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A. Overview [1,55] navigator

  1. Replacement of estrogen ± progesterone in women with natural or induced menopause
  2. Overall, HRT poses no benefits and possible harms for average woman with or without a intact uterus [4,68]
  3. HRT is no longer recommended routinely in healthy post-menopausal women [1,4,55]
  4. Components of HRT
    1. HRT refers specifically to estrogen ± progestin
    2. ERT refers only to estrogen replacment therapy
    3. Most HRT and ERT uses conjugated equine estrogen (CEE)
    4. Women with a uterus are offered combined (estrogen + progestin) therapy
    5. Women who have had a hysterectomy do not need to take a progestin
  5. Several changes in physiology have been noted after menopause
    1. Accelerated bone loss - osteoporosis
    2. Reduction in HDL cholesterol (Chol) and increases in total Chol
    3. Increase in cardiovascular disease (not completely explained by Chol profile)
    4. Hot Flashes
    5. Atrophic Vaginitis
    6. Mood Changes
    7. Memory alterations
  6. Improvement with HRT [50,51]
    1. Menopausal symptoms: hot flashes, atrophic vaginitis (vaginal dryness) [35,77]
    2. Osteoporosis is reduced [68] but discontinuation of ERT/HRT leads to rapid bone mineral density loss [57]
    3. Reduced incidence of diabetes mellitus in women with coronary artery disease (CAD) [60]
    4. HRT use over 4 years did not improve cognitive function in postmenopausal women with cardiovascular disease [56]
    5. In women without symptoms, HRT does not improve quality of life [35]
    6. Reduced risk of colon cancer [4,19]
  7. HRT Harms [50,51]
    1. Overall slight increase in cardiovascular disease which disappear within 3 years of stopping []
    2. Increased thromboembolic events, particularly stroke [61,68]
    3. Increased incidence of dementia [29] and small increase in cognitive decline [30]
    4. Increases risk (1.6-2X) of gallstones, cholecystitis, any gallbladder disease [74]
    5. Possible increased risk of breast cancer with >5 years of use 1.3-2.0X [64,68]
    6. Small increased risk (1 additional case per 2500 users) in ovarian cancer over 5 years [32]
    7. Causes small increase in mild-moderate but not severe flares of systemic lupus [76]

B. Estrogens [2]navigator

  1. Natural Estrogens
    1. Estrone (E1) - normal serum levels 30-200 pg/mL
    2. 17ß-estradiol (E2) - normal serum levels 40-500 pg/mL
    3. Estriol (E3) - normal levels 3-16 pg/mL
  2. Synthesis of Natural Estrogens
    1. All derived from cholesterol
    2. Cytochrome P450 enzymes in mitochondria catalyze synthesis
    3. Steroidogenic acute regulatory protein is responsible for cholesterol transfer to mitochondria
    4. Aromatization of is last step in estrogen formation by P450 aromatase complex
    5. Androstenedione aromatized to E1
    6. Testosterone aromatized to E2
    7. 16alpha-hydroxyandrostenedione aromatized to E3
  3. Location of Estrogen Production
    1. Primary source of E2 in women is theca and granulosa cells of ovarias
    2. During pregnancy, E3 is synthesized in syncytiotrophoblast
    3. 16alpha-hydroxyepiandrosterone is produced in fetal adrenal gland
  4. Phytoestrogens [3]
    1. Plant-based preparations with "natural" estrogenic activity
    2. Variable levels of estrogenic activity
    3. "Natural" products have variable purity and unknown side effects
    4. Caution should be used when taking unpurified "herbal" supplements
    5. Potential for endometrial hyperplasia and cancer are not known
  5. Estrogens and Gene Expression
    1. Estrogens bind to their receptors (ER) and modulate gene expression
    2. Free ER is found in cytoplasm or nucleus bound to chaperones
    3. Estrogen binding to ER displaces chaperone and drives nuclear localization
    4. Estrogen-ER complex binds to DNA in transcriptional regulatory elements
    5. Estrogen-ER complex also binds to other transcription factors and modulate activity
    6. These factors include AP-1 (activator protein 1) and nuclear factor kappa B (NF-kB)
  6. Estrogen Receptors (ER)
    1. ER are members of nuclear hormone receptor superfamily
    2. Two types of ER: alpha and beta, coded on different chromosomes
    3. DNA binding domains of ER alpha and beta similar, but low homology elsewhere
    4. Consensus DNA binding domain is 5'-GGTCAnnnTGACC-3'
    5. ER alpha and beta expressed in some of the same, some different, cell types
    6. E2 has highest affininy for both ER (100% each)
    7. E3 has lowest affinity (15-20% compared to E2) for both ER
    8. E1 has 60% affinity for ER alpha, 37% affinity for ER beta, compared with E2
    9. ER alpha T>C polymorphism associated with increased cardiovascular disease risk [67]
  7. Sites of Physiologic Actions of Estrogens
    1. Breast Tissue: stimualtes growth and differentiation of ductal epithelium
    2. Central Nervous System: mood, thought processes
    3. Vasculature: short term vasodilator, endothelial cell protection, increase coagulation
    4. Higher serum estrogen levels in men associated with reduced cardiovascular events [24]
    5. Bone: blockade of osteoclast differentiation
  8. Progestins - medroxyprogesterone acetate (MPA) is usually used

