Alternative Menopausal Hormone Therapies.pdf

Alternative Hormonal Treatments
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
yoldemirtevfik
tevfikyoldemir

Effects of selected ERAAs on target tissues in humans
TABLE 2. Effects of selected ERAAs on target tissues in humans
ERAA
Effects on target tissue
Endometrium Vagina Breast Bone
Ospemifene Partial agonist43<46
Agonist43<46
Neutral (limited data)43<46
Agonist (limited data)47,48
& Up to 52-wk RCT & Up to 52-wk RCT & Up to 52-wk RCT & 3-mo RCT
& Slight j in thickness from
BL by TVU
& SS j in superficial cells & No clinically significant
abnormalities by
mammography
& Positive effects of bone
turnover on biomarkers
& Generally no histologic
changes from BL
& SS , in parabasal cells & No reports of cancer
during these RCTsa
& No reports of cancer & SS , in pH
& P G 0.001 for all vs PBO
Tamoxifen Agonist49<51
Agonist52
Antagonist51
Agonist53
& Meta-analysis of four trials & Prospective study & Meta-analysis of four
trials
& 2-y RCT
& SS j in cancer (P G 0.001)
vs PBO
& SS j in MI across 24 mo vs
controls (P G 0.0001)
& SS , in cancer vs PBO
(P G 0.0001)
& SS j in lumbar spine BMD
vs PBO (P G 0.001)
& j in thicknessb
& SS , in serum osteocalcin
from BL vs PBO
(P G 0.001)
Raloxifene Neutral or antagonist51,54<58
Neutral54,59
Antagonist51
Agonist60,61
& Meta-analysis of three trials & Up to 6-mo CT & Meta-analysis of five trials & Up to 24-mo RCT
& No difference in thickness
by TVU and in incidence
of bleeding vs controls
& No difference in VMV or parabasal,
intermediate, or
superficial cells by smear vs
controls
& SS , in all breast cancers
(P G 0.0001)
& SS j in BMD vs PBO or BL
(P G 0.05)
& No increase in cancer & SS , in biomarkers of bone
turnover vs PBO or BL
(P G 0.05)
Bazedoxifene
(monotherapy)
Antagonist62
Antagonist63
Neutral or antagonist 64,65
Agonist66<68
& 7-y RCT & 12-wk RCT & 24-mo RCT & Up to 5-y RCT
& No difference in thickness
by TVU and in incidence
of hyperplasia vs PBO
& Little change in superficial cells vs BL;
parabasal cells increased; intermediate
cells decreasedc
& No j in density by
mammography vs PBO
& SS , in incidence of new
vertebral fractures vs PBO
(P G 0.05)
& SS , in incidence of cancer
vs PBO (P = 0.02)
& No difference in cancer
rates or pain vs PBO
& SS j in lumbar spine BMD
vs PBO (P e 0.023)
& SS , in serum osteocalcin/
CTX vs PBO (P e 0.009)
ERAA, estrogen receptor agonist/antagonist; RCT, randomized clinical trial; (j) increase; BL, baseline; (,) decrease; TVU, transvaginal ultrasound; SS, statis-
tically significant; PBO, placebo; MI, maturation index; BMD, bone mineral density; CT, clinical trial (randomized or not); VMV, vaginal maturation value; CTX,
ARCHER ET AL
Menopause 2014: Vol. 22, No. 7, pp. 786-796

Tissue selective estrogen complex (TSEC)
Menopause 2018 Vol. 25, No. 9, pp. 1033-1045

conjugated estrogens/bazedoxifene treatment &
vasomotor symptoms
JOURNAL OF WOMEN’S HEALTH
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Mean daily number of hot flashes
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Mean daily hot flash severity score
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Number and severity of hot flash
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Effect of years since menopause
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Menopause-specific quality of life
Volume 25, Number 11, 2016: 1102-1111
Bazedoxifene

Bazedoxifene & BMD & Fracture
Clinical Reviews in Bone and Mineral Metabolism (2018) 16:22–32
Bazedoxifene

BZD 20 mg & vertebral / non-vertebral fractures
Clinical Reviews in Bone and Mineral Metabolism (2018) 16:22–32
Vertebral fracture Non-vertebral fracture
Bazedoxifene

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

Rates of cumulative amenorrhea
Maturitas 80 (2015) 435–440
Bazedoxifene

Effects of CE/BZD on BMD
Therapeutics and Clinical Risk Management 2016:12 549–562
Bazedoxifene

Breast pain during treatment
Bazedoxifene

Breast tenderness in daily diaries
Bazedoxifene

Bleeding/ spotting
Bazedoxifene

Strenght of the antagonist and agonist effect of
ospemifene compared with other SERMS
L. Del Pup
European Review for Medical and Pharmacological Sciences
2016; 20: 3934-3944
Ospemifene

A non-estrogen selective estrogen receptor modulator
Intentiontotreatpopulation perprotocolpopulation
Maturitas 78 (2014) 91–98
Ospemifene
The intent-to-treat (ITT) population, which consisted of all randomised participants who took at least one dose
of the study medication.
The per-protocol (PP) population completed at least 10 weeks of treatment, took ≥85% of the study
medication and did not have any other major protocol violation, vaginal infection or any other medical
condition that would confound the primary efficacy assessment.

