BIOIDENTICAL BIOIDENTICAL

HORMONEHORMONE

REPLACEMENTREPLACEMENT

M. LITMAN, M.D.M. LITMAN, M.D.JUNE, 2009JUNE, 2009

WOMEN’S HEALTH WOMEN’S HEALTH INITIATIVE STUDYINITIATIVE STUDY

OVER 16, 000 WOMEN.OVER 16, 000 WOMEN.

PREMPRO (PREMARIN/PROVERA)VS.PLACEBOPREMPRO (PREMARIN/PROVERA)VS.PLACEBO

Breast cancer increased by 26%Breast cancer increased by 26%

CVD increased by 29%CVD increased by 29%

Stroke increased by 41%Stroke increased by 41%

Blood clots increased by 100%Blood clots increased by 100%

WHIWHI

“ “ It remains possible that transdermal estradiol It remains possible that transdermal estradiol

with progesterone, which more closely mimics with progesterone, which more closely mimics

the normal physiology and metabolism of the normal physiology and metabolism of

endogenous sex hormones, may provide a endogenous sex hormones, may provide a

different risk-benefit profile.”different risk-benefit profile.”

Writing Group for WHI, July Writing Group for WHI, July 20022002

HORMONE PATHWAYS IN HORMONE PATHWAYS IN OVARIES AND ADRENAL OVARIES AND ADRENAL

GLANDSGLANDSCholesterolCholesterol

PregnenolonePregnenolone

Progesterone Hydroxypregnenolone DHEAProgesterone Hydroxypregnenolone DHEA

Deoxycorticosterone Hydroxyprogesterone AndrostenedioneDeoxycorticosterone Hydroxyprogesterone Androstenedione

Corticosterone Deoxycortisol Oestrone Testosterone Corticosterone Deoxycortisol Oestrone Testosterone

Aldosterone Cortisol Oestriol OestradiolAldosterone Cortisol Oestriol Oestradiol

ESTROGENESTROGEN

3 main human estrogens3 main human estrogens

EstradiolEstradiol

EstroneEstrone

EstriolEstriol

ESTRADIOLESTRADIOL

Most potentMost potent

Primarily from ovaryPrimarily from ovary

ESTRONEESTRONE

Conversion from estradiolConversion from estradiol

Produced in adrenals Produced in adrenals

Produced in tissues eg. fatProduced in tissues eg. fat

ESTRIOLESTRIOL

Weak estrogenWeak estrogen

Little stimulation of breast and uterusLittle stimulation of breast and uterus

High levels in pregnancyHigh levels in pregnancy

CENTRAL NERVOUS CENTRAL NERVOUS SYSTEMSYSTEM

EFFECTS OF ESTROGENEFFECTS OF ESTROGEN

aids in synthesis of neurotransmitters eg. aids in synthesis of neurotransmitters eg.

serotonin, noradrenaline, dopamineserotonin, noradrenaline, dopamine

resulting effects on moodresulting effects on mood

effects on sleepeffects on sleep

sensitizes neurons to nerve growth factorsensitizes neurons to nerve growth factor

CARDIOVASCULAR SYSTEMSCARDIOVASCULAR SYSTEMS

EFFECTS OF ESTROGENEFFECTS OF ESTROGEN

Inhibits vasoconstrictionInhibits vasoconstriction

Lowers fibrinogenLowers fibrinogen

Decreases LDL, increases HDLDecreases LDL, increases HDL

Improves insulin sensitivityImproves insulin sensitivity

BONE EFFECTS OF BONE EFFECTS OF ESTROGENESTROGEN

Inhibits osteoclastsInhibits osteoclasts

Decreases bone resorptionDecreases bone resorption

UROGENITAL EFFECTSUROGENITAL EFFECTS Preserves pelvic tissuesPreserves pelvic tissues

Growth of endometriumGrowth of endometrium

Growth of follicleGrowth of follicle

Growth of breastsGrowth of breasts

METABOLIC EFFECTSMETABOLIC EFFECTS Stores fat (esp. hips/thighs)Stores fat (esp. hips/thighs)

PROGESTERONEPROGESTERONE

One moleculeOne molecule

Primarily produced in ovary after ovulationPrimarily produced in ovary after ovulation

Small amounts from adrenalsSmall amounts from adrenals

PROGESTERONEPROGESTERONE

BONE EFFECTSBONE EFFECTS

Stimulates osteoblastsStimulates osteoblasts

Bone formationBone formation

GENITAL EFFECTSGENITAL EFFECTS

Maintains pregnancyMaintains pregnancy

Induces maturation of endometriumInduces maturation of endometrium

PROGESTERONEPROGESTERONE

CVS Effects- inhibition of induced coronary CVS Effects- inhibition of induced coronary spasm in monkeysspasm in monkeys

