The Pharmacologic Management of Endometriosis

Abstract and Introduction

Abstract

Endometriosis is an estrogenmediated growth of endometrial tissue outside the uterus. Patients with this gynecologic condition, for which there is no cure, experience debilitating pelvic pain during menstruation and have a greater chance of infertility. Endometriosis affects about 10% of women of childbearing age. Management of endometriosis involves the use of nonsteroidal anti-inflammatory drugs and hormonal therapies, which have been observed to reduce endometrial proliferation. Following an evaluation of patient-specific toxicities, oral contraceptives, progestins, danazol, or gonadotropin-releasing hormone agonists are used to suppress estrogen levels. Surgery is considered if a pelvic mass is detected or if the patient is planning a pregnancy.

Introduction

Endometriosis, which is the estrogen-dependent growth of endometrial tissue outside the uterus, causes inflammation, pelvic pain, dysmenorrhea, painful intercourse, and infertility in approximately 10% of females of reproductive age.^[1] As of 2010, an estimated 176 million women of childbearing age worldwide were affected.^[2] Although it is considered a benign disorder, endometriosis can affect the patient's quality of life. In addition to causing debilitating pain, endometriosis results in worse clinical outcomes in women undergoing assisted reproductive technology, adding to the negative social and psychological impact of this chronic gynecologic condition.^[3] Endometriosis occurs rarely in postmenopausal women.^[4]

Table 1. Drug Therapy for the Management of Endometriosis
Drug Category	Drugs	Mechanism of Action in Endometriosis	Dosing	Toxicity
NSAIDs	Ibuprofen, naproxen	Reversibly inhibits COX-1 and COX-2, resulting in decreased prostaglandin formation	May be prescribed at maximal doses. Ibuprofen: 400 mg po q4-6h prn. Naproxen: 500 mg po q12h prn	Epigastric pain/bleeding, edema, cross sensitivity with aspirin containing products, renal impairment
Combined estrogen-progestin contraceptives	Ethinyl estradiol combined with norethindrone, norgestrel, levonorgestrel, or desogestrel	Inhibits FSH and LH. Decreases cell proliferation and enhances endometrial apoptosis	Prescribed in monthly cycles for up to 3 mo or more	Thromboembolism, MI (age-dependent; highest in female smokers), increased risk of estrogen-dependent cancers
Progestin-only preparations	Norethindrone, medroxy-progesterone, levonorgestrel	Inhibits FSH and LH and stimulates atrophy or regression of endometrial lesions. Appropriate for patients with reported estrogen contraindications or those who are breastfeeding	Medroxyprogesterone acetate: initially 10 mg/day po; may in-crease up to 50 mg/day, depending on tolerance. Norethindrone acetate: initially 2.5 mg/day po; may increase to 30 mg/day	Weight gain, acne, breast tenderness, increase in LDL levels
Androgen	Danazol	Antiestrogen; inhibits enzymes involved in steroid formation. Decreases the release of gonadotropin	Mild disease: initially 200–400 mg/day in 2 divided doses; continue for 3–9 mo. Moderate-to-severe disease: initially 800 mg/day in doses; continue for 3–9 mo	Teratogenic; hepatic injury, pseudotumor cerebri (rare; black box warning)
GnRH agonists	Leuprolide, goserelin	Chronic administration inhibits steroidogenesis due to reduced LH and FSH levels. The initial hormone flare is characteristic of GnRH agonists	Leuprolide: 3.75 mg IM q4w or 11.25 mg IM q12w. Goserelin: 3.6 mg SC every 28 days for 6 mo. Add-back therapy: norethindrone 5 mg/day	Hot flashes, vaginal atrophy, bone loss
Aromatase inhibitors	Letrozole, anastrozole	Blocks conversion of androgens to estrogen, which decreases endometrial proliferation	Letrozole: 2.5 mg/day. Anastrozole: 1 mg/day	Hot flashes, bone loss

Table 1. Drug Therapy for the Management of Endometriosis

Drug Category

Drugs

Mechanism of Action in Endometriosis

Dosing

Toxicity

NSAIDs

Ibuprofen, naproxen

Reversibly inhibits COX-1 and COX-2, resulting in decreased prostaglandin formation

May be prescribed at maximal doses. Ibuprofen: 400 mg po q4-6h prn. Naproxen: 500 mg po q12h prn

Epigastric pain/bleeding, edema, cross sensitivity with aspirin containing products, renal impairment

Combined estrogen-progestin contraceptives

Ethinyl estradiol combined with norethindrone, norgestrel, levonorgestrel, or desogestrel

Inhibits FSH and LH. Decreases cell proliferation and enhances endometrial apoptosis

Prescribed in monthly cycles for up to 3 mo or more

Thromboembolism, MI (age-dependent; highest in female smokers), increased risk of estrogen-dependent cancers

Progestin-only preparations

Norethindrone, medroxy-progesterone, levonorgestrel

Inhibits FSH and LH and stimulates atrophy or regression of endometrial lesions. Appropriate for patients with reported estrogen contraindications or those who are breastfeeding

Medroxyprogesterone acetate: initially 10 mg/day po; may in-crease up to 50 mg/day, depending on tolerance. Norethindrone acetate: initially 2.5 mg/day po; may increase to 30 mg/day

Weight gain, acne, breast tenderness, increase in LDL levels

Androgen

Danazol

Antiestrogen; inhibits enzymes involved in steroid formation. Decreases the release of gonadotropin

Mild disease: initially 200–400 mg/day in 2 divided doses; continue for 3–9 mo. Moderate-to-severe disease: initially 800 mg/day in doses; continue for 3–9 mo

Teratogenic; hepatic injury, pseudotumor cerebri (rare; black box warning)

GnRH agonists

Leuprolide, goserelin

Chronic administration inhibits steroidogenesis due to reduced LH and FSH levels. The initial hormone flare is characteristic of GnRH agonists

Leuprolide: 3.75 mg IM q4w or 11.25 mg IM q12w. Goserelin: 3.6 mg SC every 28 days for 6 mo. Add-back therapy: norethindrone 5 mg/day

Hot flashes, vaginal atrophy, bone loss

Aromatase inhibitors

Letrozole, anastrozole

Blocks conversion of androgens to estrogen, which decreases endometrial proliferation

Letrozole: 2.5 mg/day. Anastrozole: 1 mg/day

Hot flashes, bone loss