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HRT & Endometrial cancer
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Overview
Oestrogen only RCT Increase the risk of endometrial hyperplasia
Besides, the longer the duration and the higher the dose of oestrogen onlyRCT, the higher of the risk of endometrial hyperplasia
Endometrial hyperplasia can progress to endometrial carcinoma withatypical 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 withmore 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 forat least 10 days.
Continuous combined therapy had protective effect not only inpreventing hyperplasia but also in the correction of pre-existinghyperplasia.
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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:
Simple hyperplasia Complex hyperplasia Atypical hyperplasia
HRT Placebo HRT Placebo HRT Placebo
27.7% 0.8% 22.7% 0.8% 11.7% 0.7% P
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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)
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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
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.
Dosage of CEE 0.3 mg 0.4 mg 0.625 mg
1 year 0% 7% 10%
2 year 3% 15% 27%
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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)
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Endometrial hyperplasia; risk of
progression to endometrial cancer
Reference Simple Complex Atypical
Wentz 26.7 88.9
Sherman 19.8 57.1
Kurman 1.1 3.4 29Norris 2 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.
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Furthermore, in hysterectomy specimens performedafter a biopsy or curettage with a diagnosis ofatypical hyperplasia, co-existing endometrial
adenocarcinoma is found in 4050% of cases.
Edris F, Vilos GA, Al-Mubarak A et al. Resectoscopic surgery may bean alternative to hysterectomy in high risk women with atypicalendometrial hyperplasia. J Minim Invasive Gynecol 2007; 14: 68
73.
Shutter J &Wright TC. Prevalence of underlying adenocarcinoma inwomen with atypical endometrial hyperplasia. Int J Gynecol Pathol2005; 24: 313318.
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Oestrogen & progestrogen HRT &
endometrial hyperplasia
Sturdee DW, Ulrich LG, Barlow DH et al. Theendometrial response to sequential and continuouscombined 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 2.56years, 5th95th centile 0.778.49 years) had endometrialaspiration biopsies taken by Pipelle during the progestogenphase of the cycle.
Results: 47.4% had a secretory endometrium
5.5% had complex hyperplasia
0.7% atypical hyperplasia
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Combined HRT & endometrial
carcinoma
Reference > 5 years > 5 years
Beresford JAA Not increase RR 2.5 (95% CI 1.15.5).
Weiderpass E OR 1.5 (95% CI 1.02.2), OR 2.9 (95% CI 1.84.6).
Beresford JAA, Weiss NS
, Voigt LF et al. Risk of endometrial cancer in relation touse of estrogen combined with cyclic progestogen therapy in postmenopausal
women. Lancet 1997; 349: 458461.
Weiderpass E. Risk of endometrial cancer following estrogen replacement withand without progestins. J Nat Cancer Inst 1999; 91: 11311137.
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Pukkala E, Tulenheimo-Silfvast A & Leminem A.Incidence of cancer among women using long versusmonthly cyclical HRT, Finland 19941997. CancerCauses Control 2001; 12: 111115. long-cycle HRT was associated with a higher RR of
endometrial pathology than monthly-cycle HRT, with astandardized incidence ratio (SIR) for the quarterly cycle of2.0 (95% CI 1.62.6), compared with a SIR for the monthlycycle of 1.3 (95% CI 1.11.6).
Therefore, progestogens will reduce the risk of endometrialhyperplasia and carcinoma, but the duration ofprogestogen in each cycle is important and should be for atleast 10 days.
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Continuous combined therapy
Wells M, Ulrich LG, Sturdee DW et al. Effect onendometrium of long term treatment with continuouscombined estrogen/progestogen replacement therapy:follow up study. BMJ 2002; 325: 239242.
prospective study of women taking CCT followed 534postmenopausal 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 orunassessable.
Furthermore, in 42 women who had previously been taking
sequential HRT before the study, and who were found to havecomplex endometrial hyperplasia, all of these cases reverted tonormal results on histological examination after just 9 months oftreatment, and this was maintained with continuation of the studyup to 5 years.
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Lethaby A, Suckling J, Barlow DH et al. Hormone replacementtherapy in postmenopausal women: endometrial hyperplasia andirregular 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 replacementtherapy on endometrial histology in postmenopausal women. ThePostmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA1996; 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 HRTand 0.8% of different types and routes of oestrogen.
