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Ed ti l C C t ti dEducational Course: Contraception and HRT for Women in Contemporary
Clinical PracticeClinical Practice
HOW HORMONE THERAPY MAY HELP SEXUAL FUNCTION AT MENOPAUSE
Dr. Santiago PalaciosgInstituto Palacios, Salud y Medicina de la Mujer
Antonio Acuña, 9 - 28009 Madrid – Spain - Phone +34 91 578 05 17E-mail: [email protected] @ p
www.institutopalacios.com
www.institutopalacios.com
Diapositivas / Slides
Natural vs Surgical Menopause
Natural Menopause Surgical MenopausePhysiological processNatural transition Gradual decline of sex hormone levels Gradual, variable presence of symptoms
Medical intervention (potentially distressing)Sudden onsetSteep decline of sex hormone levelsStronger, more severe symptoms
Menopause↓Hormone levels↓Hormone levels
End of fertile phase
Symptoms/ImpactHot flushes
Sleep disturbanceMood changesgMemory loss
Loss of energyUrogenital problemsSexual problemsp
Adapted from Nappi RE et al. Gynecol Endocrinol 2006; 22:318-323Source: FSDeducation.eu
Role of Estradiol & Testosterone in the Onset of Sexual Symptoms at MenopauseOnset of Sexual Symptoms at Menopause
Estradiol DeficiencyH t fl h / t
Testosterone DeficiencyDiminished sense ofHot flushes/sweats
Sleep disturbanceMood changes
Diminished sense ofwell-beingDecreased energyI d d iVaginal dryness Increased depressionReduced sexual desire, receptivity and arousal
Impairment of Sexual Function
Source: FSDeducation.eu
“Domino Effect” of Climacteric C l i t S l S tComplaints on Sexual Symptoms
NegativeEmotional Feelings
SEXUALity
(depression, anxiety,panic, loss of interest…)
SEXUALDYSFUNCTION
Inte
nsi
Poor Physical Health(loss of fitness, fatigue,weight gain headache )I weight gain, headache…)
Genito-Urinary Problems(recurrent vaginal infections(recurrent vaginal infections,involuntary loss of urine…)
RE Nappi et al, 2002
Nappi RE, et al. (2002) Gynecol Obstet Invest; 53: 181-7
Body PhysiologyBody Physiology
PartnerHormones
BrainBrain
SEXUAL FUNCTIONSEXUAL FUNCTION
Mean Plasma Hormone Levels:Pre and Post Menopausal
ld
Pre- and Post-Menopausal
Below assay Below assay 40 ± 3Oestradiol (pg/ml)
Surgical Menopause (Oophorectomy)Natural MenopauseReproductive
Age
100 ± 20200 ± 20
detection limit
((400 ± 30Testosterone
detection limit40 ± 3Oestradiol (pg/ml)
1260 ±
100 ± 20
1970 ±
200 ± 20
((4200 210DHEA ( / l)
(75%)
(50%)400 ± 30(pg/ml)
Androgens are present at higher circulating levels than oestradiol
1260 ±360
1970 ±430
(70%)
(53%)4200 ± 210DHEA (pg/ml)
Androgens are present at higher circulating levels than oestradiolAndrogen levels fall more dramatically after surgical menopausePost menopause, androgen levels decline by 50% compared with
Lobo, RA (2001) Obstet Gynecol Surv 56: 361-76
pre-menopausal levels
Menopause-Associated Clinical Profile
Hormonal InstabilityInstability
SleepHotDepression
Sleepdisturbance
Hotflashes
Windows of Vulnerability y
•Heightened prevalence of psychiatric conditions during periods of intense hormone
i bilit fl t ti ( PMDD PPD)variability, fluctuation (e.g., PMDD, PPD)
•Symptoms adverse outcomes resulting from •Symptoms, adverse outcomes resulting from the disruption of hormone milieu
•Windows of sexual dysfunction
Cohen LS et al Arch Gen Psychiatry 2006;63:385-390Cohen LS, et al. Arch Gen Psychiatry. 2006;63:385-390.Soares CN. Expert Rev Neurother. 2007;7:1285-1293. Rocca W, et al. Neurology. 2007;69:1074-1083.Almeida OP, et al. Arch Gen Psychiatry. 2008;65:283-289.
