 1.13-1.34; P heterogeneity = 0.15). We did not find significant differences between oral and transdermal administrations, nor between doses of estrogens. Use of hormone therapy, especially estrogen therapy, was associated with an increased risk of cutaneous melanoma. EPT use of less than 5 years was not associated with an increased risk of cutaneous melanoma. Our results add to the growing body of epidemiologic evidence that the use of unopposed estrogens in menopause increases the risk of cutaneous melanoma, while the addition of progestins might counteract the detrimental effect.

ACOG Committee Opinion No. 734: The Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Women With Postmenopausal Bleeding.

Cancer of the endometrium is the most common type of gynecologic cancer in the United States. Vaginal bleeding is the presenting sign in more than 90% of postmenopausal women with endometrial carcinoma. Clinical risk factors for endometrial cancer, including but not limited to age, obesity, use of unopposed estrogen, specific medical comorbidities (eg, polycystic ovary syndrome, type 2 diabetes mellitus, atypical glandular cells on screening cervical cytology), and family history of gynecologic malignancy also should be considered when evaluating postmenopausal bleeding. The clinical approach to postmenopausal bleeding requires prompt and efficient evaluation to exclude or diagnose endometrial carcinoma and endometrial intraepithelial neoplasia. Transvaginal ultrasonography usually is sufficient for an initial evaluation of postmenopausal bleeding if the ultrasound images reveal a thin endometrial echo (less than or equal to 4 mm), given that an endometrial thickness of 4 mm or less has a greater than 99% negative predictive value for endometrial cancer. Transvaginal ultrasonography is a reasonable alternative to endometrial sampling as a first approach in evaluating a postmenopausal woman with an initial episode of bleeding. If blind sampling does not reveal endometrial hyperplasia or malignancy, further testing, such as hysteroscopy with dilation and curettage, is warranted in the evaluation of women with persistent or recurrent bleeding. An endometrial measurement greater than 4 mm that is incidentally discovered in a postmenopausal patient without bleeding need not routinely trigger evaluation, although an individualized assessment based on patient characteristics and risk factors is appropriate. Transvaginal ultrasonography is not an appropriate screening tool for endometrial cancer in postmenopausal women without bleeding.

ACOG Committee Opinion No. 734 Summary: The Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Women With Postmenopausal Bleeding.

Cancer of the endometrium is the most common type of gynecologic cancer in the United States. Vaginal bleeding is the presenting sign in more than 90% of postmenopausal women with endometrial carcinoma. Clinical risk factors for endometrial cancer, including but not limited to age, obesity, use of unopposed estrogen, specific medical comorbidities (eg, polycystic ovary syndrome, type 2 diabetes mellitus, atypical glandular cells on screening cervical cytology), and family history of gynecologic malignancy also should be considered when evaluating postmenopausal bleeding. The clinical approach to postmenopausal bleeding requires prompt and efficient evaluation to exclude or diagnose endometrial carcinoma and endometrial intraepithelial neoplasia. Transvaginal ultrasonography usually is sufficient for an initial evaluation of postmenopausal bleeding if the ultrasound images reveal a thin endometrial echo (less than or equal to 4 mm), given that an endometrial thickness of 4 mm or less has a greater than 99% negative predictive value for endometrial cancer. Transvaginal ultrasonography is a reasonable alternative to endometrial sampling as a first approach in evaluating a postmenopausal woman with an initial episode of bleeding. If blind sampling does not reveal endometrial hyperplasia or malignancy, further testing, such as hysteroscopy with dilation and curettage, is warranted in the evaluation of women with persistent or recurrent bleeding. An endometrial measurement greater than 4 mm that is incidentally discovered in a postmenopausal patient without bleeding need not routinely trigger evaluation, although an individualized assessment based on patient characteristics and risk factors is appropriate. Transvaginal ultrasonography is not an appropriate screening tool for endometrial cancer in postmenopausal women without bleeding.

