1. Back to the Future: Applying New Evidence in Menopause Management
Michael Policar, MD, MPH

2. Topics To Be Discussed New information from the WHI
The expanding range of treatments for managing menopausal symptoms
Which treatments are available to your patient?
Practice Recommendations
How can your patient use these treatments safely, effectively, and conveniently?

3. NAMS Definitions Progestogen Progesterone or progestin (P)
ET Estrogen (E) therapy
EPT Combined E+P therapy
HT Hormone therapy (ET and EPT)
CC-EPT Continuous-combined E+P therapy
- E+P given every day
CS-EPT Continuous-sequential E+P therapy
- E daily with P added on set sequence
NAMS position statement. Menopause 2007.

4. The WHI Re-analyzed
Act 1
Let’s Get This Out of the Way….

5. Background: HRT s
Menopause seen as endocrine deficiency requiring hormone replacement therapy
1960s: successful oral contraceptive introduction
“The Pill” freed women from fear of pregnancy
HRT offered women freedom from fear of aging
1972: Forever Feminine by Robert A. Wilson, MD
1980s: Expanding uses of HRT
Initially used to treat hot flashes, vaginal sxs
Later uses…protection of bone and heart 5

7. Background: Late 1980s
In 40 retrospective observational studies, both EPT and ET reduced the risk of heart attack by 50%
Most studies included women in their 50s
Women were self-selected for hormone use (or not); studies were subject to selection bias
Conventional wisdom
All women should use HT for heart protection, unless there was a reason not to do so
Women with CVD risk factors, especially previous MI, stroke, HTN or diabetes, should use HT 7

8. Background:1990s
1990: Wyeth requested that FDA add labeling to HT products that included cardioprotection
FDA insisted that RCTs be performed to prove that HT improved CVD outcomes vs. placebo
Two RCTs initiated to evaluate cardioprotection
HERS: secondary prevention trial
WHI: primary prevention trial

9. HERS Study: 1998 Does EPT reduce MIs in women with CHD?
2,763 women randomized to CC-EPT or placebo
Entry: MI, CABG, balloon angioplasty, + angiogram
Menopausal, intact uterus, years of age
Average follow up: 4.1 years
Study findings
EPT had no value in reduction of MIs or CHD deaths
More deaths in year 1; neutral thru year 8
Not seen in prior observational studies
3-fold increased risk of VTE events
Hulley, JAMA 1998:280:605 9

10. Women’s Health Initiative (WHI): 2002
: RCT with 17,000 women
Postmenopausal women years old
33%: yrs old; 45%: yo; 22% yo
Average age: 64 years old
End points
Primary prevention of MI and stroke
Hip fracture, various cancers
Treatment arms
If uterus: CC-EPT (CEE+MPA) vs. placebo
If no uterus: ET (CEE) vs. placebo 10

11. WHI: EPT Arm Study Results Released July 2002: Findings after 5
WHI: EPT Arm Study Results Released July 2002: Findings after 5.2 years
Event RR Risk/10K/yr Benefit/10K/yr
Heart attack
Stroke
Breast cancer
TE event
Colorectal CA
Hip fractures
Discontinued early, as “risks greater than benefits” 11

14. WHI : ET-Only Study Arm Released 2004: Findings after 7 years
Outcome Change vs. Placebo
Coronary heart disease No difference in risk
Breast cancer No difference in risk
Stroke Increased risk
Hip fractures Decreased risk
Dementia, cognitive Trend toward increased
Change (> 65 years old) risk 14

15. WHI and HERS: The 2004 Take Home Message
HT does not protect women from heart attacks over the long term
…and actually may increase the risk of MI in the first year of HT use
The rest is “specialty-specific” perception of benefit and risk 15

16. Was the WHI designed to evaluate the safety and efficacy of EPT in treating menopausal changes?
The Women’s Health Initiative
Was not a menopause study
Was a drug study of the effect of hormones on CVD, cancer, fractures, and memory in older women (average 64 year old)

