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Cihat ÜNLÜ, M.D.Acibadem Hospital Bakırköy-Istanbul-Turkey
HRT Post Hysterectomy for Endometriosis and Supracervical Hysterectomy: What
Should We Know?
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DISCLOSURE
“No financial relationships to disclose.”
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Objective
– Assess the recurrence risk of endometriosis afterHRT
– Arrange the timing of HRT after surgery– Adjust the risk of malignant transformation after
HRT– Choose treatment options in menopausal
women with endometriosis– Assess HRT for supracervical hysterectomy
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HRT
• HRT remains the most efficient treatment to alleviate climacteric symptoms.
• Benefits might be more important than harm in 50-60 year- old women .
• Younger women with surgical menopause or premature ovarian failure may use HRT for many years, until the age that natural menopause would be expected to occur.
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Extend of Endometriosis
• In 25% of women undergoing hysterectomy
• 6% of women undergoing routine tubalsterilization
• 2.2% of postmenopausal women haveendometriosis and adenomyosis
Punnonen et al, Eur J Obstet Gynecol Reprod Biol, 1980; Mahmood et al Hum Reprod 1991
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Concomitant Cancer, Infection andEndocrine Disease Among Endometriosis Patients
Gemmill JA et al, Fertil Steril 2010
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From the Ovarian Cancer Association Consortium Lancet Oncology 2012
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There is a morphological andbiological difference
Normal endometrium
Progesteron, estrogen
content differs
Ectopicendometrium
Proliferativeactivity↑
Menopause causes:atrophy in normal endometriumwhereas ectopic endometirum can persist,
even advance.
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Menopause in Endometriosis
• May be part of the treatment
– Medically induced by GnRHa
– Surgically induced after hysterectomy &
bilateral oophorectomy
• May be a complication of ovarian surgery
• May occur naturally
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Definitive SurgeryWhen all else fails, and childbearing no longer desired
• Traditionally TH-BSO
• Now often performed laparoscopically
• The relative importance of bilateral oophorectomy vs. hysterectomy has been debated
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TH Alone vs. TH-BSOEndometriosis-Associated Pain
Hysterectomy(n=29)
TH-BSO(n=109)
Recurrent Pain 62 % 10 %Re-operation 31 % 4 %
Relative Risk for Pain Recurrence
6.1(95% CI 2.5-14.6)
1
Relative Risk for Re-operation
8.1(95% CI 2.1 31.3)
1
Namnoum, Fertil Steril 1995
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Surgical Menopause
• Patients are relatively young• Start HRT after Surgery to prevent
– Urogenital atrophy– Loss of libido– Bone loss– Prevention of cardiovascular disease in early
menopause
Palep-Singh et al, Menopause Int, 2009
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HRT Surgicalmenopause
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Recurrence during HRT
• The risk of endometriosis recurrence during HRT is not completely defined.
• Theoretically, oestrogen therapy can re-activate the disease, even where there has been apparent surgical removal of all the endometriotic tissue, but the risk appears to be small.
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Estrogen threshold theory
• Various tissues differ in their sensitivity to estrogen.
• Calcium metabolism is the most sensitive.
• A dose of estrogen sufficient to provide bone protection would not necessarily be highenough to reactivate endometriosis.
Barbieri RL, 1998
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‘E’ or ‘E+P’
• E+P HRT: oral combined, Estrogen TTS+cyclic MPA– 0-2.4% recurrence of endometriosis– 0-4% recurrence of pain
• Estrogen only: oral or Estrogen TTS– 2% recurrence of endometriosis– 6% recurrence of symptoms
Moen et al, Maturitas, 2010; Rattanachaiyanont et al, J Med Assoc Thai, 2003; Matorras et al, Fertil Steril 2002; Fedele L, Maturitas, 1999
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• There were only two randomized controlledstudies that addressed the controversial issue of the use of HRT for women with endometriosis and postsurgical menopause:– Fedele 1999 – Matorras 2002
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• From two non-blinded randomizedcontrolled trials;
Hormone replacement therapy for women with endometriosis and post-surgicalmenopause may lead to pain and disease recurrence.
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Higher Recurrence Risk after HRT
• Presence of deep infiltrating endometriosis
• Residual disease on intestine, bladder
• Peritoneal involvement >3cm
• Incomplete surgery for endometriosis (6%)
– Residual disease despite TH+BSO
Moen et al, Maturitas, 2010; Palep-Singh, Menopause Int, 2009
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Timing of HRT after surgery
Pain recurrence– 7% in early HRT group (within 6 weeks of
surgery)– 20% in late HRT group (after 6 weeks of surgery)
We could recommend commencing HRT shortly after surgery
Hickman et al, Obstet Gynecol, 1998
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Risk of malignant transformation
• Oestrogen only therapy has been associated with an increased risk of malignant transformation of ectopic foci (Oxholm, 2007).
• Extragonadal adenocarcinoma may develop after BSO even at sites far from the pelvis (Brunson, 1988)
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Tumors arising in endometriosis
Most commonly endometrioid adenoCa
Confined to the site of origin
Predominantly low grade
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TreatmentStrategies
Avoidance of estrogen-only
tx
In severe & residual disease
In obesity
Use of continuous
combined tx
Risk of breast CAProgesteroneintolerance
Use thelowest dose
Use of tibolone
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Rationale for the use of tibolone in menopausal women with residual endometriosis
• at the ectopicendometrial level
A tissue-specificprogestogenic
effect
• on climatericsymptoms and boneAn estrogenic
effect
Markiewicz, 1990
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Alternative SymptomaticMenopause Treatments
• Clonidine• Serotonin re-uptake inhibitors (SSRI)• Serotonin and nor-adrenalin reuptake
inhibitors (SNRI)• Gabapentin• Lubricants• Moisturizers
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No difference in UrinaryBowel
Sexual function
Length of operation(11 min) ↓
Amount of blood loss(57 ml) ↓in subtotal
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Sub-total hysterectomy
• There may be concern that there is a remnant of endometrium in the cervical stump.
• If this is the case, the presence or absence of bleeding induced by monthly sequential HRT may be a useful empirical diagnostic test.
Evidence is lacking to guide HRT prescription following SH and BSO
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HRT and Cervical Cancer
• Squamous cell Ca is not estrogen dependent
• HRT have no effect on HPV carriage or replication
• Prolonged use of OC increases the risk of adenoCa of the
cervix
• Unopposed estrogen increases the risk of cervical adenoCa
(OR:2.7)
• Estrogen metabolite 16α hydroxyestrone acts as a co factor
together with oncogenic HPVSingh P, Maturitas, 2010; Smith JS, Lancet, 2003
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Conclusion
• Estrogen based HRT is essential for womenwith premature menopause until avarageage of natural menopause
• E+P and tibolone therapies may be safer forhyterectomized and nonhysterectomizedwomen
• Risk of recurrence and malignanttransformation may be reduced with E+P ortibolone
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• Matorras R, Elorriaga MA, Pijoan JI, Ramón O, Rodríguez-Escudero FJ. Recurrence of endometriosis inwomen with bilateral adnexectomy (with or without total hysterectomy) who received hormonereplacement therapy. Fertil Steril. 2002 Feb;77(2):303-8.