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Menopause & Hormone Therapy Decisions. Lisa Keller, M.D. Limited goals for the next 45 minutes:. Define the syndrome, physiology, epidemiology. Symptoms, potential pathophysiology. At-risk groups by age, time from menopause, as well as known risk profiles.

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limited goals for the next 45 minutes
Limited goals for the next 45 minutes:
  • Define the syndrome, physiology, epidemiology.
  • Symptoms, potential pathophysiology. At-risk groups by age, time from menopause, as well as known risk profiles.
  • What we know about hormone therapy, what has shifted over the past decade, and where there is consensus.
  • What we don’t know, what appears likely, and how to synthesize all the above into therapeutic recommendations.
why menopause
Why menopause?
  • So there can be grandmothers. Childbearing is a huge physiological burden.
  • Ovarian follicles: millions as fetus, thousands in youth, none by menopause.
  • Also CNS aging within the hypothalamic-pituitary axis, still being defined.
postmenopausal women in us

100,000

90,000

80,000

70,000

60,000

50,000

40,000

30,000

20,000

10,000

0

Postmenopausal Women in US

Age

65 years

60-64 years

55-59 years

50-54 years

45-49 years

Population

2000

2010*

2020*

2030*

2040*

2050*

Years

*Projected estimate.

US Census Bureau. Statistical Abstract of the United States. 2000:15.US Census Bureau. National population projections. Available at: http://www.census.gov/population/www/projections/natsum-T3.html. Accessed January 3, 2002.

perimenopausal transition years
Perimenopausal Transition Years

100

75

50

25

0

Reproductive Years

Women (%)

Postmenopause

60

50

55

35

40

45

30

Age (years)

perimenopause
Perimenopause
  • Reduction in viable ovarian follicles and follicular resistance to gonadotropins
  • Erratic hormonal milieu, erratic symptomatology
  • Although cycle length begins to shorten, potential for ovulation and pregnancy is preserved for a number of years
menstrual cycle changes
Menstrual Cycle Changes
  • Usually shorter cycle length (eg, by 2 to 7 days)
  • Longer or irregular later in transition
  • Changes in quality
  • Lighter volume. If heavier, more likely due to myomata or hyperplasia
  • Spotting prior to menses is common
menopause related changes
Menopause-Related Changes
  • Vasomotor symptoms
  • Sleep quality
  • Mood changes
  • Urogenital symptoms
  • Sexual well-being
  • Skin changes
  • Bone loss
  • Coronary heart disease (CHD) risk increases
  • Eye dryness
  • Joint inflammation
hormone deficiency effects
Hormone Deficiency Effects

Last period

Vasomotor symptoms

Sexual complaints

Urogenital atrophy and symptoms

Vascular and heart disease

Bone loss/osteopenia

Osteoporosis

40

45

90+

50

55

60

65

70

75

80

85

Age (year)

hot flushes may continue years after menopause
Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes

0

2

4

6

8

10

12

14

16

18

20

22

24

28

30

36

41

Hot Flushes May Continue Years After Menopause

Ages 29 to 82 Years

Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.

Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86. Used with permission.

non hormonal therapies
Non-hormonal Therapies
  • Herbal therapy — black cohosh, St. John’s wort
  • Biologically based substances — phytoestrogens: isoflavones from soy protein or red clover (unknown breast effects)
  • Lifestyle modifications — relaxation, paced respiration, moderate physical activity, modulation of responsibilities, sleep time
slide12

Treatment of moderate to severe vasomotor symptoms

  • Prescription systemic hormone therapy, either as combined estrogen-progestogen therapy (EPT) or estrogen (ET), remains the gold standard for treatment in women without contraindications
  • Oral contraceptives are an option for perimenopausal women, especially those needing contraception
genitourinary symptoms associated with menopause
Genital

Irritation, burning, pruritus

Leukorrhea

Dyspareunia

Decreased vaginal secretions

Shortening/lessening of vaginal distensibility

Urinary

Frequency, urgency

Dysuria

Nocturia

Incontinence*

Genitourinary Symptoms Associated With Menopause

*Controversial.

