HRT & Endometrial cancer

Overview
Oestrogen only RCT

Increase the risk of endometrial hyperplasia Besides, the longer the duration and the higher the dose of oestrogen only RCT, the higher of the risk of endometrial hyperplasia

Endometrial hyperplasia can progress to endometrial carcinoma with atypical type is the highest followed by complex and simple hyperplasia Oestrogen & progestrogen HRT:

Progestrogen is protective to endometrial hyperplasia Endometrial cancer was not increased with up to 5 years of use, but with more than 5 years of use. Progestogens will reduce the risk of endometrial hyperplasia and carcinoma, but the duration of progestogen in each cycle is important and should be for at least 10 days.

Continuous combined therapy had protective effect not only in preventing hyperplasia but also in the correction of pre-existing hyperplasia.

Endometrial hyperplasia & oestrogen

Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996; 275: 370375.

Study population: 596 postmenopausal women receiving 0.625 mg CEE or placebo over 36 months Type of study: RCT (randomized to placebo) Results: Complex hyperplasia Atypical hyperplasia HRT 22.7% Placebo 0.8% HRT 11.7% Placebo 0.7% P <0.001

Simple hyperplasia HRT 27.7% Placebo 0.8%

Duration of HRT & endometrial hyperplasia

Lethaby A, Suckling J, Barlow DH et al. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004; (3).CD000402.
30

randomized controlled trials Results

6 months of unopposed oestrogen: OR 5.4 (95% CI1.4 20.9)  36 months of unopposed oestrogen: OR16.0 (95% CI 9.3 27.5)


Dose & endometrial cancer

Pickar JH, Yeh IT, Wheeler JE et al. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: 2-year substudy results. Fertil Steril 2003; 80: 12341240. Results
Dosage of CEE 1 year 2 year 0.3 mg 0% 3% 0.4 mg 7% 15% 0.625 mg 10% 27%

Weiderpass E. Risk of endometrial cancer following estrogen replacement with and without progestins. J Nat Cancer Inst 1999; 91: 11311137. There is no evidence that use of the weaker ostrogen oestriol, either vaginally or orally, has any less effect on the risk of endometrial hyperplasia.

Stopping HRT ???

Paganini-Hill A, Ross RK & Henderson BE. Endometrial cancer and patterns of use of estrogen replacement therapy: a cohort study. Br J Cancer 1989; 59: 445447.
the

risk of endometrial cancer remains increased for many years after stopping oestrogen therapy. Even after 15 years or more without therapy, there is still a significantly increased risk of 5.8 (95% CI 2.0 17)

Endometrial hyperplasia; risk of progression to endometrial cancer

Reference Wentz Sherman Kurman Norris 1.1 Simple Complex 26.7 19.8 3.4 2 Atypical 88.9 57.1 29 52

Kurman RJ, Kaminski P & Norris H. The behaviour of endometrial hyperplasia. A long term study of untreated hyperplasia in 170 patients. Cancer 1985; 56: 403412. Wentz WB. Progestin therapy in endometrial hyperplasia. Obstet Gynecol 1974; 2: 362367. Sherman AI. Precursors of endometrial cancer. Isr J Med Sci 1978; 14: 370378. Norris HJ, Connor MP & Kurman RJ. Preinvasive lesions of the endometrium. Clin Obstet Gynaecol 1986; 13: 725738.

Furthermore, in hysterectomy specimens performed after a biopsy or curettage with a diagnosis of atypical hyperplasia, co-existing endometrial adenocarcinoma is found in 4050% of cases.
Edris F, Vilos GA, Al-Mubarak A et al. Resectoscopic surgery may be an alternative to hysterectomy in high risk women with atypical endometrial hyperplasia. J Minim Invasive Gynecol 2007; 14: 68 73. Shutter J &Wright TC. Prevalence of underlying adenocarcinoma in women with atypical endometrial hyperplasia. Int J Gynecol Pathol 2005; 24: 313318.