NERVOUS SYSTEM EFFECTSNERVOUS SYSTEM EFFECTS attaches to GABA receptorsattaches to GABA receptors produces calming, relaxing effectproduces calming, relaxing effect NMDA antagonist-may have analgesic effectsNMDA antagonist-may have analgesic effects stimulates synthesis of myelinstimulates synthesis of myelin repair of injured nervesrepair of injured nerves

PROGESTERONEPROGESTERONEMETABOLIC EFFECTSMETABOLIC EFFECTS

Diuretic-blocks aldosterone receptorsDiuretic-blocks aldosterone receptors

Improves insulin sensitivity Improves insulin sensitivity

Enhances thyroid hormone functionEnhances thyroid hormone function

Anti-androgen eg. on hair folliclesAnti-androgen eg. on hair follicles

Anti-estrogenic in breast, uterus, brainAnti-estrogenic in breast, uterus, brain

Antagonizes hypercortisol states eg. Antagonizes hypercortisol states eg.

“ “anti-stress”anti-stress”

ThermogenicThermogenic

PREMARIN / PROVERA PREMARIN / PROVERA EFFECTS ON CLOTTING EFFECTS ON CLOTTING AND INFLAMMATION AND INFLAMMATION

FACTORSFACTORS Increase in fibrinogen 1 & 2Increase in fibrinogen 1 & 2

Increase in factor VII, VIIaIncrease in factor VII, VIIa

Decrease in Antithrombin IIIDecrease in Antithrombin III

Decrease in Interleukin – 6Decrease in Interleukin – 6

CHEST 2002CHEST 2002

PROGESTERONE EFFECTS PROGESTERONE EFFECTS ON CLOTTING AND ON CLOTTING AND

INFLAMMATION FACTORSINFLAMMATION FACTORS NO CHANGE IN:NO CHANGE IN: Factor VFactor V Factor VII, VIIaFactor VII, VIIa FibrinogenFibrinogen Antithrombin IIIAntithrombin III TNF -alphaTNF -alpha Interleukin-6Interleukin-6 PAIPAI CRPCRP

BLOOD 2004BLOOD 2004

PROGESTERONEPROGESTERONE promotes cell differentiationpromotes cell differentiation

promotes apoptosis (normal cell death)promotes apoptosis (normal cell death)

decreases estrogen induced mitosis decreases estrogen induced mitosis

(cell division)(cell division)

Promotes suppressor gene activityPromotes suppressor gene activity

STUDY OF 722 WOMEN WITH LOWSTUDY OF 722 WOMEN WITH LOW

PROGESTERONEPROGESTERONE

Followed for 33 years Followed for 33 years

10 times increased risk of death from all cancers 5.4 times 10 times increased risk of death from all cancers 5.4 times

increase in premenopausal breast cancerincrease in premenopausal breast cancer

PROGESTERONE VS. MPA PROGESTERONE VS. MPA (PROVERA)(PROVERA)

EFFECTS ON MYOCARDIAL ISCHEMIAEFFECTS ON MYOCARDIAL ISCHEMIA JAm Coll Card 2000JAm Coll Card 2000

Estradiol/progesterone increased exercise time Estradiol/progesterone increased exercise time

to myocardial ischemia compared to to myocardial ischemia compared to

estradiol/MPAestradiol/MPA

Consistent with animal studies showing Consistent with animal studies showing

progesterone protective against coronary progesterone protective against coronary

vasospasm and plaque formation while MPA vasospasm and plaque formation while MPA

increased risk of CAD and vasospasmincreased risk of CAD and vasospasm

PROGESTINSPROGESTINS developed for effects on uterus- decreased growth of developed for effects on uterus- decreased growth of

endometriumendometrium

contraindicated in pregnancy contraindicated in pregnancy

increases salt and water retentionincreases salt and water retention

negative effects on mood eg. depressionnegative effects on mood eg. depression

increased risk of breast cancerincreased risk of breast cancer

hair losshair loss

SIGNIFICANT CONFUSION EXITS IN SIGNIFICANT CONFUSION EXITS IN

MEDICAL LITERATUREMEDICAL LITERATURE

progesterone and progestin often used interchangeablyprogesterone and progestin often used interchangeably

WHI—2007WHI—2007

NEJM 2007NEJM 2007

Women between 50-59 yrs at the start of Women between 50-59 yrs at the start of estrogen replacement and on hormones for estrogen replacement and on hormones for average of 7.5 yrsaverage of 7.5 yrs