17. How Different Were WHI Findings Compared to Earlier Studies?
Manson JE, Menopause 2006;13:139

18. WHI: HT and Risk of CV Disease by Age and Years Since Menopause
Roussow JE. JAMA. 2007: Combined secondary analysis
Age at HT initiation
Heart attack
Stroke
Death from any cause
50–59 years
↓ 7%
↑ 13%
↓ 30%
60–69 years
↓ 2%
↑ 50%
↑ 5%
70–79 years
↑ 26%
↑ 21%
↑ 14%
A combined secondary analysis of WHI studies to determine if age at initiation of HT affected cardiovascular risk was published in the Journal of the American Medical Association (JAMA) in Both arms of the WHI were combined for this analysis, which allowed for evaluation of more than 26,000 women.
This secondary analysis revealed that women who initiated HT closer to the age of menopause had a significantly reduced risk of death from any cause compared to women who took placebo. Additionally, risk of heart attack was reduced in women receiving HT closer to the age of menopause, but not at a significant level. On the other hand, stroke risk was elevated for all groups regardless of years since menopause.
“Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion* for statistical significance.”
*Statistically significant defined as p<0.01.

19. WHI (EPT arm) Re-analyses Age vs. Years Since Menopause
Age (years)
50–59
60–69
70–79
Years Since Menopause
<10
10–19
20
1.27
1.05
1.44
0.89
1.22
1.71
Manson et al evaluated the risk of CHD in certain subgroups of the WHI, designated by factors such as age and years since menopause to determine whether women were at a higher or a lower risk for CHD with CEE/MPA compared with placebo,
In this analysis, no significant interaction between age or years since menopause and treatment was observed (P = 0.36 for the age analysis and P = 0.33 for years-since-menopause analysis), although there was a numerical trend towards a higher risk with CEE/MPA use among those women with the longest times since menopause.
While the investigators noted that the findings of the subgroup analyses should be interpreted with caution because of the small size of many of the subgroups as well as the large number of comparisons performed (approximately 36 tests were performed), these findings are consistent with accumulating data that the timing of initiation of HT in relation to the development of atherosclerosis is an important variable that may influence the potential risks and benefits of HT.
Hypertension per se should not be considered contraindication to estrogen therapy since research shows that replacement doses of estrogen have little effect on blood pressure.
The WHI combined estrogen-progestin trial noted only a small increase (1.5 mmHg) in systolic pressure compared with placebo.86 In the WHI trial of unopposed estrogen, a similar difference between the hormone and placebo groups of 1.1 mmHg was observed.
References
Manson JE, et al. N Engl J Med. 2003;349:
Rossouw, JE, Anderson, GL, Prentice, RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
Anderson, GL, Limacher, M, Assaf, AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
Hazard Ratio for CHD
Manson JE, et al. N Engl J Med. 2003;349:523-34
Manson JE, et al. N Engl J Med. 2003;349: 19

20. WHI: Estrogen and Major Health Outcomes in Women Under 60 Years of Age
% difference in relative risk
Events/ 10,000 WY of CEE therapy
Total mortality
-29 (
-11
Coronary heart disease
-37 ( )
Stroke
-11 ( -2
New onset DM
-12 ( )
-14
Fracture
-30 ( )
-56
Breast cancer
-18 ( ) -8
VTE
+37 ( ) +4
Hodis HN, Mack WJ. Menopause Management 2008

21. The Unified Hypothesis 2005
WHI
Phillips LS, Langer RD,
Postmenopausal hormone
therapy: critical reappraisal
and a unified hypothesis.
Fertility and Sterility 2005;
83:558-66

22. Clinical Implications: Unified Hypothesis
Mild cardioprotection
Women in their early-mid 50s, who
Initiate HT soon after menopause, with
Few or no heart disease or stroke risk factors
And who use estrogen-only regimens
Increased heart disease risk
Women in their mid-60s or later, who
Initiate HT long after menopause, who have
Heart disease or stroke risk factors
And who use estrogen and progestin regimens

