Endometriosis –

Endometriosis –
Where Do We Go
Next?
Joseph R. Johnson, DO, FACOOG
Department Chair Ob/Gyn
Residency Director
Disclosures
• Clinic Trials – Phase 1b and Phase 3
• Safety, Tolerability, Immunogenicity and
Efficacy of NDV-3A Vaccine in Preventing
Recurrent Vulvovaginal Candidiasis
• A Clinical Study to Evaluate the Safety and
Efficacy of Elagolix in Subjects With Moderate
to Severe Endometriosis-Associated Pain
• No financial interest represents a conflict for
the content of this presentation
Learning Objectives
• Understand the pathophysiologic basis for
endometriosis
• Understand medical and surgical treatments
for endometriosis
• Ascertain randomized control trails for
symptom management
• Develop a plan for treatment protocols and
referrals
Endometriosis
• Gynecologic condition affecting 10% of
reproductive women: of those affected
• Pain association – 60%
• Infertility – 50%
• Dyspareunia – 36%
• Dysmenorrhea – 30%
Holoch KJ, Lessey BA, Endometriosis and Infertility. Clin Ob Gyn.
2010;53:429-438
Theories of the Pathologic
Process
• Retrograde menstrual flow – leading to
transplantation
• Coelomic metaplasia
• Immunomodulation
• Genetic predisposition – 7p15.2
• Congenital aberrations
• Triggers caused by the environment
Painter JL, etal Genome-wide association study identifies a locus associated with
endometriosis. Nat Genet. 2011;43:51-54
Anger DI, etal. The link between environmental toxicant exposure and
endometriosis. Front Biosc. 2008;13:1578-1593
Retrograde Flow
• Sampson’s theory -retrograde
menstruation
• Albany Medical College, NewYork
• “Process produced by the escape of
menstrual debris including
endometrial tissue that escapes
retrograde through the fallopian tubes
into the pelvis. This then leads to
secondary reactions of inflammation,
repair, and scar formation.
Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of
endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 14:422, 1927
Estrogen Dependent Lesion
• Rarely seen prior to thelarche – Tanner stage 2
breast bud development
• Increased in prolonged estradiol exposure
• Early menarche
• Nulliparous
• Late menopause
The Bizarre
• A woman with a history of pelvic endometriosis
and Behcet's syndrome was diagnosed with
nasal endometriosis after episodes of
perimenstrual epistaxis and nasal pain. J
Minim Invasive Gynecol. 2012 JulAug;19(4):514-6
• A case of a 32-year-old women, synovial
sarcoma was suspected on the basis of the
histologic findings on frozen section, but final
pathologic sections showed endometriosis. Clin
Orthop Relat Res. 1982 Nov-Dec;(171):140-4
Endometriosis and Progesterone
Resistance
• Stimulation by estradiol E2 - mitogen for the
growth and inflammation
• Normal endometrium, progesterone acts on
stromal cells to induce secretion of paracrine
factor
• Progestin's used as counter-interaction
• Endometrosis lesions found to be progestin
resistant – decrease in 17β-hydroxysteriod
dehydrogenase type 2
Serdar E Bulun, etal. Progesterone resistance in endometriosis: Link to failure to
metabolize estradiol. Molecular and Cellular Endocrinology. 3-2006;248:94-103
Progesterone Resistance
Evidence For Inflammation
• Elevation of similar factors
• CRP, TNF-α, MCP-1, IL-6, IL-8 in the peripheral
blood of patients with endometriosis
• CD44+ and CD14+ monocytes are significantly
increased
• CD3+ T lymphocytes and CD20+ B lymphocytes
show significant decrease in peripheral blood of
women with endometriosis
• Factors in peripheral blood - potential use as
diagnostic tools in patients with endometriosis.
Agic A, Xu H, et.al. Is Endometriosis Associated with Systemic Subclinical
Inflammation?
