1. AUB, DUB, and Dysmenorrhea Conservative Treatment
Denny R. Martin DO, FACOOG
Asst. Professor Obstetrics, Gynecology, Reproductive Biology
College of Human Medicine, Michigan State University
MSU Women’s Healthcare
Today we will be covering the causes of abnormal uterine bleeding and their conservative, non-invasive treatments both medical and surgical.

2. Introduction
In the United States 650,000 women undergo hysterectomy each year
36% of women in the US over the age of 60 have had a hysterectomy
40% of Australian women have had a hysterectomy
5 to 6% of women in Italy and France
25% of the hysterectomies are done for abnormal uterine bleeding (AUB)
Remaining causes related to other disorders such as chronic pelvic pain, uterine prolapse or other pelvic organ proglapse and a small percentage due to complications of pregnancy/delivery.

3. Abnormal Uterine Bleeding
Abnormal bleeding with an identified organic cause
>10 million women in the U.S.
Impacts daily activities and quality of life
May cause anxiety
Timing of bleeding, volume, inability to plan life
May lead to iron-deficiency anemia/fatigue
Affects:
Adolescents
Women of reproductive age
Peri- and postmenopausal women
Wether we are talking about the volume of blood loss or the unpredictable timing of bleeding, this disorder dramatically affects a significant percentage of women in our country everday. You must consider not only the potential social effects on women but also the physical implications.

4. Impact of AUB
AUB accounts for 20% of gynecologic office visits or nearly 4 million visits/yr. in (Vital Health Stat 13, 1998)
A significant quality of life and loss of work problem for women.
25% of middle aged British women reported bleeding that interfered with their lives (Gath et al, BMJ 1987)
Cost to US health care system for hysterectomy is several billion dollars each year (Easterday et al, Obstet-Gynecol 1983)
This makes up a significant portion of our daily practice as gynecologists and for family physicians as well.
Work up and evaluation of AUB is significant when you consider cost of office visits, pathology evaluation, radiologic studies, lab costs, etc. That is all before we even start talking about treatment costs.

5. Causes of AUB Endometrial Polyps
Hysteroscopic view. The following are identifiable causes of AUB. Images all taken from Google images search with basic searches.
ivf-infertility.com
lapscope.com

6. Uterine Fibroids
acfs2000.com
obgyn.net

7. Endometrial Cancer
en.wikipedia.org
liv.ac.uk

8. Dysfunctional Uterine Bleeding
Defined as abnormal bleeding, with no definable organic cause (fibroids, polyps, endometrial ) in patients in absence of pregnancy.
Terms such as menorrhagia, metrorrhagia, oligomenorrhea, polymenorrhea, etc. used to specifically describe the bleeding pattern

9. DUB – Differential Dx Pregnancy Complications/Dx of Pregnancy
Uterine Pathology
Uterine leiomyomas, Endometrial Polyps
Endometrial Cancer or Hyperplasia
Cervical Pathology
Cancer, Pre-Neoplastic Conditions
Adenomyosis
Pathologic diagnosis…..
Must rule out all these causes before the diagnosis of exlusion, Dysfunctional uterine bleeding can be given.
Pretty good data on diagnosis of adenomyosis with pelvic ultrasound and MRI.

10. Diagnostic Tools - DUB Proper evaluation and diagnosis
History and Physical exam
Endometrial biopsy
Pap Smear
CBC
Transvaginal ultrasonography (TVS)
Hysteroscopy
In office vs. OR
Saline infusion sonography (SIS)
Magnetic resonance imaging (MRI)
A complete history will often lead us to the correct diagnosis.

11. Pelvic Ultrasound Transvaginal sonography (TVS) very helpful
measure endometrial lining/stripe, detects fibroids, etc.
Sensitivity for endometrial abnormalities 41%, specificity 98%, positive predictive value 95% and negative predictive value 64%
Saline Infusion Sonography (SIS) or sonohysterography (SHG) more accurate, higher specificity, 36% of normal TVS found to have pathology on SIS.
Ko, et al, abstract JOGC, Oct. 2001
Preferred over office hysteroscopy by patients.
Widrich, et al Am J Obstet Gynecol. 1996
Timmerman, et al Am J Obstet Gynecol. 1998
JOGC- journal of obstetrics and gynecology Canada.

