Treatment of Endometriosis and Dysfunctional Uterine Bleeding (DUB) Dr. Piascik 3/26/15

Endometriosis

Risk Factors for Endometriosis Nulliparity 1+ female relatives with endometriosis (mother, sister, aunt) Menstrual cycle < 27 days with 8+ days of bleeding Any medical condition that affects menstrual blood flow Personal history of pelvic infection Age: late 20s to early 30s

Goals of Treatment Minimize or remove endometrial lesions Prevent disease progression Minimize painful symptoms Maintain and/or improve fertility

Treatment Options for Endometriosis Expectant management Drug therapy Surgical treatment Combination of drug therapy and surgical treatment

Expectant Management “Watchful Waiting” Best for asymptomatic patients because therapy is only indicated if the patient becomes symptomatic

Choosing Therapy: Medications vs. Surgical Treatment Location/extent of disease Desire for future fertility Cost Contraindications to therapy Potential adverse effects of therapy

Treatment: Drug Therapy Good ◦ Avoids risks/short-comings of surgery Bad ◦ Does NOT preserve fertility ◦ Adverse effects of medications ◦ High recurrence rates  Although patient may go into remission for months or years, recurrence rates are high (30-75% within 2 years)

Treatment: Drug Therapy 1 st line ◦ OCPs and/or NSAIDs Alternatives ◦ Progestins ◦ Danazol ◦ GnRH Analogs

1 st Line Treatment Options- Oral Contraceptives MOA: decrease menstrual flow and cause regression of endometrial implants Dose: 1 tablet PO daily ◦ Continuous dosing may be beneficial ADRs: nausea, bloating, HA, breakthrough bleeding CI: history of thromboembolism (TE); age 35+ years and smoker Cost: ~$10-$50 per month

1 st Line Treatment Options- NSAIDs MOA: interfere with production of prostaglandins  reduced pain Dose: ibuprofen ( mg po q4-6h) or naproxen (250mg po q6-8h) ◦ Must be taken 24 hours before expected pain ◦ ATC dosing may be beneficial ADRs: nausea, epigastric pain, heartburn Precautions: reactive airway disease, renal impairment, or history of GI ulcer Cost: ~$20 per month

Treatment Alternatives- Progestins MOA: inhibit growth of endometrial tissue through direct decidualization and eventual atrophy Dose: See next slide Duration: 6 months ADRs: weight gain, acne, hirsutism, oily skin, deepening of the voice, hot flashes, irregular bleeding, vaginal dryness, decreased libido CI: history of or current TE, venous thromboembolic disorders (DVT, PE), severe hepatic dysfunction, carcinoma of the breast or genital organs Cost: from ~$150 per month to $500 over 5 years

Dosing of Progestins DrugRouteBrandDose Medroxy- progesterone OralProvera 400mg daily IM or SC Depo- Provera 104mg Q3 months NorethindroneOralAygestin 15mg daily Levonorgestrel Intra- uterine device Mirena 20mg daily over 5 yrs

Therapeutic Alternatives - Danazol MOA: causes endometrial atrophy through inhibition of pituitary gonadotropin secretion; induces a high- androgen/low estrogen environment. Dose: mg PO daily in divided dose ADR: weight gain, muscle cramps, ↓ breast size, acne, hirsutism, oily skin, ↑ LDL, ↑ liver enzymes, hot flashes, depression Contraindication: women with hyperlipidemia or liver disease. Duration of therapy: 6 months Cost : approximately $400/month

Treatment Alternative – GnRH analogs MOA: Inhibits pituitary gonadotropin secretion, thereby suppressing ovarian estrogen production. ◦ Physiologic release of GnRH occurs every 90 minutes. ◦ Constant presence of GnRH analog causes brief stimulation followed by inhibition of gonadotropin release

Treatment Alternative – GnRH analogs Considered more effective than OC for women with moderate to severe disease leuprolide (Lupron), goserelin (Zoladex), nafarelin (Synarel) Dose: goserelin - 3.6mg SQ every month nafarelin – 200mcg (1spray) nasally BID leuprolide mg IM every 3 months

Treatment Alternative – GnRH analogs ADR: hot flashes, vaginal dryness, decreased libido, insomnia, breast tenderness, depression, headaches, loss in bone density Duration of therapy: typically 3 to 6 mo Cost: ranges from $600-$1300/month

Add-Back Therapy Administer estrogen/progestin with GnRH analog The level of estrogen needed to prevent ADRs is less than the estrogen level that allows growth of endometrial implants Effects: ◦ Prevents bone mineral density loss ◦ Treats vasomotor symptoms ◦ Maintains efficacy of GnRH agonist Indicated for GnRH regimens lasting longer than 6 months.