vaginal cytology
Vaginal Cytology

Premenopause

Postmenopause

risks and benefits of ht
Risks and Benefits of HT

It is known with good certainty that

  • Changes in the urogenital tract are among the most consistent hypoestrogenic features of the climacteric
  • HT administered vaginally or systemically provides effective relief from atrophic vaginitis, including reduction in vaginal dryness, irritation, pruritus, and dyspareunia

ACOG Task Force on HT. Obstet Gynecol. 2004;104 (suppl 4):56s-61s.

effect of delayed initiation of ht on bone loss

44

42

40

38

36

34

At Oophorectomy

3 Years After Oophorectomy

6 Years After Oophorectomy

0

2

4

6

8

10

12

14

16

Effect of Delayed Initiation of HT on Bone Loss

Metacarpal Bone Mineral

Content (mg/mm)

Years

Blue area represents placebo-treated population of oophorectomized women.

Lindsay R, et al. Lancet. 1976;1:1038-41.

whi reduction in fracture risk with e p and e alone

0.5

1.0

2.0

WHI: Reduction in Fracture Risk With E+P and E Alone

Hip

Vertebral

Lower Arm/Wrist

All Fractures

CEE/MPA (95% nCI)

CEE alone (95% nCI)

Hazard Ratio

whi fracture results clinical implications
WHI Fracture Results:Clinical Implications
  • Women treated with E alone or E+P for menopausal symptoms do not need another antiresorptive agent
  • HT is the only therapy that has been demonstrated to prevent fractures in a population of postmenopausal women at relatively low risk of fracture

ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):66s-76s.

AACE Osteoporosis Task Force. Endocrine Pract. 2003;9:544-64.

menopause ht depression
Menopause, HT, & Depression
  • Several observational studies report increased risk for onset of major depression during perimenopause
  • Perimenopause seems associated with increased risk of clinically significant depressive illness for subgroup of women
  • Some prospective studies, although not all, have demonstrated improvements of ~ 80% in newly depressed perimenopausal women started on HT (placebo 20%)
  • Insufficient evidence to support HT use for depression treatment , but consider in new onset
contraindications to ht
Contraindications To HT
  • Estrogen-dependent neoplasms (endometrial carcinoma, hyperplasia, breast cancer), venous or arterial thrombosis, high risk of cardiovascular disease, and/or liver disorders.
  • Oral conjugated equine estrogen (CEE) significantly increases triglyceride levels. So, oral estrogen therapy is not optimal for women with elevated triglycerides. But these patients may benefit from transdermal estriadol therapy.
  • Oral estrogen is not recommended for heavy smokers.
consistent terminology urged
Consistent Terminology Urged
  • ET — Estrogen therapy
  • EPT — Combined estrogen-progestogen therapy
  • HT — Hormone therapy (encompassing both ET and EPT)
  • CC-EPT — Continuous-combined estrogen-progestogen therapy (daily administration of both estrogen and progestogen)
  • CS-EPT — Continuous-sequential estrogen-progestogen therapy (estrogen daily, with progestogen added on set sequence)
  • Progestogen — Both progesterone and progestin
observational trial results
Observational Trial Results
  • 1976: Lowers risk of osteoporosis
  • 1981: CHD benefit, inconclusive for stroke
  • 1988: Reduction in mortality
  • 1994: Reduction in Alzheimer’s risk
  • Accelerated use of hormone therapy
women s health initiative whi clinical trials of ht
Women’s Health Initiative (WHI) Clinical Trials of HT
  • >27,000 postmenopausal women randomized and enrolled from 1993 to 1998
  • Mean age at baseline, ~63 years
  • Women with vasomotor symptoms discouraged from participating
  • Primary outcomes: CHD, breast cancer
  • E+P trial stopped in July 2002
    • Breast cancer crossed monitoring boundary
  • E alone trial stopped February 2004
    • Trend toward increased stroke
whi limitations
WHI Limitations
  • Only one estrogen was used (CEE, alone and with MPA) and only one progestogen (MPA)
  • Only one route of administration was used (oral) and only one dosage (0.625 mg/2.5 mg)
  • Subjects were:
    • Older (mean age, 63 years)
    • Most more than 10 years beyond menopause
    • Had more risk factors than younger women who typically use HT for menopausal symptoms
    • Largely asymptomatic
whi e p absolute risks benefits
WHI E+P: Absolute Risks & Benefits

