MHT for Endometriosis Symptoms

Endometriosis – MHT
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tyoldemir
profdrdryoldemir

I have no financial relationships to disclose.
I have no conflict of interest.

Age pattern in 42,079 patients with endometriosis
Arch Gynecol Obstet (2012) 286:667–670

Incidence of endometriosis in a UK-based population analysis
THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE, 2017
https://doi.org/10.1080/13625187.2017.1374362

Epidemiology of endometriosis
computerised databases of
Maccabi Healthcare
Services (MHS), the second
largest of four recognised
healthcare providers in
Israel.
MHS has approximately 2
million active members
BJOG 2018;125:55–62.

Time to Endometriosis Diagnosis
JOURNAL OF WOMEN’S HEALTH, 2017 DOI: 10.1089/jwh.2016.6003

Distribution of 3 typical endometriosis-related symptoms across
age groups
Gynecol Obstet Invest DOI: 10.1159/000452660

Age-related differences in the sonographic characteristics of
endometriomas
Human Reproduction, Vol.31, No.8 pp. 1723–1731, 2016

Sonographic characteristics of endometriomas
Human Reproduction, Vol.31, No.8 pp. 1723–1731, 2016

Improving strategies for diagnosing ovarian cancer
Simple Rules -International Ovarian Tumor Analysis (IOTA) group
Ultrasound Obstet Gynecol
2013; 41: 9–20

Improving strategies for diagnosing ovarian cancer
Simple Rules -International Ovarian Tumor Analysis (IOTA) group
Ultrasound Obstet Gynecol 2013; 41: 9–20

Predicting the risk of malignancy in adnexal masses
Simple Rules - International Ovarian Tumor Analysis (IOTA) group
Am J Obstet Gynecol 2016;214:424-437

Am J Obstet Gynecol 2016;214:424-437

Assessment of Different Neoplasias in the adneXa (ADNEX) model
http://www.iotagroup.org/adnexmodel/site%20iota.html

Pre- and Postmenopausal Factors Influencing
Postmenopausal Health
• Almost all physical restrictions in the
premenopausal and postmenopausal
periods correlate very strongly with the
postmenopausal target variables (general
pain experienced, pain during sexual
intercourse, and disturbances of sexual life).
• Physical fitness and an absence of physical
symptoms, a good social environment, and
psychological care not only during the
premenopausal period but also in the
postmenopausal period as well lead to
marked improvement with regard to pain,
dyspareunia, and effects on sexual life.
BioMed Research International Volume 2014, Article ID 746705

Clinical algorithm in women with deep endometriosis
Best Practice & Research Clinical Obstetrics and
Gynaecology (2018)

Pain perception in women according to different
conditions/confounders at age 46 years
Pressure-Pain Threshold
The Journal of Pain 2018 https://doi.org/10.1016/j.jpain.2018.02.005

Pain perception in women according to different
conditions/confounders at age 46 years
The Journal of Pain 2018 https://doi.org/10.1016/j.jpain.2018.02.005

Aromatase inhibitors in post-menopausal endometriosis
Reproductive Biology and Endocrinology 2011, 9:90
http://www.rbej.com/content/9/1/90.

Aromatase inhibitors in post-menopausal
endometriosis
Reproductive Biology and Endocrinology 2011, 9:90
http://www.rbej.com/content/9/1/90.

Strenght of the antagonist / agonist effect of SERMS
Figure 1. Strenght of the antagonist and agonist effect of ospemifene compared with other SERMS in (A) Breast (B) En-
dometrium and (C) Bone. (Modified from Komm BS, Mirkin SJ. An overview of current and emerging SERMs. Steroid
European Review for Medical and Pharmacological Sciences 2016; 20: 3934-3944
Ospemifene

TSEC -1
• TSEC is associated with a clinically significant reduction in the
number and severity of hot flashes (GRADE 2A). This efficacy
is similar to that recorded with MHT.
• TSEC is associated with clinically significant improvements in
health- and sleep-related quality of life (GRADE 2B). These
improvements are similar to those observed with MHT.
• TSEC decreases dyspareunia and reduces vaginal dryness
compared to placebo. In addition, the use of TSEC involves
significant improvements in sexual health. However, isolated
VVA is not an approved indication for TSEC. Gynecological Endocrinology, 2018;
34:10, 826-832

