BLOODY HELL

Abnormal Uterine Bleeding (AUB)

Dr. Christiane Kuntz MD CCFP FCFP Annual Scientific Assembly Nov. 29, 2013

Faculty/Presenter Disclosure

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Faculty: Dr. Christiane Kuntz Program: 51 st Annual Scientific Assembly

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Relationships with commercial interests:

– – – –

Grants/Research Support:

none

Speakers Bureau/Honoraria: see next slides Consulting Fees:

none

Other:

none

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Disclosure of Commercial Support

This program has received no financial support through any commercial organization.

This program has received no in-kind support from any commercial organization.

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Potential for conflict(s) of interest:

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Bayer/Berlex are makers of Mirena which will be discussed in this session; the company has provided unrestricted educational grants to fund the Benign Uterine Conditions project sponsored by the OCFP.

Mitigating Potential Bias

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The speaker has no direct involvement with Bayer/Berlex in terms of financial support; the OCFP administers the BUC program through an unrestricted educational grant.

Abnormal Uterine Bleeding Objectives

 Define AUB in pre-, peri- and post menopausal women  Explore the etiology and pathophysiology of AUB  Review assessment tools  Discuss treatment options  Apply learning pearls through clinical cases

Normal Menstrual Physiology

 average cycle 28-35 d, with approximately 14-21 d in follicular phase and 14 d in luteal phase (relatively constant)  relatively little cycle variability ages 20-40  cycle varies 5-7 y after menarche and for 10 y before menopause  cycle often shortens as women approach menopause

Normal Menstrual Physiology

 follicular phase begins with the onset of menstrual flow and ends on the day before the luteinizing hormone (LH) surge  luteal phase begins on the day of the LH surge and ends at the onset of the next menstrual period

Hormonal Changes during Normal Menstrual Cycle

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Normal Menstrual Physiology Abbreviations

 Estradiol (E)  Progesterone (P)  Gonadotropin-releasing hormone (GnRH)  Follicle-stimulating hormone (FSH)  Luteinizing hormone (LH)  Transvaginal Ultrasound (TVUS)

Normal Menstrual Physiology

     Early follicular phase: low E & P levels release from the negative feedback effects of E, P, and probably luteal phase inhibin A results in late follicular phase increase in GnRH pulse frequency and subsequent increase in FSH small increase in FSH secretion appears to be required for the recruitment of the subsequent group of developing follicles, one of which will become dominant and ultimately ovulatory follicle during that cycle rapid increase in LH pulse frequency at this time

Normal Menstrual Physiology

    Early follicular phase: TVUS has demonstrated that ovary is quiescent except for occasionally visible resolving corpus luteum from the previous cycle The endometrium is relatively indistinct during menses and then becomes a thin line once menses is complete normal to see small follicles of 3 to 8 mm in diameter at this time

Normal Menstrual Physiology

    Mid-follicular phase: Increase in FSH secretion causes follicle growth and E production Ovarian follicle granulosa cells hypertrophy and divide, producing increasing E via FSH stimulation of aromatase and then inhibin A Increase in E production feeds back negatively on the hypothalamus and pituitary, resulting in suppression of mean serum FSH and LH concentrations as well as the LH pulse amplitude

Normal Menstrual Physiology

  Mid-follicular phase: In comparison, the GnRH pulse generator speeds up slightly to a mean LH pulse frequency of about one per hour (vs. one per 90 minutes in early follicular phase)  GnRH stimulation is presumably due to release of negative feedback effects of P from the previous luteal phase

Normal Menstrual Physiology

  Mid-follicular phase: Within about 7 d from the onset of menses, several 9 to 10 mm antral follicles are visible on TVUS  increasing E results in thickening endometrium, with increase in number of glands and development of "triple stripe" pattern on TVUS

Normal Menstrual Physiology

     Late follicular phase: E and inhibin A levels increase daily during the week before ovulation due to release from the growing follicle Serum FSH and LH concentrations decrease at this time due to negative feedback effects of E As dominant follicle selected and grows, FSH induces LH receptors in the ovary and increases ovarian secretion of intrauterine growth factors such as insulin-like growth factor-I (IGF-I) Endometrium thickens further

Normal Menstrual Physiology

    Mid-cycle surge and ovulation: E continues to rise until peak approximately 1 d before ovulation Mid-cycle surge represents a switch from negative feedback control of LH secretion by ovarian hormones (such as E & P) to sudden positive feedback effect, resulting in 10X increase in LH and smaller rise in FSH other ovarian factors contribute to the LH surge besides E & P (poorly understood)