C. Overall Results in Prospective Studies [4,5]navigator

  1. CEE 0.625mg/d + MPA 2.5mg/d versus placebo in over 16,000 healthy women
  2. Goal 8.5 years but stopped early at 5.2 year mean followup
  3. Increase in Events [4,68]
    1. CAD risk increased: excess 7/10,000 person-years [5]
    2. Strokes and pulmonary embolism risk increased: excess 8/10,000 person-years each [61]
    3. Invasive breast cancer (Ca) risk increased: excess 8-12/10,000 person-years [64]
    4. Increase in total and invasive breast Ca by 1.24X [62], mainly invasive lobular Ca [63]
    5. Increased risk ~1.5X of mild cognitive decline [30,70,71]
    6. Increase in mammographic abnormalities leading to increased biopsy [62]
    7. Combination estrogen + progesterone increased risk of ovarian but not uterine Ca [66]
    8. Estrogen alone replacement increased risk of uterine Ca (1.45X risk) []
  4. Reduction in Events [68]
    1. Reduction in hip fractures of 5/10,000 [23]
    2. Reduction in colorectal Ca of 6/10,000
    3. Reduction in diabetes mellitus incidence in women with CAD [60]
    4. Combined estrogen/progestin reduced overall uterine Ca ~25%
  5. Global health index: overall increased events of 19/10,000 person-years
  6. With long-term ever-use of estrogen only, ~1.6X increased risk for ovarian cancer [13]
  7. In women without menopause symptoms, HRT does not improve quality of life [35]
  8. HRT at standard estrogen doses (0.625 CEE) can no longer be recommended routinely in healthy post-menopausal women with or without a uterus [1,68]

