Menopause

Hananja Brice-Ytsma (MNIMH, MSc)

Subjects to be covered

Physiology of the menopauseHormonal herbs and other useful

herbsSpecific conditions commonly

occurring and their treatmentOsteoporosis and prevention.

Menopause

Cessation of periodsAverage age 48-52Duration 4-5 yearsPrematureOophorectomy

perimenopause Ovulate irregularly Age 40-51 FSH increases (10-20X)

max 1-3 years after LMP. Lower oestrogen levels 6

month - 1 year before menopause.

Ovarian production of estradiol, progesterone and testosterone decrease with onset of true menopause.

1. Progesterone decline before the oestrogen levels.

2. Oestrogen low.

Pituitary gland

Prolactin; increases slightly at night, increases with stress, and during luteal phase of the menstrual cycle.

Postmenopausal LH and FSH stimulates the secretion of androgens and oestrogen.

Oestrogen: source

Ovaries, adrenals and other tissues; 1. oestrogen;

oestradiol, of which some get converted to oestrone, the weaker form.

2. Androgens; conversion from androgens to oestrone

(the weaker oestrogen) by the aromatase enzyme.

Before menopause most of the oestrogen is produced by the ovaries, and small percentage by aromatisation of

androgens to oestrogen.

Oestradiol is converted to

• 1. 2-hydroxyoestrone

• 2. 16-hydroxyoestrone

– Oestrogen enter the liver and get conjugated

– The circulating oestrogen can go to the kidneys, and changed into oestrone

The role of Oestrogen

1. Potentiate growth of nerves and nerve cells.

2. Increased blood flow to the brain, aiding brains use of glucose.

3. Prevention formation of free radical nerve toxins.

4. Inhibits deactivation of adrenaline, noradrenaline, serotonin, and enhances activity of dopamine.

The role of oestrogen (cont.)

5. Give maintenance to the structure of skin, blood vessels, bone strength.

6. Thickening, elasticate, lubricate tissue in the vagina and vulva.

7. Growth enhancing effects.

Oestrogen reduction

1. Oestrogen plays a role in the temperature regulation. (Some suggest it is imbalance in the beta-endorphins and other opiates in the brain).

Effect on Memory and Cognition.

Mood.

Oestrogen metabolism interference

1. Body weight

2. Excess fibre

3. Vitamin A deficiency

4. Antibiotics

5. Over exercising

6. Smoking

Intestinal flora

Beta-glucuronidase is bacterial enzyme that uncouples the bond between excreted toxins, and glucuronic acid.

Need healthy bacterial flora

Androgens

•1.Testosterone

•2.Dehydroepiandrosterone (DHEA).

•3. Androstenedione

Inhibin

When menopausal, FSH normal and inhibin high; poor prognostic sign.

Progesterone role

1.Stimulates the production of glandular structures

2. Generates the production of blood vessels 3. Involved in fat metabolism, diuretic,

maintenance of stable blood sugar4. Mood elevating5. Prevention of tumours6. Precursor hormone for corticosteroids 7. Progesterone is low; androgens increases

Ovarian failure

No ovulation; no progesterone.

Ovarian failure

1. Corpus luteum defect.2. Rupture ovarian follicle not occurs.3. Hypothalamic-pituitary axis

failure.

Other reasons of progesterone deficiency symptoms

1. Abnormal hormone receptivity in the follicle to LH or FSH.

Abnormal progesterone receptivity leading to cyclic breast pain.

Progesterone effect on nervous system

•1. Allopregnenolone; anxiolytic properties

•2. Pregnenolone sulfate (PS); anxiogenic.

•3. Interaction between alcohol and GABA receptors, resulted in decreasing peripheral allopregnenolone levels

Lower progesterone levels perimenopausal

Abnormal menstruation (excessive blood loss, absent period, persistent and more frequent menstruation),

interaction with the other endocrine system; low thyroid function -> higher prolactin levels ->breast soreness and swelling.

B6, Zinc, Mg deficiency can increase prolactin levels

Neurotransmitter

The endorphins regulate release of pituitary hormones.

If endorphins high, levels LH low.

Aldosterone

Fluid retention; Relative progesterone deficiency leading to

increased activity of aldosterone. Excess oestrogen leads to increase aldosterone

secretion

PMS worse around puberty, menopause, following pregnancy (anovulation).

WOMEN’S HEALTH INITIATIVE

Large scale randomised, controlled clinical trial of 16,608 menopausal women aged 50-79.

The study was halted prematurely after 5.2 years, Planned duration of trial was for 8.5 years.

stopped the trial due to increased risk of invasive breast cancer. increases in coronary heart disease, stroke, pulmonary embolism,

and clots. HRT uses had reduced risk of colorectal cancer and fractures.

Research continued with estrogen only; and did not find increase of

heart disease, but increase in strokes and clots. Recommendation for GPs; HRT only suitable for short term

treatment.

Herbal treatment

Treatment aims

Manage symptomsassist with adjustment to the change,

supporting the body to produce the required sex hormones by partly ovaries, adrenals and other parts of the body.

Help to adjust the body to new hormonal levels.

To eventually withdraw herbal treatment.

Estrogenic herbs

Phytoestrogens

Isoflavones; genistein, daidzein, and their glycosides mainly found in the Leguminosae such as soy and red clover.

Lignans; flaxseed contain lignans enterodiol, and enterolactone, formed by bacterial action on the precursor secoisolariciresinol diglucosides.

Flaxseed

absorbed in the colon and conjugated with glucuronic acid or sulfate in the liver, excreted through the bile duct, conjugated leaves the body via faeces,

deconjugated by bacteria and reabsorbed, some excreted via kidney in the urine.

Flaxseed (not flaxseed oil) is a rich source of plant lignans.