12. Pelvic Ultrasound drdach.com med.unc.edu
13 mm endometrial stripe, upper right abnormal appearing endometrial mass, solid, cystic suspicious for tumor possibly sarcoma
med.unc.edu

13. Hysteroscopy
By far the best and most informative tool in assessing the uterine cavity.
In office use of hysteroscopy is the future
Better patient satisfaction with improvement in local anesthesia, paracervical blocks, and sedation techniques
No other tool can give us a direct look inside the uterine cavity. But its limitation is it cannot see into the muscular wall of the uterine or exterior to visualize peduncuated fibroids or other abnormalities.

14. Hysteroscopy oxfordgynaecology.com advancedfertility.com
No difference in visualization if this is done in office or operating room as long as adequte paracervical/lower uterine segment anesthesia in place.
advancedfertility.com
myomectomy.net

15. Dysmenorrhea Primary Dysmenorrhea Secondary Dysmenorrhea
Excessive pelvic pain and cramping associated with the menstrual cycle
Secondary Dysmenorrhea
Excessive pelvic pain and cramping associated with the menstrual cycle secondary to identifiable pelvic pathology
Endometriosis, PID, Fibroids, etc
We will briefly discuss dysmenorrhea

16. Dysmenorrhea - Pathophysiology
Cramping and pain are due to excessive production of prostaglandins and leukotrienes in the endometrium.
Uterine effects
Myometrial contractility
Uterine vasoconstriction and ischemia
Above effects lead to pain

17. Dysmenorrhea - Rates
Studies vary widely in their rates of reproductive age women affected (6-60%)
Avant RF. Dysmenorrhea, Primary Care, 1988.
The common use of NSAID’s and Oral Contraceptives, both of which are known to decrease rates of dysmenorrhea, likely lowers the numbers reported in literature
Actual numbers likely 30-50%
Sobczyk. Dysmenorrhea: The neglected syndrome. J Repro Med, 1980.
80% of women relieved with NSAID use only
Speroff
The role of nsaids in relieving dysmenorrhea is clear. OCP’s work by creating an atrophic decidualized endometrium that produces less prostaglandins, less blood loss, and provides benefit of menstrual regularity.

18. Dysmenorrhea
7-15% of women are unable to function 1-2 days per month due to dysmenorrhea
Avant RF. Dysmenorrhea, Primary Care, 1988.
Single largest cause of missed work for women of reproductive age
Dawood MY. Dysmenorrhea, Clin Ob Gyn 1990.

19. Treatment of AUB, DUB, Dysmenorrhea
American College of Obstetricians and Gynecologists. Practice Bulletin #110.
“Noncontraceptive Uses of Hormonal Contraceptives.”
80% of women during reproductive years will use hormonal contraception
Many of these will be for non-contraceptive indications

20. Progesterone / Estrogen
Work together to cause negative feedback to CNS and suppress LH and FSH release
Hypothalamic-Pituitary-Ovarian Axis
Progesterone – LH
Estrogen – FSH
Estrogen stabilizes endometrium during periods of prolonged progesterone exposure
Minimizes “breakthrough” bleeding seen with continuous unopposed progesterone exposure
Basically we are manipulating the H-P-O axis. Basics of menstrual cycle: Early estrogen driven phase encompasses proliferation of endometrial glands, stromal cells, and expansion of spiral ateriole circulation. Result is production of an exagerrated hyperplastic endometrium. Later in cycle, low estrogen/high progesterone levels result in lower levels of estrogen receptor expression leading to slowing in endometrial cell growth/proliferation, tortuosity of glands, coiling of vessels, edema in the endometrium. Progesterone receptors are more present in cells of endometrium and vasculature. Loss of progesterone and estrogen result in endometrial breakdown and menses ensues.

