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BIOIDENTICAL HORMONE REPLACEMENT M. LITMAN, M.D. JUNE, 2009

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Presentation on theme: "BIOIDENTICAL HORMONE REPLACEMENT M. LITMAN, M.D. JUNE, 2009"— Presentation transcript:

1 BIOIDENTICAL HORMONE REPLACEMENT M. LITMAN, M.D. JUNE, 2009

2 WOMEN’S HEALTH INITIATIVE STUDY OVER 16, 000 WOMEN.
PREMPRO (PREMARIN/PROVERA)VS.PLACEBO Breast cancer increased by 26% CVD increased by 29% Stroke increased by 41% Blood clots increased by 100%

3 WHI “ It remains possible that transdermal estradiol with progesterone, which more closely mimics the normal physiology and metabolism of endogenous sex hormones, may provide a different risk-benefit profile.” Writing Group for WHI, July 2002

4 HORMONE PATHWAYS IN OVARIES AND ADRENAL GLANDS
Cholesterol Pregnenolone Progesterone Hydroxypregnenolone DHEA Deoxycorticosterone Hydroxyprogesterone Androstenedione Corticosterone Deoxycortisol Oestrone Testosterone Aldosterone Cortisol Oestriol Oestradiol

5 ESTROGEN 3 main human estrogens Estradiol Estrone Estriol

6 ESTRADIOL ESTRONE ESTRIOL Most potent Primarily from ovary
Conversion from estradiol Produced in adrenals Produced in tissues eg. fat ESTRIOL Weak estrogen Little stimulation of breast and uterus High levels in pregnancy

7 CENTRAL NERVOUS SYSTEM
EFFECTS OF ESTROGEN aids in synthesis of neurotransmitters eg. serotonin, noradrenaline, dopamine resulting effects on mood effects on sleep sensitizes neurons to nerve growth factor

8 CARDIOVASCULAR SYSTEMS
EFFECTS OF ESTROGEN Inhibits vasoconstriction Lowers fibrinogen Decreases LDL, increases HDL Improves insulin sensitivity

9 BONE EFFECTS OF ESTROGEN
Inhibits osteoclasts Decreases bone resorption UROGENITAL EFFECTS Preserves pelvic tissues Growth of endometrium Growth of follicle Growth of breasts METABOLIC EFFECTS Stores fat (esp. hips/thighs)

10 PROGESTERONE One molecule Primarily produced in ovary after ovulation
Small amounts from adrenals

11 PROGESTERONE BONE EFFECTS GENITAL EFFECTS Stimulates osteoblasts
Bone formation GENITAL EFFECTS Maintains pregnancy Induces maturation of endometrium

12 PROGESTERONE NERVOUS SYSTEM EFFECTS
CVS Effects- inhibition of induced coronary spasm in monkeys NERVOUS SYSTEM EFFECTS attaches to GABA receptors produces calming, relaxing effect NMDA antagonist-may have analgesic effects stimulates synthesis of myelin repair of injured nerves

13 PROGESTERONE METABOLIC EFFECTS Diuretic-blocks aldosterone receptors
Improves insulin sensitivity Enhances thyroid hormone function Anti-androgen eg. on hair follicles Anti-estrogenic in breast, uterus, brain Antagonizes hypercortisol states eg. “anti-stress” Thermogenic

14 PREMARIN / PROVERA EFFECTS ON CLOTTING AND INFLAMMATION FACTORS
Increase in fibrinogen 1 & 2 Increase in factor VII, VIIa Decrease in Antithrombin III Decrease in Interleukin – 6 CHEST 2002

15 PROGESTERONE EFFECTS ON CLOTTING AND INFLAMMATION FACTORS
NO CHANGE IN: Factor V Factor VII, VIIa Fibrinogen Antithrombin III TNF -alpha Interleukin-6 PAI CRP BLOOD 2004

16 PROGESTERONE STUDY OF 722 WOMEN WITH LOW PROGESTERONE
promotes cell differentiation promotes apoptosis (normal cell death) decreases estrogen induced mitosis (cell division) Promotes suppressor gene activity STUDY OF 722 WOMEN WITH LOW PROGESTERONE Followed for 33 years 10 times increased risk of death from all cancers times increase in premenopausal breast cancer

17 PROGESTERONE VS. MPA (PROVERA)
EFFECTS ON MYOCARDIAL ISCHEMIA JAm Coll Card 2000 Estradiol/progesterone increased exercise time to myocardial ischemia compared to estradiol/MPA Consistent with animal studies showing progesterone protective against coronary vasospasm and plaque formation while MPA increased risk of CAD and vasospasm

