Optimize the medical treatment of endometriosis--Use all available medications.
CASE Endometriosis pain increases despite hormonal treatment
A 25-year-old woman (GO) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient's pain. The patient sought a second opinion.
We are the experts in the management of pelvic pain caused by endometriosis
Women's health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestin contraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect. (1,2) I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (table, page 10).
Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:
* oral norethindrone acetate 5 mg daily
* oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
* subcutaneous, or depot MPA
* levonorgestrel-releasing intrauterine device (LNG-IUD).
In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively. (3) The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).
Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy. (4-7)
Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis. (4,8) In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.
The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants. (9-11)
GnRH analogue medications
Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin (12) or leuprolide acetate depot plus norethindrone add-back. (13) I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.
At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a "sweet spot" associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants. (12,14) In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression. (15) Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate. (13) A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol. (16)
The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms. (17,18) Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.
Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effective in treating pelvic pain caused by endometriosis. (19,20) However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman's voice pitch and should not be used by professional singers or speech therapists.
Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice. (21)
Don't get stuck in a rut
When treating pelvic pain caused by endometriosis, if the patient's hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every avail able hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women's health specialists, to effectively treat their disease.
High-dose progestin-only medications suppress pituitary secretion of LH and FSH thereby suppressing ovarian synthesis of estrogen
GnRH analogues reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH
Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions
Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies
Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women's Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston
Dr. Barbieri reports no financial relationships relevant to this article.
(1.) Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623-632.
(2.) Bulun SE, Cheng YH, Pavone ME, et al. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(l):36-43.
(3.) Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani PG. Treatment of symptomatic rectovaginal endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate. Fertil Steril. 2005;84(5):1375-1387.
(4.) Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database of Syst Rev. 2012;(3):CD002122.
(5.) Moghissi KS, Boyce CR. Management of endometriosis with oral medroxyprogesterone acetate. Obstet Gynecol. 1976;47(3):265-267.
(6.) Telimaa S, Puolakka J, Ronnberg L, Kauppila A. Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol. 1987;l(l):13-23.
(7.) Luciano AA, Turksoy RN, Carleo J. Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol. 1988;72(3 pt l):323-327.
(8.) Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertil Steril. 2006;85(2):314-325.
(9.) Abou-Setta AM, Houston B, Al-Inany HG, Farquhar C. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database of Syst Rev. 2013;(1):CD005072.
(10.) Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-pain: a randomized controlled trial. Obstet Gynecol. 2012;119(3):519-526.
(11.) Wong AY, Tang LC, Chin RK. Levonorgestrel-releasing intrauterine system (Mirena) and Depot medroxyprogesterone acetate (Depoprovera) as long-term maintenance therapy for patients with moderate and severe endometriosis: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2010;50(3):273-279.
(12.) Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobsen J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med. 1988;318(8):485489.
(13.) Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal addback in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998; 91(l):16-24.
(14.) Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166(2):740-745.
(15.) Hull ME, Barbieri RL. Nafarelin in the treatment of endometriosis. Dose management. Gynecol Obstet Invest. 1994;37(4):263-264.
(16.) Barbieri RL, Petro Z, Canick JA, Ryan KJ. Aromatization of norethindrone to ethinyl estradiol by human placental microsomes. J Clin Endocrinol Metab. 1983;57(2):299-303.
(17.) Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377(l):28-40.
(18.) Surrey E, Taylor HS, Giudice L, et al. Long-term outcomes of elagolix in women with endometriosis: results from two extension studies. Obstet Gynecol. 2018;132(1):147-160.
(19.) Selak V Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2007;(4):CD000068.
(20.) Barbieri RL, Ryan KJ. Danazol: endocrine pharmacology and therapeutic applications. Am J Obstet Gynecol. 1981;141(4):453-463.
(21.) Dunselman GA, Vermeulen N, Becker C, et al; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-412.
Watch for next month's guest editorial:
An oath to save lives against a backdrop of growing disparities Laurie Green, MD
TABLE Hormone medication options currently available to treat pelvic pain caused by endometriosis Medication (a) Route of Dose administration Progestins Norethindrone Oral 5 mg daily acetate# Medroxyprogesterone Oral 20 to 40 mg daily acetate Depot- Intramuscular 150 mg every 3 months medroxyprogesterone acetate Depot- Subcutaneous 104 mg every 3 months medroxyprogesterone acetate# Levonorgestrel (LNG) Intrauterine 52-mg device releasing intrauterine device device about 20 [micro]g of LNG daily GnRH analogues Nafarelin acetate# Intranasal One spray twice daily Depot-leuprolide Intramuscular 3.75 mg monthly acetate# Goserelin# Subcutaneous 3.6 mg monthly implant Elagolix# Oral 150 mg daily or 200 mg twice daily Androgen Danazol# Oral 200 mg twice daily Medication (a) Relative cost (b) Progestins Norethindrone $ acetate# Medroxyprogesterone $ acetate Depot- $ medroxyprogesterone acetate Depot- $$ medroxyprogesterone acetate# Levonorgestrel (LNG) Cost depends on number intrauterine device of months of use GnRH analogues Nafarelin acetate# $$$$$ Depot-leuprolide $$$$$ acetate# Goserelin# $$$$ Elagolix# $$$$ Androgen Danazol# $$$ (a) Italicized medications are US Food and Drug Administration approved to treat endometriosis. (b) Relative cost: $ = < $50 per month; $$ = $50 to $150 per month; $$$ = > $150 and < $250 per month; $$$$ = [greater than or equal to] 250 and < 1,000 per month; $$$$$ = > $1,000 per month. Note: (a) # medications are US Food and Drug Administration approved to treat endometriosis.
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|Author:||Barbieri, Robert L.|
|Article Type:||Disease/Disorder overview|
|Date:||Aug 1, 2018|
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