30-40% less likely to have calcium plaque in 30-40% less likely to have calcium plaque in coronary arteries compared to women on coronary arteries compared to women on placeboplacebo

Meta-analysis of HRT and Heart Meta-analysis of HRT and Heart Disease RiskDisease Risk

JGenIntMed 2007JGenIntMed 2007

32 % reduction in coronary heart disease 32 % reduction in coronary heart disease events for women who start treatment in events for women who start treatment in their 50’stheir 50’s

Previous study (meta-analysis) by same Previous study (meta-analysis) by same authors in 2004 showed an overall decrease authors in 2004 showed an overall decrease of 39% in deaths among women who began of 39% in deaths among women who began HRT before age 60 yrsHRT before age 60 yrs

ESTROGEN and ESTROGEN and THROMBOEMBOLISM RISK THROMBOEMBOLISM RISK

(ESTHER) STUDY(ESTHER) STUDY Circulation 2007Circulation 2007

271 women with first-ever VTE (venous 271 women with first-ever VTE (venous thromboembolism)thromboembolism)

Women using oral estrogen had 4.2 times the risk Women using oral estrogen had 4.2 times the risk of VTEof VTE

Women using transdermal estrogen had 0.9 times Women using transdermal estrogen had 0.9 times the riskthe risk

Certain progestins were associated with a 4 times Certain progestins were associated with a 4 times increase in VTEincrease in VTE

No association with progesteroneNo association with progesterone

EFFECTS OF HRT ON LONG EFFECTS OF HRT ON LONG TERM BONE MINERAL DENSITYTERM BONE MINERAL DENSITY

Climacteric 2007Climacteric 2007

587 women followed for 9 yrs587 women followed for 9 yrs Long-term HRT: increased BMD in hip 2.4% Long-term HRT: increased BMD in hip 2.4%

and spine 8.0%and spine 8.0% Short-term HRT(2-4 yrs): -1.6% in hip and Short-term HRT(2-4 yrs): -1.6% in hip and

-0.08% in spine-0.08% in spine No HRT: -4.2% in hip and -3.5% in spineNo HRT: -4.2% in hip and -3.5% in spine

COMPARISON OF RALOXIFINE COMPARISON OF RALOXIFINE AND LOW DOSE HRT ON BONE AND LOW DOSE HRT ON BONE

DENSITYDENSITY GynecolEndocrinol 2007GynecolEndocrinol 2007

42 postmenopausal women followed for 12 42 postmenopausal women followed for 12 monthsmonths

Raloxifine: increased BMD in hip 2.1% , Raloxifine: increased BMD in hip 2.1% , spine 2.3%, total body 2.9%spine 2.3%, total body 2.9%

Low dose HRT: increased BMD in hip 3.2%, Low dose HRT: increased BMD in hip 3.2%, spine 5.8%, total body 4.6%spine 5.8%, total body 4.6%

SERUM PROGESTERONE AND SERUM PROGESTERONE AND PROGNOSIS IN OPERABLE PROGNOSIS IN OPERABLE

BREAST CANCERBREAST CANCERBr J Cancer 1996Br J Cancer 1996 298 premenopausal women298 premenopausal women Blood taken at time of surgeryBlood taken at time of surgery No significant association between estradiol No significant association between estradiol

and survivaland survival Significantly better survival in higher Significantly better survival in higher

progesterone group-esp. in the node progesterone group-esp. in the node positive patientspositive patients

SURVIVAL OF PREMENOPAUSAL SURVIVAL OF PREMENOPAUSAL BREAST CANCER PATIENTS IN BREAST CANCER PATIENTS IN

RELATION TO MENSTRUAL RELATION TO MENSTRUAL CYCLE TIMING OF SURGERYCYCLE TIMING OF SURGERY

Cancer 1999Cancer 1999

Series of 112 premenopausal women with Series of 112 premenopausal women with operable breast canceroperable breast cancer

Increased survival rate for patients treated during Increased survival rate for patients treated during the luteal phasethe luteal phase

Cancer 1999Cancer 1999

Possible protective affect of high Possible protective affect of high progesteroneprogesterone

Possible negative effect of unopposed Possible negative effect of unopposed estrogenestrogen

Benefit in both ER/PR positive and negative Benefit in both ER/PR positive and negative tumourstumours

INTERNATIONAL JOURNAL OF INTERNATIONAL JOURNAL OF CANCER 2005CANCER 2005

54,548 post menopausal women- cohort of women 54,548 post menopausal women- cohort of women

beginning various forms of HRT and risk of beginning various forms of HRT and risk of

breast cancer.breast cancer.