Intentiontotreatpopulation perprotocolpopulation
Maturitas 78 (2014) 91–98
Ospemifene
Change from baseline was determined as
−3 being a change from ‘severe’ to ‘none’;
−2 being either a change from ‘severe’ to ‘mild’ or from ‘moderate’ to ‘none’;
−1 being either ‘severe’ to ‘moderate’, ‘moderate’ to ‘mild’, or ‘mild’ to ‘none’, and zero being no change.
A change of 1 indicated a change from ‘moderate’ to ‘severe’, ‘mild’ to ‘moderate’, or ‘none’ to ‘mild’.

Week1 Week12
Maturitas 78 (2014) 91–98
Ospemifene

Total score - Female Sexual Function Index
Intentiontotreatpopulation dyspareunia
!"#$%&'()#& *+,-./,01*2/**34*5*
Ospemifene
ITT - all randomized subjects who had received > one dose of the study
medication

Intention to treat population
!"#$%&'()#& *+,-./,01*2/**34*5*
Ospemifene

dyspareunia
!"#$%&'()#& *+,-./,01*2/**34*5*
Ospemifene

Overall Safety of Ospemifene in Postmenopausal
Women from Placebo-Controlled Phase 2 and 3 Trials
JOURNAL OF WOMEN’S HEALTH, 2017
Ospemifene

JOURNAL OF WOMEN’S HEALTH, 2017
Ospemifene

Intravaginal6.5mg(0.50%)DHEA(Prasterone)vs
0.3mgConjugatedEquineEstrogensvs
10μgEstradiol DecreaseofSeverityofDyspareunia
Journal of Steroid Biochemistry
and Molecular Biology 174 (2017) 1–8
Prasterone

10μgEstradiol vs Placebo ImprovementofDyspareunia
Prasterone

10μgEstradiol DecreaseofSeverityofVaginalDryness
Prasterone

EffectofIntravaginal6.5mg(0.50%)DHEA(Prasterone)vs
0.3mgConjugatedEquineEstrogens
ImprovementofVaginalDrynessOverPlacebo
Prasterone

SerumDHEAremainswellwithinnormalpostmenopausalvalues
followingintravaginal0.50%DHEA
Journal of Steroid Biochemistry &
Molecular Biology 159 (2016) 142–153
Prasterone

Serum testosterone shows no biologically significant change
following intravaginal 0.50% DHEA
Prasterone

Serum estradiol remains well within normal postmenopausal
values followingintravaginal 0.50% DHEA
Prasterone

Effect of Intravaginal Prasterone on Sexual Dysfunction
J Sex Med 2015;12:2401–2412
Prasterone

J Sex Med 2015;12:2401–2412
Prasterone

Effect of DHEA on vaginal dryness / pain at sexual activity
(ITT population)
CLIMACTERIC 2015;18:590–607
Prasterone

Effect of DHEA on irritation/itching (ITT population)
CLIMACTERIC 2015;18:590–607
Prasterone

Vaginal dryness
Menopause: 2009;Vol. 16, No. 5, pp. 907/922
Prasterone

Pain at sexual activity
Menopause: 2009;Vol. 16, No. 5, pp. 907/922
Prasterone

Effect of prasterone on MS or MBS pain at sexual activity
Maturitas 81 (2015) 46–56
Prasterone

Effect of prasterone on MS vaginal dryness
Maturitas 81 (2015) 46–56
Prasterone

Effect of prasterone on MS irritation/itching
Maturitas 81 (2015) 46–56
Prasterone

Menopause: 2009; Vol. 16, No. 5, pp. 923/931
Prasterone

Factors that increase or decrease levels of SHBG in women
Your Sexual Medicine Journal (2022) 34:635–641;
https://doi.org/10.1038/s41443-022-00613-0

Your Sexual Medicine Journal (2022) 34:635–641;
https://doi.org/10.1038/s41443-022-00613-0

Testosterone therapy and postmenopausal women
• Where an appropriate approved female testosterone preparation is not available, off-
label, prescribing of an approved male formulation is reasonable, provided hormone
concentrations are maintained in the physiologic female range.
• Should a trial of testosterone therapy be given for HSDD, a baseline total testosterone
and SHBG concentration should be measured before commencement, with a repeat
level 6 weeks after treatment initiation.
• Evaluation of therapy response should be monitored clinically in terms of improvement
of low sexual desire/well-being after 12 weeks of therapy.
• Patients should be monitored for their clinical response to treatment and assessed for
signs of androgen excess with a serum total testosterone level every 6 months, to
screen for overuse.
• If no benefit is experienced by 6 months, treatment should be ceased.
J Clin Endocrinol Metab, October 2019, 104(10):4660–4666
CLIMACTERIC 2021, VOL. 24, NO. 1, 46–50

The Obstetrician & Gynaecologist 2022;24:228–41.
https://doi.org/10. 1111/tog.12836

How to apply and follow
• Testosterone gel or cream should be used on clean, dry skin on the lower abdomen
and upper thighs. Skin contact with others should be avoided until the skin is dry
and hands should be washed immediately after application.
• Response to therapy usually requires at least 8 weeks to manifest, so treatment
should be trialled for a minimum of 3 months.
• If there has been no improvement after 6 months, then testosterone should be
discontinued.
• To assess whether a satisfactory response is maintained, and to identify adverse
androgenic events, regular reviews should be undertaken, at least on an annual
basis.
• The optimal duration of treatment has yet to be ascertained. Research studies
predominantly involved 6–12 months of use, so efficacy and safety beyond this
period is unclear. The Obstetrician & Gynaecologist 2022;24:228–41.