No Significant Difference in # of Cases

CEE/MPA

Placebo

More Cases in E+P Group

Fewer Cases in E+P Group

Number per Year per 10,000 Women

CHD*

Stroke

Breast

Cancer

VTE

PE

Endometrial

Cancer

Total

Deaths

Colorectal

Cancer

Hip

Fractures

whi e alone absolute risks benefits

CEE

Placebo

Strokes

VTE

CHD

Breast

Cancer

PE

Colorectal

Cancer

Total

Deaths

Hip

Fractures

WHI E Alone: Absolute Risks & Benefits

Fewer Cases in EGroup

More Cases in EGroup

No Significant Difference in # of Cases

Number per Year per 10,000 Women

more recent whi analyses of younger women 50 59 years
More Recent WHI Analyses of Younger Women (50-59 years)
  • 7% decrease in CHD with ET or EPT (2 fewer cases per 10,000 per year of use)
  • 24% increase in breast cancer with EPT (9 more cases per 10,000 per year of use)
  • 20% decrease in breast cancer with ET (7 fewer cases per 10,000 per year of use)
  • 30% decrease in total mortality with ET or EPT (10 fewer deaths per 10,000 per year of use)

ET = CE; EPT = CE + MPA

whi effect of cee alone on risk of chd by age group
WHI: Effect of CEE Alone on Risk of CHD by Age Group

Age

0.63

50–59 y

0.94

60–69 y

1.11

70–79 y

0.0

0.5

1.0

1.5

2.0

Dotted vertical line represents the HR for CHD in the overall cohort (0.95; 95% CI = 0.79-1.16)

P = .07 for interaction with age

Hsia J, et al. Arch Intern Med. 2006;166:357-65.

effect of e p on chd in postmenopausal women
Effect of E+P on CHD in Postmenopausal Women

Hazard Ratio for CHD

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Age (years)

1.27

50–59

1.05

60–69

1.44

70–79

Years Since

Menopause

Hazard Ratio for CHD

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0.89

<10

1.22

10–19

1.71

>20

Manson JE, et al. N Engl J Med. 2003;349:523-34.

whi cardiovascular summary
WHI Cardiovascular Summary

Effects per 10,000 women/year of ET use (50-59 yrs)

  • 10 fewer deaths
  • 10 fewer CHD events
  • 2 fewer strokes
  • 4 additional VTE

Effects per 10,000 women/year of EPT use (<10 years postmenopause)

  • 6 fewer deaths
  • 4 fewer CHD events
  • 5 more strokes
  • 11 additional VTE
risks and benefits of ht1
Risks and Benefits of HT

It is known with good certainty that

  • HT does not increase CHD risk in women who initiate therapy close to the onset of menopause (within ~ 9 years of last menses)
  • HT does not prevent and may increase the risk of CHD in women who initiate therapy years after menopause
whi ht trials increased risk of venous thromboembolism

0.5

1.0

2.0

5.0

WHI HT Trials: Increased Risk of Venous Thromboembolism

HR (95% CI)

E+P1

2.06 (1.57, 2.70)

E alone2

1.33 (0.99, 1.79)

Hazard Ratio

1Cushman M, et al. JAMA. 2004;292:1573-80.

2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

risks and benefits of ht2
Risks and Benefits of HT

Additional research of HT on risk of stroke is needed to clarify the effect

  • Meta-analyses find a small increased risk of stroke in postmenopausal women taking HT
  • Whether this increased risk is modified by hormone preparation, dose, or route of administration has not been established by randomized controlled trials
  • The risk of stroke for women taking HT increases with age, but the risk for younger women does not appear to be insignificant (still “rare” by WHO criterion)

ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4): 97s-105s.