Estrogen/Progestin relative risk 1.4 Estrogen/Progestin relative risk 1.4

Estrogen alone relative risk 1.1 Estrogen alone relative risk 1.1

Estrogen/Progesterone relative risk 0.9Estrogen/Progesterone relative risk 0.9

Unequal risks for breast cancer Unequal risks for breast cancer associated with different hormone associated with different hormone

replacement therapies: results from replacement therapies: results from the E3N cohort studythe E3N cohort study

Breast Cancer Research and Treatment 2007Breast Cancer Research and Treatment 2007 80,000 Postmenopausal women followed for over 80,000 Postmenopausal women followed for over

8 yrs. on various forms of HRT:8 yrs. on various forms of HRT: Estrogen only—1.29 x riskEstrogen only—1.29 x risk Estrogen/Progestin—1.69 x riskEstrogen/Progestin—1.69 x risk Estrogen/Progesterone—no increased riskEstrogen/Progesterone—no increased risk(if estrogen included Estriol, there was a decreased (if estrogen included Estriol, there was a decreased

risk compared to women who never used HRT)risk compared to women who never used HRT)

WHI-Breast Cancer WHI-Breast Cancer UpdateUpdate

Estrogen alone arm showed a decreased Estrogen alone arm showed a decreased risk of about 23%(not statistically significant) risk of about 23%(not statistically significant) of breast cancerof breast cancer

WHI---UPDATEWHI---UPDATE

Sub-group of women age 50-59 yrs(11,000) with Sub-group of women age 50-59 yrs(11,000) with hysterectomieshysterectomies

Premarin only group-44% decreased heart attacks Premarin only group-44% decreased heart attacks -28% decreased breast cancer -28% decreased breast cancer -27% decreased deaths -27% decreased deaths

-no increased strokes-no increased strokes Premarin/Provera group-26% increased heart Premarin/Provera group-26% increased heart

attacksattacks -20% increased breast -20% increased breast

cancercancer

Use of HRT After Use of HRT After Treatment of Breast CancerTreatment of Breast Cancer

Society of Obs & Gyn of Canada 2004Society of Obs & Gyn of Canada 2004

• Review of 8 studies of women given HRT after Review of 8 studies of women given HRT after treatment of breast cancertreatment of breast cancer

• All 8 studies showed no increased recurrence of All 8 studies showed no increased recurrence of breast cancer or death (overall, there was a small breast cancer or death (overall, there was a small decrease in both)decrease in both)

• HRT group and non-users did not differ with HRT group and non-users did not differ with regard to tumour stage, lymph nodes, metastisis regard to tumour stage, lymph nodes, metastisis or hormone receptor statusor hormone receptor status

2 independent Swedish prospective 2 independent Swedish prospective randomized trials of HRT after breast randomized trials of HRT after breast

cancercancer1.1. Hormone Replacement Therapy After Hormone Replacement Therapy After

Breast Cancer—Is It Safe? (HABITS)Breast Cancer—Is It Safe? (HABITS)

Lancet 2004Lancet 2004

2.2. Menopausal Hormone Therapy After Menopausal Hormone Therapy After Breast Cancer: The Stockholm Breast Cancer: The Stockholm Randomized Trial Randomized Trial

J Natl Cancer Inst 2005 J Natl Cancer Inst 2005

HABITS showed an increase in breast HABITS showed an increase in breast cancer recurrence with HRTcancer recurrence with HRT

Stockholm Trial showed no increase (small Stockholm Trial showed no increase (small decrease) in recurrence with HRTdecrease) in recurrence with HRT

Why the difference?Why the difference?

Stockholm vs HABITSStockholm vs HABITS

Stockholm trial designed hormone replacement to Stockholm trial designed hormone replacement to minimize exposure to progestin (MPA) eg. 14 days minimize exposure to progestin (MPA) eg. 14 days of MPA every 3 months vs more continuous use of MPA every 3 months vs more continuous use of progestin in HABITSof progestin in HABITS

Stockholm group based decision on prior animal Stockholm group based decision on prior animal model showing increased breast cell proliferation model showing increased breast cell proliferation following combined estrogen and progestin following combined estrogen and progestin treatment (more than estrogen alone)treatment (more than estrogen alone)

REDUCED INCIDENCE OF REDUCED INCIDENCE OF METASTASES AND LOWER METASTASES AND LOWER MORTALITY IN BREAST CA.MORTALITY IN BREAST CA. PATIENTS WITH Hx OF HRT PATIENTS WITH Hx OF HRT

AmJObstetGynecol 2007AmJObstetGynecol 2007

1072 women at time of diagnosis of breast cancer 1072 women at time of diagnosis of breast cancer with and without preoperative HRTwith and without preoperative HRT

Postmenopausal women who were not on HRT Postmenopausal women who were not on HRT had about 3x more metastases to bone, lung, and had about 3x more metastases to bone, lung, and liver and significantly lower survival than the liver and significantly lower survival than the women on HRTwomen on HRT

ARCHIVES OF PSYCHIATRYARCHIVES OF PSYCHIATRYApr. 2006Apr. 2006

2 prospective cohort studies of women 2 prospective cohort studies of women

without PH depression entering menopause.without PH depression entering menopause.

