Non-hormonal therapyNon-hormonal therapy

M. Gambacciani and P. Albertazzi

Potential health benefits of dietary Potential health benefits of dietary phytoestrogens: a review of the clinical, phytoestrogens: a review of the clinical,

epidemiological, and mechanistic evidenceepidemiological, and mechanistic evidence

• Phytoestrogens (isoflavones and lignans) are plant compounds that have been shown to have both estrogenic and antiestrogenic properties

• A wide range of commonly consumed foods contain appreciable amounts of these different phytoestrogens

• Accumulating evidence from molecular and cellular biology experiments, animal studies, and, to a limited extent, human clinical trials suggests that phytoestrogens may potentially confer health benefits related to cardiovascular diseases, cancer, osteoporosis, and menopausal symptoms

Tham DM, et al. J Clin Endocrinol Metab 1998;83:2223–35

Potential health benefits of dietary Potential health benefits of dietary phytoestrogens: a review of the clinical, phytoestrogens: a review of the clinical,

epidemiological, and mechanistic evidenceepidemiological, and mechanistic evidence

• These potential health benefits are consistent with the epidemiological evidence that rates of heart disease, various cancers, osteoporotic fractures and menopausal symptoms are more favorable among populations that consume plant-based diets, particularly among cultures with diets that are traditionally high in soy products

Tham DM, et al. J Clin Endocrinol Metab 1998;83:2223–35

Critical review of health effects of Critical review of health effects of soyabean phytoestrogens insoyabean phytoestrogens in

postmenopausal womenpostmenopausal women

• Limited evidence of the effect of phytoestrogen on hot flushes

• Concerns over long-term safety, particularly at high doses

http://phytohealth.org Cassidy A, et al. Proc Nutr Soc 2006;65:76–92

Effects superior to placeboEffects superior to placebo• Effects of a standardized soy extract on hot flushes: a multicenter,

double-blind, randomized, placebo-controlled study1

• Benefits of soy isoflavone therapeutic regimen on menopausal symtoms2

• Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study3

• Clinical effects of a standardized soy extract in postmenopausal women: a pilot study4

• The effect of dietary soy supplementation on hot flushes5

• Isoflavones from red clover (Promensil®) significantly reduce menopausal hot flush symptoms compared with placebo6

• Soy protein and isoflavone effects on vasomotor symtoms in peri- and postmenopausal women: the Soy Estrogen Alternative Study7

1Faure EA, et al. Menopause 2002;9:329–34; 2Han KK, et al. Obstet Gynecol 2002;99:389–94; 3Upmalis AH, et al. Menopause 2000;7:236–42; 4Scambia G, et al. Menopause 2000;7:105–11; 5Albertazzi P, et al. Obstet Gynecol 1998;91:6–11; 6Van de Weijer P, et al. Maturitas 2002;42:187–93; 7Burke GL, et al.

Menopause 2003;10:147–53

Is there a proven place for Is there a proven place for phytoestrogens in the menopause?phytoestrogens in the menopause?

• Phytoestrogens are estrogens derived from plants

• We need:– Differentiation of different agents– standardization of dosages– safety and efficacy labelling

• Currently, there is no reliable evidence confirming a substantial role for phytoestrogens in the treatment of postmenopausal women

• Their increasing promotion should not be endorsed by the medical profession by accepting promotional materials in journals or at meetings

Ginsburg J, Prelevic G. Climacteric 1999;2:75–8

Doses used in different studiesDoses used in different studies

• Murkies, 1995 45 mg

• Baber, 1998 40 mg

• Albertazzi, 1998 76 mg

• Nestel, 1998 40–80 mg

• Washburn, 1999 34 mg

• Nachtigall, 1999 40 mg

• Howes, 2000 38 mg

• Kok, 2005 100 mg

• Kreijkamp-Kaspers, 2005 99 mg

4 positives6 effects

not superior to placebo

Huntley AL. Maturitas 2004;47:1–9

Soy for the treatment of Soy for the treatment of perimenopausal symptoms:perimenopausal symptoms:

a systematic reviewa systematic review

• 10 clinical studies

• Doses 34–143 mg

• Time of observation 6–24 weeks

Isoflavone treatment forIsoflavone treatment foracute menopausal symptomsacute menopausal symptoms

• Double-blind prospective study

• 51 women finished the 12-week study

• In women receiving 60 mg isoflavones daily, hot flushes and night sweats were reduced by 57% and 43%, respectively

Cheng G, et al. Menopause 2007;14:468–73

Conclusions: This short-term prospective study implies that isoflavones could be used to

relieve acute menopausal symptoms

Phytoestrogen therapy for Phytoestrogen therapy for menopausal symptoms?menopausal symptoms?