18 PROGESTINS developed for effects on uterus- decreased growth of endometrium contraindicated in pregnancy increases salt and water retention negative effects on mood eg. depression increased risk of breast cancer hair loss SIGNIFICANT CONFUSION EXITS IN MEDICAL LITERATURE progesterone and progestin often used interchangeably

19 WHI—2007 NEJM 2007 Women between yrs at the start of estrogen replacement and on hormones for average of 7.5 yrs 30-40% less likely to have calcium plaque in coronary arteries compared to women on placebo

20 Meta-analysis of HRT and Heart Disease Risk
JGenIntMed 2007 32 % reduction in coronary heart disease events for women who start treatment in their 50’s Previous study (meta-analysis) by same authors in 2004 showed an overall decrease of 39% in deaths among women who began HRT before age 60 yrs

21 ESTROGEN and THROMBOEMBOLISM RISK (ESTHER) STUDY
Circulation 2007 271 women with first-ever VTE (venous thromboembolism) Women using oral estrogen had 4.2 times the risk of VTE Women using transdermal estrogen had 0.9 times the risk Certain progestins were associated with a 4 times increase in VTE No association with progesterone

22 EFFECTS OF HRT ON LONG TERM BONE MINERAL DENSITY
Climacteric 2007 587 women followed for 9 yrs Long-term HRT: increased BMD in hip 2.4% and spine 8.0% Short-term HRT(2-4 yrs): -1.6% in hip and % in spine No HRT: -4.2% in hip and -3.5% in spine

23 COMPARISON OF RALOXIFINE AND LOW DOSE HRT ON BONE DENSITY
GynecolEndocrinol 2007 42 postmenopausal women followed for 12 months Raloxifine: increased BMD in hip 2.1% , spine 2.3%, total body 2.9% Low dose HRT: increased BMD in hip 3.2%, spine 5.8%, total body 4.6%

24 SERUM PROGESTERONE AND PROGNOSIS IN OPERABLE BREAST CANCER
Br J Cancer 1996 298 premenopausal women Blood taken at time of surgery No significant association between estradiol and survival Significantly better survival in higher progesterone group-esp. in the node positive patients

25 SURVIVAL OF PREMENOPAUSAL BREAST CANCER PATIENTS IN RELATION TO MENSTRUAL CYCLE TIMING OF SURGERY
Series of 112 premenopausal women with operable breast cancer Increased survival rate for patients treated during the luteal phase

26 Cancer 1999 Possible protective affect of high progesterone
Possible negative effect of unopposed estrogen Benefit in both ER/PR positive and negative tumours

27 INTERNATIONAL JOURNAL OF CANCER 2005
54,548 post menopausal women- cohort of women beginning various forms of HRT and risk of breast cancer. Estrogen/Progestin relative risk 1.4 Estrogen alone relative risk 1.1 Estrogen/Progesterone relative risk 0.9

28 Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study Breast Cancer Research and Treatment 2007 80,000 Postmenopausal women followed for over 8 yrs. on various forms of HRT: Estrogen only—1.29 x risk Estrogen/Progestin—1.69 x risk Estrogen/Progesterone—no increased risk (if estrogen included Estriol, there was a decreased risk compared to women who never used HRT)

29 WHI-Breast Cancer Update
Estrogen alone arm showed a decreased risk of about 23%(not statistically significant) of breast cancer

30 WHI---UPDATE Sub-group of women age yrs(11,000) with hysterectomies Premarin only group-44% decreased heart attacks % decreased breast cancer % decreased deaths -no increased strokes Premarin/Provera group-26% increased heart attacks -20% increased breast cancer

31 Use of HRT After Treatment of Breast Cancer
Society of Obs & Gyn of Canada 2004 Review of 8 studies of women given HRT after treatment of breast cancer All 8 studies showed no increased recurrence of breast cancer or death (overall, there was a small decrease in both) HRT group and non-users did not differ with regard to tumour stage, lymph nodes, metastisis or hormone receptor status

32 2 independent Swedish prospective randomized trials of HRT after breast cancer
Hormone Replacement Therapy After Breast Cancer—Is It Safe? (HABITS) Lancet 2004 Menopausal Hormone Therapy After Breast Cancer: The Stockholm Randomized Trial J Natl Cancer Inst 2005

33 HABITS showed an increase in breast cancer recurrence with HRT
Stockholm Trial showed no increase (small decrease) in recurrence with HRT Why the difference?