Strong link between hormonal changes and Strong link between hormonal changes and

onset of severe depression.onset of severe depression.

Progesterone Enhances Functional Progesterone Enhances Functional Recovery After Middle Cerebral Recovery After Middle Cerebral

Occlusion in Male MiceOcclusion in Male MiceJ Cerebral Blood Flow Metab 2004J Cerebral Blood Flow Metab 2004

Mice given progesterone had significantly Mice given progesterone had significantly reduced lesion volumereduced lesion volume

Improved survivalImproved survival Recovery of motor ability comparable to Recovery of motor ability comparable to

mice not undergoing occlusionmice not undergoing occlusion

ProTECT: a randomized clinical trial ProTECT: a randomized clinical trial of progesterone for acute traumatic of progesterone for acute traumatic

brain injurybrain injuryAnn Emerg Med Sept 2006Ann Emerg Med Sept 2006

Intravenous progesterone given for 3 days Intravenous progesterone given for 3 days after acute traumatic brain injuryafter acute traumatic brain injury

13% in progesterone group died within 30 13% in progesterone group died within 30 daysdays

30% in placebo group died30% in placebo group died

ProTECTProTECT

More likely to have good functional outcome More likely to have good functional outcome with progesterone compared to placebowith progesterone compared to placebo

No serious adverse events with No serious adverse events with progesterone at very high doseprogesterone at very high dose

Effects of HRT on Cognitive Effects of HRT on Cognitive Function and Alzheimer’s DiseaseFunction and Alzheimer’s Disease

HRT started at menopause protected HRT started at menopause protected against Alzheimer’s. NEngJMedicine 1995against Alzheimer’s. NEngJMedicine 1995

Early HRT protects against later cognitive Early HRT protects against later cognitive decline. Menopause 2005decline. Menopause 2005

Caches County Study—Alzheimer’s Caches County Study—Alzheimer’s decreased by 50% in users of HRT for more decreased by 50% in users of HRT for more than 10 yrs. No benefit in established than 10 yrs. No benefit in established disease. JAMA 2002disease. JAMA 2002

2:16 RATIO2:16 RATIO

Hydroxy(OH) metabolites of estradiol and Hydroxy(OH) metabolites of estradiol and estroneestrone

2-OH—safe2-OH—safe 4-OH & 16-OH—potentially harmful4-OH & 16-OH—potentially harmful Lower breast cancer(and prostate cancer) Lower breast cancer(and prostate cancer)

with higher 2:16 ratiowith higher 2:16 ratio Can improve ratio with cruciferous Can improve ratio with cruciferous

vegetables or supplements of I3C(DIM)vegetables or supplements of I3C(DIM)

ESTRIOLESTRIOL

Study-women in upper 25% of Estriol Study-women in upper 25% of Estriol secretion during pregnancy (reflecting estriol secretion during pregnancy (reflecting estriol secretion in cycling years) had 58% less secretion in cycling years) had 58% less breast cancer over the next 15 yrs.breast cancer over the next 15 yrs.

Iodine can increase estriol and lower Iodine can increase estriol and lower estrone/estradiolestrone/estradiol

2-METHOXY-ESTRADIOL2-METHOXY-ESTRADIOL

An estrogen metabolite produced in small An estrogen metabolite produced in small amountsamounts

Has anti-cancer effectsHas anti-cancer effects Effective against fibroidsEffective against fibroids CVS protectionCVS protection Not yet commercially available(being tested by Not yet commercially available(being tested by

pharm co.)pharm co.) May be able to increase levels through increased May be able to increase levels through increased

“methylation” eg. B12, folate“methylation” eg. B12, folate

TESTOSTERONETESTOSTERONE Produced in adrenals and ovariesProduced in adrenals and ovaries

Can be converted to estroneCan be converted to estrone

NERVOUS SYSTEM EFFECTSNERVOUS SYSTEM EFFECTS aids in production of neurotransmitters eg. noradrenaline, aids in production of neurotransmitters eg. noradrenaline,

dopamine, acetylcholinedopamine, acetylcholine

sense of well-being sense of well-being

sleep regulationsleep regulation

assertivenessassertiveness

hand-eye coordinationhand-eye coordination

Testosterone-Cardiovascular EffectsTestosterone-Cardiovascular Effects

Higher physiological levels associated with lower Higher physiological levels associated with lower CVDCVD

