alternative treatment for menopausal symptoms -from...
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Alternative treatment -from an evidence based perspective-
Mette Haase MoenDep of Obst and Gyn, St. Olavs Hospital,
Trondheim, Norway
The Norwegian University of Science and Technology
Alternative treatment for menopausal symptoms
-from an evidence based perspective-
Disclosure
• Lecturer and advisor for: – Bayer Schering– MSD (Organon)– Novo Nordic– Pfizer
• Treasurer of EMAS• Certified NAMS menopause practitioner• Postmenopausal
Norway
Population: 4.5 million
Trondheim
Snøhætta
Sale of estrogen in Norway (HT)
http://www.legemiddelforbruk.no/
175.000~50%
55.000<15%
HT
Avoiding estrogen
• Side effects of HT– Fear– (Experience)
• Contraindications for HT– Breast cancer– Previous thrombosis– Other
Health food stores Internett
Alternative treatment for menopausal symptoms in Sweden
46 % of 4.504 Swedish women had use alt. treatment45 % reported effect
Stadberg, Acta Obst Gyn Scand, 1997
Alternative treatment for menopausal symptoms in Sweden
Alternative treatment for menopausal symptoms in Norway150 women 50-69 years (mammography-screening)40% had used alternative treatment (mostly soy)42% reported effect
Dahle, Lydersen, Moen, J Norw. Med Assoc. 2006
Use of alternative therapy in US
62 % of the adult population use some kind of complementary and alternative medicine.
US women desire greater professional guidance on hormone and alternative therapies for menopause symptom management.
Ma J et al, 2006
Treatment of vasomotor symptomsWhat are the alternatives?
What is the evidence?
The material
• Pub-Med search– Randomised controlled studies
• Metaanalyses• Cochrane reviews• Guidelines
Alternative treatment for menopausal symptoms
• The evidence • The mechanism of action• Side effects• Safety aspects
Alternatives to estrogen
Prescribed drugs:
• Clonidine• SSRI/SNRI• Gabapentine
Complimentary and alternative treatment (CAM):
• Phytoestrogens– Soy– Red clover
• Cimicifuga racemosa
Other•Acupuncture•Life style •Etc
Non-estrogenic hormones:• Progestins• Progesterone
ProgestinsProgesterone cream
Progestin for vasomotor symptoms
• Part of postmenopausal hormone therapy • Additive effects to estrogen• Some progestins are estrogenic
Megestrol acetate 20 mg x 2
Loprinzi, 1994Weeks: 1 4 4 4
>6 daily
Meg A
Placebo
.
Goodwin J W et al. JCO 2008;26:1650-1656©2008 by American Society of Clinical Oncology
Megestrol acetate and reduction in hot flashes at 3 months
Placebo
MA 20 mg
MA 40 mg
MA 20 mg
14%
65%
48 %
MPA inj 500 mg/14thdayMegestrol acetate oral 40 mg daily
6 weeks:86% reduction in hot flushes, n.s.
24 weeks:MPA 89% reduction, MA 45 % (p=0.03)
Bertelli, Ann Oncol, 2002
N=71 (breast cancer survivors)
Figure 4 Percentage of days with each intensity level of vasomoFigure 4 Percentage of days with each intensity level of vasomotor symptoms tor symptoms over 1 yearover 1 year for both daytime and for both daytime and nightnight--time hot flushes and night sweats during the therapies followingtime hot flushes and night sweats during the therapies following premenopausal premenopausal ovariectomyovariectomy
Prior, Prior, ClinClin. Sci. (2007) 112, 517. Sci. (2007) 112, 517--525 525
CEE 0.6mg or MPA 10mgafter premenopausal oophorectomy
n.s.