Normal Menstrual Physiology

       Ovulation: LH surge initiates substantial changes in the ovary Oocyte in dominant follicle completes its first meiotic division Local secretion of plasminogen activator and other cytokines required for ovulation increased Oocyte is released from the follicle at the surface of the ovary approximately 36 hours after LH surge Oocyte travels down fallopian tube to the uterine cavity Close relation of follicular rupture and oocyte release to the LH surge and as a result, measurements of serum or urine LH can be used to estimate the time of ovulation in women

Normal Menstrual Physiology

     Ovulation: Even before oocyte released, granulosa cells surrounding it begin to luteinize and produce progesterone Progesterone acts rapidly to slow pulse generator so that LH pulses become less frequent by the termination of surge Gradually increasing serum P has a profound impact on the endometrial lining initiating cessation of mitoses and "organization" of the glands Change can be detected on US relatively soon after ovulation: the "triple stripe" image is lost and the EE becomes more uniformly bright

Normal Menstrual Physiology

      Mid- to late luteal phase: Rising P concentrations leads to progressive slowing of LH pulses down to one pulse every four hours Pulses of P occur soon after these slow LH pulses As a result, there can be significant excursions in serum P concentrations during the luteal phase Inhibin A is also produced by the corpus luteum, and serum concentrations of inhibin A peak in the mid-luteal phase Inhibin B secretion is virtually absent and serum leptins are highest during luteal phase

Normal Menstrual Physiology

    Late luteal phase: Gradual decrease in LH secretion results in gradual fall in P & E production by the corpus luteum in absence of a fertilized oocyte If oocyte becomes fertilized, it implants in the endometrium several days after ovulation early embryo begins to make chorionic gonadotropin, which maintains the corpus luteum and P production

Normal Menstrual Physiology

    Late luteal phase: decline in E & P release from resolving corpus luteum results sequentially in loss of endometrial blood supply, endometrial sloughing, and onset of menses about 14 days after the LH surge Menses is relatively imprecise marker of hormonal events in the menstrual cycle, since there is considerable inter-individual variability in relationship between the onset of endometrial sloughing and fall in serum hormone concentrations during luteal phase In response to falling corpus luteum steroid production, the hypothalamic-pituitary axis is released from negative feedback and FSH levels rise, thereby beginning next cycle.

Abnormal Uterine Bleeding Premenopausal Women Definition

   Any variation from the normal menstrual cycle, including changes in regularity and frequency of menses, in duration of flow, or in amount of blood loss Subdivided based on volume of menstruation, regularity, frequency, duration, chronicity, and timing related to reproductive status Bleeding not related to menses may be further characterized as well

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Abnormal Uterine Bleeding Premenopausal Women Categories Ovulatory AUB

usually regular often associated with premenstrual symptoms and dysmenorrhea    

Anovulatory AUB

more common near menarche and the perimenopause often irregular, heavy, and prolonged flow more likely to be associated with endometrial hyperplasia and cancer

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Abnormal Genital Bleeding Premenopausal Women Differential Diagnosis

Anatomic categorisation : Uterus – pregnancy, menorrhagia, anovulatory – periods of transition in reproductive life including adolescence and perimenopause; PCO, endocrine, other; fibroid, polyp, adenomyosis, structural abnormalities; Ca; FB; infections like endometritis/PID; bleeding disorders; meds; ruptured ovarian cyst

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Abnormal Genital Bleeding Premenopausal Women Differential Diagnosis

Anatomic categorisation contd.: Cervix – polyps, cervicitis, ectropian, Ca, pelvic floor laxity Vagina – vaginitis, trauma, Ca, fistulas, benign neoplasms, cysts, radiation changes, FB, atrophy Vulva – infection, benign growths, Ca, trauma ***Neighbouring structures – bowel, urethra, bladder, systemic disease involving skin in region eg. Crohn’s, lichen sclerosis

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Abnormal Genital Bleeding Premenopausal Women Differential Diagnosis

In adolescent within the first 1.5-2 years following menarche, the AUB may be caused by an immature HPO axis*** Other Endocrine Causes : PCOS, CAH, hyperprolactinemia, Cushings, thyroid dysfunction, pituitary tumors Meds: see list Infections: vulva, vagina, cervix etc.