ht and venous thromboembolism
HT and Venous Thromboembolism
  • Significant increase in VTE risk in postmenopausal women using systemic HT
  • Risk increased with both EPT and ET
  • VTE risk appears during first 1-2 years after therapy initiation and decreases over time
  • Transdermal 17ß-estradiol and oral therapies may have different risk
  • Lower doses of oral estrogens may be safer than higher doses
whi and breast cancer risk
WHI and Breast Cancer Risk

With EPT use

  • Relative risk = 1.24 (24% increased risk)
  • Absolute risk = 9 more cancers per 10,000 women per year of EPT use

With ET use

  • Relative risk = 0.80 (20% decreased risk)
  • Absolute risk = 7 fewer cancers per 10,000 women per year of ET use
  • 33% statistically significant decreased risk when adherent to treatment (i.e., used ET 80% of the time)
million women study breast cancer relative risks
Million Women Study: Breast Cancer Relative Risks

Mortality

1.22

Current use

1.66

Implanted estrogen

1.65

Transdermal estrogen

1.24

Oral estrogen

1.32

Tibolone

1.45

2

E + P

1.3

Estrogen only

1

1.5

2

Lancet. 2003;362:419-427.

european trials ht after bca
European Trials — HT after BCA
  • One (HABITS) with continuous E+P showed ^ BCA recurrence risk
  • Other (Scandinavian trial) with ET and only intermittent P, showed 18% < BCA recurrence risk
risks and benefits of ht3
Risks and Benefits of HT

It is known with good certainty that

  • E+P use >5 years is associated with an increased risk of breast cancer1,2
    • Absolute risk is small; about 2 additional cases per 1000 women using E+P for 5 years1
  • Use of unopposed E does not increase breast cancer risk in women with previous hysterectomy3

1ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):11s-6s.

risks and benefits of ht4
Risks and Benefits of HT

Research is ongoing to determine the effects of HT on cognitive function and dementia

  • Like CHD, findings from observational studies and the WHI do not agree. Stratification by age and the “healthy cell bias” may explain discrepancy
  • HT initiation in older postmenopausal women appears to increase risk of dementia
ht in the woman with premature ovarian failure pof
HT in the Woman With Premature Ovarian Failure (POF)
  • POF is associated with premature osteoporosis and increased CV morbidity and mortality
  • Effective management involves early identification of POF, use of HT to relieve symptoms and prevent osteoporosis, and regular monitoring for associated conditions

Nelson LM, et al. Fertil Steril. 2005;83:1327-32.

conclusions
Conclusions
  • Extrapolate with caution WHI date when considering risks of HT during or soon after the menopausal transition
  • Future research is critical to clarify optimal timing and duration of HT
  • WHI data do not address benefits and risks in women with premature menopause

ACOG Task Force on HT. Obstet Gynecol. 2004;104(suppl 4):1s-4s.

North American Menopause Society (NAMS). Menopause. 2003;10:497-506.

progestins
Progestins

Steroids

Natural

Found in Nature

Synthetic

Laboratory Synthesized

Structurally Related to Progesterone

Structurally Related to Testosterone

  • Native  Synthetic
  • Progesterone
  • Ethinylated
    • Norethindrone
    • Norethynodrel
    • Lynestrenol
    • Norethindrone acetate (NETA)
    • Tibolone
    • Ethynodiol acetate
    • Levonorgestrel
    • Desogestrel
    • Norgestimate
    • Gestodene
  • Pregnane Derivatives
    • MPA
    • Megestrol acetate
    • Cyproterone acetate
    • Chlormadinone acetate
    • Medrogestone
    • Dydrogesterone
  • 19-Norpregnane Derivatives
    • Nomegestrol acetate
    • Demegestone
    • Trimegestone
    • Promegestone
    • Nesterone
  • Non-ethinylated
    • Dienogest
    • Drospirenone

Stanczyk FZ. Rev Endocr Metab Disord. 2002;3:211-24.

slide43

EPIC

Fournier et al, Int J Cancer, 2004.

medroxyprogesterone acetate
Medroxyprogesterone Acetate
  • Most common progestin used in USA
  • Most intensely studied progestin
  • Only progestin with substantial data proving ability to prevent endometrial cancer long term
  • Challenges regarding cardiac, thrombotic and breast effects