Add-Back Therapy Drug(s)Dose Norethindrone 5mg daily Norethindrone + estrogen 5mg daily mg daily Norethindrone + etidronate 2.5mg daily + 400mg daily x 14 days

Aromatase Inhibitors: anastrozole (Arimidex) and letrozole (Femara) MOA: Aromatase, an enzyme that produces estrogen, is found in high levels in ectopic endometrial tissue. Inhibiting aromatase suppresses growth of endometriotic lesions.

Aromatase Inhibitors: anastrozole (Arimidex) and letrozole (Femara) Investigational drugs for severe endometriosis. Dose: anastrozole – 1mg PO daily letrozole – 2.5mg PO daily ADR: irregular bleeding, mild hot flashes, decreased libido; significant bone density loss with prolonged use Cost: approximately $500/month

Treatment: Surgery Conservative surgery maintains fertility Removal of endometrial growths, scar tissue, and adhesions while keeping reproductive organs intact Usually performed laparscopically Woman is usually treated with post-op GnRH or danazol

Medical Recommendations from the ACOG Because endometriosis often is unpredictable and may regress, expectant management may be appropriate in asymptomatic patients. For pain relief, oral contraceptives and medroxyprogesterone are effective and may be equivalent to other more costly regimens.

Medical Recommendations from the ACOG Treatment with a GnRH agonist for at least 3 months or with danazol for at least 6 months appears to be equally effective in most patients. When relief of pain from treatment with a GnRH agonist supports continued therapy, the addition of add- back therapy reduces or eliminates GnRH-induced bone mineral loss without reducing the efficacy of pain relief.

Medical Recommendations from the ACOG Therapy with a GnRH agonist is an appropriate approach to the management of the woman with chronic pelvic pain, even in the absence of surgical confirmation of endometriosis, provided that a detailed initial evaluation fails to demonstrate some other cause of pelvic pain.

Case 1 PL, 28 yo, tells you she had abdominal surgery last month. The surgeon told her he saw endometrial lesions on her ovaries. She asks what you think she should do. ◦ What questions would you ask PL? ◦ What therapeutic option would you suggest?

Case 2 LT, a 31yo, has been treated unsuccessfully with several agents for endometriosis. The next treatment option is Synarel. ◦ What has she likely been treated with previously? ◦ Is Synarel an effective agent to improve LT’s fertility? ◦ What patient counseling information should you provide? ◦ LT has a family history of osteoporosis. Will this be a problem with her current therapy?

Dysfunctional uterine bleeding irregular uterine bleeding that occurs in the absence of pathology or medical illness ◦ Amenorrhea: absence of menstrual bleeding ◦ Oligomenorrhea: menstrual cycle interval >35 days ◦ Polymenorrhea: menstrual cycle interval <24 days ◦ Menorrhagia: regular menstrual bleeding with blood loss > 80mL per cycle or prolonged menstrual bleeding > 7 days ◦ Metrorrhagia: irregular menstrual bleeding ◦ Menometrorrhagia: heavy menstrual bleeding occurring at irregular intervals

Menstrual Disorders Extremely common gynecologic disorders ◦ DUB: responsible for 20% of gynecologic visits ◦ Amenorrhea prevalence - 14%  Primary vs. secondary ◦ Oligomenorrhea:prevalence -11% in adolescence Most common in early reproductive years and perimenopause ◦ Nearly 75% of gynecologic visits in perimenopausal and postmenopausal women are due to dysfunctional uterine bleeding

Causes of DUB Fibroids – benign tumors of the uterus Endometrial cancer – leading cause of bleeding in women after menopause Pelvic inflammation Endometriosis – due to excessive growth of tissue outside the uterus Thyroid disorders Clotting disorders (1 in 5 patients) – commonly von Willebrand’s disease Hormonal imbalance due to large weight change, intense exercise, stress, some medications

Goals of Treatment For all causes of dysfunctional uterine bleeding ◦ Restore cycling and fertility (if desired), decrease symptoms associated with abnormal bleeding, preserve BMD

Treatment of Amenorrhea Therapeutic options based on cause ◦ Anorexia – treat condition ◦ PCOS – clomiphene, metformin ◦ Hyperprolactinemia – dopamine agonists ◦ Other – progestin followed by ET/PT ◦ Calcium and vitamin D supplementation

Treatment of Menorrhagia Therapeutic options ◦ NSAIDs – dosed as for dysmenorrhea  Can achieve 20-50% reduction in bleeding ◦ OCs - > 35µg estrogen  Can achieve 40-50% reduction in bleeding ◦ LNG-IUS  > 90% reduction in bleeding after 12 months ◦ Progesterone – usually during luteal phase ◦ Other health needs?  Anemia, low Hgb and Hct

Treatment of Anovulatory Bleeding Therapeutic choice is usually oral contraceptive (< 35 mcg estrogen) ◦ Acts to stabilizes endometrium and provides progestin ◦ Suppresses ovarian hormones and adrenal androgens ◦ Increases SHBG that bind to androgens and reduces levels