Bleeding disorders Systemic disorders eg. DM, renal failure, SLE, Ca Structural lesions eg. fibroids, polyps Other Causes : FB, trauma

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Abnormal Uterine Bleeding Premenopausal Women History Systemic:

SOB, dizziness – consider anemia; Sx of hypothyroidism, hyperprolactinemia, coagulation disorders, polycystic ovary syndrome, adrenal or hypothalamic disorders

GU Sx:

vaginal discharge, change in odor, pelvic pain/pressure

Sexual Hx:

contraception, pregnancy risk, STDs, cervical screening

Reproductive Hx: Social Hx:

family planning, infertility impact on QOL including sexual function

Medications causing AUB

       Anticoagulants Antidepressants (selective serotonin reuptake inhibitors and tricyclics) Hormonal contraceptives Tamoxifen Antipsychotics (first generation and risperidone) Corticosteroids Herbs: ginseng, chasteberry, danshen

Abnormal Uterine Bleeding Premenopausal Women History

 PMH: hormonally dependent tumours, thromboembolic disease, or cardiovascular problems – affects Rx choices  FH: inherited coagulation disorders, PCOS, endometrial or colon cancer

Abnormal Uterine Bleeding Premenopausal Women Physical Exam

       Vital signs Weight/BMI Thyroid exam Skin exam (pallor, bruising, striae, hirsutism, petechiae) Abdominal exam (mass, hepatosplenomegaly) GU: inspection: vulva, vagina, cervix, anus, and urethra; Bimanual examination of uterus and adnexal structures; Pap smear, cervical cultures if risk for sexually transmitted infection Rectal examination if bleeding from rectum suspected or risk of concomitant pathology

AUB Management Premenopausal Women SOGC Guidelines May 2013

      Investigations: CBC Pregnancy test (urine or serum) if any chance of pregnancy TSH if there is other evidence of thyroid disease Coagulopathy tests if FH of coagulopathy or if woman has had AUB since menarche FSH – measure twice 1 month apart; irregular bleeding could herald POI (my suggestion)

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Imaging: Transvaginal US (TVUS) is first line  Saline infusion sonogram (SIS) and diagnostic hysteroscopy to be used for Dx of intrauterine abnormalities such as submucosal fibroids or polyps or abnormally structured uterus

AUB Management Premenopausal Women

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TVUS endometrial thickness in pre-

menopausal woman:  Follicular phase: as thin as 4 mm  Luteal phase: up to 16 mm

AUB Management Premenopausal Women SOGC Guidelines May 2013

    Imaging: MRI rarely used to assess the endometrium in patients who have menorrhagia may be helpful to map exact location of fibroids in planning surgery and prior to therapeutic embolization for fibroids may also be useful in assessing the endometrium when transvaginal ultrasound or instrumentation of the uterus (i.e. congenital anomalies) cannot be performed.

FIBROIDS

 Benign smooth muscle tumors of uterus  If asymptomatic do not require treatment  Symptoms: pain/pressure, bowel and bladder dysfunction, AUB/anemia & infertility  Physical exam and ultrasound  Must SAMPLE ENDOMETRIUM if AUB and risk factors for cancer present.

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Tissue sampling: Endometrial biopsy (Bx) should be considered in bleeding women over age 40 or in those with bleeding not responsive to medical therapy, as well as in younger women with risk factors for endometrial cancer.

AUB Management Risk Factors for Endometrial Ca

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Fam. Hx endometrial or colon Ca

( HNPCC) 

Age > 40

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Diabetes type II

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PCOS/Anovulatory cycles

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Obesity (BMI > 30 kg/m2)

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Nulliparity

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Tamoxifen

AUB Management Pre-menopausal Women

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Indications:

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Pre-menopausal

 Any persistent change in menstrual cycle, frequency, duration, or flow  Breakthrough bleeding  *** The average age for women with endometrial cancer is 61 years, but 5% to 30% of cases occur in premenopausal women (SOGC May 2013)

AUB Management Endometrial Biopsy

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Purpose is to evaluate the endometrial lining for:

 Cancer  Pre-cancerous tissue (hyperplasia)  Normal endometrial growth  Infertility: luteal phase defect  Small tube inserted through the os  Office procedure

AUB Management Endometrial Biopsy

 Sensitivity to detect abnormalities 81-96 %  Comparable to D&C; may be better  Less reliable than hysteroscopy  Adequate sample obtained > 85%  OHIP billing: Z770 & E542

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Tissue sampling: Office endometrial Bx should replace D&C as initial assessment of endometrium  Focal lesions of endometrium requiring Bx should be managed through hysteroscopy guided evaluation

AUB Management Interpreting Endometrial Biopsy

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Normal

 Symptoms resolve→follow  Symptoms persist→TVUS 

Unable to perform/inadequate sample

 Repeat  TVUS

AUB Management Interpreting Endometrial Biopsy

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Hyperplasia without atypia

 Provera 10mg od/ Prometrium 200 mg po/pv for 30 days or cyclic 12-14 days x 3- 6 months   Repeat biopsy 3- 6 months