Endometrial Cancer on the Rise—Again

Denise G. Link, PhD, WHNP-BC The Journal for Nurse Practitioners would like to thank Susan Wysocki for her past service as department editor and welcome the new department editor, Dr. Denise Link. Estrogenwas first approved by the Food and Drug Administration for the management of menopausal symptoms in 1942. Estrogen replacement was touted to relieve the disruptive symptoms of menopause and keep women young and feminine. This last goal is evident in the advertising that was used to encourage women to start estrogen therapy whether or not they were experiencing perimenopausal symptoms. Based on findings from large studies, physicians were recommending that women well beyond menopause start estrogen to benefit from protection from heart disease and osteoporosis. In 2 decades, as the widespread use of exogenous estrogen took hold, state vital statistics reviewers began to note a steady increase in the number of hysterectomies for endometrial cancer, particularly on the West Coast of the United States where the popularity of estrogen use was much stronger than elsewhere in the country. The rate of endometrial cancer in Alameda County, CA, alone doubled between 1970 and 1975. Similar increases began to be noticed elsewhere in the US but not in other countries. Then, in late 1975, 2 articles were published in the New England Journal of Medicine that reported findings of an association between the use of exogenous estrogens and the development of endometrial cancer. Within 3 years of the publication of these studies, a rapid decline in the sale and use of unopposed estrogen was credited with a dramatic reduction in the incidence of endometrial cancer. Researchers who reflected on what they considered at the time to be “one of the largest epidemics of serious iatrogenic disease that has ever occurred in this country” noted that it took a long time for the problem to be noticed. They made some recommendations that could be clustered under the general categories of careful patient assessment and remaining aware of the

Effect of Hormonal Changes on Voiding in the Elderly Woman

Hormonal loss after menopause result in changes that occur to the vaginal epithelium, which shares a common embryological origin with the lower urinary tract. These changes due to hypoestrogenism lead to symptoms of urinary frequency, urgency, incontinence, dysuria, and recurrent urinary tract infections. Replacement of estrogen can provide benefits to some of these conditions, but potential complications associated with the use of unopposed estrogen (including cardiovascular and oncogenic) have given clinicians pause for concern before administering it to patients without adequate counseling. This review article will examine the pathophysiology of the urogenital changes that occur after hormonal loss. We will discuss several well-designed trials that answer questions about the relationship between hormone replacement therapy and overactive bladder, stress incontinence, and recurrent urinary tract infections. In light of the controversy over estrogen therapy and patients’ warranted concerns about the risks, we will also discuss newer hormonal agents, their role in treating this condition, as well as how we counsel patients on a reasonable hormone replacement therapy (HRT) regimen.

Cadmium Exposure And Endometrial Cancer Risk

Introduction: Cadmium, a highly persistent heavy metal, is categorized as a probable human carcinogen by the US Environmental Protection Agency. Limited population data, which used dietary recall to estimate cadmium exposure, have been published with mixed findings. Methods: In our population-based case-control study of US women (Arkansas, Iowa and Missouri), we telephone-interviewed 631 women with endometrial cancer aged 25-80 years and 879 randomly selected controls of similar age regarding known and suspected risk factors. Careful instruction was provided for home collection and handling of cleaned urine collection kits. Of 1510 completed interviews, 1052 participants (70%) returned a urine sample. Cadmium was quantified using inductively-coupled plasma mass spectrometry and creatinine was measured with a colorimetric assay. A logistic regression model was developed using known and suspected risk factors. Log-transformed creatinine-adjusted cadmium level was tested in the final model. Results: Compared to controls, cases were younger (mean age 62.9 v 60.9) and less likely to be married/living with a partner; education, employment and income were similar. The known and suspected risk factors were in the expected direction or not significant except smoking (mean total pack-years: case: 15.7 v control: 20.6), history of breast cancer diagnosis (case: 2.5% v control: 6.7%), and unopposed estrogen use (mean total years: case: 0.6 v control: 6.5). In a multivariable logistic model, cases were more likely to have higher exposure to cadmium (odd ratio 1.3, 95% confidence interval 1.0-1.7, p=0.04). Model discrimination was good (C-statistic: 0.81). Discussion: This is the first study of cadmium exposure and endometrial cancer risk in a large population-based case-control study using urine as the biomarker. We found cadmium exposure was associated with an increased risk of endometrial cancer.