Gradyan D, Obstet Gynecol. 1995 Feb;85(2):304-13.

norethindrone acetate

O

OCCH2

C

CH

O

Norethindrone Acetate
  • Synthetic, patented in 1950
    • Pro-drug, rapidly converted to norethindrone
    • NETA long half life
  • Most common progestin in EU
    • NETA converts to ethinyl estradiol
    • In high dose, 0.7 - 1%
    • 6 micrograms EE/1 milligram NETA
natural progesterone

CH3

O

C

O

Natural Progesterone
  • Bioidentical
  • Several formulations
  • Short half life
  • No long term safety outcomes
primary prevention of coronary atherosclerosis with cee and mpa vs estradiol and progesterone

0.3

0.3

0.2

0.2

Coronary Plaque Size (mm2)

0.1

0.1

0

0

No TX

E2

E2 + P

No TX

CEE

CEE + MPA

MPA

Primary Prevention of Coronary Atherosclerosis with CEE and MPA vs Estradiol and Progesterone

Adams et al. Arterioscler Thromb Vasc Biol. 1997;17:217

Adams et al. Arteriosclerosis. 1990;10:1051.

coronary artery vasospasm in monkeys treated with e 2 and progesterone or mpa
Coronary Artery Vasospasm in Monkeys Treated With E2 and Progesterone or MPA

Parameter

E2 + Progesterone

E2 + MPA

Number of vasospasms

6/6

0/6

Minimum coronary artery diameter

.37 ± .02

.15 ± .04

Miyagawa et al. Nature Med. 1997;3:324.

breast vs endometrial risk
Breast vs Endometrial Risk

Million Women, Lancet 2005; 365: 1543–51

commentary
Commentary
  • If endometrial and breast cancer are regarded as equally bad events, limiting short-term (3-5 years) hormone therapy for menopausal management to use of estrogen alone even in women with an intact uterus makes considerable sense.
  • If breast cancer is regarded as clinically more serious than endometrial cancer, this conclusion only becomes stronger.

Diana Petitti, MD MPH

Kaiser Permanente Southern California, Pasadena, CA, USA

This conclusion will generate

great controversy and discussion

Million Women, Lancet 2005; 365:

off label ept uses
Off-Label EPT Uses
  • Insufficient endometrial safety evidence to recommend off-label use of:
    • Long-cycle progestogen (ie, progestogen every 3-6 mo for 12-14 days)
    • Vaginal administration of progesterone
    • The contraceptive levonorgestrel-releasing intrauterine system
    • Low-dose estrogen without progestogen
    • Micronized oral progesterone (transdermal noted to not absorb well, not advised)
  • Close endometrial surveillance recommended with these approaches
conclusions1
Conclusions
  • While implications of recent studies suggest that estrogen alone may be safer than E+P, standard of care remains combined therapy
  • It is also unclear if CCHT or SCHT offers a higher degree of safety
  • Role of progestins in breast cancer is unsettled, but in endometrial cancer its role is crystal clear
    • Is there such a thing as a good cancer?
conclusions cont
Conclusions (cont.)
  • MPA is the only progestin in the USA with data on long term endometrial safety
    • Micronized progesterone may offer some superior QOL attributes and cardiovascular protection
    • Micronized progesterone long term EM safety is not substantiated
  • Newer progestins may offer metabolic profile of micronized progesterone with the potency of MPA
international prescribing patterns
International Prescribing Patterns

Products Containing 17-Estradiol

% of

Total Rx

Products Containing CEE

IMS Database.

rationale for 17 estradiol
Rationale for 17-Estradiol
  • Biologic effects in reproductive-age women predominantly due to 17-estradiol
  • Plant sterol derived synthetic mimic of naturally occurring hormone
  • Extensive international experience
  • Therapeutic efficacy comparable to other estrogens
dose and risk of vte
Dose and Risk of VTE
  • Birth control pills
    • 80 mcg > 50 mcg > 35 mcg
    • Insufficient data on 20 mcg or less
    • Is the curve linear at the lower end
  • HT
    • Higher doses appear to carry higher risk
    • Lowest threshold for risk unknown
  • Interaction with thrombophilias
transdermal delivery systems
Avoid liver first pass