Hyperplasia with atypia, cancer

→refer

AUB Management

Medications for AUB

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NSAIDS

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Tranexamic acid (Cyklokapron)

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OCP (combined)

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Mirena

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Progestins (oral, IM)

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GNrH agonist

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Danazol

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Treatment: Non-hormonal options such as NSAIDs and antifibrinolytics (tranexamic acid or Cyklokapron) can be used effectively to treat heavy menstrual bleeding that is mainly cyclic or predictable in timing

AUB Management

Medications for AUB

        Cyclokapron: Synthetic derivative of lysine (amino acid) Antifibrinolytic effect through reversible blockade on production of plasminogen Coagulation/dysmenorrhea not affected s/e: nausea, leg cramps in 30% Dose: 2-3 tabs (500 mg) tid prn - start Rx at onset of bleeding for heaviest days Cost: $1/tab generic; $1.50 trade name **Calendar BMJ 1970;24:214-6

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Treatment: Combined oral contraceptive pills, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine systems significantly reduce menstrual bleeding and should be used to treat women with abnormal uterine bleeding who desire effective contraception

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Treatment: ****In premenopausal women who have regular periods, cyclic luteal-phase progestins do not effectively reduce blood loss and therefore should not be used as a specific treatment for heavy menstrual bleeding

AUB Management

Medications for AUB

       Danazol: Synthetic steroid with mild androgenic properties Inhibits steroid production in the ovary 80% reduction in menstrual blood loss 20% of patients develop amenorrhea; 70 % of women develop oligomenorrhea s/e – none in 50%; 20% report minor concerns like weight gain 2-6 lbs. Dose: 100-200 mg od for three months

AUB Management

Medications for AUB

  GnRH agonists: induce reversible hypoestrogenic state – like “temporary menopause”  Decrease fibroids and uterine volume by 40-60% (reverses within months of stopping Rx) which decreases blood flow  s/e: hot flashes; decreased bone density  **Friedman Obs Gyne 1991;77:720-5.

AUB Management

Medications for AUB

  GnRH agonists: Leuprolide (Lupron) depot given IM 7.5 mg q monthly or 11.25 mg q 3 months for 6-12 months – duration of Rx based on individual woman  Add back therapy – progestin +/- estradiol transdermal preferred – patch/gel

AUB Management Premenopausal Women SOGC Guidelines May 2013

   Treatment: Danazol and gonadotropin-releasing hormone (GnRH) agonists to be used when other medical or surgical treatments have failed or are contraindicated women receiving GnRH agonist for longer than 6 months should be prescribed add-back hormone therapy if not already initiated with GnRH agonist commencement

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Treatment: Progestin intrauterine system (ie. Mirena) has outcomes similar to endometrial ablation for women with heavy menstrual bleeding and thus may be considered prior to surgical intervention

Progestin Intrauterine System (Mirena)

 Indication initially: contraception  Also used for:  AUB  Endometriosis  Fibroids  Endometrial Hyperplasia

Progestin Intrauterine System (Mirena)

 Breakthrough bleeding up to 6 months  followed by amenorrhea in 70 % by one year  Mild cramps upon insertion  Possible progesterone side effects from systemic absorption in first few weeks  Expulsion, perforation rate (1/1000)

Progestin Intrauterine System (Mirena)

 T-shaped device which releases 20 ug/day of levonorgestrel locally in the uterine cavity  Inserted in the office, similar to regular IUD  Lasts 5 years  $400 + script fee ($11.99 at SDM Sept. 2013)  Device covered on ODB  OHIP billing: G378 & E430

Progestin Intrauterine System (Mirena)

 Insert early in cycle (days 4-8) to reduce spotting/bleeding  Consider priming with OCP x 1-2 months if severe menorrhagia  Warn patient about potential side-effects to improve compliance  Ovulation will continue normally in most ♀

Progestin Intrauterine System (Mirena)

 Immediately effective as contraceptive, and immediately reversible  May get free replacement if dropped, expulsed, or causing pain  No need to remove if endometritis; treat with Mirena in-situ  May do PAP, SIS, and endo biopsy with Mirena in-situ

AUB Management Premenopausal Women SOGC Guidelines May 2013

  Treatment: With the exception of NSAIDs, same medical agents used to treat heavy menstrual bleeding among women with normal coagulation can effectively be used in the setting of inherited bleeding disorders