Windows of Opportunity pp y
•A stable hormone milieu or a hormone •A stable hormone milieu or a hormone intervention may exert a prophylacticeffect effect
•Hormone intervention/modulation may •Hormone intervention/modulation may exert a therapeutic effect
Soares CN, et al. Arch Gen Psychiatry. 2001;58:529-534. Rocca WA, et al. Neurology. 2007;69:1074-1083.Joffe H, et al. J Clin Psychiatry. 2007;68:943-950.
Hot Flashes and Night SweatsHot Flashes and Night Sweats
• Hot flashes and night sweats may be associated with hormonal changes1,2
Night sweatsHot flashes - transient Night sweats– Drenching perspiration– Usually associated
Hot flashes transient episodes
– Warming sensation Usually associated with sleep disruptionto intense heat
– Reddening of the kiskin
– Perspiration
1. Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.2. North American Menopause Society. Menopause. 2004;11:11-33.
Hot Flashes: EpidemiologyHot Flashes: Epidemiology
Prevalence of Hot Flashes by Age (N=1400)100
80
90
100sh
es (
%)
1968-1969
1974 1975
Assessment year
Onset: as early as 38 years of agePrevalence peak: age 52 to 54 years
60
70
ng h
ot f
las 1974-1975
1980-1981
Prevalence peak: age 52 to 54 yearsMay persist up to 72 years of age
40
50
peri
enci
n
10
20
30
Wom
en e
xp
3
0
10
38 44 46 50 52 54 56 58 60 62 66 72
W
Data in this graph represent information collected at three intervals: 1968-1969, 1974-1975, 1980-1981.Rödström K, et al. Menopause. 2002;9:156-161.
Age (years)
For How Long Can Hot Flushes Continue? g
Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes40
45
50
untreated women who experienced hot flushes
25
30
35
Numberof
10
15
20of Subjects
0 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 410
5
10
Years after menopause
Kronenberg F. 1990
Hypothesis of Thermoregulatory Dysfunction: Core Body Temperature ThresholdsCore Body Temperature Thresholds
SymptomaticNormal Symptomatic
Sweating
Normal
Sweating
Upper threshold(Upper set
Sweating
h l
Sweating
(Upper set point)
Lower
Thermoneutral Zone
(homeostatic range)
CBT
Lower threshold(Lower set point) ShiveringShivering
Body temperature
Body temperature
Freedman RR. Am J Med. 2005;118:124S-130S
Factors that Influence the Thermoneutral Zone: The Role of 5-HT, NE and Estrogens , gModulation
Sweating Threshold
+
AsymptomaticEstrogen
Decreased Body
ratu
re +
ThermoneutralZone
Hot Flushes
Clonidine
SSRI 5-HT*
Decreased Sympathetic NS† Activity
Tryptophan Depletion
yohimbine
Core
BTe
mpe
r
Shivering
−
Threshold
* 5 HT = serontonin (5 hydroxytryptopan) 5-HT = serontonin (5-hydroxytryptopan)† NS=nervous system
HT AND VASOMOTOR SYMPTOMSHT AND VASOMOTOR SYMPTOMS
•No other medical treatment nor alternative one best offer significant relief of VMSReducing frequency and intensity is as high as 90% •Reducing frequency and intensity is as high as 90%
and sustained•The main effect was observed in the course of a The main effect was observed in the course of a month with fixed dose and route of administration
RESPONSE TO DIFFERENT DOSES OF CEE ALONE OR WITH MPA
A BPlacebo
0.3 mg/dX Placebo
0.3/1.5 mg/dX
12
10
8num
ber
12
10
8num
ber
XX X X X X X
0.45 mg/d
0.625 mg/d
0.45/2.5 mg/d
0.625/2.5 mg/d
XX X X X X
6
4
uste
d m
ean
6
4
uste
d m
ean
X X XX X X X
X X X X XX X X X
1 2 3 4
2
0
Adj
u
Week5 6 7 8 9 10 11 12 1 2 3 4
2
0
Adj
u
Week5 6 7 8 9 10 11 12
CEE Alone CEE + MPA
Utian, et al. Fertil Steril. 2001.75;1065.