TSEC -2
• TSEC is associated with a safe breast profile with the
same incidence rates of breast tenderness and effect
on mammary density as placebo (GRADE 2A).
• TSEC achieves high amenorrhea rates compared with
placebo and significantly higher rates compared with
MHT (GRADE 2A).
• TSEC exhibits a favorable endometrial safety profile
with an incidence of hyperplasia similar to that of
placebo (GRADE 2A).
Gynecological Endocrinology, 2018;
34:10, 826-832

SMART trials
Maturitas 80 (2015) 435–440
Bazedoxifene

Main efficacy results for TSEC from the SMART
trials
observed with CE/BZA compared with placebo and raloxifene.
These effects remained after 2 years of treatment [11]. However,
data comparing CE/BZA and other MHT regarding the reduction
in hot flashes are not available. Only one study showed a similar
efficacy for relieving hot flashes between CE 0.45 mg/BZA 20 mg
and CE 0.625 mg/MPA 1.5 mg, but the principal purpose of this
included 664 postmenopausal women aged 40–65 years. Women
who received CE/BZA exhibited improvement in the percentage
of superficial vaginal cells and parabasal cells in week 12 (p < .01
compared with placebo). However, significant differences in the
reduction in vaginal pH and improvement in the most bother-
some vulvovaginal symptoms (i.e., dyspareunia, vaginal dryness)
Table 1. Main efficacy results for TSEC from the SMART trials.
Study and trial registration Objective Main results
SMART 1
NCT00675688 [11]
Effects on menopausal symptoms,
metabolic parameters, and overall
safety vs. BZA, HT (CE/MPA), and PBO
Reduction of the moderate-severe daily hot flushes (p .05 vs. PBO) and its
severity (p .001 vs. PBO)
Improvements in sleep parameters (p .05 vs. PBO)
Improvements in lipid parameters and homocysteine levels, no changes in
carbohydrate metabolism, and only minor effects on some coagulation parameters
Endometrial safety
Breast pain and adverse events similar to placebo
SMART 2
NCT00234819 [12]
Safety and efficacy treating moderate to
severe vasomotor symptoms vs. BZA, HT
(CE/MPA), and PBO
Reduction in the number and severity of hot flashes (p .001 vs. PBO)
Improvements in sleep parameters (p .05 vs. PBO)
Improvements in satisfaction and quality of life (p .05 vs. PBO)
SMART 3
NCT00238732 [13]
Efficacy and safety of two doses of TSEC
vs. PBO for the treatment of moderate to
severe VVA associated with menopause
Increase in superficial and intermediate cells, and decrease in parabasal
cells (p .01 vs. PBO)
Improvements in satisfaction, vasomotor symptoms, sexual function, and quality of
life (p .05 vs. PBO)
SMART 4
NCT00242710 [14]
Endometrial safety and BMD effects
vs. HT (CE/MPA) and PBO
Endometrial safety similar to PBO
Bleeding and breast tenderness lower than HT (p .05)
Improve lumbar spine and total hip BMD (p .001 vs. PBO)
Favorable safety/tolerability profile over 1 year
SMART 5
NCT00808132 [15]
Endometrial safety and BMD
effects vs. BZA alone, HT, and PBO
Low endometrial hyperplasia incidence (1%) in all groups
Cumulative amenorrhea rates similar to PBO and BZA and higher than HT (p .001)
Improve lumbar spine and total hip BMD (p .001 vs. PBO)
Breast tenderness similar to PBO and BZA and significantly lower than HT (p .01)
Adverse event rates were similar among the groups
Serious AEs overall and AE-related discontinuation rates lower than HT
BZA: bazedoxifene; CE: conjugated estrogen; HT: hormone therapy; MPA: medroxyprogesterone acetate; PBO: placebo; SMART: Selective estrogens, Menopause, And
Response to Therapy; TSEC: tissue-selective estrogen complex; VVA: vulvar/vaginal atrophy.
Gynecological Endocrinology, 2018;
34:10, 826-832
Bazedoxifene