Hormone therapy and young-onset breast cancer.

Estrogen plus progestin hormone therapy (HT) is associated with an increased risk of postmenopausal breast cancer, but few studies have examined the impact of HT use on the risk of breast cancer in younger women. We assessed the association between estrogen plus progestin HT or unopposed estrogen HT and young-onset breast cancer using data from the Two Sister Study (2008-2010), a sister-matched study of 1,419 cases diagnosed with breast cancer before the age of 50 years and 1,665 controls. We assessed exposures up to a family-specific index age to ensure comparable opportunities for exposures and used propensity scores to control for birth cohort effects on HT use. Ever HT use was uncommon (7% and 11% in cases and controls, respectively). Use of estrogen plus progestin was not associated with an increased risk of young-onset breast cancer (odds ratio = 0.80, 95% confidence interval: 0.41, 1.59). Unopposed estrogen use was inversely associated with the risk of young-onset breast cancer (odds ratio = 0.58, 95% confidence interval: 0.34, 0.99). Duration of use, age at first use, and recency of use did not modify these associations.

Abstract 2918: Menopausal hormone therapy and B-cell non-Hodgkin lymphoma (NHL) risk in the Los Angeles County NHL Case-Control Study

Abstract Introduction: Immune modulation has long been established as a risk factor for non-Hodgkin lymphoma (NHL). Menopausal hormone therapy (MHT) has been shown to affect immune function in both animal and human studies. However, the evidence for an association between MHT and NHL remains unclear. Cohort studies have suggested either no association or increased risk between MHT use and NHL, particularly for the follicular lymphoma subtype. A recent pooled analysis of case-control studies from the United States, Europe, and Australia reported a decreased risk for NHL among women who used MHT, but this analysis was limited by the lack of information on MHT formulation, dose, and duration. Methods: The Los Angeles County NHL Case-Control Study comprises 1010 B-cell NHL patients diagnosed 2004-2008 from the Los Angeles Cancer Surveillance Program, matched 1:1 by age and race to female neighborhood controls. Extensive information on MHT use was ascertained, along with information on demographic and known NHL risk factors. Among 685 post-menopausal women diagnosed with NHL and 685 matched controls, we conducted conditional logistic regression, adjusting for age, race and socioeconomic status, to evaluate the association between MHT use, formulation, dose and duration, and risk for B-cell NHL. Results: B-cell NHL risk was reduced among women who reported having ever used MHT (HR = 0.66, 95% CI = 0.52-0.85) compared to never users. This risk reduction was similar for women who reported using unopposed estrogen only (HR = 0.75, 95% CI =0.56-1.01), estrogen plus progestin only (HR=0.62, 95% CI =0.45-0.85), sequential use of unopposed estrogen followed by estrogen plus progestin (HR=0.36, 95% CI=0.18-0.70), and sequential use of unopposed estrogen plus progestin followed by unopposed estrogen (HR=0.57, 95% CI=0.32-1.00). Among women who reported using unopposed estrogen or estrogen plus progestin by pill or patch (prescription only), reduced B-cell NHL risk was most pronounced among those who started MHT use early, at age 45 years or younger (HR=0.60, 95% CI=0.42-0.85) and generally among women with longer duration of use. The protective associations associated with MHT use were consistent among major B-cell NHL subtypes, including diffuse large B-cell lymphoma and follicular lymphoma. Conclusions: These data provide evidence for an association between MHT use - either unopposed estrogen or estrogen plus progestin use - and decreased risk of B-cell NHL, supporting a role for postmenopausal hormones in B-cell NHL etiology. Citation Format: Sophia S. Wang, Jianning Luo, Jane Sullivan-Halley, Yani Lu, James V. Lacey, Jr., Wendy Cozen, Leslie Bernstein. Menopausal hormone therapy and B-cell non-Hodgkin lymphoma (NHL) risk in the Los Angeles County NHL Case-Control Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2918. doi:10.1158/1538-7445.AM2014-2918