21. Progestins
Newer generations of progestins have benefit of decreased androgenicity and lower doses
First Gen. On US market <1973
MPA, Norethindrone +/- Acetate, Norgestrel, etc
Second Gen
Levonorgestrel
Third Gen
Desogestrel, Norgestimate, Gestodene (not in US)
Fourth Gen. >2000
Drospirenone

22. Treatment of Dysmenorrhea
Combined OCP use have been shown to decrease uterine prostaglandin production and relieve dysmenorrhea in up to 80% of women.
Vaginal ring formulation shows similar results
Single-rod progestin implant system shown to relieve up to 81% of women
Levonorgestrel IUD studies limited for this use but data extrapolated to likely be similar
We will now discuss treatment of individuals disorders of the menstrual cycle and their treatment.

23. Dysmenorrhea due to Endometriosis
Limited data to suggest combined OCP can reduce severity of dysmenorrhea due to endometriosis
Continuous combined OCP may have further benefit
Depot MPA and contraceptive implant both have been shown to reduce pain secondary to Endo.
Levonorgestrel IUD shown to decrease dysmenorrhea and chronic pelvic pain due to endo.
Best results with promoting endometrial atrophy either by continuous combined OCP or continuous progesterone exposure.

24. Cycle Control
Combined OCP’s can correct menstrual irregularities due to oligo-ovulation or anovulation and make menstruation more predictable.
Most studies have demonstrated that unscheduled bleeding is common in first 3-6 mths of any new OCP use
Progesterone only formulations likely higher initial bleeding but long-term, less blood loss possibly amenorrhea
Think about which aspect of the cycle you are trying to control. Regularity? Monthly-longer term combined OCP will make cycle predictable. Volume of blood loss but regular…Mirena. Etc.

25. Cycle Control Continued
Mono-phasic, Tri-phasic, 21 day, 24 day, Low dose, periods 4 times a year/once a year,etc ????????
Newer data suggest no difference in cycle control or menstrual blood loss between low dose monophasic and tri-phasic formulations
Not all women will equally respond to all formulations the same.
May need to try different formulations before finding best cycle control for each individual.
Remember to counsel women on initial phase of irregular bleeding, this will lead to increased compliance if they are aware this is normal.

26. Menorrhagia
Combined OCP’s can reduce menstrual blood loss by 40-50% and are a reasonable option for initial tx
Extended cycle or continuous therapies may reduce number of episodes of bleeding
Levonorgestrel IUD
Decreased blood loss by 86% at 3 months and up to 97% at 12 mths.
Amenorrhea at 12 mths 20-80%
Consider what may be causing this. If 20 week fibroid uterus, OCP’s may not be effective and uterus likely too large for IUD.

27. Menorrhagia Levonorgestrel IUD vs. Endometrial Ablation
Similar reductions in blood loss at 24 mths
Similar improvements in quality of life.
Serious adverse events lower with IUD placement vs. surgery
Again, must consider uterine size and other abnormalities present.

28. PMS and Premenstrual Dysphoric Disorder
Early studies on tx of above with OCP’s showed no difference between users and non-users
No difference with monophasic and triphasic
PMDD
More severe form of PMS
Affects psychological well being and social interactions in 3-5% of reproductive age women

29. Premenstrual Dysphoric Disorder
Formulations of 30mcg ethinyl estradiol with drospirenone as progesterone component in a 24/4 day regimen are only OCP studied to show significant decrease in PMDD.
Vaginal ring with drospirenone showed improvements with PMS.

30. Menstrual Migraines
60% of women with migraines link them to menstruation
Extended cycle OCP, continuous OCP, patch, DMPA can reduce or eliminate hormonal fluctuation and virtually eliminate headaches for some women.