23. Benchmark HT Cardioprotection Studies
Primary Prevention
“Healthy women”
Secondary Prevention
Women with known heart disease
Observational
Studies
Nurses Health Study
Various small studies
Randomized Clinical Trials
WHI
KEEPS
HERS

24. Key Points: NAMS March 2007 Position Statement on Hormone Therapy
The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007
Copyright 2007

25. HT and Coronary Heart Disease
ET/EPT not recommended as single or primary indication for coronary protection in women of any age
Data do not currently support EPT in secondary prevention of CHD
NAMS position statement. Menopause 2007.

26. HT and Stroke
Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal women
No HT regimen should be used for the primary or secondary prevention of stroke
HT should be avoided for women who have elevated baseline risk of stroke
NAMS position statement. Menopause 2007.

27. 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
NAMS position statement. Menopause 2007.

28. EPT and Breast Cancer Risk
Breast cancer risk increases with EPT use beyond 5 years
Increased absolute risk in WHI is viewed as rare (4-6 additional invasive cancers/10,000 women/year when use EPT used for ≥ 5 yrs)
Not clear whether risk differs between CC-EPT and CS-EPT
NAMS position statement. Menopause 2007.

29. ET and Breast Cancer Risk (cont’d)
Women in WHI’s ET arm had 8 fewer cases of invasive breast cancer/10,000 women/yr of ET use
Available evidence suggests ET for < 5 years has little breast cancer risk impact
Limited observational data suggest ET given longer than 15 years may increase risk
NAMS position statement. Menopause 2007.

30. 30

31. Therapeutic Interventions Non-Hormonal
Act 2
Therapeutic Interventions Non-Hormonal

32. General Health Recommendations
Exercise: aerobic + strength training
Reduction in hot flashes in some women
Healthier heart; stronger bones
National Osteoporosis Foundation (NOF) Feb 2008
Adults under age 50 need, per day
1,000 mg of calcium*
IU of vitamin D3
Adults 50 and over need, per day
1,200 mg of calcium*
800-1,000 IU of vitamin D3
* In divided doses, preferably with meals

33. Hot Flashes: Lifestyle Changes
Exercise routinely, at least 3-4 days/week
Cool room temperature, especially at night
Dress in layers (remove outer layers if warm)
Avoid hot and spicy foods
Relaxing activities
Avoid cigarettes
Minimize alcohol
A number of lifestyle and social factors may influence hot flush frequency:
Warm ambient air temperatures increase a woman’s core body temperature and make her more likely to reach the sweating threshold
Less physical activity increases the relative risk of hot flushes; daily exercise is associated with an overall decreased incidence
Anecdotally, spicy foods have been reported to trigger hot flushes, though there is no clinical evidence to support this relationship
Relaxation techniques may decrease or alleviate symptoms
Other lifestyle factors that affect vasomotor symptoms:
Cigarette smoking (past and current) increases the relative risk of hot flushes, perhaps because of its effect on estrogen metabolism
While low levels of alcohol consumption (< or =1 drink per day for women) do not have a measurable effect on occurrence of vasomotor symptoms, greater amounts of alcohol intake may promote such symptoms.
References
North American Menopause Society. Menopause. 2004;11:11-33.
Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:
Huntley AL, Ernst E. Menopause. 2003;10:
Greendale GA, Gold EB. Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side-effects of hormone therapy? Am J Med Dec 19;118 Suppl 12B:
North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med ;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:
North American Menopause Society. Menopause. 2004;11:11-33.
Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:
Huntley AL, Ernst E. Menopause. 2003;10:

34. Botanicals and PhytoSERMs
Probably better than placebo
Black cohosh
No evidence of efficacy
Soy isoflavones Not better than pbo
Red clover isoflavones Not better than pbo
Evening primrose oil Not better than pbo
Dong quai Not better (as monotx)
Ginseng Not better than pbo
Vitamin E Not better than pbo
Chasteberry (Vitex) No studies

35. Botanicals: Black Cohosh
Total of 14 trials reported, including 4 randomized trials using placebo and/or estrogen treatment arm
3 of 4 RCTs found black cohosh to be beneficial
12 of 14 trials reported some benefit
Currently, longest trial is 6 months
NIH-funded, large, randomized, prospective, 2-year trial ongoing
Preliminary data fail to show binding to E receptors
Binding to serotonin receptor noted
Four randomized trials of black cohosh with placebo or estrogen control groups have been conducted.
Tablets (40mg/d) vs placebo; duration, 2 months1—Outcomes included frequency and intensity of hot flushes; menopause symptom index (6 symptoms); global rating of health scale; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. FINDINGS: No significant difference between groups in frequency and intensity of hot flushes (decreased in both groups); significantly greater decrease in sweating in treatment group than in placebo group (P=.04); no changes in global rating scale or FSH and LH levels; study duration was short.
Liquid (40 drops twice daily) vs conjugated estrogens (0.25mg/d) vs diazepam (2mg/d); duration, 3 months2—Outcomes included Kupperman index (KI) scores (modified 5 symptoms); Hamilton Anxiety scale (HAM-A); self-assessment depression scale (SDS); clinical global impression (CGI) scale; and vaginal maturation index (VMI). FINDINGS: Kupperman index, HAM-A, SDS, and CGI showed “highly significant reductions” with all three therapies; VMI: “trend toward estrogenic stimulation” for Remifemin and estrogen; no statistical calculations were reported.
Tablets (4 mg twice daily) vs conjugated estrogens (0.625 mg/d) vs placebo; duration, 3 months3—Outcomes included Kupperman index scores (9 symptoms); hot flushes; HAM-A; VMI. FINDINGS: Significant improvement in Kupperman score, HAM-A (P=<.001), and VMI (P=<.01); no change in estrogen or placebo groups; hot flushes decreased from 4.9 to 0.7/d in Remifemin group, 5.2 to 3.2 in estrogen group, and 5.1 to 3.1 in placebo group (significance not indicated); lack of effect with estrogen calls other findings into question.
Tablets (4 mg of triterpine glycosides twice daily) vs estriol (1 mg/d) vs conjugated estrogen (1.25 mg/d) vs estrogen/progesterone combination; duration, 6 months4—Outcomes included Kupperman index scores (modified 17 symptoms), LH and FSH levels. FINDINGS: Kupperman scores improved in all groups (P=.01); no differences among treatment groups; no changes in LH and FSH levels.
Investigators note that there is a great need for alternatives to hormone therapy for use by symptomatic menopausal women. Alternatives to estrogen can encompass lifestyle change, complementary and alternative medicine (CAM), and prescription nonhormonal therapies. The use of CAM therapies for menopausal symptoms is widespread and has been increasing. A recent study indicates that relatively low concentrations of actein or the EtOAc fraction of black cohosh can cause synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents.
References
1Jacobson JS, et al. J Clin Oncol. 2001;19:
2Warnecke G. Med Welt. 1985;36:871-4.
3Stoll W. Therapeutikon. 1987;1:23-31.
4Lehmann-Willenbrock E, Riedel HH. Zentralbl Gynakol. 1988;110:611-8.
Kessel B, Kronenberg F. Endocrinol Metab Clin North Am Dec;33(4):
Einbond LS, et al. Planta Med Oct;72(13):
Four randomized trials of black cohosh with placebo or estrogen control groups have been conducted.
- Tablets (40 mg/d) vs placebo; duration, 2 months1—Outcomes included frequency and intensity of hot flushes; menopause symptom index (6 symptoms); global rating of health scale; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. FINDINGS: No significant difference between groups in frequency and intensity of hot flushes (decreased in both groups); significantly greater decrease in sweating in treatment group than in placebo group (P = .04); no changes in global rating scale or FSH and LH levels; study duration was short.
- Liquid (40 drops twice daily) vs conjugated estrogens (0.25 mg/d) vs diazepam (2 mg/d); duration, 3 months2—Outcomes included Kupperman index (KI) scores (modified 5 symptoms); Hamilton Anxiety scale (HAM-A); self-assessment depression scale (SDS); clinical global impression (CGI) scale; and vaginal maturation index (VMI). FINDINGS: Kupperman index, HAM-A, SDS, and CGI showed “highly significant reductions” with all three therapies; VMI: “trend toward estrogenic stimulation” for Remifemin and estrogen; no statistical calculations were reported.
- Tablets (4 mg twice daily) vs conjugated estrogens (0.625 mg/d) vs placebo; duration, 3 months3—Outcomes included Kupperman index scores (9 symptoms); hot flushes; HAM-A; VMI. FINDINGS: Significant improvement in Kupperman score, HAM-A (P < .001), and VMI (P < .01); no change in estrogen or placebo groups; hot flushes decreased from 4.9 to 0.7/d in Remifemin group, 5.2 to 3.2 in estrogen group, and 5.1 to 3.1 in placebo group (significance not indicated); lack of effect with estrogen calls other findings into question
- Tablets (4 mg of triterpene glycosides twice daily) vs estriol (1 mg/d) vs conjugated estrogens (1.25 mg/d) vs estrogen/progesterone combination; duration, 6 months4—Outcomes included Kupperman index scores (modified 17 symptoms), LH and FSH levels. FINDINGS: Kupperman scores improved in all groups (P = .01); no differences among treatment groups; no changes in LH and FSH levels.
1Jacobson JS, et al. J Clin Oncol. 2001;19: ; 2Warnecke G. Med Welt. 1985;36: Stoll W. Therapeutikon. 1987;1: Lehmann-Willenbrock E, Riedel HH. Zentralbl Gynakol. 1988;110:611-8.

