alternative treatment for menopausal symptoms -from...

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]