Decreases clotting tendenciesDecreases clotting tendencies Decreases fibrinogenDecreases fibrinogen Decreased Lp(a)Decreased Lp(a) Decreases TriglyceridesDecreases Triglycerides Decreases BPDecreases BP Decreases abdominal fatDecreases abdominal fat Increases HDLIncreases HDL Improves blood sugar controlImproves blood sugar control

TESTOSTERONETESTOSTERONE

SEXUAL FUNCTION EFFECTSSEXUAL FUNCTION EFFECTS

libidolibido

arousalarousal

METABOLIC EFFECTSMETABOLIC EFFECTS

inhibits fat depositioninhibits fat deposition

anabolic-tissue building anabolic-tissue building

increases bone densityincreases bone density

DHEADHEA produced primarily in adrenalsproduced primarily in adrenals

ANDROGENIC EFFECTSANDROGENIC EFFECTS

libidolibido

motivationmotivation

IMMUNE SYSTEM EFFECTSIMMUNE SYSTEM EFFECTS

low levels associated with cancer or autoimmune diseaseslow levels associated with cancer or autoimmune diseases

METABOLIC EFFECTSMETABOLIC EFFECTS

improves insulin sensitivityimproves insulin sensitivity

SYMPTOMS OF HORMONE SYMPTOMS OF HORMONE IMBALANCEIMBALANCE

ESTROGEN/PROGESTERONE ESTROGEN/PROGESTERONE DEFICIENCYDEFICIENCY

hhot flushesot flushes

night sweatsnight sweats

sleep disturbancessleep disturbances

vaginal dryness vaginal dryness

urinary incontinenceurinary incontinence

depression depression

bone lossbone loss

ESTROGEN EXCESS/ESTROGEN EXCESS/PROGESTERONE DEFICIENCYPROGESTERONE DEFICIENCY

mood changes - irritable, mood changes - irritable,

anxiousanxious

water retentionwater retention

weight gain - esp. hips/thighsweight gain - esp. hips/thighs

fibrocystic breastsfibrocystic breasts

uterine fibroidsuterine fibroids

headachesheadaches

cold bodycold body

SYMPTOMS OF HORMONE SYMPTOMS OF HORMONE IMBALANCEIMBALANCE

ANDROGEN DEFICIENYANDROGEN DEFICIENY

fatiguefatigue

decreased muscle mass decreased muscle mass

depressiondepression

decreased libidodecreased libido

muscle achesmuscle aches

sleep disturbancessleep disturbances

bone lossbone loss

ANDROGEN EXCESSANDROGEN EXCESS

acneacne

excess facial/body hairexcess facial/body hair

aggressionaggression

loss of scalp hairloss of scalp hair

DOSAGE FORMSDOSAGE FORMS

OralOral

TransdermalTransdermal

BuccalBuccal

VaginalVaginal

ORAL BIOIDENTICAL ORAL BIOIDENTICAL ESTROGENSESTROGENS

BRAND NAMEBRAND NAME

eg. Estrace (estradiol)eg. Estrace (estradiol)

Fixed doseFixed dose

COMPOUNDED CAPSULESCOMPOUNDED CAPSULES

Estradiol, Estriol, Triest, BiestEstradiol, Estriol, Triest, Biest

Made in compounding pharmacies in specified Made in compounding pharmacies in specified

dosesdoses

ORAL ESTROGENSORAL ESTROGENS

POTENTIAL SIDE EFFECTSPOTENTIAL SIDE EFFECTS first pass liver metabolismfirst pass liver metabolism

can increase triglyceridescan increase triglycerides

can increase blood pressure (through can increase blood pressure (through ↑ renin)↑ renin)

can decrease IGF-1 (growth hormone)can decrease IGF-1 (growth hormone)

Can increase clotting factorsCan increase clotting factors

ORAL PROGESTERONEORAL PROGESTERONE

BRAND NAME-PROMETRIUM BRAND NAME-PROMETRIUM

COMPOUNDED CAPSULESCOMPOUNDED CAPSULES

POTENTIAL SIDE EFFECTSPOTENTIAL SIDE EFFECTS

inconsistent absorptioninconsistent absorption

metabolites can cause drowsiness, “spaciness”metabolites can cause drowsiness, “spaciness”

TRANSDERMALTRANSDERMAL

PATCHES eg. ESTRADERM, CLIMARA PATCHES eg. ESTRADERM, CLIMARA (ESTRADIOL(ESTRADIOL))

Continuous slow releaseContinuous slow release

Fixed dosagesFixed dosages

GELS, CREAMSGELS, CREAMS

Estrogel (estradiol)Estrogel (estradiol)

Compounded-Triest, Biest creamCompounded-Triest, Biest cream

Compounded-Progesterone creamCompounded-Progesterone cream

Compounded testosterone Compounded testosterone

(commercial products designed for men)(commercial products designed for men)

TRANSDERMALTRANSDERMAL

COMPOUNDEDCOMPOUNDED - - can combine various can combine various

hormones in customized way. Avoids much of hormones in customized way. Avoids much of

side effects of oral forms.side effects of oral forms.