36. Botanicals: Black Cohosh
Available as Remifemin, Estroven, or other single or combination products
Dosage: mg daily
Adverse effects: headaches, stomach discomfort, heaviness in legs
Hot Flashes

37. Non-hormonal Hot Flash Therapies
Drug
Hot Flash Reduction
Antidepressants
Paroxetine
62-65%
Venlafaxine
38-60%
Fluoxetine
20%
Anticonvulsants
Gabapentin
45%
Antihypertensives
Methyldopa
65%
Clonidine
38%
Menopause 2004;
11(1): 11-33
ACOG Task Force on HT
Obstet Gynecol 2004; 104:106s-17s.

38. Therapeutic Interventions: Hormonal Medications
Act 2
Therapeutic Interventions: Hormonal Medications

39. Prescription HT Options: ET and EPT
Oral
Transdermal
Intravaginal ET
Micronized estradiol
Conjugated equine estrogens (CEE)
Synthetic conjugated estrogens
Esterified estrogens
Estropipate
Estradiol acetate
Patches
Gels
Emulsion
Spray
Creams
Intravaginal tablet
Rings
EPT
CC-EPT
CS-EPT
E+P (combination) patches
As you can see there are many different options and formulations for hormone therapy. Refer to your handout for more detailed information.
Med Lett Drugs Ther 2004; 46:98. 39

40. HT Regimens Month 1 Month 2 Estrogen Progestin 14d Off for 14 d
Continuous-sequential (CS) EPT
Progestin
Continuous combined (CC) EPT
Estrogen Therapy (ET) 3d
Continuous-pulsed (CP) EPT 40

41. Choice of HT Regimen If no uterus: estrogen only If uterus present
Goal is to avoid vaginal bleeding entirely, or, at least, to make it predictable
Endometrial activity predicts bleeding pattern
Recent spontaneous or induced bleeding
Continuous sequential
No bleeding for >2-3 cycles
Continuous combined 41

