2. Perimenopausal Bleeding: The Roller Coaster of Mid-life Steven R. Goldstein, M.D..FACOG,CCD,NCMP, RCOG(H) Professor of Obstetrics & Gynecology New York University School of Medicine Director of Gynecologic Ultrasound Co-Director of Bone Densitometry New York University Medical Center

3. PERIMENOPAUSE (DEFINED) PERIMENOPAUSE (DEFINED) Harlow, Siobán D., et al. Executive summary of the Stages of Reproductive Aging Workshop+ 10: addressing the unfinished agenda of staging reproductive aging. Climacteric 2012: 15.2 : 105-114. The STRAW+10 system for reproductive aging in women defined “perimenopause” as the “early” and “late” menopausal transition.

4. “Early” menopausal transition: Variable duration Cycle length variable “persistent ≥ 7day difference in length of consecutive cycles”. Lab tests – FSH: variable – AMH (Anti- Mullerian Hormone): low – Inhibin B: low Antral follicle count: low

5. “Late” Menopausal Transition Duration 1-2 years. Interval of amenorrhea of ≥ 60 days. Lab tests – FSH: elevated – AMH: low – Inhibin B: low Vasomotor symptoms “likely”.

6. PERIMENOPAUSE: CLINICAL SEQUELAE Some have likened perimenopause as the mirror image of adolescence. Corollary to this: one is the coming onto the reproductive years, the other the coming off.

7. Characterized by oligoovulation – Hallmark of ovulation: regular cyclic, predictable menses. – Hallmark of anovulation/oligoovulation: irregular timing and length of uterine bleeding. PERIMENOPAUSE: CLINICAL SEQUELAE

8. DYSFUNCTIONAL UTERINE BLEEDING (DUB): erratic estrogen production without ovulation resulting in unpredictable bleeding. Thus bleeding associated with oligo-or anovulation will be characterized by its irregular nature (heavy, light, with or without cramps, longer or shorter intervals) MENSES: “A uterine bleed preceded two weeks by ovulation”

9. PSYCHOSOCIAL SYMPTOMS PSYCHOSOCIAL SYMPTOMS Dennerstein et al Med J Aust 1993 This menstrual pattern has also been associated with psychosocial symptoms’ exacerbation or initiation, including: – Free floating anxiety – Inability to concentrate – Sleep disturbances – Mood swings – Memory changes

10. PSYCHOSOCIAL SYMPTOMS Obviously it is difficult to distinguish how much of this is hormonally mediated and how much is natural aging or situational.

11. DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206 Medical History Age of menarche and menopause Menstrual bleeding patterns Severity of bleeding (clots or flooding) Pain (severity and treatment) Medical conditions Surgical history Use of medications Symptoms and signs of possible hemostatic disorder

12. Physical Examination General physical Pelvic Examination – External – Speculum with Pap test, if needed – Bimanual DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206

13. Laboratory Tests Pregnancy test (blood or urine) Complete blood count Targeted screening for bleeding disorders (when indicated) Thyroid-stimulating hormone level Chlamydia trachomatis culture DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206

14. Available Diagnostic or Imaging Tests (when indicated) Transvaginal ultrasonography Saline infusion sonohysterography Hysteroscopy (preferably office-based) DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206

15. Available Tissue Sampling Methods (when indicated) Office endometrial biopsy Hysteroscopy directed endometrial sampling (office or operating room) DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING DIAGNOSTIC EVALUATION OF ABNORMAL UTERINE BLEEDING Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206

16. FIGO Nomenclature: PALM-COEIN Abnormal Uterine Bleeding (AUB) -Heavy menstrual bleeding (AUB/HMB) -Intermenstrual bleeding (AUB/IMB) PALM: Structural Causes Polyp (AUB-P) Adenomyosis (AUB-A) Leiomyoma (AUB-L) Submucosal myoma (AUB-Lsm) Other myoma (AUB-Lo) Malignancy & hyperplasia (AUB-M) COEIN: Nonstructural Causes Coagulopathy (AUB-C) Ovulatory dysfunction (AUB-O) Endometrial (AUB-E) Iatrogenic (AUB-I) Not yet classified (AUB-N) Adapted from Practice Bulletin No. 128. ACOG Obstet Gynecol 2012;120:197–206

17. GYN ISSUES Obviously these are FINAL diagnoses. Thus when such patients present, the diagnostic challenge is structural vs. non-structural. In the past, blind endometrial sampling (D&C, Vabra aspirator, suction piston biopsy instruments) were standard procedures.