Fatal breast cancer risk in relation to use of unopposed estrogen and combined hormone therapy

Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. To address this question, we conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT). A total of 1,288 cases and 12,535 controls were included in the analyses. Exclusive use of EHT was not associated with fatal breast cancer risk, either overall or within categories of recency or duration [odds ratio (OR) for current vs. never use=1.1; 95% confidence interval (CI) 0.8-1.3]. Use of CHT (includes women who had also used EHT) was also not associated with fatal breast cancer risk (OR for current vs. never use=0.9; 95% CI 0.7-1.3), except for a suggestion of an increased risk with current long-term use. Consistent with prior studies, we observed no increased risk of fatal breast cancer associated with use of EHT. To date only a few studies have evaluated fatal breast cancer risk in relation to use of CHT, and collectively the results are inconsistent.

Reproductive Factors and the Risk of Endometrial Cancer

Endometrial cancer is the most common malignancy of women in developed countries, and its incidence is 10 times higher than in developing countries. Endometrial cancer is most common in the sixth and the seventh decades of life; thus, postmenopausal women have a higher risk of developing the disease compared with premenopausal women. The increased incidence and prevalence of endometrial cancer can be explained by the increase in life expectancy, increased caloric intake, increased obesity rates, and other changes in lifestyle and reproductive factors. Among the reproductive factors, the risk of endometrial cancer is positively correlated with a younger age at menarche and late age at menopause, infertility, null parity, age of the first child, and long-term use of unopposed estrogens for hormone replacement therapy. Protection against endometrial cancer has been detected with increase parity, the use of combined oral contraceptives, and increased age of women at last delivery. The relationship between endometrial cancer risk and miscarriage, abortion, ovulation induction drugs and in vitro fertilization is still controversial.

Postmenopausal Estrogen Therapy and Risk of Gallstone Disease: A Population-Based Case–Control Study

Female gender and increasing age are key risk factors for gallstone disease; therefore, postmenopausal women are at high risk. Estrogen increases cholesterol saturation of bile and may further increase gallstone risk, but population-based evidence is sparse. Our objective was to examine the association between postmenopausal estrogen therapy and risk of gallstone disease and the impact of duration of treatment and use of opposing progestin. We conducted a population-based case-control study. Cases were postmenopausal women (defined as aged ≥45years) with gallstone disease identified in the period 1996-2010. For each case, we selected ten population controls matched to cases by age and sex. We defined exposure as any use of estrogen (opposed and unopposed by progestin). Cases/controls were categorized as current estrogen users if their last prescription was redeemed <90days before gallstone diagnosis (or corresponding date for controls); all other users were categorized as former users. The reference group consisted of cases/controls with no/rare estrogen use. Medical databases covering the population of Northern Denmark (2.4 million inhabitants through the period 1996-2010). We used conditional logistic regression to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of gallstone disease in women treated with estrogen. The ORs were adjusted for relevant comorbidity, other drugs known to influence gallstone risk, and parity. We identified 16,386 cases with gallstone disease and 163,860 controls. A total of 1,425 cases (8.7%) and 8,930 controls (5.4%) were current estrogen users, yielding an adjusted OR for gallstone disease of 1.74 (95% CI 1.64-1.85) compared with non-users. The corresponding adjusted OR for former users was 1.35 (95% CI 1.28-1.42). The results suggested a duration response for current users. Use of unopposed estrogen was associated with higher adjusted ORs than estrogen opposed by progestin. Postmenopausal estrogen therapy was associated with increased risk of gallstone disease in current and former estrogen users. Use of unopposed estrogen was associated with higher risk than use of estrogen opposed by progestin; this finding needs to be confirmed and explored further in future studies.