Ultra-low doseNo. of moderate and severe hot flushes per week
PlaceboUltra-low dose
Vaginal Atrophy*significantly (p=0.001) g y (p )different from placebo
Maturation Vaginal pH
Panay N et al. Climacteric 2007;10(2):120–131
Effects of E+T vs T alone over 2 years on l f tisexual function
1098765
SexualityScale
E IMPLANTSE+T IMPLANTS
Libido
ActivityScale Activity
Satisfaction
Pleasure
Fantasy
Orgasm
Relevancy
Davis et al Maturitas 1995
Transdermal Testosterone Plus OestrogenPhase III testosterone patch studies in surgically p g ymenopausal women
• Two Separate Phase III Clinical Trials:
S i l 1 (INTIMATE SM 1) 562 – Surgical menopause 1 (INTIMATE SM 1), n=562 women– Surgical menopause 2 (INTIMATE SM 2), n=532 women
• Objective:– Assess efficacy / safety of transdermal testosterone in surgically menopausal
women with Hypoactive Sexual Desire Disorder
• Design:– 24-week randomised, double-blind, placebo-controlled, multinational trial– Placebo or transdermal testosterone patch 300 μg/day– All patients on oral or transdermal oestrogenp g– Inclusion / Exclusion criteria similar
• Female testosterone patch: Alcohol free translucent matrix patch– Alcohol-free, translucent, matrix patch
– Twice-a-week application to abdomen– Contains 8.4 mg testosterone– Delivers 300 μg/day testosterone
Simon JA, et al. (2005) J Clin Endocrinol Metab 90: 5226–5233 Buster JE et al. (2005) Obstet Gynecol 105: 944–952
Source: FSDeducation.eu
APHRODITE (Transdermal Testosterone Patch Only) I d PFSF D i t 24 W kIncreased PFSF Domains at 24 Weeks
25
30Placebo
(SEM
)
* *Transdermal Testosterone Patch (300μg/day)
20
25
m B
asel
ine
*
** *
10
15
hang
e fr
om * *
0
5
Mea
n C
h
0Arousal PleasureOrgasm Reduced
Concerns Responsive-
nessSelf-imageDesire
**p<0.05, vs. placebo
Hormonal TreatmentTib lTibolone
• Tibolone is a synthetic steroidTibolone is a synthetic steroid
• It has oestrogenic, androgenic and progestogenic properties
Tibolone is indicated for the relief of climacteric symptoms in post menopausal • Tibolone is indicated for the relief of climacteric symptoms in post-menopausal women
• Data suggest a positive effect on sexual symptoms comparable to hormonal therapy via
– interaction of the the 4-isomer of tibolone with AR. d SHBG t ti d th b i – decrease SHBG concentrations and thereby increase the availability of T.
• Good overall tolerability with low incidence of vaginal bleeding and breast tenderness
• Current available data on breast and endometrial cancer risk are inconclusive• Current available data on breast and endometrial cancer risk are inconclusive
• Potential increase in risk of strokeSource: FSDeducation.eu
TIBOLONE improves sexual function in postmenopausal womenPalacios et al 1995 Palacios et al 1995
1.6Tibolone (n=14)
1.2
Tibolone (n=14)Placebo (n=14)
0.8
0.4
0
-0.4
Tibolone significantly different for all values at p <0.01 at 12 m
SEXUAL FUNCTIONSEXUAL FUNCTION
Causes of Sexual Arousal Disorder (SAD)( )
Major Biological Causes1 Psychological CausesMajor Biological Causes1
• Sex hormone deficiency• Diabetes/Vascular factors
Psychological Causes• Relationship issues• Intrapersonal issues
• Smoking• Pelvic floor disorders
• Intrapersonal issues
• Lower urinary tract symptoms (LUTS)
• Pelvic surgery
Sociocultural Causes• Poverty/Low income
• Pelvic surgery• Neurological diseases• Drugs: Anti-hormones,
• Working conditions• Sexual norms
chemotherapy
1For clinical purposes the biological focus is on factors affecting genital arousalSource: FSDeducation.eu