Oestrogen & progestrogen HRT & endometrial hyperplasia

Sturdee DW, Ulrich LG, Barlow DH et al. The endometrial response to sequential and continuous combined oestrogenprogestogen replacement therapy. Br J Obstet Gynaecol 2000; 107: 13921400.
1192 women who were taking standard sequential regimens of HRT for a mean of 3.29 years (median 2.56 years, 5th95th centile 0.778.49 years) had endometrial aspiration biopsies taken by Pipelle during the progestogen phase of the cycle. Results:

47.4% had a secretory endometrium  5.5% had complex hyperplasia  0.7% atypical hyperplasia


Combined HRT & endometrial carcinoma

Reference Beresford JAA Weiderpass E > 5 years Not increase > 5 years RR 2.5 (95% CI 1.15.5).

OR 1.5 (95% CI 1.02.2), OR 2.9 (95% CI 1.8 4.6).

Beresford JAA, Weiss NS, Voigt LF et al. Risk of endometrial cancer in relation to use of estrogen combined with cyclic progestogen therapy in postmenopausal women. Lancet 1997; 349: 458461. Weiderpass E. Risk of endometrial cancer following estrogen replacement with and without progestins. J Nat Cancer Inst 1999; 91: 11311137.

Pukkala E, Tulenheimo-Silfvast A & Leminem A. Incidence of cancer among women using long versus monthly cyclical HRT, Finland 19941997. Cancer Causes Control 2001; 12: 111115.
long-cycle HRT was associated with a higher RR of endometrial pathology than monthly-cycle HRT, with a standardized incidence ratio (SIR) for the quarterly cycle of 2.0 (95% CI 1.62.6), compared with a SIR for the monthly cycle of 1.3 (95% CI 1.11.6). Therefore, progestogens will reduce the risk of endometrial hyperplasia and carcinoma, but the duration of progestogen in each cycle is important and should be for at least 10 days.

Continuous combined therapy

Wells M, Ulrich LG, Sturdee DW et al. Effect on endometrium of long term treatment with continuous combined estrogen/progestogen replacement therapy: follow up study. BMJ 2002; 325: 239242.

prospective study of women taking CCT followed 534 postmenopausal women for a mean of 4.4 years (range 1.15.9). There were no cases of endometrial hyperplasia or malignancy, and 69% of women had an endometrium classified as atrophic or unassessable. Furthermore, in 42 women who had previously been taking sequential HRT before the study, and who were found to have complex endometrial hyperplasia, all of these cases reverted to normal results on histological examination after just 9 months of treatment, and this was maintained with continuation of the study up to 5 years.

Lethaby A, Suckling J, Barlow DH et al. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004; (3). CD000402.

endometrial hyperplasia is less likely with CCT than with sequential regimen with an OR of 0.3 (95% CI 0.10.97)

Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996; 275: 370375.

there were no cases of complex hyperplasia in women on CCT after 3 years compared with 1.7% of 118 women treated with sequential HRT and 0.8% of different types and routes of oestrogen.

HRT & Cervical cancer

Anderson GL, Judd HL, Kaunitz AM et al. Effects of estrogen plus progestin on gynaecologic cancers and associated diagnostic procedures: the Womens Health Initiative randomised trial. JAMA 2003; 290: 17391748.

women without hysterectomy aged 5079 years were randomized to receive either CEE 0.625 mg with MPA 2.5 mg daily (n = 8506) or placebo (n = 8102) for a mean follow-up of 5.6 years. The incidence of cervical cancer did not differ significantly between the treated and placebo groups (hazard ratio = 1.4, 95% (CI 0.5 4.4) Limitation:
 

The study was too short Limited statistical power to conclude that there is no effect of HRT in cervical carcinogenesis

Conclusion
Although HRT reverses many characteristics of epithelial atrophy after the menopause, it does not seem to play a significant role in cervical carcinogenesis.