Antiestrogenic effects on estrogen receptor-positive breast cancer.

lignans

decrease cell proliferation inhibit aromatase, 5-

alpha-reductase, and 17-beta-hydroxysterioid dehydrogenase activity, which may offer a reduction in the risk of breast, prostate and other hormone sensitive cancers.

increase sex-hormone-binding globulin synthesis.

randomized controlled trial in 25 hypercholesterolemic menopausal women

to assess the effects on menopausal symptoms and serum lipids of flaxseed compared with oral estrogen-progesterone replacement

Both treatments produced similar decreases in menopausal symptoms and in glucose and insulin levels.

Glycine max

Soya bean

Originally came from China, goes back to 2838 BC

Tofu; curd made from hot water extract of soy beans

Came to the western world in 18th C

Asian population consume 20-80mg/day isoflavonoids, almost entirely from soy.

The west: 1-3 mg per day

Isoflavones; genistein, daidzein, glycitein and their glucosides genistin, daidzin, glycitin, and a small amount of coumestrol.

Constituents

Epidemiology

Japan, China and Korea; Lower incidence of most common cancers in the western world.

Hormonal effect

RCT shown that soy rich diet can have an effect on hot flushes.

Overall little effect found on serum LH, FSH, with the exception of one trial showing increase in SHBG.

Little or no impact on the endometrium or vagina.

Phytoestrogens

May exert estrogenic or anti-estrogenic effects , depending concentration of endogenous estrogens.

Many health benefits may be due to properties not involving estrogen receptors.

Phytoserms

2 estrogen receptors identified ERAlpha; Preferentially expressed in ovarian cancer

lines, and Estrogen receptor node-positive breast cancers.

ERBeta; expressed preferentially in normal breast and ovarian tissue.

Genistein; has significantly higher affinity for

ERBeta than for ERAlpha.Coumestrol;

binds as strongly as 17Beta-estradiol to both human estrogen receptors.

5-Omegenistein, formononetin; Significant binding to Alpha

Pharmacodynamics

The isoflavonoids are inactive when present in the bound form as glycosides.

The glycosides undergo fermentation by the intestinal flora.

Urinary recovery can vary from 15-66% for the isoflavones.

Isoflavone content can differ between soy products.

Isoflavone content of soy products

Textured soy protein granules 1/4 cup

roasted soy nuts 1/4 cup

tofu, 1/2 cup tempeh 1/2 cupsoy milk 1 cupcooked soy beans

1/2 cup

62mg …………………………...

60mg……………………………

35mg35mg30mg35mg

Soy and effect BMDWith soy not clear if the protective effect

is due to the amino acid, or the isoflavonoids, or the combination.

Genistein stimulates osteoblastic activity and inhibit osteoclast formation, with levels equivalent to after eating soy

Increase of Bone mineral density and bone mineral content (BMC) of lumbar vertebrae gain found, no increase in proximal femur bone mass.

Oestrogen receptor Beta expression higher in osteoblastic cell line.

Soy in vivo studies have shown increase calcium absorption.

synthetic ipriflavone; dosage range 200-600 per day. Normal diet 15-50 mg isoflavonoids per day. The quantity in food would be impossible.

not clear if life long exposure to phytoestrogens plays a role in prevention of osteoporosis.

Systematic review of soy for prevention and treatment of osteoporosis.

Inclusion criteria; peri and post menopausal, soy foods, length of study.

Purpose of systematic reviews

Help decision makers to cope with the volume of studies by summarising them

provide new knowledge which may not be apparent from the individual studies where the effects under investigation are small.

Evaluated the evidence of effectivess of soy compared to placebo for treatment and prevention of osteoporosis.

BMD selected as outcome measure. (adequate reflection of prevention of fractures)

conclusion

5 out of 8 had positive effect, by either preventing bone loss, or increase BMD

negative outcome; one might be related to being perimenopause only, second lower dosage compared to the other and the third negative trial was underpowered.

All studies using 60 mg isoflavonoids and below were negative

When soy protein intake low more likely to be more negative Duration; the longest studies (3 years) had the most effect.

Long term study needed to cover a minimum of one remodelling cycle (30-80 WEEKS)

Age; increase in BMD only found in the older participants.

Antitumour activity

Genistein; inhibition of angiogenesis, inhibition of

tumour invasiveness, inhibition of cell cycle progressing, inhibition of enzymes in oestrogen biosynthesis, antioxidant effect, tyrosine kinase inhibitor.

Antiproliferative effects

Biphasic effects on stimulating proliferation;

Low dose genistein inhibitory effects, high doses increased growth.

Phytoestrogens are weak estrogens and under certain experimental conditions will stimulate proliferation and estrogen-dependent gene-expression.

Safety in relation to breast cancer

Early exposure to soy shown there is lower incidence of breast cancer.

Question; does taking soy later in life have a protective affect, or make a difference when breast cancer present?

Prevention of cancer

Japanese breast cancer and prostate cancer patients better survival than others.

Gastric cancer with high tofu consumption better outcome.

Prevention of cancer

Several studies have looked at and found no change in endometrial thickness, mammography and vaginal maturation resulted from the daily administration of soy products (Messina et al 2006).

A meta-analysis of 18 epidemiological studies (12 case-control and six cohort or case-control) indicated that Soy intake may be associated with a small reduction in breast cancer risk.

conducted year-long studies indicated that isoflavone supplements do not affect breast tissue density in premenopausal women and may decrease density in postmenopausal women.

The existing epidemiological observations in Asian women, who consume high amounts of soy foods indicate low rates of breast and endometrial cancer

A 5 year randomised double blind study with 150mg isoflavone found that 6 out of 154 patients developed endometrial hyperplasia, compare to none of 165 in placebo (Unfer et al 2004).

Leading the authors to the conclusion that long term treatment with soy phytoestrogens was associated with and increased occurrence of endometrial hyperplasia.

Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: combination of soy and tamoxifen.

Soy isoflavones consumed at levels comparable to those in Asian populations may reduce the risk of cancer recurrence in women receiving tamoxifen therapy and moreover, appears not to interfere with tamoxifen efficacy.