Controversy around degree of absorption of Controversy around degree of absorption of

progesterone.progesterone.

lower blood levelslower blood levels

VAGINAL FORMSVAGINAL FORMS

BRAND NAMES EG. ESTRING (ESTRADIOL)BRAND NAMES EG. ESTRING (ESTRADIOL)

COMPOUNDEDCOMPOUNDED – Estradiol, Estriol – Estradiol, Estriol

Estrogen mainly for local symptoms such as vaginal Estrogen mainly for local symptoms such as vaginal

dryness, atrophy or urinary stress incontinence. dryness, atrophy or urinary stress incontinence.

Progesterone creams – brand name and compoundedProgesterone creams – brand name and compounded

modern uses mainly in pregnancy eg. recurrent modern uses mainly in pregnancy eg. recurrent

miscarriages.miscarriages.

BUCCAL FORMSBUCCAL FORMS

TROCHES-LOZENGESTROCHES-LOZENGES COMPOUNDEDCOMPOUNDED – customized combinations – customized combinations

and dosages of estrogen (Triest, Biest, Estriol), and dosages of estrogen (Triest, Biest, Estriol),

progesterone, testosteroneprogesterone, testosterone

Good absorption of all hormones Good absorption of all hormones

Avoid side effects of oral formsAvoid side effects of oral forms

Pharmacokinetics of estradiol, Pharmacokinetics of estradiol, progesterone, testosterone and progesterone, testosterone and DHEA after transbuccal(troche) DHEA after transbuccal(troche)

administration to postmenopausal administration to postmenopausal womenwomen

Climacteric 2003Climacteric 2003

“ “Each of the hormones was readily absorbed via the buccal Each of the hormones was readily absorbed via the buccal mucous membrane. Peak plasma concentrations of mucous membrane. Peak plasma concentrations of estradiol and progesterone were comparable to those estradiol and progesterone were comparable to those found in young menstruating women.”found in young menstruating women.”

DOSING SCHEDULESDOSING SCHEDULES

Bioidentical Hormones utilized and metabolized Bioidentical Hormones utilized and metabolized

quickly by the body. quickly by the body.

Usually need twice daily dosing to maintain Usually need twice daily dosing to maintain

levels.levels.

MONITORING AND MONITORING AND TITRATING DOSESTITRATING DOSES

Follow blood levels of hormonesFollow blood levels of hormones

Follow symptom responseFollow symptom response

Follow signs of imbalanceFollow signs of imbalance

Transient side effects during initial stages eg. Transient side effects during initial stages eg.

spotting, breast tenderness.spotting, breast tenderness.

Screening as indicated eg. ultrasound, bone Screening as indicated eg. ultrasound, bone

density.density.

INITIAL LAB WORKINITIAL LAB WORK

EstradiolEstradiol

ProgesteroneProgesterone

TestosteroneTestosterone

DHEASDHEAS

TSHTSH

Depending on Sypmtoms: CortisolDepending on Sypmtoms: Cortisol

B12B12

Vit DVit D

MONITORINGMONITORING

Estradiol (approx. 100-250)Estradiol (approx. 100-250)

Estrone (Occasional)Estrone (Occasional)

Progesterone (approx. 10-30)Progesterone (approx. 10-30)

TestosteroneTestosterone

DHEADHEA if initially lowif initially low

TFTsTFTs

(with troche, check 6 hrs. post-dose)(with troche, check 6 hrs. post-dose)

MONITORINGMONITORING

Mammogram/Breast U/SMammogram/Breast U/S

Pelvic U/S re: endometrial thickness, fibroids, Pelvic U/S re: endometrial thickness, fibroids,

etc.etc.