Safety and Tolerability
Maturitas 80 (2015) 435–440
Bazedoxifene

Direct and indirect effects of conjugated estrogens/bazedoxifene
treatment on quality of life in postmenopausal women178 L. Abraham et al. / Maturitas 94 (2016) 173–179
Treatment
Hot Flush
Frequency
Hot Flush
Severity
Vasomotor
FuncƟon
Physical
FuncƟon
Sexual
FuncƟon
Psychosocial
FuncƟon
Indirect Eﬀectof Treatment via Hot Flush
Frequency on Vasomotor FuncƟon
SMART-1: 7.2%; SMART-2: 9.2%
Severity on Vasomotor FuncƟon
SMART-1: 57.0%; SMART-2: 42.1%
Direct Eﬀectof Treatment on Vasomotor FuncƟon
SMART-1: 35.8%; SMART-2: 48.7%
Severity on Physical FuncƟon
SMART-1: 100%; SMART-2: 100%
Severity on Sexual FuncƟon
SMART-1: 100%; SMART-2: 100%
Severity on Psychological FuncƟon
SMART-1: 100%; SMART-2: 100%
Maturitas 94 (2016) 173–179

Postmenopausal Deep Infiltrating Endometriosis of the Colon
• A course of conjugated estrogen/ bazedoxifene (CE/BZA) (Duavee: 0.45–20mg,
Pfizer)
Case Reports in Gastrointestinal Medicine Volume 2018, Article ID 9587536, 5

ovarian cancer risk increase or reduction associated
respectively with endometriosis, contraception and
menopausal hormone therapy
Endometriosis, menopausal hormone therapy and ovarian cancer risk Rozenberg et al.
of peritoneal and deeply infiltrating disease, suggesting that
surgical efforts should always aim completely to eliminate the
endometriotic lesions in order to keep the risk of recurrence
epithelial origin. Of these, 50–60% are categorized as serous,
8–10% as mucinous, and 10–15% either as endometrioid or
clear-cell13.
Table 1 Overall, and by histological type, ovarian cancer risk increase or reduction associated respectively with endometriosis, contraception
and menopausal hormone therapy (MHT)
Endometriosisa
Contraception: % reduction in risk per 5/10
years use, by ovarian tumor histology (SE)b,d
MHT: RR compared to never-users,
adjusted for age at menopause,
hysterectomy, oral contraceptive use, and
parityc
Histological type OR 95% CI RR 95% CI
Invasive cancer 1.46 1.31–1.63 Significant reduction Ϫ20.5 % (SE 1.9%)b 1.43 1.31–1.56
Serous Significant reduction Ϫ22.1% (SE 2.9%)b 1.40 1.31–1.49
low-grade (type I) 2.11 1.39–3.20 Type I, HRϭ0.54 (95% CI 0.31–0.94)d
high-grade (type II) 1.13 0.97–1.32 Type II, HRϭ0.71 (95% CI 0.51–0.97)d
Endometrioid 2.04 1.67–2.48 Significant reduction Ϫ27.1% (SE 4.8%) 1.28 1.13–1.45
Mucinous 1.02 0.69–1.50 No protection Ϫ6.7% (SE 5.8%) 0.80 0.63–0.93
Clear-cell 3.05 2.43–3.84 Significant reduction Ϫ21.3% (SE 7.3%) 0.80 0.65–0.98
RR, relative risk; OR, odds ratio; 95% CI, 95% confidence interval; SE, Standard estimates
a, Adapted from reference 22; b, per 5 years, adapted from reference 19; c, adapted from reference 1; d, per 10 years, adapted from reference 17
CLIMACTERIC 2015;18:448–452

Relative risk of the four most common subtypes of ovarian cancer
in current-or-recent users versus never-users of hormone therapy
Lancet 2015 Feb 12. pii: S0140-6736(14)61687-1.
doi: 10.1016/S0140-6736(14)61687-1