Other effects of soy

Soya decreased serum concentration total cholesterol, LDL cholesterol, triglycerides, HDL increased nonsignificantly (47.gr soy a day).

Inhibiting cell adhesions, alter growth factor activity and inhibit cell proliferation involved in atherogenic lesions formation.

Side effects attributed to soy

thyroid disease according to one study. Genistein and daidzein; can inhibit thyroid hormone synthesis, not likely when average amount of soy is consumed in the context of a

healthy diet. The clinical trials have soy consumption did not effect thyroid production.

Phytates block uptake of minerals, reduced if eaten with meat or fish, in fermented products (soy, and

miso). Allergy Difficult to digest, soya content of trypsin inhibitors can block

enzymes needed for protein digestion lower levels of antibodies in response to immunisation and more

infections than infants fed on cow’s formula or breast milk. not alter timing of puberty

conclusion

Consumption of soya and plant based foods is consistent with recommendation to increase fibre, antioxidant intake, while lowering sources of saturated fat.

Questionable; supplementation with isoflavonoids

Trifolium repens

Red clover

constituentsIsoflavones in the leaves; biochanin A,

genistein, daidzein (the isoflavone composition of soy and red clover are different).

Formononetin in the flower heads.

Red clover became of interest when in the 1940s, Australian sheep grazing large quantities, developed extensive lesions on the reproductive organs (cystic endometrial hyperplasia).

History

Traditional use

Dermatological conditions, syphilis, glandular conditions.

Topically used for growths, swellings and cancers e.g. breast cancer.

Since the 1940s included in the Hoxley anti-cancer formula, which is still used in some cancer clinics.

Clinical trials

The clinical trials contradictory results. The largest study showed no benefit for reducing symptoms associated with menopause for 2 different red clover isoflavone products compared with placebo.

One showing some promise with bone density.

May reduce risk of coronary vascular disease, by increasing arterial elasticity, although it did not improve cholesterol levels.

may slow bone loss in the spine.

no changes in thickness of lining in uterus in postmenopausal women.

No significant adverse events have been reported in the literature.

Breast cancer cells in lab; response same to red clover as did to estradiol.

Steroidal saponins

Dioscorea villosaChaemelerium luteumTribulus terrestisAsparagus racemosa (shatavari)

Herbs containing steroidal saponins

Dioscorea villosa

Constituents; steroidal saponins dioscin (only

small amounts), diosgenin, methylparvifloside and methylprotodeltonin which are the precursors of diosgenin.

the aglycone of dioscin was used industrially to produce progesterone and cortisone.

Historical use

Eclectics; favourite remedy used for spasmolytic activity

American Indians; colic, relieve of pain in childbirth

Does not contain progesterone.

Trial using wild yam cream, little effect on menopausal symptoms.

No traditional use of menopausal symptoms.

Pharmacology

Premenopausal; Because the estrogenic substances are very weak compared to the normal oestrogen; The body thinks that the oestrogen levels are lower what they really are and respond by increasing FSH, hence oestrogen production increases.

Low oestrogen environment; the steroidal compounds bind to vacant receptors in the hypothalamus and so decrease the symptoms of oestrogen withdrawal.

In the postmenopausal women sapogenin may directly or indirectly via hypothalamus and/or pituitary gland increase the production of oestrogen precursors from the adrenal cortex

Clinical trial

Reduced serum lipid peroxidation and serum Triclycerides.

Increased HDL cholesterol levels.

No changes in total cholesterol or LDL cholesterol.

Diosgenin effect on cholesterol metabolism;

Interferes with absorption of dietary and endogenous cholesterol.

Enhanced cholesterol secretion into bile.

Pharmacokinetics

Glycosides such as dioscin are broken down in the large intestine by microbial activity to form the aglucone diosgenin.

Need a healthy gut flora.

Chamaelerium luteum

False Unicorn

Old eclectic remedy

Main effect on reproductive organs.Typical picture; fullness, heaviness,

congestion in the pelvic area, it feels as if everything is going to drop out. Lumbar pains, down the thighs, and back of legs, restlessness and general weakness.

To overcome excessive fatigue.

William Cook 19th C physiomedicalist

‘It scarcely has an equal in atonic forms of prolapse, leucorrhoea, passive haemorrhage, menorrhagia, and similar enfeebled conditions. While its use in sensitive patients and irritable uterine conditions is to be avoided, it can be used to the greatest advantage in flaccid and prostated states for the maladies above named. Also to be used in general depression of the vital force.’

Substitute; Aletris farinosa

Commonly substituted but historical medical literature weighs in strongly against it. Substitution continued till the 1920’s, Felter and Cook felt any therapeutic reputation was due to the adulteration with Chamaelerium.

Actions and indications

To tone up the female reproductive organs, improving their function and nutrition. Pelvic warming. Strengthens the uterus; preventing miscarriages and tendency to abort.

Dysmenorrhoea; with bearing down feeling. Leucorrhoea, amenorrhoea. Antiemetic and antinausea; in pregnancy. General tonic; anorexia, dyspepsia of the atonic type Diuretic; strangury, acute and chronic nephritis especially if

patient depressed. Bitter, Jaundice. Some cases of rheumatism, however other more effective

remedies are around.

Constituents

Steroidal saponins; Chamelirin, which is a glycoside of diosgenin.

Pharmacology;

Amphoteric effect on hormonal secretion by the ovary, however Chamaelerium has never been subjected to the lab. Speculation that the effect is as the steroidal saponins in Dioscorea.

Comparison

Chamaelerium Trillium Dioscorea

1:3 contains0.3% steroidalsaponins

1:3 contains1.2 % steroidalsaponins

1:3 contains3% steroidalsaponins

Asparagus racemosus

Contains steroidal saponins Highly regarded in traditional

Aryuvedic medicine for its rejuvenative action on the female reproductive system

aphrodisiac, “to give the capacity to have a hundred husbands”

galactagogue, promote conception, sexual debility menopause, body ache, general debility, threatened miscarriage, leucorrhoea, gonorrhoea.