Weak/no evidence
• The association between endogenous androgen concentrations and sexual function
in women is uncertain, and there is no cut-off level that can be used to differentiate
women with or without sexual dysfunction.
• Insufficient evidence that testosterone enhances cognitive performance or improves
depressed mood.
• Insufficient evidence that testosterone improves musculoskeletal outcomes,
including bone mineral density.
• A nonsignificant trend for increased deep vein thrombosis has been seen with
transdermal testosterone; however, this could be associated with estrogen therapy.
• Safety data for testosterone therapy beyond 24 months is not available.

Limited Evidence
• A baseline total testosterone concentration should be measured before starting
treatment and repeated 6 weeks after commencement. Signs of androgen excess
can be screened for with 6-monthly levels.
• Treatment should be stopped if no benefit after 6 months. Testosterone may
improve wellbeing but data are inconclusive.
• Available data to date show that short-term transdermal testosterone therapy does
not appear to impact breask cancer risk, but RCT data for long-term breast cancer
risk is insufficient.

What should be measured
• Total testosterone levels provide a more accurate representation of therapeutic
response than free testosterone, or the calculated Free Androgen Index (FAI).
• In certain circumstances, SHBG levels may be helpful as additional supportive
information:
— Where SHBG levels are high e.g. due to high dose oral estrogen therapy, especially conjugated
estrogens. This may explain lack of therapeutic response to physiological testosterone replacement, despite
normal total testosterone levels.
— Conversely, when SHBG levels are very low. This may explain why androgenic adverse effects with
testosterone replacement have occurred, despite normal total testosterone levels.
• When treating low sexual desire /arousal it is also important that urogenital tissues
are adequately estrogenised in women with vulvovaginal atrophy / genitourinary
syndrome of the menopause e.g. through use of vaginal estrogen, to avoid
dyspareunia BRITISH MENOPAUSE SOCIETY Tool for clinicians
Testosterone replacement in menopause

Take away messages -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 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

JAMA October 24/31, 2017 Volume 318, Number 16

Neurokinin-3 receptor (NK3R) antagonists
The long-term safety of NK3R antagonists is to be established in phase III trials.
Hepatic safety is highlighted as an aspect to be appropriately monitored, particularly following the
discontinuation of pavinetant .
The relative advantages of long-term treatment with NK3R antagonists versus
HT in menopausal women also remain to be determined.
NK3R antagonists are not anticipated to elicit the peripheral side effects of hormones; for example, there
are no signs of endometrial hyperplasia, to-date, in response to fezolinetant
An expanded role for NK3R antagonists may be in the treatment of VMS triggered by hormone deprivation
therapy in women treated for estrogen-sensitive cancers (e.g. breast cancer)

neurokinin 3 receptor antagonist - (VESTA)
Menopause 2020 Vol. 27, No. 12, pp. 1350-1356
DOI: 10.1097/GME.0000000000001621
fezolinetant

0.5 or 1 mg estradiol / 100 mg progesterone
1. Kagan R, Constantine G, Kaunitz AM, Bernick B, Mirkin S. Improvement in sleep outcomes with
a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal
women. Menopause. 2018;25(6). doi:10.1097/GME.0000000000001278
2. Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor
symptoms in postmenopausal women. Obstet Gynecol. 2018;132(1):161-170.
3. Mirkin S. Evidence on the use of progesterone in menopausal hormone
therapy. Climacteric. 2018;21(4):346-354.
4. Simon JA, Kaunitz AM, Kroll R, Graham S, Bernick B, Mirkin S. Oral 17β-estradiol/progesterone
(TX-001HR) and quality of life in postmenopausal women with vasomotor
symptoms. Menopause. 2019;26(5). doi:10.1097/GME.0000000000001271
Bijuva

CEE / MPA
0.625 mg/2.5 mg continuous 0.45 mg/1.5 mg continuous
0.625 mg/5 mg continuous 0.3 mg/1.5 mg continuous
0.625 mg/5 mg sequential
Prempro & Premphase

1 mg oestradiol (as hemihydrate) and 10mg dydrogesterone. sequential
2 mg oestradiol (as hemihydrate) and 10mg dydrogesterone. sequential
1 mg 17β-estradiol (as hemihydrate) and 5 mg dydrogesterone. continuous
0.5 mg 17β-estradiol (as hemihydrate) and 2.5 mg dydrogesterone. continuous
Femoston / Femoston-conti

TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tevfikyoldemir
yoldemirtevfik

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