HRT and Ovarian cancer

American Cancer Society Cancer Prevention Study

based on mortality data of 224 307 woman-years found an RR of 1.7 (95% CI 1.12.8). A 14-year follow-up of this study confirmed these findings with:

RR of 1.5 (95% CI 1.22.0) for ever use RR of 2.2 (95% CI 1.53.2) for use of 10 years or more. Among former users, the RR decreased with time since last use.


Rodriguez C, Calle EE, Coates RJ et al. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995; 141: 828835.

Rodriguez C, Patel AV, Calle EE et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285: 14601465.

Million Women Study Collaborators. Ovarian cancer and hormone replacement therapy in the Million Women study. Lancet 2007; 369: 17031710.

an observational study of 948 576 postmenopausal women who were taking part in the NHSBSP identified 2273 incident ovarian cancers and 1591 deaths from this malignancy. For current users of HRT, the incidence of ovarian cancer increased with increasing duration of use, but did not differ significantly by type of preparation used, its constituents or mode of administration. Over 5 years, the Standardized Incidence Ratio, SIRs for ovarian cancer in
current use 2.6 (95% CI 2.42.9) per 1000 never users 2.2 (95% CI 2.12.3) per 1000

From these data, the authors calculated that there would be one extra ovarian cancer in approximately 2500 users and one extra ovarian cancer death in approximately 3300 users. The risks associated with HRT also varied significant according to tumour histology
epithelial tumours 1.53 (95% CI 1.311.79) serous 0.72 (95% CI 0.521.0), Mucinous 1.05 (95% CI 0.771.43) Endometrioid or clear cell tumours 0.77 (95% CI 0.481.23)

Anderson GL, Judd HL, Kaunitz AM et al. Effects of estrogen plus progestin on gynaecologic cancers and associated diagnostic procedures: the Womens Health Initiative randomised trial. JAMA 2003; 290: 17391748.
8506

women aged 5079 years treated with combined CEE 0.625 mg with 2.5 mg MPA daily, and 8102 untreated women. Result: a non-significant RR of 1.58 (95% CI 0.773.24)

Oestrogen only HRT vs Combined HRT

Rossing MA, Cushing-Haugen KL, Wicklund KG et al. Menopausal hormone therapy and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2007; 16: 25482556.

In a population-based study in Washington, USA, 812 women with ovarian cancer and 1313 controls were interviewed about the use of HRT and other characteristics. The risk of epithelial ovarian cancer was increased among
 

Current users or OR 1.6, 95% CI 1.12.5 recent (within the last 3 years) users of unopposed oestrogen for 5 or more years OR 1.8, 95% CI 0.83.7

Little increase was noted among users who discontinued use in the more distant past (OR 1.2, 95% CI 0.62.6). However, no increase in risk was noted among women who used combined oestrogen and progestogen therapy regardless of duration (OR 1.1, 95% CI 0.81.5)

HRT AND BREAST CANCER

Placebo controlled WHI confirmed that addition of oral continuous progestogen was responsible for increase risk of breast ca Combined HRT (1.24, 1.01-1.54) Unopposed HRT (0.77, 0.57-1.06)

Association between LNG-IUS (Mirena) with breast cancer risk

Cohort of 79women with early stage of breast ca Overall no increase of recurrence (hazard ratio 1.86, 95% CI 0.8-4.0) Increase recurrence in women used before and after diagnosis (hazard ratio 3.39, 95% CI 1.01-11.35) Risk unaffected those who used after diagnosis (hazard ratio 1.48, 95% CI 0.62-3.49)

Unopposed estrogen Risk of breast ca with hx of benign breast biopsy -no biopsy (0.57, 0.41-0.78) -one prior biopsy (1.6, 0.82-3.74) -two or more (2.54, 0.73-8.86) Breast ca risk with family history -no affected relatives (0.68, 0.5-0.78) -one or more first degree relatives (1.75, 0.95-3.22)

Colorectal Cancer
Protective effect of estrogen
13 case-control studies: 8 showed a significant protective effect, 4 showed a neutral effect 1 suggested an increased risk. 8 large cohort studies: 6 showed a significant protective effect 2 showed a neutral effect.