Demulcent for dry and inflamed membranes of lungs, stomach, kidney, sexual organs, and therefor possible for vaginal dryness.

Herb used traditionally to promote health, longevity, improve defence mechanism, as adaptogen.

Tribulus terrestris

Used in Europe for menopausal symptoms, contains steroidal saponins.

Open study; 98% of 50 menopausal women symptoms relieve but not after placebo. (52% natural menopause, 48% postoperative)

relieve with hot flushes, sweating, insomnia and depression.

Dosage 20-30 g of leaf.

Cimicifuga racemosa

Black cohosh

Frequency of use

In 1997 over ten million monthly units of Cimicifuga racemosa extract was sold in Germany, United States and Australia.

constituents

Triterpene glycosides xylosides, actein, cimicifugoside, 27-deoxyactein.

Isoflavone formonetin, however is more concentrated in aerial parts of the plant.

Isoferulic and salicylic acids.

Importance of using the whole plant

Efficacy of methanolic extracts of the root is dependent upon at least three different fraction with a synergistic action.

Europe

In use since the 17thC for problems of the female reproductive organs.

Germany; introduced in the late 19th C

History, used by American Indians

TonicRheumatismAnalgesicDiureticEmmenagogu

e

Historical use

An alcohol extract was adopted by the eclectics

Used widely by the American physicians over the 18-19thC for different gynaecological conditions.

felt it was especially efficacious in maladies of the female reproductive organs chronic ovaritis, endometritis, menstrual derangement, amenorrhoea, dysmenorrhoea, menorrhagia, frigidity, sterility, threatened abortion, uterine subinvolution, stimulate labour.

Recent history

Since the mid 1950s widely used by German gynaecologists

by 1962 there are 14 clinical studies involving 1500 patients, for perimenopausal symptoms

1944 Gizycki provided first evidence of estrogenic effects.

Oestrogenicity was measured by effect on the uterus, with the understanding of ERBeta could explain the contradictory results in the past if CR was estrogenic or not.

Pharmacology

reduce serum LH levels.

effects on bone to prevent osteoporosis.

estrogenic effect in the urinary bladder.

no uterotrophic effects. an ideal Selective

Estrogen Receptor Modulator.

Mode of action

Jarry et al 2003 in vitro tests were able to separate the dopaminergic compounds and to distinguish between dopaminergic and estrogenic activity.

Both are contributing to the overall pharmacological profile.

Inhibitory effects on the pituitary LH secretions, so mimicking the negative feedback effects of estradiol within the hypothalamus.

Dopaminergic activity which could explain the reduction of hot flushes.

Dopaminergic agonist also cause decrease in proliferation of MCF-7 cells.

Antiproliferative action of CR

Inhibitory action of CR on proliferation of the ER Alpha MCF-7 cells.

CR inhibited estradiol induced MCF-7 cell growth.

CR does not bind to the known estrogen alpha or beta receptors, so the anti-tumour activity may be mediated via another mechanism.

Three modes of possible action

CR compounds potently inhibit growth of human prostate cells in vitro, which may be mediated via the AhR. Aryl hydrocarbon receptors activation leads to inhibition of growth of tumours

Dopaminergic antiproliferative action. Or CR constituents address a yet unknown third

subtype of ER.

CR with tamoxifen

combined a greater inhibition in cell growth was seen than in tamoxifen alone.

Clinical trials showed that a combination therapy of tamoxifen and CR helped with reduction of hot flushes, and improved quality of life.

Effect on bone metabolism

Clinical trial (Wuttke 2003) showed that CR and conjugated estrogen have comparable effects on serum markers of bone metabolism, and thus have osteoprotective effects.

Effects on bone metabolism

Decreased activity of the osteoclast cells, responsible for bone degradation.

The bone specific alkaline phosphatase, the marker for bone formation, increased under CR

Effect on the endometrium and vagina

No change with CR on the endometrium, unlikely that CR will stimulate the uterus to develop uterine cancer.

Increased amount of superficial cells in vaginal smear seen with CR, which will lead to lowering pH.

Increase lubrication upon sexual activity.

Other effects Favourable effect on

hepatic and lipid metabolism, leading to prevention of atherosclerosis.

effect on leptin, a hormone produced by the fat cells, feeds back into the hypothalamic satiety centre, to reduce food intake. CR vivo shown the same effect.

Effects on urinary bladder

Changes of tone, increased muscle tone was measured in the bladder (animal studies)

possibility of effect on urinary incontinence.

Recent trials

Indicated CR is effective for patients suffering from moderate symptoms as supposed to mild symptoms.

Supported by another trial indicating that CR is effective in relieving early climacteric symptoms.

Statistically significant improvement of bone metabolism seen with CR.

Trials on breast cancer patients

One trial indicating lower of the most debilitating symptoms of sweating.

Another trial where CR used for over 12 months, pt younger and more severe symptoms showed significant reduction.

Dosage

One clinical trial compared 40mg CR vs. 127 mg per day, similar results in safety and efficacy was observed in both dosages.

Side effects

GIT disturbances. Dizziness, headache,

weight gain. Overdose; nausea,

vomiting, vertigo, headache, hypotension, impaired vision, impaired circulation.

Mutagenicity, teratogenicity and carcinogenicity tests negative

hepatotoxicity

Total 69 adverse reactions recorded In general the CH poorly documented failure to identify CR product, or form of CR treatment use of herbal mix, multiple ingredients co-medication of synthetic drugs, and supplements missing time related association between CR and

development of liver disease failure to re-challenge after discontinuation pre-existing liver disease insufficient exclusion of other liver diseases presence of alternative liver disease

Conclusion

Effective especially in perimenopausal women with more severe symptoms

Looks promising on the effect of bone metabolism and may have a role to play in osteoporosis.

Helpful in menopausal symptoms in breast cancer patients.