34 Stockholm vs HABITS Stockholm trial designed hormone replacement to minimize exposure to progestin (MPA) eg. 14 days of MPA every 3 months vs more continuous use of progestin in HABITS Stockholm group based decision on prior animal model showing increased breast cell proliferation following combined estrogen and progestin treatment (more than estrogen alone)

35 REDUCED INCIDENCE OF METASTASES AND LOWER MORTALITY IN BREAST CA
REDUCED INCIDENCE OF METASTASES AND LOWER MORTALITY IN BREAST CA. PATIENTS WITH Hx OF HRT AmJObstetGynecol 2007 1072 women at time of diagnosis of breast cancer with and without preoperative HRT Postmenopausal women who were not on HRT had about 3x more metastases to bone, lung, and liver and significantly lower survival than the women on HRT

36 ARCHIVES OF PSYCHIATRY Apr. 2006
2 prospective cohort studies of women without PH depression entering menopause. Strong link between hormonal changes and onset of severe depression.

37 Progesterone Enhances Functional Recovery After Middle Cerebral Occlusion in Male Mice
J Cerebral Blood Flow Metab 2004 Mice given progesterone had significantly reduced lesion volume Improved survival Recovery of motor ability comparable to mice not undergoing occlusion

38 ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury
Ann Emerg Med Sept 2006 Intravenous progesterone given for 3 days after acute traumatic brain injury 13% in progesterone group died within 30 days 30% in placebo group died

39 ProTECT More likely to have good functional outcome with progesterone compared to placebo No serious adverse events with progesterone at very high dose

40 Effects of HRT on Cognitive Function and Alzheimer’s Disease
HRT started at menopause protected against Alzheimer’s. NEngJMedicine 1995 Early HRT protects against later cognitive decline. Menopause 2005 Caches County Study—Alzheimer’s decreased by 50% in users of HRT for more than 10 yrs. No benefit in established disease. JAMA 2002

41 2:16 RATIO Hydroxy(OH) metabolites of estradiol and estrone 2-OH—safe
4-OH & 16-OH—potentially harmful Lower breast cancer(and prostate cancer) with higher 2:16 ratio Can improve ratio with cruciferous vegetables or supplements of I3C(DIM)

42 ESTRIOL Study-women in upper 25% of Estriol secretion during pregnancy (reflecting estriol secretion in cycling years) had 58% less breast cancer over the next 15 yrs. Iodine can increase estriol and lower estrone/estradiol

43 2-METHOXY-ESTRADIOL An estrogen metabolite produced in small amounts
Has anti-cancer effects Effective against fibroids CVS protection Not yet commercially available(being tested by pharm co.) May be able to increase levels through increased “methylation” eg. B12, folate

44 TESTOSTERONE NERVOUS SYSTEM EFFECTS Produced in adrenals and ovaries
Can be converted to estrone NERVOUS SYSTEM EFFECTS aids in production of neurotransmitters eg. noradrenaline, dopamine, acetylcholine sense of well-being sleep regulation assertiveness hand-eye coordination

45 Testosterone-Cardiovascular Effects
Higher physiological levels associated with lower CVD Decreases clotting tendencies Decreases fibrinogen Decreased Lp(a) Decreases Triglycerides Decreases BP Decreases abdominal fat Increases HDL Improves blood sugar control

46 TESTOSTERONE SEXUAL FUNCTION EFFECTS METABOLIC EFFECTS libido arousal
inhibits fat deposition anabolic-tissue building increases bone density

47 DHEA produced primarily in adrenals ANDROGENIC EFFECTS libido
motivation IMMUNE SYSTEM EFFECTS low levels associated with cancer or autoimmune diseases METABOLIC EFFECTS improves insulin sensitivity

48 SYMPTOMS OF HORMONE IMBALANCE
ESTROGEN/PROGESTERONE DEFICIENCY hot flushes night sweats sleep disturbances vaginal dryness urinary incontinence depression bone loss ESTROGEN EXCESS/ PROGESTERONE DEFICIENCY mood changes - irritable, anxious water retention weight gain - esp. hips/thighs fibrocystic breasts uterine fibroids headaches cold body

49 SYMPTOMS OF HORMONE IMBALANCE
ANDROGEN DEFICIENY fatigue decreased muscle mass depression decreased libido muscle aches sleep disturbances bone loss ANDROGEN EXCESS acne excess facial/body hair aggression loss of scalp hair

50 DOSAGE FORMS Oral Transdermal Buccal Vaginal

51 ORAL BIOIDENTICAL ESTROGENS
BRAND NAME eg. Estrace (estradiol) Fixed dose COMPOUNDED CAPSULES Estradiol, Estriol, Triest, Biest Made in compounding pharmacies in specified doses

52 ORAL ESTROGENS POTENTIAL SIDE EFFECTS first pass liver metabolism
can increase triglycerides can increase blood pressure (through ↑ renin) can decrease IGF-1 (growth hormone) Can increase clotting factors

53 ORAL PROGESTERONE BRAND NAME-PROMETRIUM COMPOUNDED CAPSULES
POTENTIAL SIDE EFFECTS inconsistent absorption metabolites can cause drowsiness, “spaciness”

