Microsoft powerpoint - schlaff - cme presentation

NEW MEDICAL THERAPIES
FOR ENDOMETRIOSIS
William D. Schlaff, M.D.
Professor and Vice-Chairman
Department of Ob-Gyn
University of Colorado
Health Sciences Center
Denver, CO
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Dr. Schlaff discloses the following
relationships within the past 2 years:
Consultant: Pfizer, Solvay
Sponsored research: Organon, Wyeth,
MEDICAL TREATMENT OF
ENDOMETRIOSIS
PSEUDO-PREGNANCY
(OVULATION SUPPRESSION)
–OCP’s
–Progestins
–Danazol
–GnRH analogs
MEDICAL TREATMENT OF
ENDOMETRIOSIS
Approach to treatment has
traditionally been indirect, i.e.
suppression of ovulation.
Is the future of treatment
evolving?
ENDOMETRIOSIS IS DIFFERENT
FROM ENDOMETRIUM
• Lesions differ histologically from
endometrium obtained from the
same patient at the same time
• Lesions obtained at the same time
commonly differ histologically
from each other
ENDOMETRIOSIS IS DIFFERENT
FROM ENDOMETRIUM
Endometrium was obtained at various
stages of the menstrual cycle from
nonmenopausal fertile controls and
compared to peritoneal endometriotic
lesions from women undergoing
laparoscopy for pain (n=10) or infertility
(n=20)
Beliard et al, 2004, Fertil Steril 82:80-5 (Liege, Belgium)
ENDOMETRIOSIS IS DIFFERENT
FROM ENDOMETRIUM
• Maximal proliferation of endometrium
is in the proliferative phase and
decreases throughout the secretory
phase. Proliferative activity in
endometriosis tissue was less than in
endometrium and constant throughout
the cycle.
• ER and PR in endometrium highest in
the proliferative phase.
Beliard et al, 2004. Fertil Steril 82:80-5 (Liege, Belgium)
ENDOMETRIOSIS IS DIFFERENT
FROM ENDOMETRIUM
• ER and PR did not vary during the
cycle in endometriotic lesions
• PR receptors were higher in endome-
triotic lesions than endometrium
• Endometriotic lesions demonstrated
less apoptosis which could promote
the dissemination and implantation of
these cells to ectopic sites
Beliard et al, 2004. Fertil Steril 82:80-5 (Liege, Belgium)
ESTROGEN RECEPTORS AND
ENDOMETRIOSIS
13 baboons underwent experimentally induced
endometriosis by peritoneal injection of
menstrual endometrium
• ER alpha and PR expressed in both
endometrium and endometriosis from 1 to 10
months after inoculation
• ER beta was also expressed at all stages, but
only in ectopic endometriotic lesions
• Aromatase expression was only evident in
lesions 10 months after inoculation
Fazleabas et al, Fertil Steril, 2003; 8820-8827
ANTI-ESTROGEN THERAPY
Anastrozole, an aromatase inhibitor,
decreases conversion of androgen to
estrogen in endometriotic cells
• 16 patients with endometriosis randomized
to receive either Anastrozole or Danazol for 3
months
• Both Anastrozole and Danazol reduced
levels of aromatase activity (equally)
• Luteal phase progesterone reduced with
Danazol but increased with Anastrozole
Moegini et al, Abstract 0-38, World Congress on Endometriosis, 9/05
SPRM’s IN ENDOMETRIOSIS
Ovarian endometrioma cyst tissue (n=22) and
endometrium (n=13) were obtained from
women undergoing endometriosis surgery
• ER and PR expression varied in ectopic vs.
eutopic endometrium; RU-486 down-
regulated ER and PR in both tissues
• “Different steroid receptor expressions
indicate different hormonal regulation
between endometriotic and endometrial
cells.”
Jiang et al. 2002 Fertil Steril. 77:995-1000 (China)
CLINICAL APPLICATION OF
ANGIOGENESIS INHIBITORS
• Vascular endothelial growth factor
(VEGF-A) is the most abundantly
expressed angiogenic factor in human
endometrium.