E
E
PP
Progestin side effect and safety
• Weight gain• Oedema• Hirsutism• Mood depression
No data • On breast cancer• Long-time safety
aspects– Liver– Lipids
Suitable for women with•A history of endometriosis•Increased risk of endometrial cancer
Progesterone cream
‘Natural progesterone’ extracted from wild yams
Pharmacy dispensed: 1.7% progesterone in Decubal cream
Internett:
Progesterone Cream: 20-30 mg daily
ProgestaCare ™ : 20 mg x 2 daily
Progesterone cream for menopausal symptoms-placebo controlled studies-
n.s.6 monthsProg. cream
5-60 mg223Benster2009
n.s.12 weeksProg. cream32 mg pr day
68Wren2003
n.s.3 monthsWild yam cream
23Komesaroff2001
Sign.(83 % ↓ versus 19 % ↓)
4 monthsProg. cream20 mg pr day
56Leonetti1999
StatDurationProgestinNStudy
Non-hormonal drugs
• Clonidine• SSRI -SNRI• Gabapentine
Nelson HD et al, JAMA 2006, 295: 2057-71
Clonidine
•α2 adrenergic agonist•Inhibiting sympaticus-tonus•Mechanism: increased threshold for sweating in symptomatic women
Dosage for hot flushes: 25-75g x 2
Freedman et al, Fertil Steril, 2000
Copyright restrictions may apply.Nelson, H. D. et al. JAMA 2006;295:2057-2071.
Metaanalysis of Clonidine
4 weeks
8 weeks
Clonidine-side effects and safety-
• Dry mouth• Drowsiness• Sleep disturbances• Constipation• Hypotension
Withdrawal: 5-10%
• In use for several years on other indications
Suitable for women with1. Migraine2. Hypertension
Use of Clonidine in Ontario
Austin et al, Can J Clin Pharmacol, 2004
SSRI-SNRI - selective serotonin reuptake inhibitors
-serotonin noradrenalin reuptake inhibitors-
• Antidepressants• Reuptake inhibitors of serotonin/noradrenalin in CNS• Mechanism in vasomotor
symptoms:– Unknown
• More rapid effect than as antidepressants
Meta-analysis SSRI-SNRI
Nelson, H. D. et al. JAMA 2006;295:2057-2071.
Forest plots of hot flash reduction in newer antidepressant studies.
Loprinzi C L et al. JCO 2009;27:2831-2837
©2009 by American Society of Clinical Oncology
Zoloft®
Non sign4 weeksPlaceboSertralin25-100 mg
46Wu2009
Sign in subgroups
8 weeksPlaceboSertralin50 mg
102Kerwin2007
Non sign6 weeksPlaceboSertralin50-100mg
99Grady2007
Sign. 6+6 weeksPlaceboSertralin50 mg
62Kimmick2006
Sign. 4+4 weeksPlacebo Sertralin50 mg
102Gordon2006
StatDurationControlSSRINStudy
Cipralex® and Cipramil®
Sign(20 mg)
6 weeksPlaceboCitalopram 10-30 mg244Barton2010
Sign. 8 weeksPlaceboCitalopram 10-20 mgHT Citalopram+HT
100Kalay2007
Non sign.8 weeksEE 5mg/Prog.Cipralex 10-20 mg40Soares2006
StatDurationControlSSRINStudy
Effexor® and Pristiq®
Equaleffect
12 weeks1 years obs.
AcupunctureVenalafaxine37,5-75mg
50Walker2010
Moderate equaleffect
8+8 weeksClonidine50µg x2
Venlafaxine75 mg
60Buijs2009
N.S.26 weeksSign.12 weeksPlaceboDesvenlafaxine
100-150 mg567Archer
2009
Sign(100 mg)
12 weeksPlaceboDesvenlafaxine50-200 mg
620Speroff2008
Sign. (75 mg)
14 weeksPlaceboVenlafaxine 37,5-75 mg
77Carpenter2007
StatDurationControlSNRINStudy
Side effects SSRI-SNRI
• Gastro-intestinal problems• Tiredness• Headache • Insomnia• Loss of libido Withdrawal: 10-25%May interact with the metabolism of tamoxifen
(especially fluoxetine and paroxetine)Bordeleaue, 2010
Suitable for women with depression and anxiety
GabapentinUsage
AntiepilecticPain relief• Neuropatic pain.