• The lifetime risk of ovarian cancer varies between 0.47% in Japan
and 1.8% in the US.
• The use of menopausal hormone therapy (MHT) for 5 – 10 years,
from around the age of 50 years, is associated with approximately
one extra ovarian cancer per 1000 – 2000 women.
• Endometriosis is associated with a 50% increase in the risk of
epithelial ovarian cancer.
• Ovarian preservation has been reported to carry a six-fold risk of
recurrent pain and eight-fold risk of reoperation.
• The risk of recurrence was related to the incomplete surgery

• The use of oral contraceptives for more than 10 years was
associated with about 80% reduction in risk among women with
endometriosis.
• Ovarian endometrial cysts often have a monoclonal origin; the
prevalence of endometriosis is increased in ovarian cancer patients
(ranging from as low as 3.4% to as high as 52.6%) and, inversely, the
prevalence of ovarian cancer is increased in endometriosis patients,
ranging between 2.0 and 17.0%.
• The correlation between endometriosis and ovarian cancer is highly
dependent on which histological type is being investigated, with
clear-cell and endometrioid subtypes showing the strongest
correlation.

Impact of endometriosis on risk of further gynaecological
surgery and cancer
BJOG 2017; https://doi.org/10.1111/1471-0528.14793.
+6 per 1000
+1 per 1000
+3 per 1000

Endometriosis and risks for ovarian, endometrial and breast cancers
Gynecologic Oncology (2016) http://dx.doi.org/10.1016/j.ygyno.2016.07.095
45,790 women with a clinical diagnosis of endometriosis during 1977–2012.

Gynecologic Oncology (2016) http://dx.doi.org/10.1016/j.ygyno.2016.07.095

Endometriosis recurrence in women on HRT
Human Reproduction Update, Vol.23, No.4 pp. 481–500, 2017

Dosages and regimens associated with recurrent
postmenopausal endometriosis

malignant transformation of endometriotic foci after HRT in
women with a history of endometriosis

Quality assessment of observational and clinical trials assessing
risk of endometriosis recurrence after HRT

effects of estrogen exposure on endometriosis recurrence and
risk of malignant transformation
Climacteric, 2017;20:2:138-143, DOI: 10.1080/13697137.2017.1284781

Nezhat F, 12th Turkish German Gynecologic Congress 2018

Suggested clinical approach to postmenopausal patients with a
history of endometriosis

Emerging treatment of endometriosis
• GnRH antagonists
• Aromatase inhibitors
• Selective estrogen receptor modulators
• Progesterone antagonist
• Selective progesterone receptor modulators
• Angiogenesis inhibitors
• Immunomodulators
• Matrix metalloproteinase
• 5-Fluorouracil
• Thiazolidinediones
• Metformin
Middle East Fertility Society Journal (2015) 20, 61–69

Investigated drugs
Expert Opinion on Investigational Drugs, 2018; 27:5, 445-458

MHT in endometriosis patients after the menopauseEndometriosis, menopausal hormone therapy and ovarian cancer risk Rozenberg et al.

Algorithm of endometriosis management in postmenopausal
women
Climacteric, 2017;20:2:138-143, DOI: 10.1080/13697137.2017.1284781

Human Reproduction, 2016 doi:10.1093/humrep/dew078

Thank you for your attention
Tevfik Yoldemir MD. BSc. MA. PhD.
tevfik.yoldemir@marmara.edu.tr

NETA
• In a randomized controlled trial (RTC), Vercellini et al.
compared NETA (2.5 mg/day) with a COC regimen (EE 0.01
mg + cyproterone acetate [CPA] 3 mg).
• In a patient-preference parallel cohort study, continuous
NETA (2.5 mg/day) was compared to surgery for the
treatment of 154 patients with endometriosis-associated
deep dyspareunia.
• Ferrero et al. investigated the efficacy of NETA for the
treatment of pain and gastrointestinal symptoms in 40
women with colorectal endometriosis.
Expert Opinion on Drug Metabolism Toxicology, 2018

NETA
• A prospective, non-randomized, open-label study including 40
patients compared the changes in the volume of ovarian
endometriotic cysts during 6-month treatment with NETA alone or
combined with letrozole.
• In a long-term retrospective cohort study, 103 women with pain
symptoms caused by rectovaginal endometriosis received NETA (2.5
mg/day up to 5 mg/day) for a 5-year therapy.
• A patient preference prospective study demonstrated that NETA
(2.5 mg/day) and a 91- day extended-cycle COC (LNG plus EE
150/30 μg for 84 days and EE 10 μg for 7 days) have similar efficacy
in treating pain symptoms related to endometriosis.