• Anti (human) VEGF-A antibody
(Avastin, Genentech, San Francisco,
CA) has been shown in concept to be
effective in treatment of human cancer
McCarthy, Lancet, 2003. 361:959
Ferrara, Semin Oncol, 2002. 29 (Suppl16);10-14
ANGIOGENESIS INHIBITORS AND
ENDOMETRIOSIS
• Proliferative endometrium obtained from
laparoscopy performed in 6 women with
normal ovulatory cycles and transplanted
into a nude mouse model
• Angiostatic compounds (anti-human VEGF,
TNP-470, endostatin, and anginex) inhibited
angiogenesis and reduced growth and
proliferation of established endometriosis
• Overall health of the mice unaffected
Nap, et al, JCEM 2004;1089-1095 (Maastricht, Netherlands)
ANGIOGENESIS INHIBITORS TO
PREVENT ENDOMETRIOSIS
• Anti-angiogenic factors (anti-human
VEGF-A) dramatically reduced the
effectiveness of inoculating cultured
endometrium into the nude mouse
model.
• Could this be a potential approach to
reducing recurrence in surgically
treated women or reducing the risk of
devloping endometriosis in women at
risk?
Hull et al, JCEM, 2003. 88:2889-99
FUTURE DIRECTIONS IN
DIAGNOSIS
• PCR analysis for estrogen beta and
progesterone receptors showed an
increase in menstrual blood samples of
women with endometriosis compared
to controls.
• No difference in peripheral blood levels
Kissler et al, abstract PA.3, Ninth World Congress on Endometriosis 9/05
FUTURE DIRECTIONS IN
DIAGNOSIS
PCR performed on whole blood obtained
from 132 Japanese women with
surgically confirmed endometriosis and
compared to umbilical cord blood from
Japanese female infants
Polymorphisms in the estrogen receptor
beta gene but not the alpha gene are
associated with an increased risk of
developing endometriosis
Wang, et al. Fertil Steril, 2004 81:1650-6
PROGESTIN TREATMENT
Mechanisms of Action
INDIRECT EFFECTS
Suppression of ovulation
Decidualization and atrophy
DIRECT EFFECTS
Inhibition of angiogenesis
Inhibition of matrix metalloproteinases
Suppression of intraperitoneal inflammation
--reduction of intraperitoneal macrophages
--increase in natural killer cells
MIRENA INTRAUTERINE DEVICE
• Delivers levonorgestrel directly into the
uterine cavity at a steady rate of 20
ug/day over a 5 year period
• Systemic levels of levonorgestrel are
lower than achieved with oral
administration
• Use of this device has been shown to
be effective in reducing menstrual flow
in many women
TREATMENT OF ENDOMETRIOSIS
WITH MIRENA IUD
34 women with endometriosis confirmed
by laparoscopy (stage 1=13, 2=15, 3=6).
Mirena inserted at the time of surgery;
endometriosis was not treated.
• Continuation rate=85% at 6 mos; 68% at
12 mos; 62% at 24 mos; 56% at 36 mos
• 8/15 removed for persistent pain;
remainder removed for acne, weight
gain, bleeding, personal reasons
Lockhat et al. 2005, Hum Reprod. 20:789-93 (Leicester,
TREATMENT OF ENDOMETRIOSIS
WITH MIRENA IUD
Lockhat et al, 2005 Hum Reprod 20:789-93, (Leicester, UK)
VAS=Visual analog scale. VRS=Verbal rating score
MIRENA IUD AND ANGIOGENESIS
• Vascular endothelial growth factor
(VEGF) is a potent angiogenic factor
• Mirena IUD significantly reduced VEGF
expression in endometrial glands and
stroma when sampled 3 months after
insertion (Laoag-Fernandez et al. 2003,
Hum Reprod 18:694-9)
• Levonorgestrel levels in peritoneal fluid
are similar to serum levels (Lockhat et
al. 2005, Fertil Steril 83:398-404)
THE FUTURE MEDICAL OF
MEDICAL THERAPY FOR
ENDOMETRIOSIS?
DIRECT ACTION, INDIRECT ACTION,
CONCLUSIONS
• Intensive, collaborative investigation is
succeeding in better characterizing the
differing biochemical, hormonal, and
genetic characteristics of women with
endometriosis as well as endometriotic
implants.
• Better understanding of these
relationships coupled with developing
pharmacologic options will allow more
focused treatment of endometriosis
CONCLUSIONS
• While encouraging data have been
published, as of yet these factors have
not been clearly characterized
• Recent clinical studies from all over the
world provide new and valuable
insights, but I do not think we are to
the point where these new therapeutic
approaches are beyond the pilot stage
of development.

Source: http://www.endometriosisassn.org/pdfs/Schlaff_CME.pdf