Medical Management of Endometriosis in Patients with Pain and/or Infertility

Anthony A. Luciano, M.D.Professor Obstetrics and Gynecology

University of Connecticut School of MedicineDirector Center for Fertility

Disclosure

• Dr.Luciano serves as advisory board member, speaker or principal investigator of clinical research for the following pharmaceutical companies:

• Baxter, Covidien, AbbVie, Bayer, Boehringer Ingelheim, Intuitive

• Neither Dr. Luciano nor any member of his family own stocks or have direct financial interest in any pharmaceutical companies

• Dr. Luciano will not discuss the use of any off-labeled products

• This CME activity has no commercial support

Endometriosis: Management Dilemma

Pain

Deep endometriosisRecurrences and Sequelae

Ovarian cyst

Infertility

Asymptomatic

Infertility

Hormonal Treatment of Endometriosis is based on the fact that Estrogen stimulates the growth and function of endometriosis lesions.

Goals of hormonal therapy should:

Suppress estrogen production GnRH-a, GnRH-ant,, Arom. Inhib. SERMS

Oppose estrogen action Progestins (MPA, NETA) Androgens (Danazol, Gestrinone)

Medical Management of Endometriosis-Related Infertility

• Medical treatment does not improve fertility. • LuD,SongH,LiY,ClarkeJ,ShiG. Pentoxifylline for endometriosis.

Cochrane Database Syst. Rev. 1, CD007677 (2012).

• Women with endometriosis may benefit from:• O. C. for 6-8 weeks treatment prior to IVF

• de Ziegler D, Gayet V, Aubriot FX et al. Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes. Fertil. Steril. 94(7), 2796–2799 (2010).

• GnRH-a for 3-6 months before IVF• Surrey ES. Endometriosis and assisted reproductive

technologies: maximizing outcomes. Semin. Reprod. Med. 31(2), 154–163 (2013).

Nafarelin VS Danazol for EndometriosisHenzl MR, et al: N Engl J Med 1988;318:485-9

0

10

20

30

40

50

60

70

80

Danazol Nafarelin

Months on treatment

Placebo-Controlled Comparison of Danazol and MPA in the Treatment of Endometriosis

Telimaa S, et al.:Gynecol Endocrinol 1987;1:13-23

0

10

20

30

40

50

60

70

80

90

100

Endo. Score Pain

Baseline Placebo

MPA 100 mg/d Danazol 600 mg/d

Oral MPA in Endometriosis-Related PainLuciano AA, et al. Obstet Gynecol 1988;72:323

AFS-Classification

DMPA-SC Versus Leuprolide for the Treatment of Endometriosis-Associated Pain: Study Designs

• Two 18-month, randomized, evaluator-blinded, comparator-controlled Phase 3 studies– Study 1: United States and Canada– Study 2: Europe, Latin America, and Asia

Off medicationLeuprolide

11.25 mg IM every 3 months

DMPA-SC 104 mg/0.65 mL every 3 months

12 Months Follow-Up6 Months Treatment

% of Patients that Improved at the End of Therapy (6 M) and 12 Months after Therapy

0

10

20

30

40

50

60

70

80

90

100

Dysm Dysp Pain Tender Indur

Lupr 6 M

MPA 6 M

Lupr 12 M

MPA 12 M

% o

f Pat

ient

s Im

prov

ed fr

om P

re-T

reat

men

t

Crosignani PG, LucianoAA, RayA, Bergqvist A. Subcutaneous depot MPA versus Depolupron in the treatment of endometriosis-associated pain. Human Reproduction 2006;21 (1):248-256.

DMPA-SC: Less BMD Decline at Month 6 and 12 Months Follow-up (ITT), Study 1

-0.3

-1.1

0 0.2

-1.65

-3.95

-1.3-1.7

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

Med

ian

% C

hang

e in

BM

D

DMPA-SC Leuprolide

Femurn = 77/98P<.001*

Spinen = 77/98P<.001*

Femurn = 32/42P=.004*

Spinen = 31/42P=.021*

Month 6: End of Treatment 12 Months Off Treatment Follow-Up

*Statistically significantly greater decline observed in the leuprolide group vs DMPA-SC group.

Schlaff W, Carson SA, Luciano AA, Bergqvist A. Fertil Steril 2006Feb;85(2):314-25

Median Average Daily Number of Hot Flushes by Month (ITT)

0

0.5

1

1.5

2

2.5

3

3.5

PT 1 2 3 4 5 6

Month

DMPA-SC Leuprolide

Study 1* Study 2*

*Differences between groups significant from Month 1 through Month 6, P<.001.PT = pretreatment.