18. THE STANDARD OF CARE HAS CHANGED!!!!

19. BUT HOW MANY CLINICIANS ARE AWARE OF IT?

20. “DIAGNOSIS OF AUB IN REPRODUCTIVE AGED WOMEN” HIGHLIGHTS OF NEWEST ACOG BULLETIN HIGHLIGHTS OF NEWEST ACOG BULLETIN Practice Bulletin No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206

21. “One third of outpatient visits to the gynecologist are for AUB and it accounts for more than 70% of GYN consults in the perimenopausal and postmenopausal years ” ACOG PRACTICE BULLETIN JULY 2012

22. “AUB most frequently occurs in women 19-39 as a result of pregnancy,structural lesions (polyps, myoma), anovulatory cycles (e.g.PCOS),hormonal contraception and endometrial hyperplasia.EM carcinoma is less common but may occur in this age group” ACOG PRACTICE BULLETIN JULY 2012

23. “In women aged 40 to menopause AUB may be due to anovulatory bleeding which represents normal physiology in response to declining ovarian function. It may also be due to EM carcinoma or hypeplasia, EM atrophy or leimyomas” ACOG PRACTICE BULLETIN JULY 2012

24. BASIC COURSE IN HISTOLOGY

25. HORMONAL STATUS OBVIOUSLY EFFECTS ENDOMETRIAL THICKNESS THE ENDOMETRIUM CONSISTS OF A BASALIS AND A FUNCTIONALIS ESTROGEN CAUSES THE FUNCTIONALIS TO PROLIFERATE

26. PROLIFERATIVE EM Characterized by abundant mitoses In the following slide taken from a nysterectomy specimen done in the proliferative phase note the AMOUNT (or HEIGHT) of glandular tissue

31. PROGESTERONE (OR IN SEQUENTIAL HORMONE THERAPY THE USE OF A PROGESTIN) WILL CONVERT AN ESTROGEN PRIMED ENDOMETRIAL FUNCTIONALIS TO A SECRETORY PHASE

32. SECRETORY EM The following slide is also from a hysterectomy specimen but done in the luteal phase Note the thickness of the functionalis as well as the way the glands line up

35. AFTER SHEDDING OF THE FUNCTIONALIS THE BASAL ENDOMETRIUM THAT REMAINS IS INITIALLY QUITE THIN AND APPEARS AS A THIN ECHOGENIC LINE ON TV U/S

36. SINCE THERE IS NO”NORMAL’ WIDTH OF ENDOMETRIAL THICKNESS… WHAT IS THE PROPER USE OF THE ENDOMETRIAL ECHO CLINICALLY?

37. ANSWER THE HIGH NEGATIVE PREDICTIVE VALUE OF A THIN DISTINCT ECHO IN PATIENTS WITH BLEEDING WHEN U/S IS PERFORMED JUST AS THE BLEEDING ENDS

38. “The primary imaging test of the uterus for the evaluation of AUB is transvaginal ultrasonography.” ACOG PRACTICE BULLETIN JULY 2012

39. “If transvaginal ultrasonographic images are not adequate or further evaluation of the cavity is necessary, then sonohysterography (also called saline infusion sonohysterography) or hysteroscopy (preferably in the office setting is recommended).” ACOG PRACTICE BULLETIN JULY 2012

40. “An office endometrial biopsy is the first-line procedure of tissue sampling in the evaluation of patients with AUB.” ACOG PRACTICE BULLETIN JULY 2012

41. “Endometrial biopsy has high overall accuracy in diagnosing endometrial cancer when an adequate specimen is obtained and when the endometrial process is global” ACOG PRACTICE BULLETIN JULY 2012

42. “If the cancer occupies less than 50% of the surface area of the endometrial cavity, the cancer can be missed by a blind endometrial biopsy sample.” ACOG PRACTICE BULLETIN JULY 2012

