O ffice hysteroscopy in postmenopausal women on HRT with uterine bleeding

1. Office hysteroscopy in postmenopausal women on HRT with uterine bleeding Branka Žegura Gynecologic Clinic, University Clinical Centre Maribor, Slovenia Brijuni; 11.9.2011

2. AUB and HRT Abnormal uterine bleeding (AUB) with HRT is unscheduled bleeding. It affects around 40 to 60% on combined HRT. Commonly leads to discontinuation of the therapy. Hickey M. Maturitas 2009.

3. AUB and HRT AUB occurs with cyclical and continuous combined regimens. 38% on sequential and 41% on combined HRT in one year. 12% and 20%, respectively require endometrial biopsy. Ettinger B. Fertil Steril 1998

4. AUB and HRT Unscheduled bleeding is most common in the initial months and tends to settle with long-term use.

5. Mechanisms of endometrial bleeding and combined HRT wide range of combined HRT varying prescribing schedules no correlation between endometrial histology with the type or dose of HRT individual variations in response to the same HRT

6. AUB and HRT poor compliance systemic or pelvic pathology 40% of women with endometrial polyps and sub mucus fibroids in the majority - no pathological cause for the bleeding

7. HRT and endometrial hyperplasia Sequential HRT - 2.7 - 5% in over 3 years. Combined continuous HRT - <1% Sturdee DW. Br J Obstet Gynecol 2001

8. Unopposed estrogen and endometrial carcinoma (ERT) RR 2,8 duration of treatment increased risk persists for up to 15 years after treatment dosage type of estrogen - no difference

9. Duration of treatment (ERT) in 10% endometrial hyperplasia after 1 year of ERT 50% after 2 years 62% after 3 years, 50% complex or atypical The Writing Group for PEPI Trial. Effects of HRT on endometrial histology in postmenopausal women. The PEPI trial. J Am Assoc 1996; 275: 370-5.

10. Duration of therapy (ERT) after 4 months of ERT, simple endometrial hyperplasia progresses to atypical. Kurman RJ at al. The behaviour of endometrial hyperplasia. A long-term untreated hyperplasia in 170 patients. Cancer 1985; 56 (2): 403-12. 10 years of ERT increases the incidence of endometrial cancer from 1:1000 to 10:1000 Shapiro S et al. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. New Engl J Med 1985; 313 (16): 969-72.

11. Combined HRT Relative risk for endometrial cancer Sequential: progestogen <10 days: 2 progestogen >10 days: 1,3 12 to 14 days of progestogen for the protection of endometrium. Continuous: 0,9

12. The safety of sequential HRT 3 years study: protective effect of 10 mg MPA or 200 mg micronised progesterone 1 year study: protective effect of 5 mg MPA The Writing Group for PEPI Trial. Effects of HRT on endometrial histology in postmenopausal women. The PEPI trial. J Am Assoc 1996; 275: 370-5. 2 year study: protective effect of 10 mg didrogesterone Van der Mooren MJ et al. Changes in the withdrawal bleeding pattern and endometrial histology during 17ßestradiol-dydrogesterone therapy in postmenopausal women: a 2-year prospective study. Maturitas 1995; 20: 175-80.

13. After 5 Years? 2,5 fold increased risk Beresford SAA et al. Risk of endometrial cancer in relation to use of estrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997; 349: 458-61. RR 2,9 for progesterone and RR 0,9 for testosterone derivatives Weiderpass E et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91 (13): 1131-7. no increased risk (RR 1,07) Pike MC et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89 (15): 1110-6.

14. Long-cycle progestogen regimens progestogen is added every 3 to 6 months 15% of endometral hyperplasia after 3 months the addition of progestogen reverses hyperplasia, but 2% remains after 2 years Scandinavian Long-Cycle study prematurely terminated Sturdee DW et al. Is timing of withdrawal bleeding a guide to endometrial safety during sequential oestro-progestagen replacement therapy? Lancer 1994; 344:979-82.

15. Continuous HRT • no endometrial hyperplasia after 3 years CEE+MPA The Writing Group for PEPI Trial. Effects of HRT on endometrial histology in postmenopausal women. The PEPI trial. J Am Assoc 1996; 275: 370-5. • after 1 year of E2+NETA atrophic endometriom at hysteroscopy Piegsa K et al. Endometrial status in postmenopausal women on long termcontinuous combined HRT. Eur J Obstet Gynecol 1997; 72:175-80. • decreased risk f endometrial cancer (RR 0,2) Weiderpass E et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91 (13): 1131-7. • WHI: decreased risk for endometrial cancer Anderson GL et al. Effects of estrogen plus progestin on gynaecologic cancers and associated diagnostic procedures. JAMA 2003; 290 (13): 1739-48. • long term therapy (>5 years) Pike MC et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89 (15): 1110-6. Hill et al. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gynecol 2000; 183: 1456-61.