42. ET Oral Tablets Product Brand Standard dose Low dose Estropipate Ogen
Ortho-est
Generic
0.625 m
none
Micronized E2
Estrace
1.0 mg
0.5 mg
Estradiol acetate
Femtrace
0.9 mg
0.45 mg

43. ET Transdermal: Patch*
Brand name
Mg/24 hr
Use/ wk
Alora
0.025, 0.05, 0.075, 0.1 2
Esclim
0.025, , 0.05, 0.075, 0.1
Estraderm
0.05, 0.1
Vivelle
Vivelle-Dot
Climara
0.025, ,0.05, 0.06, 0.075, 0.1 1
Menostar
0.014 ☼
* All contain 17B- estradiol only
☼ Indicated only for prevention of osteoporosis

44. ET Transdermal: Gels, Emulsions, Sprays*
Brand name
Type
mg/24 hr
Use
Divigel
Gel
0.25, 0.5, 1 mg/ packet
1 packet daily
Elestrin
0.87 gm pump
1 pump daily
EstroGel
1.25 gm pump
Estrasorb
Emulsion
1.74 gm/ pouch
2 pouches daily
Evamist
Spray
1.53 mg/ spray
1 spray daily
* All contain 17B- estradiol only

45. Choice of Estrogens Start low dose transdermal or oral estrogen
If suboptimal response, modify by:
Change the estrogen dose (upward)
Change the estrogen preparation
Change delivery systems (oral transdermal)
Consider an estrogen-androgen combination
Injectable estrogen not recommended
Dosage equivalencies are not known
Estrogen cannot be discontinued easily

46. 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 increased breast cancer risks with oral and transdermal estrogens, per large observational study
NAMS position statement. Menopause 2007.

47. Oral vs. TD-E: The Risk of VTE
The ESTHER Study
OR = 4.0 ( )
Adjusted Odds Ratio (95% CI)
In the WHI, postmenopausal women randomly assigned to oral hormone therapy had 2.1 times higher risk of venous thromboembolic events than those receiving placebo.
A large case-control study of postmenopausal women was conducted in order to explore the relationship between estrogen use and venous thromboembolism (VTE) risk. A total of 155 postmenopausal women with a first documented episode of idiopathic VTE were compared with 381 control women matched for age, study center, and time of recruitment. The case subjects included 92 women with pulmonary embolism and 63 women with deep vein thrombosis.
After adjusting for potential confounding factors, women taking oral estrogen therapy had 3.5 times higher risk of VTE as compared with nonusers and 4.0 times higher risk as compared to those taking transdermal estrogen. Transdermal estrogen users did not have an increased risk of either DVT or PE. These results show that oral estrogen—but not transdermal estrogen—is associated with increased risk of VTE in postmenopausal women.
Reference
Scarabin P-Y, Oger E, Plu-Bureau G, et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:
Scarabin P-Y, et al. Lancet. 2003;362:

48. “First Line” Use of Transdermal Estrogen
Underlying medical conditions
History of DVT or PTE
High triglyceride levels
Gall bladder disease
Need for “steady state” drug release
Daily mood swings (especially while on oral HT)
Migraine headaches
Inability to use oral tablets
Stomach upset due to oral estrogen intake
Problems with taking a daily pill

49. Lower HT Doses
Provide nearly equivalent vasomotor and genital skin symptom relief and preservation of BMD compared to standard doses
Additional local ET may be required for persistent vaginal symptoms
Lower HT doses better tolerated and may have a better risk-benefit ratio than standard doses
(cont’d)
NAMS position statement. Menopause 2007.

50. Lower HT Doses (cont’d)
Lower-than-standard ET/EPT doses should be considered, such as daily doses of
0.3 mg oral conjugated estrogens
mg oral micronized 17β-estradiol
0.025 mg transdermal 17β-estradiol patch
or the equivalent
NAMS position statement. Menopause 2007.