AUB Management Premenopausal Women SOGC Guidelines May 2013

   Treatment: Acute heavy menstrual bleeding should be managed promptly and systematically to minimize patient morbidity and the need for blood transfusion using high-dose estrogen and tranexamic acid Consider possible bleeding disorder in recently menarchal adolescents

AUB Management Premenopausal Women Surgery

   D&C: out of favor; bleeding decreased for a couple of months after procedure and then returns to pre-treatment levels Endometrial ablation: than amenorrhea usual outcome markedly decreased menstrual flow rather Hysterectomy

AUB Management Premenopausal Women Surgery

    Endometrial Ablation: surgical destruction of the endometrium Resectoscopic ablation performed under hysteroscopic guidance, using resectoscopic instruments to ablate or resect the endometrium Non-resectoscopic ablation performed with a disposable device which is inserted into the uterine cavity and delivers energy to uniformly destroy the uterine lining

AUB Management Premenopausal Women Surgery

     Endometrial Ablation: Designed for women who have completed their families Contraception still required for those who are sexually active Pre-op: biopsy needed to rule out Ca and hyperplasia Post-op: cramping and vaginal discharge

AUB Management Premenopausal Women Surgery

   Endometrial Ablation: Presence of submucosal fibroids make procedure less effective; may need to be removed prior to ablation Endometrial preparation using GnRH agonists recommended prior to ablation (using either resectoscope or non resectoscope procedure)

AUB Management Premenopausal Women Surgery

 Resectoscope vs. Non-resectoscope endometrial ablation:  Equal efficacy and patient satisfaction  Resectoscopic ablation - regional or general anesthesia  Non-resectoscopic uses local, regional, or general anesthesia

AUB Management Premenopausal Women Surgery

   Resectoscopic endometrial ablation Cons: more frequent use of general anesthesia, longer duration, increased risk of surgical complications like fluid overload Pros: less costly per procedure; optimal for women with acute flexion or version of the uterus that does not allow a non-resectoscopic ablation device to reach the uterine fundus; better for women undergoing repeat procedure

AUB Management Premenopausal Women Surgery

  Hysterectomy (minimally invasive): option in women who desire definitive therapy and who are willing to accept the risk of perioperative complications

AUB Management Premenopausal Women Surgery

  Endometrial ablation vs. hysterectomy: ablation less costly, lower complication rates of bleeding and infection (sexual effects?), less recovery time post-op  At 2 yrs. post-op patient satisfaction favored hysterectomy (79 vs. 71%) but at 4 yrs. basically the same

Abnormal Uterine Bleeding Postmenopausal Women (PMW)

 Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal woman (other than that expected with progestin withdrawal in cyclic combined postmenopausal hormone therapy)  Unexpected vaginal bleeding in PMW must be investigated

Abnormal Uterine Bleeding Postmenopausal Women (PMW)

    Vaginal bleeding occurs in 4-11% of PMW In PMW with vaginal bleeding, the risk of uterine Ca is 7.3% if the endometrial thickness or echo (EE) is >5 mm and <0.07% if EE is thin < or = 5 mm** As age increases the risk for endometrial Ca for each EE measurement increases **Smith-Bridman Ultrasound Obstet Gynecol 2004;24(5):558

Causes of AUB Postmenopausal Women

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Atrophy**

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Endometrial Polyp

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Endometrial Hyperplasia

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Endometrial Cancer

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Hormonal effect

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Cervical Cancer

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Other 59% 12% 10% 10% 7% <1% 2% Source: Karlsson et al 1995

AUB Management Endometrial Biopsy

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Indications in PMW:

 Vaginal bleeding > 12 months after last period  Bleeding > 6-12 months after initiating HT

AUB Management PMW

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If AUB occurs, evaluate endometrium and uterine cavity as well as the genital tract and external genitalia

 Either endometrial Bx, TVUS or both can be done to initially assess the endometrium  Can base choice of first investigation upon patient preference, physician comfort with procedure, US availability

Abnormal Uterine Bleeding Postmenopausal Women (PMW)

 If TVUS done as initial investigation, endometrial cancer can reasonably be excluded in postmenopausal women with a thin (<5 mm), homogeneous endometrium.

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AUB Management Endometrial Biopsy Endometrial tissue sampling required if:

 Endometrial thickness > 4 mm  Endometrium heterogeneous or irregular in thickness within various areas of the cavity  Endometrium not adequately examined  PMW bleeds persistently

AUB Management PMW

 Once endometrial Ca excluded no need for further treatment of bleeding  Endometrial ablation not recommended for PMW – can be difficult to assess for Ca after procedure