Mechanism of action• partly unknown• Increases GABA synthesis
Sign (75 mgx2)
6 weeksPlaceboPregabalin150-300 mg
163Loprinzi2010
Gaba=Estradiol8 weeksEstradiolpatch 25µg
Gabapentin 600 mg45Aguirre2010
Gaba=CE>placebo12 weeksPlaceboGabapentin →2400mgCE 0.625
46Reddy2006
Sign. 4 weeksPlaceboGabapentin 900 mg197Butt2008
Sign. (900 mg)
8 weeksPlaceboGabapentin300 mg og 900 mg
420Pandaya2005
Sign.12+5 weeksPlaceboGabapentin 900 mg59Guttuso2003
StatDurationControlTreatmentNStudy
Gabapentin-Neurontin®
Metaanalysis of gabapentin
Loprinzi, 2009
Side effects of gabapentin
• Tiredness• Dizziness• Headache• Ataxia
Withdrawal: ~ 5 %
Suitable for women with epilepsyand pain such as fibromyalgia
CAM Complementary and alternative
medicine
Phytoestrogens
Definition:• Herbs containing substances with estrogenic structures
and estrogenic effect. • Estrogen-receptor-binding: -receptor Subtypes:• Isoflavones (genistein, daidezin ): soy, vegetables• Lignans: cereals, flaxeed, linseed• Coumestans: red clover
Phytoestrogens
Isoflavones Coumestan
Estradiol
The role of soy
• Extensively used Japan (tofu)• Japanese women less climacteric symptoms• Less breast cancer in Japan
Evidence
Nedrow A et alComplementary and alternative therapies for
the management of menopause-related symptoms: a systematic evidence review.
Arch Intern Med. 2006; 166: 1453-65.
Studies on Soy (isoflavones)
Nedrow A, Arch Int Med. 2006
4 w
12 w
6 m
Isoflavones-soy
Daily recommendations: 50-150 (2.000) mg
Soy products
2Soy sauce10Soy milk16Tofu yoghurt27Tofu ’Silken’60Miso soup97Soy protein
148Soy flour
151Soy beans, green, raw
Rec.dose: 50-(2.000 mg) mg Isoflavon per 100g
100 g
20 bottles
Equol
Isoflavone supplementation improves only in women with the ability to produce equol. (30-50%)
Jou et al , 2009Equol, a gut bacterial metabolite of the isoflavone
daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens.
Törmälä et al, 2007
Red clover
PromensilTrifolium pratense
Rimostil
Red clover
Nelson HD et al JAMA. 2006; 295: 2057-71
Phytoestrogens (promensil) for vasomotor menopausal symptoms
Cochrane collaboration 2007:There is no evidence of effectiveness
Phytoestrogens
• Are they safe?– Breast – Endometrium
• The effect of soy on the breast of young women cannot be transferred to postmenopausal women
• Three cases of endometrial stimulation (Chandrareddy A, 2008)
Phytoestrogens
Side effects: metaanalysisTempfer et al, 2009Conclusion:• Safe side effect profile• Moderate gastrointestinal side effects
Soy
Side effects: meta-analysisMyung, 2009Conclusion:• Protective effect on
– Endometrial cancer– Ovarian cancer
Debated by Cohain, 2010Soy >0.07 g daily associated with endometrial bleeding (2-9%)
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001395.Phytoestrogens for vasomotor menopausal symptoms.
Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J.
• AUTHORS' CONCLUSIONS: There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments.
Cimicifuga racemosa
Actaea racemosaBlack cohoshRemifeminKlimadynonMenofem
Cimicifuga racemosa
Medicine of North American Indians
1989 in Germany approved for menopause symptoms
Effect mostly unknownSERM? SSRI? (Not a phytoestrogen)
Positive studies on Cimicifugaracemosa
TurkeyCR>Fluox6 monthsFluoxetineDose?
Cimicifuga racemosaDose?