Endometriosis Cascade
Increased Estrogen Millu
Tariverdian Nadja et al. Neuroendocrine–immune disequilibrium and endometriosis:
an interdisciplinary approach. Semin Immunopathol (2007) 29:193–210
Endometrial Implants
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Ovary
Anterior and posterior cul-de-sac
Posterior broad ligament
Uterosacral ligament
Uterus
Fallopian tube
Sigmoid colon
Appendix
Round ligament
Pertinent History
• Secondary dysmenorrhea
• Dyspareunia, especially with deep penetration
• “Delayed” first pregnancy in association with
regular, ovulatory menses
• Dysmenorrhea unresponsive to medical
therapy
Physical findings
• Unusual tenderness and thickness (a doughlike consistency) in the adnexal areas
• Tender nodules along the uterosacral ligament,
usually appreciated best on combined rectovaginal bimanual exam
• Tender nodules at the junction of the bladder
and the uterus
• Tender nodules over the uterine corpus
Physical Findings
• Nodular uterosacral ligaments
• Cul-de-sac tenderness
• A fixed adnexal mass
Endometriosis – What Your Patients Are
Hearing
Imaging Studies – Lab Studies
• Rarely helpful in diagnosis
• Ultrasound usefull in severe disease with
evidence of endometriomas
• Serum CA 125 – not sensitive
• 54% Of women with stage III and IV disease
have levels > 35 IU/ml
Chang YM, et. Al., Serume CA-125 in preoperative patients at high risk
for endometriosis. Ob Gyn 2002;99:375
Barbieri RL, et. al., Elevated serum concentration of CA-125 in
patients with advanced endometriosis. Fertil Steril 1986;45:630
Endometrioma
• Ovaries : ~ 75%
• Anterior / posterior cul-de-sac : ~ 70 %
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Posterior broad ligament : ~ 50%
Uterosacral ligaments : ~ 35%
Uterus : ~ 10 %
Colon : ~ 5%
Natural Course of Endometriosis
• Second look laparoscopy – performed 6-12
months – 29-45% have progressive disease
• Progressive disease found in 29-45%
• Staple disease found in 33-42%
• Regressive disease found in 22-29%
• Pregnancy improves disease – felt d/t
decidualization – but may worsen during the
1st trimester
Brosen IA, et.al., Endometrosis is a risk for spontaneous hemoperitoneum during
pregnancy. Fertil Steril 2009;92:1243
Abbott J, et.al., Laparoscopic excision of endometriosis: a randomized, placebocontrolled trial. Fertil Steril 2004:82:878
Economic Burden
• Annual US burden:
• Headaches - $15 billion
• Crohn’s disease - $865 million
• Endometriosis - $22 billion
Classification
• Introducted by Americian Society for Reproductive
Medicine in 1979 – revised 1996
• Minimal disease – isolated implants – no significant
adhesions
• Mild disease – implants < 5 cm aggregate – no
significant adhesions
• Moderate disease – multiple implants – superficial
and invasive – tubal or ovary adhesions
• Severe disease – implants superficial and deep –
endometriomas – filmy and dense adhesions
Endometriosis Staging
Treatments for Endometriosis
• Surgical – first line
• Medical
• Surgical followed by medical management
Surgical Appearance of
Endometriosis
• Lets take a look at some of the appearances of
endometriosis
Laparoscopic Surgery for Pain
• Five studies including a meta-analysis
• Looked at diagnostic vrs surgical laparoscopy
for endometriosis related pain
• Surgical excision improved outcomes and pain
suppression
• OR 5.72-7.72, CI 2.97-20.06
Jacobson Tai, et.al., Laparoscopic surgery for pelvic pain associated with
endometriosis. Cochrane Menstrual Disorders and Subfertility Group, 7 Oct 2009
Incidental Diagnostic
Laparoscopy
• 6% to 43% of women undergoing sterilization
• 12% to 32% of women undergoing laparoscopy
for pelvic pain
• 21% to 48% of women undergoing laparoscopy
for infertility
• 50% of teenagers undergoing laparoscopy for
chronic pelvic pain or dysmenorrhea
Pathogenesis Treatment
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NSAID’s
OCP
Progestin's
Danazol
GnRH-a
Levonorgestrel intrauterine device
Tubal ligation
Hysterectomy
Hormone Replacement
• Two clinical trials looking at hormone
replacement
• Non-stop transdermal, 17 B-Estradiol 0.5
mg/day and medroxyprogesterone acetate 10
mg/day x 12days/mo
• Sequential, Estradiol patch 0.05 mg/day for 14
days and micronized progesterone 200mg/day
for 14 days
• Results in pain and disease reoccurrence
Kadri Hana, et.al. Hormone therapy for endometriosis and surgical menopause.