Humulus lupulus

Among the possible estrogenic compounds ;

8-prenylnaringenin Xanthohumol

prenylflavonoids from hops have potential for application in cancer prevention programs and in prevention or treatment of (post-)menopausal 'hot flashes' and osteoporosis.

Humulus lupulus

Randomised, double-blind, placebo-controlled study.

The daily administration of the extract, for 6 weeks, to postmenopausal women decreased the

incidence of hot flushes, sweating, insomnia, heart palpitation, irritability.

The decrease in LH serum levels

Effect of beer drinking on ultrasound bone mass in women.

Cross-sectional study of 1697 healthy women (mean age 48.4 y)

CONCLUSION: The greater bone density found in women beer drinkers might be a result of the phytoestrogen content of beer. However could also be the silicon content of beer

Other herbs affecting hormones

Vitex agnus castus

Chaste tree

Effective for irregular bleeding, at the perimenopausal state.

Traditional use of Vitex

Long history of use in the Mediterranean area.

Dioscorides; makes the menses come.

Traditional use

Hippocrates

Ancient Greeks and Romans

Pliny the 1st

Traditional use

Some said it cools passions others said it had stimulating properties.

Eclectics; impotence and sexual melancholia, but don’t say if this is for women, men or both.

In France it is used traditionally to relieve minor sleep disorders in adults and children.

In Jordan and Israel, used traditionally and joint pains.

More recently in Germany used for acne and premenstrual oral herpes.

Survey in U.K and republic of Ireland 1997, peri- for headaches, stomach pains menopausal, including hot flushes.

80% of herbalist used it for acne, in an open clinical trial after 3 month of treatment 70% had improvement of acne.

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Research

First major study published in 1954 on women with amenorrhoea.

Studies on guinea pigs in the 1960; LH increase.

ConstituentsA number of

diterpenes, the major dopaminergic compounds are the clerodadienols

Highly lipophilicMany other

constituents

New Research (1993);

Dopaminergic activity

Wuttke et al 2003

After 3 month treatment the supraphysiological release of prolactin normalised

as a result the LH pulses did now induce increased progesterone and estradiol levels.

Basal progesterone and estradiol were in normal range.

Shortened luteal phase were normalised and progesterone deficiencies were corrected

PMS symptoms significantly reduced and 2 out of the 37 women became pregnant.

Dopaminergic system

Highly lipophilic compounds.

Can have access to other brain dopaminergic systems.

The diterpenes may modulate the locomotor unrest and behaviour instability.

Study in males

Low doses of mother tincture (1:10) used.

Clinical study involving men showed lower doses caused a rise in prolactin(120 mg, 2-3gtt of F.E or 5gtt of 1:2)

higher doses led to a much reduced secretion (480mg, 10 gtt of F.E. or 20 gtt of 1:2)

Hyperprolactinaemia; Prolactin causes lack of

progesterone sensitivity. Prolactin increases

slightly at night and during the luteal phase of the menstrual cycle.

Pre-menstrual mastalgia Corpus luteal insufficiency Infertility Reduces aromatase

activity Stress

Melatonin release;

Clinical trial (2003); effect of Vitex (0.6 to 2.4g day given in divided doses TDS) on circadian rhythm of melatonin secretion.

Caused dose dependent increase in melatonin secretion especially during the night (compared to placebo treatment).

Total melatonin output 60% higher, and began one hour after the lights had turned off.

Oestrogenic compounds

Vitex showed estrogenic binding.Apigenin (flavonoid); major

compound in Vitex, agonistic activity to the Beta estrogen receptor.

Vitex shown to have no uterine effect (ERAlpha).

After three months a slight, osteoporosis protecting effect.

Very helpful perimenopausal, with PMS symptoms which tend to get worse around that time.

Serum leptin; reduced in animal studies, involved in the regulation of fat tissue.

Small study; combination of Vitex and Hypericum provided relieve of PMS-like symptoms in a small number of late perimenopausal women.

Dosage; 1 g Vitex, and 5.4 g Hypericum daily 7ml plus 35ml

RCT, double blind 100 late perimenopausal women (hypericum plus vitex)

Significant improvements in placebo and herbal groups for hot flushes, green climacteric scale scores and depression at week 16

subpopulation analysis, PMS like symptoms of perimenopause Confound dietary and lifestyle factors were monitored.

Herbal superior to placebo for total PMS scores, preliminary results suggest that Vitex and

Hypericum may provide relieve of PMS like symptoms in late perimenopausal symptoms

When to take Vitex

Many herbalist use Vitex in the morning, and they argue that use as a single morning dose because the body more hormonally active or receptive in the morning.

morning dose related to the first trials in the 1950s, but does not reflect the more recent research which has been done on prolactin levels.

If aim to block prolactin sleep time peaks, need to use at night as one needs to do in the treatment of prolactin associated infertility.

lower overall high basal prolactin levels as seen in pituitary gland tumours then need throughout the day. If significant hyperprolactinaemia, use throughout the day.

PMS, corpus luteal insufficiency, latent hyper prolactinaemia, infertility; 120-240mg (0.25-0.5ml, 5-10 gtt of a 1:2) in a survey of UK herbalist dose was 200-500mg

(0.5ml-1ml, 10-20 gtt) per day (however drops a very inaccurate way of measuring).

Hyperprolactinaemia; up to 2000mg a day (4ml of 1:2) Germany; 40mg per dayFrance, Britain; 40 - 300mg per day.

Fibroids and endometriosis, heavy bleeding; 2000mg per day ( 4 ml per

day of a 1:2, but have gone to 10 ml per day in some cases).

PCOD; 200-1000mg/day (0.5-2ml,

10-40gtt) Sleeping disorders, poor sleep

maintenance , problems associated with shift work, jet lag; 1500-2500mg/day 3-5ml

(1:2) per day

BMJ report

A women on fourth cycle of a drug-free in vitro fertilisation program, self-administered Vitex (dose not stated), produced increased number of ovarian follicles and developed symptoms of mild ovarian hyperstimulation (symptoms not stated).