Assumptions about TD route being safer than oral delivery

Patches

Gels

Creams

Sprays

Transdermal Delivery Systems

Evamist

transdermal estrogen benefit
Transdermal Estrogen Benefit
  • Circumventing first-pass metabolism
  • Non-elevation of triglycerides or high-density lipoproteins
  • Stable levels of circulating estrogen
  • Comparable efficacy at lower concentrations
  • Reduced frequency of dosing
  • Suitable alternative for women who chose not to use oral medication
  • Evidence of less thrombogenic potential
ht therapy and lipid levels
HT Therapy and Lipid Levels

E+P is estrogen + progestin combination. Parentheses indicate blunted effect relative to unopposed estrogen.

lipid profile and et

CEE 0.625 mg/d (n=1513)

Oral estradiol 1 mg/d (n=94)

Transdermal estradiol 0.05 mg/d (n=267)

Lipid Profile and ET

*

*

*

*

*

*

*

*

*

*

*

*

Total cholesterol

LDL- cholesterol

HDL- cholesterol

Triglycerides

*P<0.05 vs. baseline.

†Analysis of 248 studies of postmenopausal women.

Godsland IF. Fertil Steril. 2001;75:898-915.

LDL = low-density lipoprotein; HDL = high-density lipoprotein

route of administration
Route of Administration
  • Non-oral routes of ET/EPT administration may offer advantages and disadvantages vs. oral routes, but the long-term risk-benefit ratio has not been demonstrated
  • Possible lower risk of deep venous thrombosis (DVT) with non-oral route
  • Similar breast cancer risks with oral and transdermal estrogens per large observational study
slide63

Testosterone Treatment

Indicated for diminished libido and sexual response in postmenopausal women on ET

Politically charged. No FDA approval yet.

EstraTest in 2 dosages, is oral Estrone and Methyltestosterone, FDA approved for hot flashes not responsive to ET alone

Particularly helpful in oovariectomized women

management recommendations
Management Recommendations:

Before initiating testosterone treatment:

  • Establish baseline profiles for serum lipids and liver function tests, blood pressure
  • Consider retesting at 3 months
  • If stable, annual testing is advised
management recommendations during testosterone treatment
Management Recommendations:During Testosterone Treatment

Testosterone therapy should be

administered at the lowest dose for the

shortest time that meets treatment goals

compounded testosterone products
Compounded Testosterone Products
  • Use with caution. Understand transdermal dosage adjustments (2% = 20 mg/gm = 10x recommended female dosage). Know your pharmacist.
  • Dosing may be more inconsistentvs. government-approved products
long term use of testosterone
Long-Term Use of Testosterone
  • Due to insufficient data, conclusions cannot be made regarding the efficacy and safety of testosterone therapy exceeding 6 months
  • Therapeutic monitoring should include subjective assessments of:
    • sexual response, desire, and satisfaction and
    • evaluation for potential adverse effects
testosterone contraindications
Testosterone Contraindications
  • Similar to those associated with estrogen therapy
  • Do not initiate testosterone therapy in postmenopausal women with:
    • Breast or uterine cancer
    • Cardiovascular disease
    • Liver disease
custom compounded ht
Custom-Compounded HT?
  • Lack of controlled clinical trials of safety and efficacy
    • No evidence that they are safer
    • Clinical trials unlikely to be performed because of high cost and lack of patent protection
  • Compounding is allowable for individual patients unable to tolerate FDA-approved products
  • Mass production and marketing beyond state lines does not meet federal guidelines
  • Prescribers are responsible for risk/benefit education

Boothby LA, et al. Menopause. 2004;11:356-67.