D. Other Effects of Hormone Replacement [4,6,7] navigator

  1. Substantial osteoporosis and fracture risk reduction (see below)
  2. Cardiovascular (CV) Disease [4,7,8]
    1. No reduction in overall CV events in prospective study [10] or meta-analysis [49]
    2. Overall increased CAD, stroke [61], and pulmonary embolism risk [4]
    3. Increased risk of venous thromboembolism with use of HRT [9]
    4. No effect on progression of established coronary atherosclerosis in women [8]
    5. Three years after HRT (for 5.6 years), CV disease risk similar to no therapy [28]
    6. ERT after stroke or TIA does not reduce recurrence or improve outcomes over ~3 years [12]
    7. HRT increases levels of C-reactive protein (systemic inflammation) [52]
    8. HRT does not prevent atherosclerosis progression in postmenopausal women [54]
    9. Estrogen alone [58] or combined HRT [59] did not prevent reinfarction in postmenopausal women with a history of heart attack
    10. HRT reduces rise of blood pressure with age [11]
  3. Thromboembolic Disease
    1. Idiopathic thromboembolic events with current ERT: ~12 per 10,000 person-years
    2. Overall 1.5-3.5X risk of deep vein thrombosis (DVT) with current HRT use [9,21,22,72]
    3. Risk for venous thromboembolism highest in year 1 of HTR: ~3.5X increased risk [21]
    4. Estrogen+progestin HRT increased risk 2.0X overall; 7.5X for women >69 years and
  4. 7X in women with Factor V Leiden [73]
    1. Risk occurs with oral conjugated estrogens but not transdermal forms of HRT [65]
    2. Esterified estrogens do not carry increased DVT risk overall [73]
    3. Pulmonary embolism risk with current ERT use ~1.2-2X increased [4]
    4. Factor V Leiden mutation increases risk ~5X
    5. Deficiencies of AT III, protein C or protein S are contraindications to ERT use [21]
    6. Aspirin or statin use reduced risk of DVT by 50% or more and may counteract risk increases associated with HRT [22]
  5. Cognitive Function and Alzheimer's Disease (AD)
    1. A prospective study (4381 women) with HRT versus placebo showed no reduction in dementia risk [29] and no improvement in cognitive function [30] in women >65 years
    2. ERT associated with ~35-50% reduction in risk of AD in retrospective studies [14,53]
    3. HRT acutely improved cognitive abilities in some women with symptomatic menopause [14]
    4. HRT over 4 years had no effect on cognitive abilities in menopausal women with cardiovascular disease [56]
    5. ERT for one year did not prevent decline in mild to moderate AD [15]
    6. ERT/HRT cannot be recommended for prevention of demenia or congitive decline
  6. Breast Cancer Risk [4,16,64]
    1. Most studies show a 1.2-3.0X increased incidence of invasive breast cancer with long term use of ERT or HRT [17]
    2. Net increase in 8-12 new cases per 10,000 person-years (with >5-10 years of use)
    3. Risk increased with estrogen alone and estrogen-progesterone combinations
    4. Major increase in risk is for lobular carcinoma [17]
    5. CEE 0.625mg/day) for up to 7 years in women with hysterectomy showed no increase in breast ca, possible slight reduction in another study [16]
    6. Three years after stopping combined HRT (5.6 years) had 1.27X increased breast ca risk [28]
    7. HRT may may reduce sensitivity of mamography slightly [16,18]
    8. Women with breast risk >2X general population should consider SERM rather than HRT
  7. Colon Cancer Risk [4,19]
    1. Risk with current ERT/HRT users may be reduced ~20-45%
    2. Within 5 years of cessation of ERT/HRT, risk reduction is attenuated to ~15%
  8. Ovarian cancer increased 1.2-2.0X with 10 years of use [13,20]
  9. Reactivation of endometriosis possible
  10. Symptomatic Gallstones: 30-45% increased risk [9]
  11. Raynaud Phenomenon [25]
    1. Estrogens appears to increase risk for 2.5 fold
    2. ERT but not HRT carries this risk
  12. Menopausal Symptoms
    1. Hot flashes (flushing) are reduced or eliminated [26]
    2. Atrophic vaginitis improved or eliminated
    3. HRT improves cognitive functions in symptomatic women [14]
  13. ERT is associated with increased risk of any urinary incontinence within 1 year in continent women initiating ERT [39]
  14. Minimal overall effects on quality of life [4,26]
    1. Overall, depressive and mood symptoms not improved
    2. Quality of life improves clearly in women with hot flashes (flushing)
    3. Overall health effects may be detrimental [4]

E. Contraindications to HRT [4,27]navigator

  1. Absolute Contraindications to HRT
    1. Pregnancy
    2. Unexplained vaginal bleeding
    3. Active or chronic liver disease
    4. History of endometrial cancer (consider raloxifene (RAL); see below)
    5. History of breast cancer (SERM should be used; see below)
    6. Recent vascular thrombosis
    7. Informed patient refusal
  2. Relative Contraindications
    1. Hypertriglyceridemia (oral HRT or ERT only; does not occur with transdermal estrogen)
    2. History of thromboembolic disease
    3. Gallbladder disease
    4. Migraine headaches
    5. Uterine leiomyoma
    6. Seizure disorder
    7. Ovarian cancer
  3. Breast Cancer (Breast Ca)
    1. History of breast Ca is a strong relative contraindication to taking standard HRT
    2. Patients with a history of breast Ca should take SERMs: tamoxifen (TAM) or RAL
    3. TAM and RAL reduce the risk of developing breast Ca
    4. TAM and especially RAL improve bone density and lipid parameters