Woman with fibroids, bleeding most days during the month, severe anaemic, high doses of Vitex reduced bleeding to 10 days. Woman with fibroids; severe bleeding, used high doses, bleeding under control, however commented on that her breasts were getting smaller.

Anecdotal

Adrenal support

As the ovaries slow down perimenopausal, adrenal glands take over the role producing the hormones, and hence the adaptogens play an important role.

Glycyrrhiza glabra

Estrogenic (beta-sterol, formononetin, coumarin, and other flavonoids).

Glycyrrehetinic acid has shown in vivo to inhibit the effect of estradiol on uterine growth in ovariectomised animals.

Encourages aromatase activity.

Probably the effect of Licorice on oestrogen minimal.

Glycyrrhizin has little intrinsic glucocorticoids or mineralcorticoid activity, but effect by altering the way these compounds are metabolised.

Eleutherococcus senticosis

Normalise the hypothalamic-pituitary-adrenal function.

Study; improve symptoms of fatigue, insomnia, and depression in women with menopausal symptoms.

Some estrogenic properties

Russians started looking into it in 1955, and defined it as an adaptogen.

Able to restore harmony in the body when stress applied, restoring body processes to normal.

Eleutherococcus able to restore body more quickly to normal after stressful event, stress a major impact on lowering oestrogen levels and therefor menopausal symptoms.

Clinical trials

Double blind trial, found Eleutherococcus beneficial in depression with patients with neurasthenia, similar to tricyclic antidepressant imipramine

In uncontrolled trials, case observation studies; improved cardiovascular function and general well being in atherosclerotic patients

lowered BP in hypertensive and raised in hypotensive

increased well-being and improved sleep in “neurotic” patients.

Astragalus membranicus

In vivo experiments Iinhibited tibia and lumbar bone loss and did not cause uterine hypertrophy.

A 6-month RCT of the effect of a 1 : 5 combination of Angelica sinensis, Astragalus membranacus) on acute menopausal symptoms.

There was a significant reduction in the number of mild hot flushes per month in the treatment group but not in the placebo group

CONCLUSIONS:combination herbs were statistically superior to placebo only in the treatment of mild hot flushes.

Panax ginseng

Historically used as tonic for invigoration and fortification in times of fatigue, debility, declining capacity for work and concentration.

used for longevity, improve general health, appetite and restore memory

Tonification of the vital energy, calming nerves, chronic general weakness with irritability, insomnia and organ prolapse.

Estrogenic effect in pre and postmenopausal

protecting body against effects of stress, chronic stress, restores body to mid-line regardless of direction.

increases testosterone levels in vivo.

Panax ginseng

Results from two trials suggest that Panax ginseng may be moderately effective in relieving post-menopausal symptoms.

Some studies report improvements in depression and sense of well-being, without changes in common hormone levels.

In a review by Geller, mood and anxiety were reportedly improved in postmenopausal women using ginseng.

Turnera diffusa

Shown in small placebo controlled study improving sexual desire and satisfaction

a combination product including ginseng, damiana, and gingko shown in small placebo controlled study, improved sexual desire and satisfaction.

Withania somnifera

General debility, nervous exhaustion, loss of muscle strength, brain fog.

used in debility and nervous exhaustion, especially due to stress.

Salvia officinalis

Old French saying; “sage helps the nerves and its powerful might palsy is cured and fever put to fight”

Gerard; “sage singularly good for the head and brain, it quickeneth the senses and memory, and taketh away shakey trembling of the members.”

culpeper; “it heals the memory, warming and quickening of the senses”

Hill 1756; “sage will retard that rapid progress of decay that threads upon our heels so fast in latter years of life, will preserve faculty and memory more valuable to the rational mind than life itself.”

Old European reference books, document that Salvia officinalis (sage) and Melissa officinalis (balm) have memory-improving properties

recently ;cholinergic activities have been identified in extracts of these plants.

Extracts found to have antioxidant, anti-inflammatory, cholinesterase-inhibiting activities

Estrogenic activity: Induction of beta-galactosidase activity in yeast cells, a measure of estrogenic activity, was found in the essential oil (0.01mg/ml).

Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease

1. At 4 months, S. officinalis extract produced a significant better outcome on cognitive functions than placebo

Moreover, S. officinalis may well reduce agitation of patients but this needs to be confirmed.

2. another placebo controlled study in Alzheimer's patients, an ethanol extract of sage (60 drops daily) produced a significant improvement in cognition after four months.

3. Dried sage leaf (300 or 600mg) has been shown in a double-blind, placebo controlled, crossover study to improve mood, alertness, and cognitive performance.

Randomised , placebo controlled, double blind, cross-over design

to investigate effects of single dose of sage over 6 hours period in healthy older volunteers (around 73y). N20 improved cognitive function , significant enhancement of

secondary memory also improvements to

accuracy of attention. efficient processing of stimuli

and consolidation of memory,

optimum dosage was 2.5 g.

Bone resorption inhibition activity

In vivo study, sage, sage essential oils, and monoterpene essential oil components were found to inhibit bone resorption.

The monoterpenes borneol, thymol, and camphor were found to be directly inhibitory in the osteoclast resorption pit assay.

A study shown to reduce sweat production in patients with hyper hydrosis, in a number of open studies.

Clinical trials Sage; GnRH and TRH tests were performed in 8

women to evaluate TSH and Prl responses before and after 3 months of therapy.

a significant increase in Prolactin and TSH response to TRH.

Basal levels of estradiol, LH, FSH, Prolactin and TSH were unchanged.

The product seams to have a central slight antidopaminergic action without side effects and is an effective agent in the treatment of menopausal symptoms.

Other useful herbs

Ginkgo biloba Not been specifically studied in

menopausal women. Clinical trials indicated to be

effective for mild to moderate primary dementia of the Alzheimer type or multi-infarct dementia.

Shown to improve memory and attention improvement, significant improvements in cognitive function tests and depression.