CPA
• In a RCT, Vercellini et al. compared the efficacy and safety of low-dose CPA
(12.5 mg/day) with a COC (EE 0.02 mg + desogestrel, DSG, 0.15 mg) in 90
women with recurrent moderate or severe endometriosis-related pelvic
pain persisting after conservative surgery.
• Regarding safety profile of CPA as monotherapy for endometriosis, in the
study by Vercellini et al. the main AEs experienced were bloating or
swelling (n=14, 32%), spotting (n=12, 28%) and weight gain (n=8, 19%).
• A pilot study by Moran et al. on seven women with surgically confirmed
endometriosis evaluated the effectiveness of 6-month cyclical CPA (10
mg/day for 20 days, followed by 10 days without medication).

Desogestrel
• In the first study reported, continuous oral DSG (75 μg/day) was
compared to COC (EE 20 μg + DSG 150 μg /day) for the treatment of
40 patients with stage I-II endometriosis.
• In 2014, a patient preference trial compared the contraceptive
vaginal ring (EE 15 μg + ENG 120 μg), administered cyclically, with
oral DSG (75 μg/day) for the treatment of women with
symptomatic rectovaginal endometriosis.
• Oral DSG (75 μg/day) and cyclic COC (EE 20 μg + DSG 150 μg) were
administered to 74 women with symptomatic rectovaginal implants
and migraine without aura, which has been demonstrated to be
often associated to endometriosis.

MPA
• In two RCTs, Telimaa et al. demonstrated that the administration of
MPA (100 mg/day) for 6 months is as effective as danazol in the
treatment of pain both after diagnostic laparoscopy and after
surgical excision of endometriosis.
• One prospective double-blind RCT, involving 48 women with
surgical diagnosis of endometriosis, compared MPA (45 mg/day)
with naferelin (400 μg intranasal) for treating pain.
• a Cochrane review reported that MPA (100 mg daily) appears more
effective in reducing all symptoms up to 12 months of follow-up
(MD -0.70, 95% CI -8.61 to -5.39; P 0.00001) compared with
placebo.

DMPA
• A RTC (80 women), Vercellini et al. compared DMPA-M (150 mg/3 months)
to cyclic COC plus oral danazol (50 mg/day) for 1 year to treat
endometriosis-related pelvic pain.
• A RCT compared a 3-years regimen of DMPA-M (150 mg/3 months) with
the levonogestrel- releasing intrauterine system (LNG-IUD) in 30 patients
after conservative surgery for endometriosis.
• In two large RTCs, Crosignani et al. and Schalff et al. compared DMPA-SC
(104 mg/0.65 ml) with leuprolide acetate (given every 3 months for 6
months).

DNG
• In a 6-months double-blind multicenter RTC, DNG (2 mg/day) efficacy and
safety were evaluated in 255 Chinese patients with laparoscopically
diagnosed endometriosis.
• Morotti et al. investigated the DNG efficacy for the treatment of women
with rectovaginal endometriosis who had persisting pain symptoms during
the administration of NETA.
• In a prospective study, Leonardo-Pinto et al. evaluated the effectiveness of
DNG for the treatment of 30 women with DIE.
• Vercellini et al., through a before-after study design, compared NETA and
DNG for the treatment of women with endometriosis.
• In a comparative study, Lee et al. administered DNG (2 mg/day) or GnRH-a
plus add-back therapy (NETA 0.5 mg/day or E2 1 mg/day) for the
treatment of endometriosis.

MHT for Endometriosis Symptoms

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