F. HRT and Osteoporosis [4,23] navigator

  1. Estrogen strongly blocks osteoclast function [23]
    1. Improves bone mineral density in peri-menopausal women
    2. Reduces vertebral fractures >30-50%
    3. HRT also prevents non-vertebral fractures by ~27% [31]
    4. All types of HRT reduced fractures overall 38% during use; protection begins rapidly on initiation of therapy and disappears rapidly after use ceases [69]
    5. Reduces osteoclast markers alkaline phosphatase and urine N-telopeptide levels
  2. Most effective in newly menopausal women for preventing bone loss
    1. Estrogen is often combined with other modalities to prevent or arrest osteoporosis
    2. Benefits in older woman, particularly with low BMD and no previous ERT use
    3. In women who are undecided on ERT, bone densitometry q2-5 years may be helpful
  3. Dosages
    1. Long term ERT (0.625mg conjugated estrogen qd po) reduced height loss
    2. Dose of 0.3mg po qd increased BMD in lumbar spine without endometrial effects
    3. Combination HRT with low dose equine estrogen (0.3mg/d) increased BMD and improved bone turnover parameters [33]
    4. Conjugated estrogens 0.45 or 0.3 mg qd, with or without medroxyprogesterone, increase BMD and improve markers of bone turnover in early post-menopause [34]
    5. Low dose estrogen patch (Menostar®) delivers 14µg/d 17ß-estradiol and is well tolerated with good improvements in BMD [48]
  4. Amenorrhea
    1. Idiopathic amenorrhea is a risk factor for osteoporosis (bone loss)
    2. In exercise induced amenorrhea or oligomenorrhea, risk is quite low
    3. Megoxyprogesterone (10mg for 10d q month) increases bone density in amenorrhea
  5. Smoking while on HRT increases risk of thromboembolic events

G. HRT Dosages [27,36] navigator

  1. Estrogens
    1. 300µg conjugated (such as Premarin®) or Estinyl 20µg (lower cost) po qd
    2. Synthetic conjugated estrogen (Cenestin®) 0.625mg qd (non-equine), but this dose is no longer generally recommended [36]
    3. Transdermal Estrogen Patch is effective and may provide more constant estrogen levels
    4. Low dose (0.3mg/d conjugated or equivalent) appears to have major benefits without endometrial effects or increased stroke risk [37]
    5. Plant derived phyto-estrogens (estropipate, Ogen®) may be safer [29]
  2. Oral Estrogens
    1. Conjugated, synthetic estrogens - Cenestin® (0.625mg and 0.9mg)
    2. CEE - Premarin® (0.625mg or 0.3mg)
    3. Esterified estrogens - dose 1-2mg po qd: Estratab®, Menest®
    4. Estradiol (micronized) - dose 0.6mg-5.0mg qd: generic, Ogen®, Ortho-Est®
    5. Estrace tablets (0.5, 1 or 2mg estradiol) - dose 1-2mg/day [38]
  3. Estrogen Transdermal Patch
    1. Transdermal agents have decreased hepatic effects
    2. This leads to a reduction in gallstone formation
    3. However, transdermal estrogens do not improve lipid profiles as well as oral agents
    4. Dose range 25-100µg qd delivered by patch for most patches; low dose is 14µg qd
    5. Alora® - 1 patch twice per week
    6. Climera® - 1 patch per week
    7. Estraderm® - 1 patch twice per week
    8. Vivelle-Dot - 1 patch twice per week
    9. Menostar (low dose 14µg/day) - 1 patch weekly
    10. Estradiol/Norethrindone (Combipatch®) 1 patch per week
    11. Albra® - low dose (0.025, 0.05, 0.075, or 0.1 mg/day estradiol): 1 patch twice per week [38]
  4. Sprays and Gels (Low Dose Estrogens) [38]
    1. Estradiol sprays: Elestrin (0.52mg/spray) and Evamist (1.53mg/spray) approved 1-2 actuations once/day applied to upper arm or shoulder
    2. Divigel: 0.1% in foil packets (0.25, 0.5, 1.0 mg estradiol) 1 packet/day to upper thigh
  5. Progesterones
    1. Estrogens without progesterones cause endometrial hyperplasia and adenocarcinoma
    2. Therefore, women who have not had a hysterectomy should add a progesterone
    3. MPA 5-10mg qd for last 12 days of each cycle (menstruation)
    4. Alternatively, continuous estrogen/progestin will prevent menstruation
    5. Progesterone is included to prevent endometrial hyperplasia
    6. Continuous progesterone (2.5-5mg MPA) is quite effective [23]
    7. Combination HRT lowers total Chol and raises HDL Chol
    8. Prempro®: Conjugated estrogen (0.625mg) + MPA 2.5mg
    9. Continuous combination HRT with 0.3mg/d conjugated equine estrogen and MPA 2.5mg daily increased BMD and improved bone turnover parameters [40]