Affect on sex drive; effective in antidepressant induced sexual dysfunction in women as well as men.

Hypericum perforatum

One trial related to menopausal women, found that 900 mg of Hypericum for 12 weeks significantly improved the psychological and psychosomatic symptoms, as well as a feeling of sexual well being.

Combination black cohosh and Hypericum trial

Placebo controlled; reducing menopausal symptoms, including the psychological component.

Significant superior to placebo on both general menopause rating scale and depression scale.

Observation studies found the combination superior to Cimicifuga alone in alleviating menopausal mood symptoms.

Other herbal trials

Double blind, placebo controlled trial, researching effects on menopausal symptoms, serum lipids, and some hormone indicators of menopause.

Capsules of arctium lappa, glycyrrhiza, leonurus cardiaca, angelica sinensis, Dioscorea vill. 2 caps, three times a day.

Treatment group showed greater response rate. The herbs were most effective in hot flushes, mood changes and insomnia.

resveratrol

A phenolic compound Found in red wine and purple grape juice in experimental studies

bind and activate oestrogen receptors improved cognitive function in Alzheimer disease neuroprotective reduced formation sclerotic plaques, inhibit initiation and growth and wide variety of tumours, anti inflammatory and antioxidant extended life span of several species. Suggested mode of action of on sirtuin 1, an enzyme involved in

cellular regulation, including reaction to stressors and longevity, also inhibits apoptosis (a mechanism of cell death)

Study (National Institute of Health)

Epidemiological study; linking the use of multinutritional supplements by women with preservation of telomeres.

51% longer in daily users, compared to non users.

No single nutrient was singled out, reducing oxidative stress and inflammation.

Nutritional supplement

Broad spectrum may enhance longevity by

helping protect chromosomal telomeres.

Shorter telomeres have been linked with higher risk of degenerative disease and mortality within a given time period.

Treatment aims

Manage symptomsassist with adjustment to the change,

supporting the body to produce the required sex hormones by partly ovaries, adrenals and other parts of the body.

Help to adjust the body to new hormonal levels.

To eventually withdraw herbal treatment.

GIT and liver

Most herbs need healthy digestion to be of any use in the body.

Common conditions

Five of seven trials of St. John's wort for mild to moderate depression showed a significant improvement in menopausal women.

The one randomised, controlled trial of ginseng in postmenopausal women reported improvements in mood and anxiety.

All three randomised, controlled trials of ginkgo found no effect on depression.

Black cohosh significantly reduced depression and anxiety in all studies reviewed.

Mood and anxiety in menopausal women; clinical trials.

Hypericum perforatumMelissa officinalisRosa damascenaPanax ginsengAvena sativaCimicifuga racemosa

Vaginal dryness

Vitamin E in Aloe gelCimicifuga racemosaSteroidal saponins (Dioscorea villosa,

Chamaelerium, Trillium)Phytoestrogen rich dietOmega 3

Thrush

Pessaries of Tea tree EO, Thymus linalool EO, Lavendula EO

Restore mucous membranes and pH with Cimicifuga rac., Chamaelerium lut., Hydrastis canadensis.

Immune supportDietIncrease pelvic circulation; uterine tonicsAcidophilus

Uterine prolapse

Pelvic floor exercisesUterine tonics;

Angelica sinensis Leonurus cardiaca Capsella bursa pastoris Chamaelerium luteum Astragalus membranicus Panax ginseng.

Recurrent urinary tract infections Cimicifuga racemosa Chamaelerium luteum Equisetum arvense Glycyrrhiza Hydrastis canadensis Diet Acidophilus Cranberry Vitamin C the usual antiseptic, plus

soothing healing herbs, immune support

Reduced sexual desire

If ovaries taken out, less testosterone, and worse impact on this

Panax ginseng Turnera Asparagus racemosa Rhodiola Hypericum perforatum

A double-blind placebo-controlled study of ArginMax; extracts of ginseng, ginkgo, and damiana, L-arginine, multivitamins, and minerals.

In women who reported a lack of sexual desire.

improvements observed in sexual desire, reduction of vaginal dryness, frequency of sexual intercourse

and orgasm, and clitoral sensation.

The largest number of improvements were seen in PRE and PERI women. Level of desire was shown to increase significantly in POST women.

Hot flushes

Sage, Astragalus membranicus, Panax ginseng, Zizyphus spinosa Cimicifuga racemosa, Dioscorea villosa, Soy.

Insomnia

Vitex agnus castusHumulus lupulusLactuca virosaValeriana officinalisHypericum perf.………….

CVD

Multiple reasons for increased incidenceCardioprotective

Crataegus laevigata

Cholesterol lowering (?) Turmeric Artichoke Trigonella Dioscorea villosa, Cimicifuga racemosa Soy Eleutherococcus senticosis

HRT withdrawal and herbal support.

Gradually reduction of the HRT, to minimise the rebound effects of hormone withdrawal.

Start herbal treatment before reducing HRT

after 4 weeks reduce dosage when symptoms control lower HRT dosagecan take 3-6 months

Osteoporosis

Widespread metabolic bone disorder

1/ 3. Asian population lower incidence., and higher femoral and lumbar spine BMD.

Pathophysiology

Low bone mass and micro-architectural deterioration of bone tissue

Age; decreases levels of

parathyroid hormone and calcitonin levels.

Osteoblasts function and calcium absorption decreases with age

Bone building in women nearly complete at age of 17.

Peak bone mass around 28 years.

After menopause rate faster.

Over 70 at much slower rate.

1. Osteoclast promote bone resorption.

2. Osteoblast promoting bone formation.

3. Bone remodelling

75% Cortical bone. Trabecular bone 25%; Vertebrae are made up of

90% of trabecular bone, and 10 % cortical.

the hip is 50/50. the extremities are 90%

cortical bone. trabecular bone is

concentrated in vertebrae, pelvis, and other flat bones, and at the ends of long bones.

Trabecular bone loss occurs with low estrogen levels, steroid use, immobilisation.