There's no good evidence that it's any better than placebo

• Women experiencing mild menopausal symptoms may gain relief by dietary modification and lifestyle changes, such as reducing smoking and consumption of caffeine and alcohol, stress management, and increased exercise

• However, there is no evidence to support the belief that even a very high intake of soy products will alleviate hot flushes, night sweats, and other symptoms such as vaginal dryness, mood changes, and musculoskeletal symptoms

• No absolute conclusions can be drawn from the few studies of the effects of phytoestrogens on bone. As with other interventions of unproved efficacy, long-term randomized trials will be required to determine the place (if any) of phytoestrogens in the management of postmenopausal women

Davis SR. Br Med J 2001;323:354–5

PhytoestrogenPhytoestrogenand climacteric symptomsand climacteric symptoms

• 25 randomized controlled trials (Medline and the Cochrane Library, 1996–2004)

• 2348 postmenopausal women (mean age 53.1 years, mean time since menopause 4.3 years , 7.1 hot flushes/day)

• No significant effects vs. placebo

• The available evidence suggests that phytoestrogens available as soy foods, soy extracts, and red clover extracts do not improve hot flushes or other menopausal symptoms

Krebs EE, et al. Obstet Gynecol 2004;104:824–36

Menopausal complementary and alternative Menopausal complementary and alternative therapies unsupported by systematic reviewtherapies unsupported by systematic review

• Medline and the Cochrane Library database: 70 relevant trials were identified

• 48 of the studies looked at soy-derived phytoestrogens, vitamins, proteins, diets, osteopathic manipulation, mind-body therapies, meditation, Chinese and ayurvedic medicine, energy-based treatments such as reflexology and magnet therapy or other biologically based treatments

• There was not enough good-quality data to recommend any of the treatments

• Many of the studies had a large placebo effect that might contribute to the expanding market of dietary menopausal supplements

Nedrow A, et al. Arch Intern Med 2006;166:1453–65

HRT versus placeboHRT versus placebofor hot flushesfor hot flushes

• In a Cochrane review of 24 trials involving 3329 participants, there was an overall reduction in hot flushes– 75% (95% CI 64–82%) with oral estrogen– 57% (95% CI 45–67%) with placebo

MacLennan AH, et al. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No CD002978. DOI: 10.1002/14651858.CD002978.pub2

Not all placebosNot all placebosare equally pleasingare equally pleasing

• Given the 57% reduction in hot flushes seen in the placebo groups of randomized controlled trials of oral HRT, there is understandable scepticism about claims for the efficacy of products, usually complementary medicine, which find a reduction in vasomotor symptoms equal to or less than the normal 57% placebo effect

• A statistically significant effect may be claimed in such studies because the placebo effect was unusually small

Sturdee DW, MacLennan AH. Climacteric 2006;9:401–3

The effect of isoflavone extracts on The effect of isoflavone extracts on menopausal symptomsmenopausal symptoms

Double-blind, placebo-controlled prospective trialDouble-blind, placebo-controlled prospective trialof 37 postmenopausal women randomized to of 37 postmenopausal women randomized to

receive placebo, or 40 mg or 160 mg of an receive placebo, or 40 mg or 160 mg of an isoflavone extractisoflavone extract

Knight DC, et al. Climacteric 1999;2:79–84

-35-29

-34

-46 -44

-26

-100

-80

-60

-40

-20

0

Placebo 40 mg 160 mg

% V

ari

ati

on

aft

er

12

we

ek

s

Number hot flushes

Greene score

Effect of isoflavonesEffect of isoflavoneson hot flush frequencyon hot flush frequency