16. Combined HRT and endometrial cancer

17. AUB and HRT At hysteroscopy (HSC) the majority of combined HRT users will have no intrauterine pathology. Hickey M. Menopause International 2007

18. Hickey M. Maturitas 2009.

19. transvaginal ultrasonography saline infusion sonohysterography the gold standard is hysteroscopy with endometral biopsy no evidence that changing the estrogen or progestogen or the mode of delivery are effective Management of AUB • lack of consensus • persistent bleeding • when to reinvestigate? Hickey M. Maturitas 2009

20. no anaesthesia vaginoscopic approach/atraumatic insertion technique no cervical dilatation no additional costs, no operative theatre diagnostic and operative procedure, see and treat procedure (>90%), fast patient’s recovery, reduced complications, few limitations Office hysteroscopy

21. the diagnostic accuracy of HSC is high for endometrial cancer and focal lesions (Clark TJ. JAMA 2002) 92% sensitivity and 82% specificity for diagnosis of endometral polyps (Dueholm M. Fertil Steril 2011) 10% asymptomatic postmenopausal women with normal ultrasound had endometrial pathology on office HSC (Marello J Am Assoc Gynecol Laparosc 2000) PPV of office HSC in postmenopausal women with thickened endometrium is 97% and NPV 100% (Lozzi V. J Am Assoc Gynecol Laparosc 2000) Office hysteroscopy

22. Office operative hysteroscopy 1. biopsy 2. polipectomy 3. miomectomy (max. 1.5 cm) 4. metroplasty 5. sinechiolysis 6. tubal sterilization

23. 190 women with AUB on HRT, office HSC • 48.4% normal uterine cavity, 20% atrophic endometrium, 27.4% endometrial polyp, 0.5% myoma, 2.63% endometrial hyperplasia, 1.58% adenocarcinoma Outcome of outpatient micro-hysteroscopy performed for abnormal bleeding while on hormone replacement therapy Okeahialam MG et al. J Obst Gyn 2001

24. 410 women with AUB (94 users, 191 non-users), office HSC • endometrial polyp 23.7% (users) vs. 30.8% (non-users), myoma 6.8% (users) vs. 11% (non-users) • intrauterine disease is more frequent in postmenopausal women who do not use HRT Hysteroscopic findings in postmenopausal AUB: a comparison between HRT users and non-users Perone G et al. Maturitas 2002

25. 503 women with AUB (204 users, 299 non-users), office HSC • higher incidence of endometrial carcinoma in non-users (RR>10) • protective effect of HRT on the endometrium The value of outpatient hysteroscopy in diagnosing endometrial pathology in postmenopausal women with and without HRT Elliot J et al. Acta Obstet Gynecol 2003

26. 587 women, 16.7% HRT users, office HSC • HRT users had signif. increased endometrial thickness (>5 mm) and higher incidence of AUB • no difference in the incidence of endometral carcinoma between HRT users and non-users • cut-off point for HSC - endometrial thickness of 8 mm in HRT users HRT and evaluation of intrauterine pathology in postmenopausal women: a ten year study Mossa B et al. Eur J Gynaecol Oncol 2003

27. 99 women with AUB, office HSC • 18.6% intrauterine pathology • 4 times higher frequency of intrauterine pathology in those with AUB after achieving amenorrhea • higher frequency of intrauterine pathology when AUB lasted for more 6 months • office hysterocopy with endometrial biopsy if AUB continues after 6 months of HRT or if it recurs after amenorrhea Intrauterine pathology in women with abnormal uterine bleeding taking HRT Leung PL et al. J Am Assoc Gynecol Laparosc 2003

28. 77 women with AUB, office HSC • 14% endometrial polyp • low incidence of significant pathology • recommendation: office hysteroscopy where facilities are available, if not ultrasonography Do we really need to hysteroscope all women who have irregular bleeding on HRT? Lalchandani S. Gynecol Surg 2004

29. Office hysteroscopy - Maribor • Dec 2010 - July 2011 • 43 women • mean age 57.18 years (45-60 years) • 68.7% continuous combined HRT

30. Instrumentation • 3 mm telescope, 30o fore-oblique lens (Olympus) • 4.5, 5.5 continuous-flow sheath • 3 Fr, 5 Fr operative channel • grasping forceps, scissors • high-intensity xenon cold-light source • Gynecare Versacsope system (Alphacsope 1,9 mm hystroscope) • Gynecare Versapoint system (bipolar 5Fr electrodes)

31. AUB and HRT 1. Normal uterine cavity (50.4%) 2. Abnormal uterine cavity: • endometrial polyps (36.8%), • myomas (10.2%) 3. Intracervical pathology: • cervical polyp (2.6%)

32. Conclusions • The incidence of significant pathology in patients with AUB on HRT is very low. However benign polyps are common. • The gold standard for investigation of AUB is HSC with endometrial biopsy, if AUB continues after 6 months of HRT or if it recurs after amenorrhea

33. Thank you! Hvala!