0

0.5

1

1.5

2

2.5

PT 1 2 3 4 5 6

Month

DMPA-SC Leuprolide

No.

of H

ot F

lush

es

Luciano AA 13

Medical Management of Endometriosis-Associated Pain

GnRH-a; Progestins; Danazol1. All medical therapies seem to be effective 2. No treatment is more effective than the others3. Preference of any one therapy should be based on

tolerability, degree of adverse effects (bone loss), and (when everything else is equal) cost.

Pelvic Pain and Suspected Endometriosis

NSAID or OC’s Success

Continue RXFailure

HST Failure

Surgery

Success

Continue Rx HST

HST = Hormonal Suppressive Therapy [GnRH-a, MPA, O.C.; Danazol; etc.]

Recurrence Rates of Endometriosis According to Phase of the Menstrual Cycle when Laparoscopy Was Done

Macroscopic 6 Months 12 Months• Follicular 3.2% 8.1% • Periovulatory 2.2% 6.6• Luteal 14.9% 20.9%Microscopic• Follicular 1.6% 8.1%• Periovulatory 1.1% 6.6%• Luteal 9% 14.9%

Schweppe KW, et al Fertil Steril 2002;78:763-6

Luciano AA 16

Pain Recurrence

37.5

51

31 33 30

0

10

20

30

40

50

60

Sutton 1994 Hornstein 1993 Redwine 1991Howard 1993 Sutton 1990

%Recurrence

Sutton CJ, et al. Fertil Steril. 1994;62:696-700. Redwine DB. Fertil Steril. 1991;56:628-634.Howard FM. Obstet Gynecol Surv. 1993;48:357-387. Sutton C, Hill D. Br J Obstet Gynecol. 1990;97:181-185.

Luciano AA 17

Endometriosis: Absence of recurrence in patients after endometrial ablation.

28 patients with symptomaic endometriosis underwent laparoscopic conservative surgery;

14 underwent endometrial ablation and 14 did not 2 years later all patients underwent second look laparoscopy Endometriosis recurrence was found in none of the ablation

and in 9 of 14 non-ablation patients. 13/14 ablation patients reported resolution or significant

improvement of symptoms; while only 3/14 non-ablation patients experienced significant improvement.

Bulletti C, et al Hum Reprod 2001;16:2676

Luciano AA 18

In one small RCT*, 40 symptomatic patients with stagesIII or IV disease were randomized to either LNG-IUS insertion or control after conservative laparoscopicsurgery. There was a significant (p = .012) reduction in pain recurrence in the LNG-IUS group compared to the control group (10% vs 45%). 75% vs 50& satisfied or very satisfied with treatment.

* Vercellini P, et al. Comparison of levonorgestrel-releasing intrauterine deviceversus expectant management after conservative surgery for symptomaticendometriosis: a pilot study. Fertil Steril 2003;80 305-309

Luciano AA 19

Progestin-IUD and Menorrhagia

Levonorgestrel-releasing intrauterine system (Mirena) releases 20 mcg/day of L-norgestrel directly to the endometrium inducing decidualization and atrophy of the endometrium

Serum levels of L-norgestrel reach 0.1-0.2 ng/mL (compared to 3-6 ng/ml when taking Alesse which has 100 mcg of L-norgestrel per pill)

Mirena reduces menstrual blood loss by 80% at 3 months and nearly 100% at 1 year, comparable to endometrial ablation^

Mirena has been reported to reduce the volume of fibroids and uterus, as well as MBL in women with menorrhagia. May be particularly useful in younger, symptomatic women who wish to delay childbearing**

*Milson I, et al. Am J Obstet and Gynecol 1991;164:879. ^Romer T., et al. Mirena vs roller-ball ablation. Europ J Obstet GynecolReprod Biol. 2000;90:27-29 **Grigorieva V, et al. Use of Mirena to treat menorrhagia due to uterine fibroids. Fertil Steril 2003;79:1194

Luciano AA 20

Postoperative oral contraceptive exposureand risk of endometrioma recurrence

0

0.2

0.4

0.6

0.8

1

1.2

0 6 12 18 24 30 36

NeverTempEver

Vercellini P, et al Am J Obstet Gynecol 2008;198:504.e1-504.e5.

Luciano AA 21

Long-Term Cyclic and Continuous Oral Cotraceptive Therapy and Endometrioma Recurrence: A randomized controlled trial

0%

5%

10%

15%

20%

25%

30%

Control Cyclic Continuous

After laparoscopic excision of endometriomas, 239 women were randomized to no therapy or to cyclic or continuous oral contraceptives for 24 months and followed semiannually. Serracchioli R et al. Fertil Steril 2010;93:52-56

Rec

urre

nce

Luciano AA 22

IN CONCLUSION

• Although we cannot yet prevent endometriosis, we have the tools that allow us to minimize the risk of recurrence and prolong the disease-free interval in the majority of women afflicted by the disease.