Bone DensityBone Density

TYPICAL DOSE RANGESTYPICAL DOSE RANGES

Triest/Biest 1.5-2.5 mg/day given BIDTriest/Biest 1.5-2.5 mg/day given BID

Progesterone 150-250 mg/day given BIDProgesterone 150-250 mg/day given BID

Testosterone 0.5-2.0 mg/day given BID Testosterone 0.5-2.0 mg/day given BID

(if needed)(if needed)

OTHER CONSIDERATIONS OTHER CONSIDERATIONS OF POOR RESPONSEOF POOR RESPONSE

Thyroid function –”sub-clinical”Thyroid function –”sub-clinical”

- “sub-optimal”- “sub-optimal”

Cortisol levels – too high or too lowCortisol levels – too high or too low

B12 levels – low or low normalB12 levels – low or low normal

Vit DVit D

Can effect hormone receptors, responsiveness or Can effect hormone receptors, responsiveness or

metabolismmetabolism

SUPPORTIVE NUTRIENTSSUPPORTIVE NUTRIENTS For optimal responsiveness of hormonesFor optimal responsiveness of hormones

For proper metabolism.For proper metabolism.

For anticancer effects.For anticancer effects.

1)1) Omega- 3 Fatty Acids (EPA, DHA)Omega- 3 Fatty Acids (EPA, DHA)

2)2) Vitamin DVitamin D

3)3) B VitaminsB Vitamins

4)4) Minerals eg. Zinc, SeleniumMinerals eg. Zinc, Selenium

5)5) I3C, DIM (cruciferous vegetables)I3C, DIM (cruciferous vegetables)

6)6) CurcuminCurcumin

Current “official” recommendations Current “official” recommendations for HRT (largely based on WHI for HRT (largely based on WHI

study)study) HRT should only be used for treatment of HRT should only be used for treatment of

vasomotor symptoms (sweats and flushes) and for vasomotor symptoms (sweats and flushes) and for the shortest period of time necessarythe shortest period of time necessary

Based on negative effects in that study on breast Based on negative effects in that study on breast cancer, blood clots and cardiovascular disease.cancer, blood clots and cardiovascular disease.

BUT…BUT…

More recent evidence shows:More recent evidence shows:

There is no increase in breast cancer if There is no increase in breast cancer if synthetic progestins not usedsynthetic progestins not used

There is no increase in blood clots if oral There is no increase in blood clots if oral estrogens and certain progestins not usedestrogens and certain progestins not used

There is apparent protection against There is apparent protection against cardiovascular disease and cognitive cardiovascular disease and cognitive decline if started before established disease decline if started before established disease has occurredhas occurred

HRT IN POSTMENOPAUSE: A HRT IN POSTMENOPAUSE: A REAPPRAISALREAPPRAISAL

AnnEndocrin 2007AnnEndocrin 2007

From Univ of Brussels, School of MedicineFrom Univ of Brussels, School of Medicine “ “ HRT is the most effective treatment currently HRT is the most effective treatment currently

available for vasomotor and urogenital symptoms available for vasomotor and urogenital symptoms and decreased libido. Because harmful effects and decreased libido. Because harmful effects were evidenced in some clinical trials, health were evidenced in some clinical trials, health authorities now consider that the risk-benefit authorities now consider that the risk-benefit considerations do not favour the use of HRT for considerations do not favour the use of HRT for prevention of CVD and bone fractures in prevention of CVD and bone fractures in postmenopausal women… postmenopausal women…

AnnEndocrinol 2007AnnEndocrinol 2007 “ …“ …However, experimental and clinical studies indicate that However, experimental and clinical studies indicate that

adverse effects of HRT may largely depend on the adverse effects of HRT may largely depend on the estrogen and progesterone/progestin formulation, dosage, estrogen and progesterone/progestin formulation, dosage, mode of administration, patient’s age, associated diseases, mode of administration, patient’s age, associated diseases, and duration of treatment….But cardiovascular and and duration of treatment….But cardiovascular and invasive breast cancer risks are higher with oral estrogen invasive breast cancer risks are higher with oral estrogen than with transdermal estradiol, and also higher with many than with transdermal estradiol, and also higher with many progestin compounds than with micronized progestin compounds than with micronized progesterone….In the author’s-heterodox-opinion, HRT progesterone….In the author’s-heterodox-opinion, HRT may also be a good therapeutic choice to prevent bone may also be a good therapeutic choice to prevent bone loss, since alternative medications, including raloxifene and loss, since alternative medications, including raloxifene and bisphosponates, may have dramatic harmful effects in bisphosponates, may have dramatic harmful effects in some patients.”some patients.”

BIODENTICAL HORMONE BIODENTICAL HORMONE REPLACEMENTREPLACEMENT

Relieving symptoms of hormone Relieving symptoms of hormone

deficiency / imbalance with the use of the same deficiency / imbalance with the use of the same

hormones produced by the body at physiological hormones produced by the body at physiological

levels and in balanced combinations.levels and in balanced combinations.