54 TRANSDERMAL GELS, CREAMS Continuous slow release Fixed dosages
PATCHES eg. ESTRADERM, CLIMARA (ESTRADIOL) Continuous slow release Fixed dosages GELS, CREAMS Estrogel (estradiol) Compounded-Triest, Biest cream Compounded-Progesterone cream Compounded testosterone (commercial products designed for men)

55 TRANSDERMAL COMPOUNDED - can combine various hormones in customized way. Avoids much of side effects of oral forms. Controversy around degree of absorption of progesterone. lower blood levels

56 VAGINAL FORMS BRAND NAMES EG. ESTRING (ESTRADIOL)
COMPOUNDED – Estradiol, Estriol Estrogen mainly for local symptoms such as vaginal dryness, atrophy or urinary stress incontinence. Progesterone creams – brand name and compounded modern uses mainly in pregnancy eg. recurrent miscarriages.

57 BUCCAL FORMS TROCHES-LOZENGES
COMPOUNDED – customized combinations and dosages of estrogen (Triest, Biest, Estriol), progesterone, testosterone Good absorption of all hormones Avoid side effects of oral forms

58 Pharmacokinetics of estradiol, progesterone, testosterone and DHEA after transbuccal(troche) administration to postmenopausal women Climacteric 2003 “Each of the hormones was readily absorbed via the buccal mucous membrane. Peak plasma concentrations of estradiol and progesterone were comparable to those found in young menstruating women.”

59 DOSING SCHEDULES Bioidentical Hormones utilized and metabolized quickly by the body Usually need twice daily dosing to maintain levels.

60 MONITORING AND TITRATING DOSES
Follow blood levels of hormones Follow symptom response Follow signs of imbalance Transient side effects during initial stages eg. spotting, breast tenderness. Screening as indicated eg. ultrasound, bone density.

61 INITIAL LAB WORK Estradiol Progesterone Testosterone DHEAS TSH
Depending on Sypmtoms: Cortisol B12 Vit D

62 MONITORING Estradiol (approx. 100-250) Estrone (Occasional)
Progesterone (approx ) Testosterone DHEA if initially low TFTs (with troche, check 6 hrs. post-dose)

63 MONITORING Mammogram/Breast U/S
Pelvic U/S re: endometrial thickness, fibroids, etc. Bone Density

64 TYPICAL DOSE RANGES Triest/Biest 1.5-2.5 mg/day given BID
Progesterone mg/day given BID Testosterone mg/day given BID (if needed)

65 OTHER CONSIDERATIONS OF POOR RESPONSE
Thyroid function –”sub-clinical” - “sub-optimal” Cortisol levels – too high or too low B12 levels – low or low normal Vit D Can effect hormone receptors, responsiveness or metabolism

66 SUPPORTIVE NUTRIENTS For optimal responsiveness of hormones
For proper metabolism. For anticancer effects. Omega- 3 Fatty Acids (EPA, DHA) Vitamin D B Vitamins Minerals eg. Zinc, Selenium I3C, DIM (cruciferous vegetables) Curcumin

67 Current “official” recommendations for HRT (largely based on WHI study)
HRT should only be used for treatment of vasomotor symptoms (sweats and flushes) and for the shortest period of time necessary Based on negative effects in that study on breast cancer, blood clots and cardiovascular disease. BUT…

68 More recent evidence shows:
There is no increase in breast cancer if synthetic progestins not used There is no increase in blood clots if oral estrogens and certain progestins not used There is apparent protection against cardiovascular disease and cognitive decline if started before established disease has occurred

69 HRT IN POSTMENOPAUSE: A REAPPRAISAL
AnnEndocrin 2007 From Univ of Brussels, School of Medicine “ HRT is the most effective treatment currently available for vasomotor and urogenital symptoms and decreased libido. Because harmful effects were evidenced in some clinical trials, health authorities now consider that the risk-benefit considerations do not favour the use of HRT for prevention of CVD and bone fractures in postmenopausal women…

70 AnnEndocrinol 2007 “ …However, experimental and clinical studies indicate that adverse effects of HRT may largely depend on the estrogen and progesterone/progestin formulation, dosage, mode of administration, patient’s age, associated diseases, and duration of treatment….But cardiovascular and invasive breast cancer risks are higher with oral estrogen than with transdermal estradiol, and also higher with many progestin compounds than with micronized progesterone….In the author’s-heterodox-opinion, HRT may also be a good therapeutic choice to prevent bone loss, since alternative medications, including raloxifene and bisphosponates, may have dramatic harmful effects in some patients.”

71 BIODENTICAL HORMONE REPLACEMENT
Relieving symptoms of hormone deficiency / imbalance with the use of the same hormones produced by the body at physiological levels and in balanced combinations.


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