-40

-45

-50 -50

-43

-61-59

-40

-80

-70

-60

-50

-40

-30

-20

-10

0

% R

ed

uc

ati

on

in n

um

be

r o

f h

ot

flu

sh

es

/da

y

Placebo in HRT studies

Murkies,1995

(53 mg/day)

Albertazzi,1998

(76 mg/day) Scambia,2000

(50 mg/day)

Albert,2001

(35 mg/day)

Faure,2002

(70 mg/day)

Penotti,2003

(72 mg/day)Knight,2001

(77 mg/day)

Burke,2003

(58 mg/day)

†

Effect of soy isoflavonesEffect of soy isoflavoneson vasomotor symptomson vasomotor symptoms

*33.3 mg taken 3 times/day for 4 months†p < 0.01 for change from baseline, and for placebo vs. isoflavones at 4 months

Han KK, et al. Obstet Gynecol 2002;99:389–94

10

11.3

9.9

8.2

12

10

8

6

4

2

0Baseline Post-treatment

Rat

ing

on

Ku

pp

erm

an I

nd

ex(m

ean

± S

E)

Placebo (n = 40)Isoflavones* (n = 40)

Alternative therapiesAlternative therapies

Safety

The four harmsThe four harmsof harmless therapies of harmless therapies

• There may be recognized or unrecognized side-effects or drug interactions

• The high cost of using ineffective treatments and the waste of health dollars

• The possibility that effective evidence-based treatment may be delayed or denied

• Increasing disappointment, disillusionment and also depression, when the placebo effect wears off and the promises of each unproven therapy are unfulfilled

MacLennan AH. Climacteric 1999;2:73–4

The four harmsThe four harmsof harmless therapies of harmless therapies

“The word natural is often extensively used and abused in the advertising of these products, with

the subliminal message being that anything from a natural source cannot be dangerous and must be

what our bodies ‘naturally’ need”

MacLennan AH. Climacteric 1999;2:73–4

Endometrial effects of long-term treatment Endometrial effects of long-term treatment with phytoestrogenswith phytoestrogens

• Randomized, double-blind, placebo-controlled trial

• 298 women completed the 5-year treatment

• The occurrence of endometrial hyperplasia was significantly higher in women receiving soy tablets vs. placebo (3.37% vs. 0%)

• Long-term treatment (up to 5 years) with soy phytoestrogens was associated with an increased occurrence of endometrial hyperplasia

• These findings call into question the long-term safety of phytoestrogens with regard to the endometrium Unfer V, et al. Fertil Steril 2004;82:145–8

PhytoestrogensPhytoestrogensin breast cancer survivorsin breast cancer survivors

• Most phytoestrogens act like estrogen on the estrogen receptor

• Clinical and experimental data are questionable regarding the antiestrogenic activity or SERM-like action of phytoestrogens

• Whether these herbal remedies can be used to treat hot flushes effectively and safely in women who have had breast cancer is still unknown

Genistein stimulates growthGenistein stimulates growthof human breast cancer cells in aof human breast cancer cells in a

novel, postmenopausal animal modelnovel, postmenopausal animal model

Average tumor surface areas (mm2)

0

20

40

60

80

100

120

Control Genistein E2 E2 + genistein

Ju YH, et al. Carcinogenesis 2006;27:1292–9

Black cohosh may increase Black cohosh may increase breast cancer spreadbreast cancer spread

• 200 female mice

• Black cohosh given was comparable to the amount that women take to relieve menopausal symptoms (45 mg for every 1800 calories in the diet)

Animals with breast cancer spread to the lungs

0

5

10

15

20

25

30

Standard diet Standard diet + black cohosh

%

Davis VL, et al. American Association for Cancer Research Annual Meeting, July 11–14, 2003, Washington, DC, abstract #R910

MHRA warning:MHRA warning:black cohosh is causallyblack cohosh is causallylinked to liver disorderslinked to liver disorders

• The UK Medicines and Healthcare Regulatory Agency (MHRA) has increased warnings about the use of black cohosh, after a series of reports of adverse liver reactions