43. “A positive test result is more accurate for ruling in disease than a negative test result is for ruling it out.” ACOG PRACTICE BULLETIN JULY 2012

44. “These tests are only an endpoint when they reveal cancer or atypical complex hyperplasia.” ACOG PRACTICE BULLETIN JULY 2012

45. “Persistent bleeding with a previous benign pathology, such as proliferative endometrium, requires further testing to rule out nonfocal endometrial pathology or a structural pathology, such as polyp or leiomyoma.” ACOG PRACTICE BULLETIN JULY 2012

46. NOW THE STANDARD OF CARE CORROBORATES THAT A NEGATIVE BLIND BIOPSY IS NOT A STOPPING POINT. CLINICIANS CAN STILL BEGIN WITH A BIOPSY BUT UNLESS IT IS MALIGNANT (OR COMPLEX ATYPICAL HYPERPLASIA) THE ENDOMETRIAL EVALUATION IS NOT COMPLETE!

47. SALINE INFUSION SONOHYSTEROGRAPHY (SIS) THE NEXT FOUR SLIDES ARE SONOHYSTEROGRAMS OF PERIMENOPAUSAL WOMEN WHO ALL PRESENTED WITH IRREGULAR BLEEDING

52. TREATMENTS ANATOMIC LESIONS will usually be removed (polyps, submucous myomas) Complex atypical hyperplasias and malignancy almost always require hysterectomy (remember we are dealing with perimenopause so PRESUMABLY childbearing is complete) DYSFUNCTIONAL UTERINE BLEEDING (DUB) and HEAVY MENSTRUAL BLEEDING (HMB) are usually treated expectantly or hormonally

53. Thus some women however will require hormonal cycle control This is not the same as hormone replacement

54. THE KEY TO DIAGNOSIS IS… IS THERE STILL OVARIAN FUNCTION (albeit erratic & pulsatile) …or NOT?

55. The key to successful hormonal treatment in perimenopause is SUPPRESION of ovarian function (i.e. ultra low dose birth control pills in non smokers with normal blood pressure)

56. Traditional HRT does not suppress ovarian function and thus may make perimenopausal bleeding symptoms worse!

57. BIRTH CONTROL PILLS: SO MISUNDERSTOOD !!!

58. BIRTH CONTROL PILLS: CANCER REDUCING AGENTS OVARIAN CANCERS UTERINE CANCERS BREAST CANCERS (? In the low doses currently being employed)

59. WHAT IS “NATURAL”?

60. Women stop being “natural” when they do not have 8 children, nurse them all for 12-15 months (no bottles or formula in nature) and probably would have had 3 miscarriages along the way

61. WOMEN ARE HAVING TOO MANY CYCLES! Reproductive life roughly 40 years (age 11-51) 13 lunar months in each calendar year results in ~ 520 cycles Typical patient: 2 children, nurses 3 mos each = 24 cycles eliminated That leaves 496 cycles !!!

62. LEFT TO NATURE... 8 kids x 9 months = 72 8 kids x 15 months = 120 3 miscarriages x 3 mos = 9 201 Leaves maybe 320 cycles

63. … for those women whose bleeding symptoms are significant enough

64. USE OF BIRTH CONTROL PILLS… Suppresses erratic, pulsatile ovarian function takes the hormonal component “off the table” For most women this gives incredible improvement, and can allow them to drift into menopause without major surgical intervention

65. IN SUMMARY Perimenopause is characterized by oligo and anovulation resulting in often erratic pulsatile estradiol production Perimenopause is also a time of increasing incidence of STRUCTURAL reasons for AUB (polyps, myomas, adenomyosis, hyperplasias and even occassional malignancies)

66. Adequate diagnostic measures can distinguish between structural vs. non structural causes Pathologies are often not global so blind biopsy (when negative) is not an end point Increasingly TV U/S, sonohysterography and office hysteroscopy will be employed IN SUMMARY

67. Appropriate treatment mandates adequate and proper diagnosis Structural lesions are usually approached surgically Non structural lesions are usually treated expectantly or hormonally IN SUMMARY