51. Progestogen Indication
Primary menopause-related indication is endometrial protection from unopposed ET
Adequate progestogen (as CC-EPT or CS-EPT) recommended with intact uterus
Progestogen not generally indicated with ET post-hysterectomy
NAMS position statement. Menopause 2007.

52. Progesterone/ Progestin Products
Oral Progestin
Equiv dose
Available doses
MPA
5-10 mg
1.2, 2.5, 5, 10 mg
Micronized progesterone mg
100, 200 mg
Drospirenone
0.5 mg/d
Norethindrone acetate
1.0 mg/d
0.5, 1.0 mg/d
Norethindrone
mg/d
0.35 mg
Norgestimate
0.09 mg
Norgestrel
150 mcg/d

53. EPT Oral Tablets Estrogen Progestin Dosing Activella 17-E2 1 mg
NETA 0.5 mg
Once daily oral
Angeliq
Drosperinone
0.5 mg
FemHRT
EE 5 g
EE 2.5 g
NETA 1 mg
NETA 0.5 mg
Prefest
17- E2 1 mg
Micronized
NGM 0.09 mg
E (alone) 3 days
E+P 3 days
Premphase
14 active
14 placebo
CEE mg
MPA 5 mg
(CS-EPT)
Prempro
28 active
CEE
0.625 mg
0.45 mg
0.3 mg
MPA
5.0 mg; 2.5 mg
2.5 mg
1.5 mg
(CC-EPT)

54. EPT Transdermal Patches
Estrogen
Progestin
Dosing
CombiPatch
17-E2
0.05 mg
NETA 0.14
0.25 mg
Twice weekly
Climara Pro
17-E mg
LNG
0.015 mg
Once weekly

55. Off-Label EPT Uses
Insufficient endometrial safety evidence to recommend off-label use of
Long-cycle progestogen (ie, P every 3-6 months for days)
Vaginal administration of progesterone
Levonorgestrel intrauterine system (Mirena)
Low-dose estrogen without progestogen
Close endometrial surveillance recommended with these approaches
NAMS position statement. Menopause 2007.

56. Compounded Bioidentical Hormones
“Then, suddenly, the Seven Dwarfs of Menopause arrived at my door without warning: Bitchy, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried-Up….What was it that sent those wretched dwarfs packing? Natural bioidentical hormones.”
Here we have Suzanne Sommers, who is largely responsible for bringing the concept of bioidenticals into the mainstream.
Somers S. The Sexy Years: Discover the Hormone Connection: The Secret to Fabulous Sex, Great Health, and Vitality for Women and Men. Front Matter Random House, Crown Publishing, NY.

57. Compounded Hormone Therapy
The marketing of compounded hormonal therapy
Only bioidentical hormones are used
Combination of 2 or 3 estrogens is more “natural”
Dosage is tailored to the individual
More “pure” than commercial products
Safer delivery systems (no dyes, etc)
The reality
The same hormones are used in commercial and compounded 17b-E2 and progesterone

58. Sources of Exogenous Hormones

59. Compounded Hormone Therapy
Compounded hormones will probably work, but…
Salivary hormone levels are not useful
The value of adding E1 + E3 has not been evaluated
Progesterone skin cream is not absorbed
Compounded hormone doses are not standardized
FDA-approved HT products will offer
Bioidentical hormones
Choice of delivery systems
Formulary coverage/ lower out-of-pocket costs

62. Act 3
Practice Guidelines How can your patient use these treatments safely, effectively, and conveniently?

63. Treatment of Hot Flashes
If mild sxs, try exercise, black cohosh + phytoSERM
Initiate low dose HT if
Moderate or severe symptoms
Non-hormonal treatments have failed
No interest in non-hormonal therapy
Titrate estrogen dosage upward if needed
When estrogen can’t be used, offer
SSRI or SNRI
Gabapentin, clonidine, a-methyldopa,
MPA or Megesterol (Megace)
Attempt discontinuation after 1-2 years 63

