Dr. Mohammed Abdalla Egypt, Domiat general hospital

1. Post-Menopausal Bleeding Dr. Mohammed Abdalla Egypt, Domiat general hospital

2. Menopause • is the permanent cessation of menstruation resulting from loss of ovarian follicular activity. • It can only be determined after 12 months' spontaneous amenorrhoea. • Mean age is 51 years.

3. Menopause transition • is the period of time in which the ovaries are beginning to fail, where endocrine, biological, and clinical changes are seen. It ends with the final menstrual period. • Length of the transition is approximately 4 years

4. Perimenopause is the time period over which the ovaries are failing (when symptoms begin) up until the cessation of menstruation, and ends 12 months after the final menstrual period.

5. Postmenopause is the time after the menopause, that is, after the permanent cessation of menstruation. It can only be determined after 12 months of spontaneous amenorrhoea. In practice this definition is difficult to apply, especially in women who have started hormone replacement therapy (HRT) in the perimenopause. It has been estimated that by the age of 54 years, 80% of women are postmenopausal [McKinlay et al, 1992; DTB, 1996].

6. Surgical menopause occurs after bilateral oophorectomy with or without hysterectomy. Premature menopause may also be radiation- or chemotherapy-induced, or occur after hysterectomy with ovarian conservation.

7. Primary Premature menopause • A premature menopause is one that occurs before the age of 40 years. • Primary premature menopause may occur at any age and present as amenorrhoea. Not all women have acute symptoms. FSH levels are elevated. Spontaneous fertility may recur.

8. It is possible to discontinue the HRT or COC pill and measure the follicle-stimulating hormone (FSH) level after 6-8 weeks. The POP does not affect FSH levels and so does not need to be stopped for FSH testing [Gebbie, 1998]. • An FSH value over 30 IU/L is in the postmenopausal range, but should be repeated 4-8 weeks later to confirm this. • Even if the FSH levels are in the postmenopausal range, this may not reliably indicate infertility, and contraception should be continued for a further 1 year if the woman is over 50 years old, or a further 2 years if she is under 50 years old .

9. Risk assessment Benign conditions is most frequent causes of PMB but endometrial cancer is the most serious potential underlying cause

10. Risk assessment 75% of women with endometrial cancer are postmenopausal.

11. Risk factors for endometrial cancer are conditions typically associated with chronic elevations of endogenous estrogen levels or increased estrogen action at the level of the endometrium. These include • Obesity. • history of chronic anovulation. • diabetes mellitus. • estrogen-secreting tumors. • exogenous estrogen unopposed by progesterone . • tamoxifen use. • a family history of Lynch type II syndrome (hereditary nonpolyposis colorectal, ovarian, or endometrial cancer).

12. Risk assessment Investigate all bleeding during menopause unless the patient is on cyclic replacement therapy with normally anticipated withdrawal bleeding. The duration or amount (staining vs gross) of bleeding does not make any difference.

13. Tamoxifen use Risk assessment Tamoxifen therapy is associated with a two- to threefold increased risk of endometrial cancer in postmenopausal women. TVUS of patients on this therapy typically shows an increased endometrial thickness. Risk appears to increase with higher cumulative doses of tamoxifen and longer duration of treatment.

14. Postmenopausal bleeding and HRT • The occurrence of uterine bleeding or spotting after the initiation of HRT is not unusual. More than half of HRT users will have some spotting or bleeding at the beginning of therapy. • Usually such bleeding is lighter than a menstrual period and lessens with time; after 6 months, it stops completely in most women.

15. Postmenopausal bleeding and HRT Sequential (or cyclical) combined regimens cause scheduled bleeding in most users. Continuous combined regimens are associated with a reduced relative risk of endometrial cancer but may cause unpredictable spotting or bleeding during initial use.

16. Systemic conditions Abnormalities of the hematologic system also must be considered as a possible cause of postmenopausal bleeding. On rare occasions, AUB will be the first sign of leukemia or a blood dyscrasia. Overuse of anticoagulant medications such as aspirin, heparin, and warfarin-which are taken with greater frequency by patients in this age group-may contribute to postmenopausal bleeding.

17. Pathophysiology • Once menopause occurs, estrogen and progesterone are no longer produced by the ovaries; nor are they produced in any appreciable amounts by the liver and fat. The endometrium regresses to some degree, and no further bleeding should occur. When bleeding does resume, therefore, endometrium must be evaluated.

18. Endometrial evaluation

19. Endometrial evaluation is called for when : • any menopausal woman not taking HRT develops uterine bleeding after more than 1 year of amenorrhea. • any postmenopausal woman on HRT for 6 months or more with persistent uterine bleeding. • and any previously amenorrheic woman on HRT who begins bleeding without apparent cause.

20. Endometrial evaluation As TVUS is a non invasive test with 91 % sensitivity and 96 % specificity . it should be done for all women with postmenopausal bleeding. if the endometrial thickness is >5mm. and if the patient pre test probability is low ,office endometrial biopsy and SIS should be done to determine whether the endometrium is symmetrically thickened. BUT if the patient pre test probability is high , a fractional curettage biopsy or a hysteroscopic guided biopsy is recommended.