Menopausal hormone therapy and risk of endometrial cancer

Endometrial cancer is clearly a hormonally responsive tumor, with a critical role played by estrogens unopposed by progestins. Numerous epidemiologic studies have shown substantial risk increases associated with use of unopposed estrogens, especially among thin women. This risk, however, can be reduced if progestins are added to the therapy. The manner in which progestins are prescribed is a critical determinant of risk. Most studies show that women who have ever used progestins continuously (>25 days/months) are at somewhat reduced risk relative to non-users (meta-analysis relative risk, RR, based on observational studies=0.78, 95 confidence intervals, CI, 0.72–0.86). The reduced risk in greatest among heavy women. In contrast, women who have ever used progestins sequentially for <10 days each month are at increased risk, with meta-analysis results showing on overall RR of 1.76 (1.51–2.05); in contrast, progestins given for 10–24 days/month appear unrelated to risk (RR=1.07, 0.92–1.24). These risks were based on varying patterns of usage, with little information available regarding how endometrial cancer risk is affected by duration of use, type and/or dose of estrogen or progestin, or mode of administration. Effects may also vary by clinical characteristics (e.g., differences for Type I vs. II tumors). Further resolution of many of these relationships may be dependent on pooling data from multiple studies to derive sufficient power for subgroups of users. With changing clinical practices, it will be important for future studies to monitor a wide range of exposures and to account for divergent effects of different usage patterns.This article is part of a Special Issue entitled ‘Menopause’.

Postmenopausal unopposed estrogen and estrogen plus progestin use and risk of non-Hodgkin lymphoma in the American Cancer Society Cancer Prevention Study-II Cohort

Results of epidemiologic studies on postmenopausal hormone (PMH) use and non-Hodgkin lymphoma (NHL) are inconsistent. To help clarify this issue, PMH and NHL incidence was examined in the Cancer Prevention Study-II Nutrition Cohort. Between 1992 and 2007, 616 cases of NHL were identified among 67 980 postmenopausal women who were cancer-free at baseline. PMH use was updated during follow-up. Using extended Cox regression, we observed a statistically significant 29% higher risk of NHL for ever unopposed estrogen use compared to never use, which was restricted to follicular lymphoma (current estrogen compared to never use, hazard ratio [HR] = 2.25, 95% confidence interval [CI]: 1.17–4.33) and diffuse large B-cell lymphoma (DLBCL, HR = 1.95, 95% CI: 1.13–3.35). There was no association between current estrogen plus progestin (E + P) use and NHL incidence overall, but a suggested positive association between current E + P use and DLBCL, as well as former E + P use and follicular lymphoma. These results suggest that postmenopausal hormones might play a role in NHL etiology, particularly for follicular lymphoma and DLBCL.

Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?

Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk; however, the moderating effects of usage patterns or patient characteristics, including body mass index (BMI), are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n = 885) in 68,419 postmenopausal women with intact uteri enrolled in the National Institutes of Health-American Association of Retired Persons Diet and Health study. Participants completed a risk factor questionnaire in 1996-1997 and were followed up through 2006. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer (RR = 0.88; 95% CI = 0.74-1.06). Long-duration (≥ 10 years) sequential (<15 days progestin per month) estrogen plus progestin use was positively associated with risk (RR = 1.88; 95% CI = 1.36-2.60], whereas continuous (>25 days progestin per month) estrogen plus progestin use was associated with a decreased risk (RR = 0.64; 95% CI = 0.49-0.83). Increased risk for sequential estrogen plus progestin was seen only among thin-to-normal weight women (BMI < 25 kg/m(2); RR = 2.53). Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins, whereas decreased endometrial cancer risk was observed for users of short-duration continuous progestins. Risks were highest among thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.