31. Hirsutism and Acne All combined OCP’s have potential to improve both
Increase in Sex Hormone Binding Globulin
Decrease LH driven ovarian androgen production
Do not eliminate existing hair
Combined OCP’s can reduce both inflammatory and non-inflammatory facial acne lesions
Acne lesion counts, severity grade, self-assessed acne
Few differences with type of OCP used
Increase in SHBG production results in less free androgens in circulation as they are now bound. Weight and insulin are two major factors for lower levels of SHBG.

32. Hirsutism and Acne
Contraceptives that bypass the liver (patch and vaginal ring) may have lesser effect on sex hormone binding globulin production
Higher levels of free circulating androgens
Progesterone only formulations not considered effective for acne.
Progesterone, like higher weight and insulin, act to decrease SHBG.

33. Cancer Prevention Endometrial Cancer
Strong evidence supporting a 50% decrease in cancer among women who have used combined OCP’s
Longer duration of use showed greater decreases
Up to an odds ratio of 0.2
Effects last up to 20 years
Overall death from endometrial cancer significantly reduced in past OCP users

34. Cancer Prevention - Endometrial
Limited data on newer formulations and low-dose OCP’s
Greater risk reduction with higher doses of progesterone
Levonorgestrel IUD
Achieves endometrial concentrations several hundred fold higher than systemic therapy.
Now approved as progestin component of hormone therapy in some countries

35. Cancer Prevention - Endometrial
Levonorgestrel IUD
Effective tx for endometrial hyperplasia WITHOUT atypia
Regression in 96%
Limited effects when atypia present
Shown to protect endometrium in women taking tamoxifen for adjuvant breast cancer therapy

36. Cancer Prevention Ovarian Cancer
Large scale re-analysis of data including 45 studies, 23,000 cancer cases, and 87,000 controls agree
Combined OC decreases risk of ovarian cancer by 27%
Longer duration of use – greater risk reduction
20% for every 5 years of use
Low dose pills have been shown effective
? Future use in BRCA mutation carriers ?

37. Cancer Prevention Colorectal Cancer 18% reduction in OC users
Greatest for recent use
No duration effect seen
Meta analysis of 6 cohort studies and 14 case-control studies

38. Ovarian Cysts
Preventing ovulation should reduce follicular and corpus luteal cysts
Not all follicular activity suppressed with low-dose pills
No difference in monophasic or triphasic formulations
Older studies show users of progesterone only formulations may develop/rupture cysts in 10-20% of cycles
Most are asymptomatic

39. Bone Mass and Fracture Risk
Estrogen strong inhibitor of bone resorption
Combined OCP use is associated with increased BMD in women in later reproductive years
Longer the duration of use(>10yrs) greater BMD
May not have same result in younger women
Adolescents and young adult women shown to have lower BMD than non-users
Quick return to normal density levels after stopping OCP

40. Bone Mass and Fracture Risk
Adolescents
Higher calcium intake may help decrease BMD compared to non-users
Perimenopausal and postmenopausal women taking OC’s preserved bone mass where non-users lost.
Studies looking at risk of fracture have somewhat mixed results
3 large studies show no effect, 3 studies showed increased risk of fracture, and 3 studies showed protective effects.
Cochrane review of OC’s with primary outcome of fracture risk

41. Bone Mass and Fracture Risk
Depo MPA and progesterone implant users have been found to have decreased BMD
Rapidly recovered after stopping use
Does this correlate with increased fracture risk?
No data on fracture risk for postmenopausal women who previously used DMPA
Key question that needs further study is does this decrease in BMD result in increased fracture risk? Studies not conclusive at this time.

42. Uterine Leiomyomas
Effects of combined OCP’s on leiomyoma formation and growth not well understood.
Studies show conflicting data with case studies showing no effect or small reduced risk
Large cohort studies show no association between OC use and leiomyomas
Data limited on use of combined OCP’s in controlling bleeding from leiomyomas
Levonorgestrel IUD shown to reduce overall uterine volume with no effect on size of leiomyomas

43. ACOG Practice Bulletin, 110 Noncontraceptive Uses of Hormonal Contraceptives (January 2010, Reaffirmed 2012), (Replaces Committee Opinion Number 337, June 2006)

44. Questions?