120Oktem2007
Israelsign3 monthsPlaceboCimicifuga racemosa and other plants
50Rotem2007
ChinaCR=Tibolone12 weeksTibolone 2.5 mgCimicifuga racemosa40 mg
244Bai2006
Germanysign12 weeksCE 0.6 mgPlacebo
Cimicifuga racemosa40 mg
62Wuttke2006
Germanysign12 weeksPlaceboCimicifuga racemosa40 mg
304Osmers2005
ItalyCR=E12 weeksEstradiol patch 25 µg
Cimicifuga racemosa40 mg
64Nappi2005
Switzerlandsign12 weeksPlaceboCimicifuga racemosa42 mg
122Frei-Kleiner2005
Venezuelasign12 monthsPlaceboCimicifuga racemosa40 mg
136Munoz2003
Germanysign12 weeksPlaceboCimicifuga racemosa80 mg
80Stoll1987
CountryStatDurationControlTreatmentNStudy
Negative studies on Cimicifugaracemosa
AustraliaNon sign16 weeksPlaceboCimicifuga racemosa350 mg +Chinese herbs
93Van der Sluijs2009
USNon sign12 monthsPlaceboCimicifuga racemosa128 mgRed clover 120 mgCE 0.625/MPA 2,5mg
89Geller2009
USNon sign52 weeksPlaceboCimicifuga racemosa160 mg
164Newton (HALT)2006
USNon sign.4+4 weeksPlaceboCimicifuga racemosa40 mg
132Pockaj2006
USNon sign.8 weeksPlaceboCimicifuga racemosa40 mg
85Jacobson2001
CountryStatDurationControlTreatmentNStudy
Studies on cimicifuga racemosa
TurkeyOktem2007
IsraelRotem2007
ChinaBai2006
GermanyWuttke2006
GermanyOsmers2005
ItalyNappi2005
SwitzerlandFrei-Kleiner2005
VenezuelaMunoz2003
GermanyStoll1987
CountryStudy
AustraliaVan der Sluijs2009
USGeller2009
USNewton (HALT)2006
USPockaj2006
USJacobson2001
CountryStudy
Positive results Negative results
HALT-study
Newton et al, Ann Int Med 2006; 145: 869-79
N=351
8076793284
The National Institute on Aging and the National Center for Complementary and Alternative Medicine.
The Herbal Alternatives for Menopause Trial
Warning
• Norwegian Medicines Agency 18 Oct 2006Cimicifuga racemosa: liver toxic (autoimmune reaction)
• United States Pharmacopeia determines that black cohosh products should be labeled with a cautionary statement (Menopause, 2008)
• EMEA (European medicines agency) 17 Sep 2009– Not for more than 3 months without medical advice– Caution in patients with liver disorders– Not to be used together with estrogens– Not to be used in breast cancer patients
Nelson HD. Lancet, 2008
Conclusion
Progestins Cimicifuga rasemosa
Life style and other therapies
Quit smoking
Weight reductionExercise
Relaxation
Acupuncture
Stellatum block
Thank you for your attention
Soy products
2Soy sauce10Soy milk16Tofu yoghurt27Tofu ’Silken’60Miso soup97Soy protein
148Soy flour
151Soy beans, green, raw
Daily recommendations: 50-(2.000 mg) mg Isoflavones per 100g
K. Winther, E. Rein and C. HedmanClimacteric 2005; 8(2): 162-170
Design: double-blind, parallel groups,placebo controlled
Patients: 54 women
Mean age: 51,6 years (placebo)51,2 years (Femal)
Treatment time: 3 months
(Follow-up: 3 months)
Femal, a herbal remedy made from pollen extracts, reduces hot flushes and improves quality of life in menopausal women
K. Winther, E. Rein and C. HedmanClimacteric 2005; 8(2): 162-170
Follow-up after 6 months
Hot flushes: further 45% reduction
Changes of underwear: further 42% reduction
No further side effects reported
K. Winther, E. Rein and C. HedmanClimacteric 2005; 8(2): 162-170
Gabapentin• Its exact mechanism of action is unknown, but its
therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the α2δ subunit (1 and 2)[3] of the voltage-dependent calcium channel in the central nervous system.[4]
• Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis, probably by modulating, as it does in vitro, the action of the GABA synthetic enzyme, glutamic acid decarboxylase(GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase.[5]