Latent classes analysisof FSD by risk factorsof FSD by risk factors
Predictors Sexual pain Arousal disorders
Adjusted OR (95% CI)
Predictors pdisorders
LLower
Urinary Tract Symptoms
7.61 4.02Symptoms (4.06-14.26) (2.75-5.89)
Laumann, Paik & Rosen, JAMA, 1999
Estradiol deficiency
Vulvo-vaginal atrophy
D i / it l l Dyspareunia / genital arousal
Negative effecton sexual function
CONSEQUENCES AND MANAGEMENT OF UROGENITAL ATROPHYUROGENITAL ATROPHY
UROGENITAL ATROPHY
1 UG changes in menopause1 UG changes in menopause
2 Prevalence of vaginal atrophy
3 Management options
4 Hormone therapy.Vaginal route
5 Potencial barriers to management UGA5 Potencial barriers to management UGA
Postmenopausal changes in the vaginal mucosa
Premenopausal Postmenopausal
VaginaF ld
Erectile tissue
Loss of folds
Folds or rugae
Muscular coat
I li i L f i Inner mucous liningcontains large
amount glycogen
Loss of inner mucous lining and glandular function
Vaginal Changes in Menopause
B f • Before menopause– Vaginal epithelium is thick and nonkeratinized– Glycogen is abundantGlycogen is abundant– Normal acidic pH is 3.5 to 4.5
Impact of menopause on the urogenital Urogenital
system• Impact of menopause on the urogenital system – Estrogen declines
system
Estrogen declines– Vaginal epithelium loses rugae– Tissues grow thin and pale– Vaginal secretions decrease– Glycogen diminishes
V i l H i– Vaginal pH increases
Pandit and Ouslander. Am J Med Sci 1997; 314:228-231.
Compared to premenopausal women, postmenopausal ith t g d fi i hwomen with estrogen deficiency have
FEWER:– Facultative lactobaccilli
Gardenerella aginalis– Gardenerella vaginalis– Coryneforms– YeastsYeasts– Prevotella bivia– Staphlococci– Mycoplasma hominis – Ureaplasma urealyticum
BUT MORE:Coliforms – Coliforms
– Streptococi viridans
Atrophic vaginitis under the microscopep g p
Normal:Squamous cellsCells with enough cytoplasm an low nucleus/cytoplasm ratio
Atrophic vaginitis:Presence of parabasal cellsSquamous cells with enlarged nucleuslow nucleus/cytoplasm ratio
Pyknosis presentnucleusInflammation exudat“Blue Blobs” – characteristic, round basophilic structuresround basophilic structures
Bachmann GA, Nevadunsky NS; http://www.aafp.org/afp/20000515/3090.html; Accessed May 2004 & October 2006
Vaginal Atrophy
S t P t l P l • Symptoms– Vaginal dryness– Decreased lubrication
Postmenopausal woman treated with estrogen
Postmenopausal woman without estrogen
Decreased lubrication– Discomfort, burning,
soreness
• Predisposition to:
– Urinary tract infectionsParabasal
cellsSuperficial
cells
– Vaginal infections
• Advanced signsRugae
– Contraction of vagina– Loss of distensibility Vaginal
epitheliump
Pandit, et al. Am J Med Sci. 1997;314:228-31.
CONSEQUENCES AND MANAGEMENT OF UROGENITAL ATROPHYUROGENITAL ATROPHY
UROGENITAL ATROPHY
1 UGA changes in menopause
2 Prevalence of vaginal atrophy
3 Management options
4 Hormone therapy.Vaginal route
5 Potencial barriers to management UGA
Increase in Vaginal Dryness with Menopause
50
with Menopause
40
30
erce
nt
10
20Pe
0
10
Pre Early Late Post Post PostPre-menopause(n = 172)
EarlyPeri-
menopause(n = 148)
LatePeri-
menopause(n = 106)
Post-menopause
1 year(n = 72)
Post-menopause
2 years(n = 54)
Post-menopause
3 years(n = 31)
Dennerstein L, et al. Obstet Gynecol. 2000;96:351-8. (Slide provided by the Council on Hormone Education, 2002)(Slide provided by the Council on Hormone Education, 2002)
( ) ( ) ( ) ( ) ( )
Dryness increased significantly in late perimenopause and postmenopause (P < .001).