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HRT & Cervical cancer
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Anderson GL, Judd HL, Kaunitz AM et al. Effects of estrogenplus progestin on gynaecologic cancers and associateddiagnostic procedures: the Womens Health Initiativerandomised trial. JAMA 2003; 290: 17391748.
women without hysterectomy aged 5079 years were randomizedto 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 betweenthe 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 incervical carcinogenesis
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Conclusion
Although HRT reverses many characteristics of
epithelial atrophy after the menopause, it does not
seem to play a significant role in cervical
carcinogenesis.
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HRT and Ovarian cancer
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American Cancer Society Cancer
Prevention Study
based on mortality data of 224 307 woman-years foundan RR of 1.7 (95% CI 1.12.8).
A 14-year follow-up of this study confirmed these findingswith: 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 andfatal ovarian cancer. Am J Epidemiol 1995; 141: 828835.
Rodriguez C, Patel AV, Calle EE et al. Estrogen replacement therapy andovarian cancer mortality in a large prospective study of US women.JAMA 2001; 285: 14601465.
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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 postmenopausalwomen who were taking part in the NHSBSP
identified 2273 incident ovarian cancers and 1591 deathsfrom this malignancy.
For current users of HRT, the incidence of ovarian cancerincreased with increasing duration of use, but did notdiffer 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
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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)
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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)
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Oestrogen only HRT vs Combined HRT
Rossing MA, Cushing-Haugen KL, Wicklund KG et al. Menopausalhormone therapy and risk of epithelial ovarian cancer. CancerEpidemiol Biomarkers Prev 2007; 16: 25482556.
In a population-based study in Washington, USA, 812 women with ovariancancer and 1313 controls were interviewed about the use of HRT and othercharacteristics.
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 yearsOR 1.8, 95% CI 0.83.7
Little increase was noted among users who discontinued use in the moredistant past (OR 1.2, 95% CI 0.62.6).
However, no increase in risk was noted among women who used combinedoestrogen and progestogen therapy regardless of duration (OR 1.1, 95%CI 0.81.5)
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HRT AND BREAST CANCER
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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)
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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)
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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)
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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 effect2 showed a neutral effect.
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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
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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
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Gallbladder Cancer
Oral estrogen cause change in content of bile,decrease in bile acids, increase cholesterolsaturation favours gallstone formation
2 randomized double-blind placebo controlled-trials Both oral CEE alone and CEE combined with MPA
associated with greater likelihood for cholecystectomywhile 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
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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 hormonescontribute significantly to an increased risk of
melanoma
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Lung Cancer
1 case control
Reduced risk with HRT use
effects were similar with unopposed oestrogen or
combined oestrogen and progestogen therapy, but thestatistically relevant decrease was only seen in current
smokers
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Esophageal & Gastric Ca
Male predominance = estrogen protective?
1 case control study
>50% reduced risk of gastric adenocarcinoma among
HRT users compared with non-users
no association between HRT and oesophageal
adenocarcinoma
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Summary
Increased Risk Protective No Association
Breast Endometrial Melanoma
Ovarian Colorectal Esophageal
Cervical Lung
Gallbladder Gastric
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Practice point
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Breast cancer risk is not increased with short-term use (3 years forcombined HRT, up to 5 years for unopposed oestrogen)
For longer term use, the degree of increase in breast cancer risk willbe dependent on an individuals baseline breast cancer risk
Women with a high-risk benign breast condition or a family historyhave greater absolute risk; it is essential to communicate this whencounselling women and, in doing so, acknowledge that uncertaintystill prevails
There is no indication for additional mammographic screening forwomen using HRT; this will only generate unnecessary additionalconcern where none should exist
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Decisions regarding any intervention for symptom relief in breastcancer survivors should be made jointly with the patient, theirspecialist and gynaecology-endocrine specialists
There is a paucity of clinical evidence evaluating efficacy, toxicityand the potential for antagonism of concurrently prescribed breastcancer therapy with the use of HRT alternatives for vasomotorsymptom 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 trialsare unlikely to be implemented successfully in the near future
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Unopposed oestrogen should only be given to women following hysterectomy
Very occasionally, women who have severe progestogen intolerance may besuitable for unopposed oestrogen. They will need regular endometrialassessment 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 menopausalsymptoms, but for long-term use, a change to CCT is advisable for endometrial
protection and also better patient satisfaction with the loss of monthlywithdrawal bleeds
The development of ultra-low-dose combinations may be even more acceptablefor long-term use because of the reduced endometrial simulation and bleeding
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Reference
Jo Marsden, David Sturdee; Cancer Issues; Best
Practice & Research Clinical Obstetrics and
Gynaecology 23 (2009) 87107
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