Abstract 4475: Association of endometrial cancer risk factors and DNA methylation in benign endometrial tissue

Abstract Background: Increased risk for endometrial cancer is related to factors such as use of unopposed estrogen and obesity, and decreased risk is associated with oral contraceptive use and smoking. However, little is known about the molecular mechanisms by which these factors influence cancer risk. DNA methylation of promoter regions in tumor suppressor genes has been linked to endometrial cancer, suggesting DNA methylation may mediate the effects of risk factors on normal endometrium, leading to increased risk for cancer. Accordingly, we explored relationships between risk factors for endometrial cancer and DNA methylation patterns assessed in normal endometrial tissue. Materials and Methods: Formalin fixed paraffin embedded endometrial tissues from 63 women aged 28-53 (median= 43) who underwent a hysterectomy for benign indications were studied. DNA isolated from 1.0-mm cores was bisulfite treated and methylation profiles were generated using Illumina's GoldenGate array which includes 1505 CpG sites representing over 800 genes. Unsupervised hierarchical clustering analysis was used to identify groups of patients with similar methylation patterns and class comparison analysis was employed to identify differentially methylated genes based on predefined categories, representing endometrial cancer risk factors. Results: Global changes in DNA methylation, as measured by total or average methylation levels or clustering analysis were not associated with age. However, methylation levels of MT1A (p=0.0002) and CDH13 (p=0.0009) were increased and methylation levels of PKD2 (p=0.0009) were decreased among older women. Increased methylation of HS3ST2 (p=0.00006), MLF1 (p=0.0001), PLAUR (p=0.0004), MLH3 (p=0.0007), ISL1 (p=0.0007), and RASSF1 (p=0.0009) was related to women with a lifetime menstrual span of more than 30 years compared to those who reported having menstruated for less than 15 years. One gene (MMP3) was more methylated in women who had an older age at menarche (14+ years old) compared to those who had a younger age at menarche (&amp;lt;12 years old, p=0.0008). Furthermore, unsupervised hierarchical clustering suggested that age at menarche (p=0.05) distinguished three groups of women who had distinct methylation patterns. Conclusions: Our results suggest that DNA methylation patterns at specific loci from normal tissue are related to attained age, age at menarche and the lifetime menstrual span of women. In conjunction with methylation profiling of endometrial cancer, these data may demonstrate the importance of DNA methylation as a mechanism in the pathogenesis of endometrial cancer and lead to potential biomarkers for early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4475. doi:1538-7445.AM2012-4475

Unopposed estrogen and estrogen plus progestin menopausal hormone therapy and lung cancer risk in the NIH–AARP Diet and Health Study Cohort

Previous studies have reported that lung cancer risk may be decreased, increased, or unaffected by prior use of menopausal hormone therapy (MHT). To assess this issue further, we examined relationships among 118,008 women, ages 50-71years who were recruited during 1995-1996 for the NIH-AARP Diet and Health Study and in whom 2,097 incident lung carcinomas were identified during follow-up through 2006. Multivariable Cox proportional hazards models estimated relative risks (RR) and 95% confidence intervals (CIs) associated with various measures of self-reported MHT use. We found no evidence that either estrogen therapy (ET)-only or estrogen plus progestin therapy (EPT) use was substantially related to subsequent lung cancer risk (respective RRs and 95% CIs for ever use=0.97, 0.86-1.09 and 1.03, 0.90-1.17). There were no significant variations according to currency or duration of use of either formulation, nor was there evidence that risks varied within subgroups defined by cigarette smoking or body size. The absence of effect was seen for nearly all lung cancer subtypes, with the exception of an increased risk of undifferentiated/large cell cancers associated with long-term ET-only use (p (trend)=0.02), a relationship not observed among EPT users. Our results failed to support any substantial alterations in lung cancer risk associated with use of either unopposed estrogen or estrogen plus progestin MHT, even when detailed exposure measures and other risk predictors were considered.