©JL Alexander, www.afwh.org
RELEVANCE OF SEXUAL ISSUES AT MENOPAUSE
66%No periods for 1+ years
37%
43%
52%
I it bilitSleeplessness
Hot flushes
36%37%37%
Reduced sex driveMood swings or mood changes
Irritability
25%
28%Depression
Headaches or migraines
14%
21%21%
Very occasional periodsVaginal pain, dryness or discomfort
Involuntary urine loss
14%Very occasional periods
Q2A Are you currently experiencing or have you experienced any of the following in the past year?Base: Total Sample (n=1805) of European (from Italy Switzerland UK Germany France The Base: Total Sample (n=1805) of European (from Italy, Switzerland, UK, Germany, France, The Netherlands) menopausal women (age: 50-60 yrs) interviewed by phone
Nappi & Nijland, 2008
SEXUAL SYMPTOMS &SURGICAL MENOPAUSEVAGINAL DRYNESSQ Aft i l did
SEXUAL DESIREQ Aft i l did Q: After surgical menopause did you
noticed the appearance/worsening of…Q: After surgical menopause did younoticed a reduction of…
0 9%0 5%22.4%
0.9%20.2%
0.5%
55.5%46.8%
29.9%23.8%
Yes NoSample: 568 women withsurgical menopause
Most of the time No Answersurgical menopause
Nappi et al, submitted
CONSEQUENCES AND MANAGEMENT OF UROGENITAL ATROPHYUROGENITAL ATROPHY
UROGENITAL ATROPHY
1 UGA changes in menopause
2 Prevalence of vaginal atrophy
3 Management options
4 Hormone therapy.Vaginal route
5 Potencial barriers to management UGA
MANAGEMENT OPTIONS
a) Lifestyle modifications
a) Non-hormonal treatment (lubricants, moisturizers)
a) Hormonal therapy, systemic or local a) Hormonal therapy, systemic or local
a) Others: herbal, soy, vitamins
LIFE STYLE MODIFICATIONS
1 .Cessation of smokinggKalogeraki. In Vivo. 1996
2 Sexual activity 2. Sexual activity. Both regular coital activity and masturbation provide protection
“USE IT OR LOSE IT”
Leiblum et al. JAMA. 1983
3. Cranberry - lingonberry juice concentrate reduces risk of UTIin postmenopausal women.
Kontiokari. BMJ. 2001
NON HORMONAL THERAPY
LUBRICANTS Temporary measures to relieve vaginal dryness during intercourse,
Combination of protectants and thickening agents in water soluble p g gbase.Short duration of action, needs frequent application and reapplication before sexreapplication before sex.
- Astroglide
- K-Y jelly
- Lubrin
- H-R jelly
- Surgilube Surgilube
- Touch Wilhite et al. Pharmacology. 2001
MOISTURIZERS
Bioadhesive polycarbophil-based polymer which adheres to mucin p y p p yand epithelial cells on vaginal wall
Carry up to 60x its weight in water and holds water in place y p g pagainst vaginal epithelium until cells sloughs off, about 24 hours.
