Post on 07-Apr-2018
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.