2 large randomized clinical trials

WHI

43 invasive colorectal cancer cases in CEE and MPA group  72 in placebo group  Risk reduction confined to local disease, not regional or metastatic disease  unopposed estrogen: no difference in the risk for colorectal cancer compared with the placebo group


Heart


and Estrogen/Progestin Replacement Study (HERS)

11 cases of colon cancer in HRT group  16 in placebo

Protective Mechanism?
Undefined Possibilities:
inhibitory

effect of oestrogen on cellular proliferation

Women with a high-risk profile for the development of colon cancer could be advised to use HRT as a chemopreventive agent

Gallbladder Cancer
Oral estrogen cause change in content of bile, decrease in bile acids, increase cholesterol saturation favours gallstone formation 2 randomized double-blind placebo controlled-trials

Both oral CEE alone and CEE combined with MPA associated with greater likelihood for cholecystectomy while receiving therapy

1 case control study

Increased risk of gallbladder cancer for ever used HRT Risk increase with longer duration of use

Transdermal route less likely to affect gallbladder

Melanoma
Not associated with ever being pregnant, age at first pregnancy, ever use of oral contraceptives or current use of replacement oestrogen therapy. Neither exogenous nor endogenous hormones contribute significantly to an increased risk of melanoma

Lung Cancer
1 case control
Reduced

risk with HRT use effects were similar with unopposed oestrogen or combined oestrogen and progestogen therapy, but the statistically relevant decrease was only seen in current smokers

Esophageal & Gastric Ca

Male predominance = estrogen protective? 1 case control study
reduced risk of gastric adenocarcinoma among HRT users compared with non-users no association between HRT and oesophageal adenocarcinoma
>50%

Summary
Increased Risk Breast Protective No Association

Endometrial

Melanoma

Ovarian

Colorectal

Esophageal

Cervical

Lung

Gallbladder

Gastric

Practice point

Breast cancer risk is not increased with short-term use (3 years for combined HRT, up to 5 years for unopposed oestrogen) For longer term use, the degree of increase in breast cancer risk will be dependent on an individuals baseline breast cancer risk Women with a high-risk benign breast condition or a family history have greater absolute risk; it is essential to communicate this when counselling women and, in doing so, acknowledge that uncertainty still prevails There is no indication for additional mammographic screening for women using HRT; this will only generate unnecessary additional concern where none should exist

Decisions regarding any intervention for symptom relief in breast cancer survivors should be made jointly with the patient, their specialist and gynaecology-endocrine specialists There is a paucity of clinical evidence evaluating efficacy, toxicity and the potential for antagonism of concurrently prescribed breast cancer therapy with the use of HRT alternatives for vasomotor symptom control in breast cancer survivors. HRT may still have a role in subgroups of women treated for breast cancer, but the current clinical climate is so HRT adverse that trials are unlikely to be implemented successfully in the near future

Unopposed oestrogen should only be given to women following hysterectomy Very occasionally, women who have severe progestogen intolerance may be suitable for unopposed oestrogen. They will need regular endometrial assessment by ultrasound and, if evidence of thickening, an endometrial biopsy Endometrial cancer is still a risk for postmenopausal women taking HRT Sequential HRT regimens are suitable for the short-term relief of menopausal symptoms, but for long-term use, a change to CCT is advisable for endometrial protection and also better patient satisfaction with the loss of monthly withdrawal bleeds The development of ultra-low-dose combinations may be even more acceptable for long-term use because of the reduced endometrial simulation and bleeding

Reference
Jo Marsden, David Sturdee; Cancer Issues; Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 87107