2-3 applications per week.pp p
No need for reapplication prior to sex
Symptomatic relief, acidic PH
Some effect on vaginal elasticitySome effect on vaginal elasticity
Replens
Moist Again d d h M t it 1996Moist Again Bygdeman and Swahn. Maturitas. 1996
CONSEQUENCES AND MANAGEMENT OF UROGENITAL ATROPHYUROGENITAL ATROPHY
UROGENITAL ATROPHY
1 UGA changes in menopause
2 Prevalence of vaginal atrophy
3 Management options
4 Hormone therapy.Vaginal route
5 Potencial barriers to management UGA
Meta analysis of placebo controlled trials revealed Meta analysis of placebo controlled trials revealed
estrogen to be more effective than placebo for all
variables measured
Cardozo et al.Obstet Gynecol. 1998
Th i l t f d i i t ti l t d ith b ttThe vaginal route of administration correlated with betterreports of symptomatic relief, greater improvement in cytologic findings
Cardozo et al.Obstet Gynecol. 1998
Low dose vaginal estradiol was the most efficacious
Cardozo et al.Obstet Gynecol. 1998
Major effect on patient report occurs between
1 and 3 months after the start of treatment and is maintained thereafter
Cardozo et al.Obstet Gynecol. 1998
Vaginal application formsg pp
Creams
Premarin®
i l
Vaginal Ring
Estring®
t i
Vagitories
Ortho Gynest®
i l t i l
Vaginal tablets
Vagifem®
fi t d l vaginal cream (PVC) conju-gated equine estrogens (CEE)
contains estradiol,releases estradiol in a consistent
vaginal estriol suppositories
first and only vaginal oestrogen tablet
Estrace®
estradiol cream in an applicator-free tube
a consistent manner over 90 days
free tube
Vagifem® 10µg provides a very low dose f t di lof estradiol
• 1.14 mg exposicion annual al estrogenoDose and administration
Initial Dose:1 tablet inserted into the vaginadaily for 2 weeks. = 14 tabletsMaintenance:
bl d ll k1 tablet inserted vaginally twice per weekfor 50 weeks = 100 tabletas
Total per year:Total per year:114 tablets x 10µg = 1140µg
1140µg of estradiol1140µg of estradioladministered to the patient in 1 year = 1.14 mg
Degree of vaginal healthg g
2,0
2,5lt
h
1,5
inal
Hea
l
0 5
1,0
core
Vag
i
p<0.001
p<0.001 p<0.001 p<0.001 p<0.001
0,0
0,5
Mea
n S
Baseline 2 4 8 12 (LOCF)52 (LOCF)Weeks
Placebo 10µg E2
Simon JA et al. Obstetrics & Gynecology 2008; 12(5): 1053–60
Other Treatments - SERMs
• SERMs elicit different effects in differential tissues– Agonist (bone)– Antagonist (breast)
• Previous SERMs have different actions:– Tamoxifen and raloxifene both act as antagonist in the breast and
agonist in the boneg– Only tamoxifen acts as agonist in the uterus– Neither tamoxifen nor raloxifene have an effect on the vagina
• New SERM – Lasofoxifene
– Agonist behavior in bone, the vagina, and the cardiovascular system g , g , y
– Antagonist behavior in breast and uterine tissue
• New SERM ospemifenep
Dutertre, Smith. Pharmacol and Experimental Therapeutics. 2000;295:431-7.
CONSEQUENCES AND MANAGEMENT OF UROGENITAL ATROPHYUROGENITAL ATROPHY
UROGENITAL ATROPHY
1 UGA changes in menopause
2 Prevalence of vaginal atrophy
3 Management options
4 Hormone therapy.Vaginal route
5 Potencial barriers to management UGA
Initiation of dialogue about vaginal dryness
WWomen
Selection:respondents having discussed “vaginal dryness” with physician?
6680
(%
)
respondents having discussed vaginal dryness with physician?
40
56
40
60
espo
nden
ts
27
20
Perc
ent
of r
e
0The doctor Respondent herself
Non HRT-patients (n = 74) HRT-patients (n = 189)
P
HRT Market Understanding, TNS EMNID 2002
p ( ) p ( )
Potential Barriers to Discussing S l H lth ith P ti tSexual Health with your Patients
Patient barriers Doctor barriersPatient barriers• Emotional factors
(shame, anxiety, embarrassment)Age (life stage)
• Embarrassment1
• Feeling overwhelmed by more urgent healthcare issues• Age (life stage)
• Perception that sexual functioning is not an important medical problem
urgent healthcare issues• Lack of specific training in sexual
medicine2
F li th ti ll h l l• Lack of awareness about treatment possibilities
• Physician characteristics
• Feeling therapeutically helpless • Lack of awareness of associated
comorbid conditions(gender, age, speciality)
Contextual barriersf f• Lack of confidentiality
• Lack of privacy• Poor reimbursement3
1. Korenman S.G (1998) Am J Med. 105: 135-144; 2. Broekman CPM, et al.(1994) Int J Impot Res. 6: 67-72;3. Baum N, et al.(1998) Patient Care Spring (suppl):17-21
Source: FSDeducation.eu
SEXUAL FUNCTIONSEXUAL FUNCTION
Co-occurrence of Core M “B i ” SMenopause “Brain” Symptoms
SleepVasomotor Symptoms Symptoms
Depression
Odds Ratios (ORs) of Hormones From the Final Multivariable Model for Onset of Depressive Symptoms (CES-D Scale Score >= 16) for 116 Participants
At the time of high CES-D scores a At the time of high CES D scores, a woman was more likely to have an increased variability around her own levels of estradiol (P 03) FSH levels of estradiol (P = .03), FSH (P<.001), and LH (P = .005) than she did before the high CES-D scores
Freeman E W et al Arch Gen Psychiatry 2006;63:375 382
Copyright restrictions may apply.