So higher at risk for vertebrae and hip fractures.

Because of the differences in cortical and trabecular bone, it is preferable to measure bone the hip and spine when doing bone density testing.

Risk factors

1. Genetic, FH 2. Smoking, 3. Exercise 4. Alcohol 5. DIET

Vegetarian diet associated lower risk, BMD not different in 30-50 but significant differences later on.

Lower intake proteinPhosphorus; high in

many animal protein and fizzy drinks.

6. Age of menarche, menstrual regularity, amenorrhoea.

7. Ageing; Renal enzymatic activity

that produce vitamin D metabolites reduces,

decreased gastric acidity in 40% of postmenopausal women, not absorb calcium

8. slender physical frame 9. Medical conditions

10. Medication

11. female 12. Post menopausal;

Higher risk; oestrogen associated with loss of bone mass

Diagnosis

No symptomsHeight lossexcessive kyphosis, dental caries, tooth

loss, receding gums, back pain is suspicious.

BMD dexa ; dual energy x-ray absorptiometry for hip and lumbar spine.

Vitamin K

Vitamin K; role in converting inactive osteocalcin to its active form. Osteocalcin the major non

collagen protein in the bone, anchors calcium molecules into the protein matrix.

(dark green leafy vegetables., broccoli, lettuce, cabbage, oats, spinach, green tea, asparagus, wheat, green peas.

Boron

Boron increases 17 beta estradiol, and needed for conversion of vitamin D to its most active form.

Calcium

Calcium supplementation lowers bone loss in perimenopausal women.

Clinical studies showed no difference among various forms of calcium supplements.

Importance of supplementation before menopause

Study over two years of 214 perimenopausal women

control group lost 3.2% of bone density of the spine

calcium treated group increased by 1.6%

supplemented with 1000 and 2000 mg, no difference between the 2 calcium groups.

Recommended intake

9-10 yr. 1300mg19-50 yr. 1000mgover 50yrs 1200mg

Vitamin D

Synthesised by the action of sunlight, on 7-dehydrocholesterol, in the skin.

7-dehydrocholesterol ->cholecalciferol (D3) -> in liver converted to 25-hydroxycholecalciferol which is five times then D3 -> by kidneys converted to 1,25-dihydroxycholecalciferol which is 10X more potent then D3.

Disorders liver, and kidneys; affect Vitamin D, many with osteoporosis high level 25-OH-D3 but low 1,25-(OH)2D3

One study looked at vitamin D supplementation alone reduces the annual rate

of hip fracture from 1.3% to 0.5%, nearly a 60% reduction.

ability to reduce the risk of falling in the elderly population by 22% in the elderly with mean age of 60.

Need 800-1000IU daily.

Magnesium

Women with osteoporosis have lower bone magnesium content.

Mg deficiency linked to 1,25-(OH)2D3 (most potent Vitamin D) deficiency.

250mg

Onion consumption survey

Bone density increased as the frequency of onion consumption increased.

Those who consumed onions once a day or more had overall BD that was 5% greater than those who consumed onions once a month or less.

Equisetum arvensis

Silicon; Necessary for cross-linking collagen strands, supporting strength and integrity of connective tissue matrix of bone.

Silicon concentrations increased at the calcification sites in growing bone, recalcification in bone remodelling may depend on levels of silicon.

Equisetum

One human trial found that horsetail effectively raised bone density as well as calcium supplements.

122 women were randomised to placebo, no treatment, horsetail dry extract (dose not specified), or Osteosil® calcium 270mg twice daily (a horsetail-calcium combination used in Italy to treat osteoporosis and fractures.

After 40, 80, and 365 days, a statistically significant improvement in bone density was reported in both the horsetail and Osteosil® calcium groups, with an average improvement of 2.3% in vertebral bone density in the latter group.

Camelia sinensis

Evidence that green tea contains many bioactive ingredients that support some protection against osteoporosis.

supported by data from in vitro, ex vivo, and in vivo animal studies and human epidemiological findings.

The beneficial effects of tea bioactive products seem to be mediated through antioxidant or anti-inflammatory pathways

components promote bone formation by decreasing oxidative stress (ROS) and proinflammatory mediators (TNF-alpha, COX-2)

by increasing OB activity and survival , resulting in enhanced mineralization.

suppress bone resorption by inhibiting OC formation.

Herbs for osteoporosis

Soy, Trifolium, Equisetum, Humulus lupulus, Cimicifuga racemosa, Salvia officinalis, Camelia sinensis.

Overview

Hormonal; Soy, Trifolium, Linum sativa, Dioscorea vill., Trillium er. , Humulus lup, Salvia off., Glycyrrhiza glab., Vitex agnus castus, Peaony lact. + Glycyrrhiza glab., Asparagus rac., Cimicifuga rac.

Adrenal support such as the adaptogens, e.g. Panax, or Eleutherococcus, Cimicifuga racemosa, Astragalus, Salvia.

Sweating; Salvia, Astragalus, Panax gins., Eleutherococcus. Nervine; Hypericum, Verbena officinalis (cooling), Avena

sativa, Leonurus card, Melissa off. Circulatory herbs; Angelica sinensis (this is not an

oestrogen herb), Ginkgo bil., Achillea millefolium.

Digestive, assimilation, gut flora; Verbena officinalis, Berberis vulgaris, Taraxacum officinalis, radix, Artemisia absinthum (bitters are cooling)

Elimination; Tarax rad., Carduus marianus, Schisandra chin. Cholesterol lowering; Turmeric, Cynara, Allium, Trigonella Cardio protective; Crataegus laev. Maintaining Bone Density; Soy, Humulus, Salvia, Cimicifuga

rac., Panax ginseng, Equisetum, Astragalus mem., Trifolium rep., Camelia sinensis.

Protect and moistened the mucous membranes; Cimicifuga rac., Chamaelerium lut., Althea fol, Zea mays, Plantago lanc., Glycyrrhiza glab.