21. TVUS endometrial thickness is > 5mm endometrial thickness is < 5mm If high risk If low risk follow office endometrial biopsy and SIS D/C biopsy OR hysteroscopy But symptoms persist In women with continued bleeding after a negative initial evaluation, further testing with hysteroscopically directed biopsy is essential,

22. Diagnostic tools

23. Vaginal ultrasonography. • Hydrosonography. • Endometrial biopsy. • Office biopsy. • D/C biopsy. • Hysteroscopic guided biopsy.

24. Sensitivity and specificity are often used to summarise the performance of a diagnostic test. Sensitivity is the probability of testing positive if the disease is truly present. Specificity is the probability of testing negative if the disease is truly absent.

25. Vaginal ultrasound

26. Vaginal ultrasound Transvaginal ultrasound has a good correlation with pathologic endometrial findings. Using an endometrial thickness from myometrium to myometrium of 5 mm (considered the upper limit of normal) sensitivity is 91 percent and specificity is 96 percent. Although the test is very specific , it isn't sensitive. Many women without endometrial cancer will have an endometrial thickness of 5 mm or more

27. Vaginal ultrasound Identification and measurement of the endometrial echo and descriptions of the echogenicity and heterogeneity of the endometrium are key to defining endometrial health

28. A cut-off threshold of 3 mm or 5mm ? A ‘negative’ TVUS result for a local cut-off point of 3 mm is therefore less likely to miss cancer (i.e. have a greater sensitivity) than cut-offs of 5 mm. But unfortunately a lower cut-off points also result in a greater proportion of ‘false positives’ requiring further investigation.

29. A cut-off threshold of 3 mm or 5mm ? Adopting more than one cut off value may allow the interpretation of the test to be tailored to the patient’s pre-test probability (i.e. the patient risk group).

30. the patient risk group • Low pre-test probability • On HRT • On tamoxifen therapy • High pre-test • Probability (high risk) Cut off threshold 5mm Cut off threshold 3mm

31. If both pre-and post test probability are reassuring, no further action need be taken. Further investigations should be carried out if symptoms recur.

32. If both pre-and post test probabilities are not satisfactory with this level of reassurance, further investigation is justified. This should include an endometrial biopsy to obtain a histological assessment.

33. For women on sequential combined HRT presenting with unscheduled bleeding, or those who are tamoxifen users, TVUS using a cut-off point of 5 mm or less should be used to exclude endometrial cancer.

34. Vaginal ultrasound

35. Vaginal ultrasound One of the difficulties with using the endometrial stripe as a criterion for further diagnostic tests (eg, endometrial biopsy) is that several conditions may be present that give a false reading on the endometrial stripe. This is particularly true in a patient who might have an endometrial polyp or who has been taking tamoxifen.

36. saline-infusion sonography

37. saline-infusion sonography The introduction of intrauterine fluid (saline-infusion sonography) during transvaginal ultrasound is one of the most significant advances in ultrasonography of the past decade.

38. saline-infusion sonography Uterine fibroids and adenomyomas generally are apparent on ultrasound. Uterine polyps may appear as a thickened endometrial stripe, but these and submucous myomas can be clearly identified as filling defects when a sonohysterography is performed

39. saline-infusion sonography At transvaginalUS, when the endometrium cannot be accurately measured or whenthere is a nonspecific thickened central endometrial complex,sonohysterography can provide additional information and can be used to directthe patient to a visually guided hysteroscopic procedure ratherthan a potentially unsuccessful blind biopsy procedure.

40. At transvaginal ultrasonography, the finding of a thickened central endometrial complex,with or without cystic changes, is often nonspecific.

41. The Thickened endometrium may be a polyp CYST POLYP With polyps the endometrial-myometrialinterface is preserved well-defined, homogeneous, isoechoic to the endometrium

42. The Thickened endometrium may be a polyp catheter POLYP With polyps the endometrial-myometrialinterface is preserved

43. The Thickened endometrium may be a Submucosal leiomyomas With myomas the endometrial-myometrialinterface is distorted broad-based, hypoechoic,

44. The Thickened endometrium may be an endometrial hyperplasia Endometrium thickness = A-B A B diffuse thickening of the echogenic endometrial stripewithout focal abnormality

45. Endometrial cancer Endometrial cancer is typically a diffuse process,but early cases can appear as a polypoid mass

46. Endometrial biopsy

47. Endometrial biopsy The role today of the formal D&C probably is very limited because the diagnosis usually can be made in the office. Dilatation and curettage

48. Endometrial biopsy Hysteroscopic visualization has several advantages: • immediate office evaluation, • visualization of the endometrium and endocervix, • the ability to detect minute focal endometrial pathology and to perform directed endometrial biopsies. Hysteroscopic-directed biopsy

49. Thank you