Freeman, E. W. et al. Arch Gen Psychiatry 2006;63:375-382.
Risk of First Onset of Depressive Symptoms in Premenopausal and PerimenopausalWomen With No Lifetime History of Major DepressionWomen With No Lifetime History of Major Depression
Cohen, L. S. et al. Arch Gen Psychiatry 2006;63:385-390.
PREMENOPAUSAL WOMEN WITH NO LIFETIME HISTORY OF MAJOR DEPRESSION WHO ENTERED PREMENOPAUSAL WOMEN WITH NO LIFETIME HISTORY OF MAJOR DEPRESSION WHO ENTERED THE PERIMENOPAUSE WERE NEARLY TWICE AS LIKELY TO DEVELOP DEPRESSIVE SYMPTOMS AS WOMEN WITH NO HISTORY OF DEPRESSION WHO REMAINED PREMENOPAUSAL
EFFECTS OF E/TE ON FUNCTIONAL MRI
Estrogen Modulation of Key Regions/SystemsBrain regions involved in mood and menopausal symptomsBrain regions involved in mood and menopausal symptoms
= Areas directly influenced by estrogen
Estrogen has multiple effects on neurotransmitter systems and brain regions involved in mood and menopausal symptoms menopausal symptoms (VMS)
During times of estrogenDuring times of estrogenfluctuations/decline, loss of these effects might predispose some women to dysregulation of affected brain regions
Figure adapted from Charney DS. Am J Psychiatry. 2004;161:195-216.
brain regions
Effects of estrogens on serotonergic and noradrenergic neuronsnoradrenergic neurons
Deecher et al. Psychoneuroendocrinology 2008; 33:3-17
Am J Obstet Gynecol 2009
Estrogen Therapy for M R l t d D iMenopause-Related Depression
Treatment n Population Main FindingsTreatment n Population Main Findings
Transdermal E2(50 mcg/d), DB, PL, 6 weeks1
36 Perimenopausal women with depressive disorders
• POSITIVE: Partial/full response –80% with E2, 22% with placebo. No association with hot flashes
Transdermal E2(100 mcg/d), DB, PL, 12 weeks2
50 Perimenopausal women with depressive disorders
• POSITIVE: Remission – 68% with E2, 20% with placebo. Sustained antidepressant response despite , , p p precurrence of hot flashes
Oral E2 (0.3 mcg/d),
3
10 Perimenopausal women with major depression
• POSITIVE: Remission in 60% of patients treated with E2
open, 8 weeks3
Transdermal E2(100 mcg/d), open 4 weeks4
22 Mixed menopausal status with depressive disorders
• POSITIVE: Peri: 66% remission• NEGATIVE: Post: 18% remission
open, 4 weeks4
Transdermal E2(100 mcg/d), DB, PL, 8 weeks5
57 Postmenopausal women with depressive disorders
• NEGATIVE: Response to E2(40%) was similar to placebo (44%), , ( )
DB = double-blind; PL = placebo-controlled.
1. Schmidt PJ, et al. Am J Obstet Gynecol. 2000;183:414-420. 2. Soares CN, et al. Arch Gen Psychiatry.2001;58:529-534. 3. Rasgon NL, et al. Am J Psychiatry. 2001;158:1738. 4. Cohen LS, et al. Am J Psychiatry. 2003;160:1519-1522. 5. Morrison M, et al. Biol Psychiatry. 2004;55:406-412.
Conclusion HT
•Impact on the risk for depression, sleep disruption, VMS, cognitive decline
•Impact on brain functioning/structure
• Impact on depressive symptoms, response to tid tantidepressants
Impact on sexual function•Impact on sexual function