64. Treatment of Sleep/ Irritability Sxs
If mild symptoms
Lifestyle change, black cohosh, phytoSERMs
If severe symptoms or no response to above
Low dose HT, then titrate upward
If mood swings, transdermal E preferred
Depression component, or no response to HT
SNRI or SSRI

65. HT and Vaginal Atrophy
When HT is considered solely for this indication, local (not systemic) vaginal ET is generally recommended
Progestogen generally not indicated with low-dose, local vaginal ET
Vaginal lubricants often improve vaginal dryness and painful intercourse
NAMS position statement. Menopause 2007.

66. Vaginal Estrogen Therapies
Product
Brand
Dosage
Dose
Conjugated estrogen cream
Premarin cream
0.625 mg/ gram
Daily, then 1-3 time/wk
Estradiol cream
Estrace
0.01%
(0.1 mg/ gm)
Estradiol vaginal tablet
Vagifem
25 micrograms
Daily for 2 wks, BIW
Estradiol ring
Estring
7.5 mcg/ 24 hrs
Every 90 days
Estradiol ring*
Femring
0.05 mg/d
0.1 mg/d
Every 3 months
*Intended to be used as systemic HT

67. Vaginal ET: Endometrial Surveillance?
There are insufficient data to recommend annual endometrial surveillance in asymptomatic women using low-dose, local vaginal ET
Closer surveillance may be required if a woman is
At high risk for endometrial cancer
Using a greater dose of vaginal ET
Having symptoms such as spotting, breakthrough bleeding
NAMS position statement. Menopause 2007.

68. HT and Cognition
Initiating EPT after age 65 not recommended for primary prevention of dementia or cognitive decline
Insufficient evidence to support ET/EPT for primary prevention of dementia when therapy is initiated during perimenopause or early postmenopause
ET does not appear to convey direct benefit or harm for treatment of Alzheimer’s disease
NAMS position statement. Menopause 2007.

69. HT and Cognition
Many women experience worsening of short term memory with onset of menopause
9 RCTs and 8 cohort studies
HT does not improve cognitive performance in women without symptoms
If symptoms, HT improved verbal memory, reasoning, and motor speed tests
Reasonable to provide HT to lessen cognitive changes in symptomatic menopausal women

70. Hormone Therapy and Fracture Prevention
Pros
Good data on fracture prevention (mainly 2o prevention)
Relatively lower cost than boisphosphonates
Less concern of adverse effects with ET alone (vs EPT)
Cons
Requires long term use and surveillance
Post-menopausal bleeding can be troublesome
Increased risk of breast cancer after 5 years of use
Utility
Fracture prophylaxis if using HT for another indication
Otherwise, consider bisphosphonates as first line 70

71. HT and “Quality of Life”
RCTs and retrospective studies show that HT has no effect on “quality of life” measures
Many woman who wean from HT state that they “feel worse”…even after 20 years after menopause!
Conventional wisdom
In women who “feel better on/ worse off” of HT, continue low dose HT if few or no risk factors
When (& how often) to re-attempt wean uncertain
Don’t start HT for solely for improving QOL

72. Act 4
The Finale

73. Discontinuation of HT
After 2 years, recommend a trial of HT discontinuation
Is tapering from hormone therapy necessary?
Grady D, Obstet Gynecol 2003;102:1233
n= 377 who attempted discontinuation of HT
74% successfully stopped; 26% resumed
71% stopped abruptly; 29% tapered: equal success
“Rebound” hot flashes occur in some women and can last up to 3 months…many experts recommend a taper
Taper hormone therapy over 8-12 weeks
Reduce dose or extend intervals (every 2, then 3 days)
Cut patches in half

75. If what I just said sounded unusually clear, then you must have misunderstood me
Alan Greenspan