• Since 2004, when several reports linked the herb to liver disease, the MHRA has issued an alert to health-care professionals about the treatment

• All black cohosh products should contain a warning saying that they can cause liver damage

• Women with a history of liver complaints should not use such products without consulting their doctor

Posted: 20 July 2006

Effect of St. John's Wort Effect of St. John's Wort on drug metabolism by inductionon drug metabolism by inductionof cytochrome P450 3A4 enzymeof cytochrome P450 3A4 enzyme

• St. John's Wort is of questionnable value in treating depression

• St. John's Wort alters the activity of cytochrome P-450 enzymes, which play a key role in drug metabolism and pharmacokinetics

• Administration of St John's Wort may result in diminished clinical effectiveness or increased dosage requirements for at least 50% of all marketed medications (including simvastatin, alprazolam, immunosuppressant drugs, amitriptyline and digoxin)

Markowitz JS. JAMA 2003;290:1500–4

Alternative therapiesAlternative therapies

Neuroactive drugs

Biglia N, et al. Maturitas 2003;45:29–38

Menopausal symptoms after chemotherapy Menopausal symptoms after chemotherapy in women treated for breast cancer (%)in women treated for breast cancer (%)

0 10 20 30 40 50 60 70 80

Fatigue

Hot flushes

Anxiety

Insomnia

Depression

Sweating

Nervousness

Dyspareunia

Loss of libidoNot menopausal at the diagnosis

Menopausal at the diagnosis

Antidepressant drugsAntidepressant drugs

• Selective serotonine reuptake inhibitors (SSRIs)Selective serotonine reuptake inhibitors (SSRIs)– FluoxetineFluoxetine– ParoxetineParoxetine– SertralineSertraline– CitalopramCitalopram

• Serotonin noradrenergic reuptake inhibitors (SNaRIs)Serotonin noradrenergic reuptake inhibitors (SNaRIs)– VenlafaxineVenlafaxine– NefazodoneNefazodone

• Noradrenergic and specific serotoninergic antidepressantNoradrenergic and specific serotoninergic antidepressant (NaSSA)(NaSSA)– MirtazapineMirtazapine

• Noradrenaline reuptake inhibitor (NaRI)Noradrenaline reuptake inhibitor (NaRI)– ReboxetineReboxetine

Citalopram and fluoxetineCitalopram and fluoxetinein the treatment of in the treatment of

postmenopausal symptomspostmenopausal symptoms

• Compared with placebo, citalopram and fluoxetine have little effect on hot flushes and cannot therefore be recommended for the long-term treatment of menopausal symptoms, if vasomotor symptoms are the main complaint

• Whether the improvement of insomnia by means of citalopram affects the quality of sleep needs further investigation

Suvanto-Luukkonen E, et al. Menopause 2005;12:18–26

Paroxetine controlled release in the Paroxetine controlled release in the treatment of menopausal hot flushes:treatment of menopausal hot flushes:

a randomized controlled trial a randomized controlled trial

• Hot flush median reductions after 4 weeks of treatment:– 62.2% in 12.5-mg/day paroxetine CR – 64.6% in 25.0-mg/day paroxetine CR– 37.8% in the placebo group

Conclusion: Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other

therapies in treating menopausal hot flush symptoms

Stearns V, et al. JAMA 2003;289:2827–34

Median decrease (%) from baseline to week 4 (95% CI)

37.5 mg 75 mg 150 mg (n = 50) (n = 49) (n = 43) (n = 49)

Frequency 19 (14–28) 30 (22–53) 46 (36–63) 58 (42–67)

Score 27 (11–34) 37 (26–54) 61 (50–68) 61 (48–75)

Loprinzi CL. Lancet 2000

Venlafaxine in breast cancer survivors:Venlafaxine in breast cancer survivors:hot flush frequencies and scores from baseline to hot flush frequencies and scores from baseline to

treatment week 4treatment week 4

VenlafaxinePlacebo

Guttuso T Jr, et al. Obstet Gynecol 2003;101:337–45

Gabapentin's effects on hot flushesGabapentin's effects on hot flushesin postmenopausal womenin postmenopausal women