saliva and hair tests for hormones
Saliva and Hair Tests for Hormones
  • No reference standards available
  • Lack of correlation with serum levels
  • Data from saliva does not tell you what is going on in the target tissue
  • No way to determine appropriate dosing through these tests
  • Inter- and intrapatient variability
  • In reality, dosage adjustments based on symptomatology
  • No evidence to suggest that “individualized estrogen or progesterone regimens” based on these tests increase efficacy or improve safety
duration of ht use
Duration of HT Use
  • FDA 20031
    • Recommends shortest duration and lowest dose consistent with treatment goals
  • ACOG 20042
    • The lowest effective estrogen dose should be used for the shortest possible time to alleviate symptoms
  • NAMS 20043
    • Recommends duration and dose consistent with treatment goals
optimal dose of estradiol
Optimal Dose of Estradiol
  • Optimal dose for vasomotor symptoms
    • at serum level of 60 pg/ml  50%, 120 pg/ml  100%
  • Optimal dose for bone is the highest dose
    • 0.5 mg arrest losses in 60%, while 1-2 mg superior efficacy
  • Optimal dose for endometrium, breast, triglyceride and coagulation
    • lowest
estradiol therapeutic range
Estradiol Therapeutic Range

0 25 50 75 100 125 150 175

Optimal 40-80 pg/ml

Acceptable 35-125 pg/ml

if you must use prempro
If you must use PremPro:
  • Standard dose = 0.625/2.5
  • Newer options = 0.45/1.5 and
  • 0.30/1.5
  • Less is probably better
lowest effective dose has yet to be determined for most products
Lowest effective dose has yet to be determined for most products
  • CEE 0.3 mg
    • 0.15 mg appears ineffective
  • Oral estradiol 0.5 mg
    • 0.25 mg appears ineffective
  • TD estradiol 25 mcg
    • 20 mcg in trials
indications for extended use of ht
Indications for Extended Use of HT
  • After informed discussion and with ongoing supervision
    • For the woman for whom, in her opinion, benefits of symptom relief outweigh risks, notably after failing an attempt to withdraw from HT
    • For women with moderate-to-severe menopausal symptoms and at high risk for osteoporotic fracture
    • For prevention of osteoporosis in a high-risk woman when alternate therapies are not appropriate

North American Menopause Society. Menopause. 2003;10:497-506.

discontinuing ht use
Discontinuing HT Use
  • Symptoms have ~50% chance of recurring when HT is discontinued, independent of age and duration of HT use
  • The decision to continue HT should be individualized, based on severity of symptoms, current risk-benefit ratio considerations, and when the woman in consultation with her healthcare provider believes that continuation is warranted
ht related breakthrough bleeding
HT-Related Breakthrough Bleeding
  • All available continuous-combined E+P regimens are associated with breakthrough bleeding
  • Less breakthrough bleeding with lower doses
  • Most postmenopausal women will experience amenorrhea within 1 year of initiating therapy
  • All bleeding other than withdrawal bleeding should be investigated
    • Workup can include vaginal sonogram and endometrial biopsy or both
    • Endometrial sonogram showing 5 mm or more endometrial thickness should be followed by a biopsy
pretreatment evaluation
Pretreatment Evaluation
  • Complete health evaluation including history, lipids
  • Mammography as per national guidelines and age, preferably within 12 months of therapy
  • Other specific examinations, (eg, bone densitometry) on a case-by-case basis
shared decision making on ht
Shared Decision-Making on HT
  • No universal recommendation for all women regarding the use of HT
  • The decision to use (or not use) HT is a personal one that should be made in consultation with a woman’s health care provider
  • The decision should be based on a woman’s individual health needs, concerns, and risk factors, taking into account menopause-associated symptoms and their effect on quality of life
summary
Summary
  • The benefits of using E+P therapy in healthy early postmenopausal women with symptoms outweigh the risks
  • Women using E-only have fewer risks than those shown in the E+P arm of the WHI
  • Alternate estrogens and progestins appear to carry less risk than oral CEE/MPA. Studies ongoing re: formulations, delivery route.
  • Postmenopausal HT should be prescribed at the lowest dose for the shortest amount of time, consistent with treatment goals
more info on the web
More Info on the Web

www.HormoneCME.org

www.Hormone.org

www.familydoctor.org

www.menopause.org

(North American Menopause Society NAMS)

www.afwh.org

(Alexander Foundation for Women’s Health)