Cochrane Menstrual Disorders and Subfertility Group. 21 Jan 2009
Ovulation Suppression Agents
• 25 Trials, N=3043
• Looked at OCP, Danazol and GnRHa for
endometriosis patients and sub fertility
• Odds ratio 1.38, CI 0.24-2.05
• No improvement for infertility
Hughes, Edward, et.al. Ovulation suppression for endometriosis for
women and subfertility, Cochrane Menstrual Disorders and Subfertility
Group, 20 Jan 2010
Danazol
• 5 Trials looking at Danazol for pain control
• Findings – improvement of laparoscopy scores
• Improvement of pain scores
• Limitation to long term use secondary to
androgen effects
• Greater weight gain and ance
• Limits use to 6-9 months
Ferquhar, Cindy, et.al. Danazol for pelvic pain associated with
endometriosis. Cochrane Menstrual Disorders and Subfertility Group, 20
Jan 2010
Gonadotropin-Releasing
Hormone Analogues
• 42 Studies, N=4742
• Slight GnRH-a drug over Danazol for
laparoscopic improvement
• No significant differences in patient
perception
• Greater vaginal dryness and hot flashes with
GnRH-a
Brown, Julie, et.al., GnRH analogues for pain associated with
endometriosis. Cochrane Menstrual Disorders and Subfertility Group, 8
Dec 2010
Medication Dosing
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NSAID’s – anti-inflammatory drug of choice
BCP – choose by body habitus
Danocrine – Danazol 100-400 mg PO bid
Depo-Lupron – Leuprolide 3.75 IM q month, 11.25 IM q 3
months
Zoladex – Goserelin 3.6 mg SQ q 28 days
Synarel – Nafarelin 200 mcg/spray – 1 each nostrile bid
Depo-provera , Provera – Medroxyprogesterone 150 mg
IM q 12 weeks
Prometrium – 17 OH-progesterone 100-300 mg PO q day
Types of Progestational Agents
• Most of these synthetic progestins are
chemical derivatives of testosterone: 19nortestosterone derivatives
• Estrane family - first generation progestins consist of norethindrone and ethynodiol
diacetate
• Gonane family - second generation progestins,
- consist of varying degrees of androgenic and
estrogenic activities - include levonorgestrel
and norgestrel
Types of Progestational Agents
• Newer gonane family - third generation
progestins - have the least androgenic effects
- include desogestrel and norgestimate
• Drospirenone – 4th generation progestin, is
also the newest (4th) generation.
Drospirenone differs and is derived from 17aspirolactone - not from the 19-nortestosterone
derivatives
• Third and fourth generation progestins - highly
selective and minimal androgenic properties
Progestin Examples
• First generations
• Norethidrone – Ortho 777
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Norethindrone acetate – Estrostep
Ethynodiol diacetate – Zovia
Second generations – high androgenic activity
Levonorgestrel – Seasonique, Triphasil
Norgestrel – Lo/Ovral
Progestin Examples
• Third generations
• Desogestrel – Ortho-Cept – decreased weight
gain and androgen effects – higher non-fatal
leg clots – Cyclessa has decrease estrogen
• Norgestimate – Sprintec, Tri-Cyclen – minimal
effect on lipoproteins and carbohydrate
metabolism
• Fourth generation – Beyaz – lessens PMS
symptoms – watch it elevates K levels
Male Endometriosis
• Several case reports noted in PubMed search
• All associated in individuals needing estrogen
treatment – most prostate cancer
• Artin JD, et.al., Endometriosis in the male. Am
Surg. 1985 Jul;51(7):426-30
Endometriosis – Dr. Oz
Patient News
Endometriosis Studies
• 177 Clinical Trials in various stages
• Recruitment
• Completed
• Withdrawn
Questions