• Randomized controlled trial, 59 postmenopausal women with Randomized controlled trial, 59 postmenopausal women with ≥ 7≥ 7 hot flushes/day, examining effects of gabapentin 900 hot flushes/day, examining effects of gabapentin 900 mg/day on hot flush frequency after 12 weeks of treatmentmg/day on hot flush frequency after 12 weeks of treatment

• Reduction in hot flush scoreReduction in hot flush score– 54% in gabapentin 900 mg/day group54% in gabapentin 900 mg/day group– 31% in placebo group (31% in placebo group (pp = 0.01) = 0.01)

• 4 patients (13%) in the gabapentin group and 1 (3%) in the 4 patients (13%) in the gabapentin group and 1 (3%) in the placebo group withdrew from the double-blind study because placebo group withdrew from the double-blind study because of adverse events. 15 patients (50.0%) in the gabapentin of adverse events. 15 patients (50.0%) in the gabapentin group reported at least one adverse event, compared with 8 group reported at least one adverse event, compared with 8 patients (27.6%) in the placebo grouppatients (27.6%) in the placebo group

Gabapentin for hot flushes in Gabapentin for hot flushes in women with breast cancerwomen with breast cancer

Percentage decreases in hot flush severity score Percentage decreases in hot flush severity score between baseline and week 8between baseline and week 8

-70

-60

-50

-40

-30

-20

-10

0

Placebo Gabapentin 300 mg Gabapentin 900 mg

p = 0.007

Pandya KJ. Lancet 2005;366:818–24

Gabapentin, estrogen and placebo Gabapentin, estrogen and placebo for treating hot flushes for treating hot flushes

• Randomized controlled trial (n = 20 in each group)

• 12th week reduction in hot flush score

-100

-80

-60

-40

-20

0

Placebo CEE 0.625 mg Gabapentin

p = 0.016 p = 0.004

Reddy SY, et al. Obstet Gynecol 2006;108:41–8

Non-hormonal therapies for Non-hormonal therapies for menopausal hot flushesmenopausal hot flushes

• Systematic review, meta-analysis of data sources:– Medline (1966–Oct 2005), PsycINFO (1974–Oct

2005), and the Cochrane Controlled Clinical Trials Register Database (1966–Oct 2005) were searched for relevant published randomized controlled trials

• Study selection:– All English-language, published, randomized,

double-blind, placebo-controlled trials of oral non-hormonal therapies for treating hot flushes in menopausal women measuring and reporting hot flush frequency or severity outcomes

Nelson HD, et al. JAMA 2006;295:2057–71

Non-hormonal therapies for Non-hormonal therapies for menopausal hot flushesmenopausal hot flushes

• Data synthesis:– 43 trials met inclusion criteria

• 10 trials of antidepressants• 10 trials of clonidine• 6 trials of other prescribed medications• 17 trials of isoflavone extracts

Nelson HD, et al. JAMA 2006;295:2057–71

Non-hormonal therapies for Non-hormonal therapies for menopausal hot flushesmenopausal hot flushes

• Mean difference in number of daily hot flushes with placebo in meta-analyses of:

-4

-3

-2

-1

0

Clonidine SSRI/SNRI Gabapentin

Nelson HD, et al. JAMA 2006;295:2057–71

Non-hormonal therapies for Non-hormonal therapies for menopausal hot flushesmenopausal hot flushes

• Few high-quality trials have been published; most of them have methodological deficiencies; hence, generalizability is limited

• No effects of red clover isoflavone extracts and results were mixed for soy isoflavone extracts

• The effects are less than for estrogen

• The SSRIs or SNRIs, clonidine, and gabapentin trials provide some evidence for efficacy

• These therapies may be useful for highly symptomatic women who cannot take estrogen

• Possible adverse effects and the high cost in different countries may restrict use for many women

Alternative treatmentsAlternative treatments

• The efficacy and safety of complementary alternative medicines have not been demonstrated and further studies are required

• SSRIs, SNRIs and gabapentin are effective in reducing vasomotor symptoms in short-term studies. Their long-term safety needs further evaluation

IMS Position Statement. Climacteric 2007;10:181–94