H. Raloxifene (Evista®) [41,42,43,44] navigator

  1. Selective estrogen receptor modulator (SERM)
    1. Nonsteroidal benzothiophene with high affinity for ER
    2. Complex of raloxifene and estrogen receptor does not bind estrogen response elements
    3. The raloxifene - ER complex binds to "raloxifene-response element" on DNA
    4. Binding the raloxifene response element has different effects on different tissues
    5. Differential effects of raloxifene versus estrogen likely due to distinct interactions with specific domains of the estrogen receptor (ER) called AF-1 and AF-2
    6. In addition, a second ER has been discovered and may play a role in these differences
  2. Pharmacological Effects
    1. Reduces bone turnover
    2. Reduces serum cholesterol concentrations (improves lipid profiles)
    3. Improves responsiveness of vascular endothelium
    4. Antagonist effects on uterus, without causing endometrial hyperplasia
  3. Clinical Utility
    1. Approved for reduction in postmenopausal fracture risk
    2. Shows 45-75% reduction in risk of developing invasive breast cancer [45,78]
    3. No effect on primary cardiac events, but slightly increased stroke []
    4. Reduces LDL-C and Lipoprotein(a) and fibrinogen levels [42]
    5. Increased HDL2-C and had no effect on triglycerides or total HDL or PAI-1
    6. Does not alter length of menstrual cycle or inhibit ovulation [41]
    7. Does not alter nor improve cognitive function in postmenopausal osteoporotic women [47]
  4. Side Effects
    1. Hot flashes but does not increase breast tenderness or uterine bleeding
    2. Does not cause endometrial hyperplasia or Ca [39]
    3. Increased deep venous thrombosis (DVT) risk 44% versus placebo [78]
    4. Reduced cardiovascular events 40% in high risk women with osteoporosis [46]
    5. Increases risk of venous thromboembolism by 1.5-3X <1.5 per 1000 women-years
  5. Doses
    1. Dose response observed across 30-150mg per day orally
    2. FDA approved for postmenopausal osteoporosis dose is 60mg po qd

I. Other Agents [2]navigator

  1. These are typically estrogen derivatives with mixed agonist/antagonist properties
  2. Desire cardiovascular and bone benefits without uterine and breast cancer risks
  3. Tamoxifen (Nolvadex®) [43,44]
    1. Common hormonal treatment for breast cancer
    2. Mixed agonist-antagonist activities
    3. Increases bone mineral density (BMD) and stimulates uterine hyperplasia
    4. Antagonist activity on breast tissue
    5. Currently may be useful for improving BMD in women with (history of) breast cancer
    6. Uterine (endometrial) hyperplasia (and uterine cancer) must be monitored
    7. Endometrial tumors in patients on tamoxifen tend to be high grade and poor prognosis [67]
    8. Raloxifene, which does not cause uterine proliferation, may be preferred
  4. Additional novel SERMs are in clinical trials

I. Testosterone Supplements [79] navigator

  1. Men 60-80 years often have low-normal serum testosterone levels (<13.7nmol/L)
  2. Testosterone supplements for 6 months did not affect functional status or cognition, but increased lean body mass and had mixed effects on metabolic parameters [79]
  3. Testosterone supplements in men with low-normal levels not currently recommended
  4. Testosterone supplements important in adrenal and pituitary insufficiency

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