1. Menopause Management Esther Eisenberg, MD MPH
Professor of Obstetrics and Gynecology
Vanderbilt University Medical Center
Nashville, TN

2. Objectives
Discuss clinical manifestations of hormonal changes during menopause
Understand the role of hormone therapy in the menopausal woman
Review benefits and risks of menopausal hormone therapy

3. MENOPAUSE Permanent cessation of menses Ovarian follicular depletion
Final menstrual period
Clinical definition – no menses x 1 year
Context of age and symptoms
Median age of LMP is 51.3 y

4. Menopause: Clinical Manifestations
Vasomotor symptoms-hot flashes, night sweats
Sleep disturbances- insomnia, poor quality sleep
Mood changes-irritability, anxiety, depression
Urogenital effects- vaginal dryness, urinary incontinence
Sexual well-being-decreased libido
Menstrual cycle -amenorrhea
North American Menopause Society; consensus opinion Menopause 2000; 7:5.
Guthrie JR, et al. Climacteric. 2004;7:375-89
Cohen LS, et al. Arch Gen Psychiatry. 2006;63:385-90;
Leiblum SR, et al. Menopause. 2006;13:46-56;
Versi E, et al. Int Urogynecol J. 2001;12:
Brincat M, et al. Obstet Gynecol. 1987;70:840-.

5. Menopause-Associated Changes
Accelerated bone loss –osteoporosis, fracture
Coronary heart disease
1Guthrie JR, et al. Climacteric. 2004;7:375-89; 2Cohen LS, et al. Arch Gen Psychiatry. 2006;63:385-90;
3Leiblum SR, et al. Menopause. 2006;13:46-56; 4Versi E, et al. Int Urogynecol J. 2001;12:
5Brincat M, et al. Obstet Gynecol. 1987;70:840-5; 6Sowers MF, et al. J Clin Endocrinol Metab. 2006;91:1261-7; 7Sowers MF, et al. J Clin Endocrinol Metab. 2003;88:

6. Consequences of Estrogen Loss on Target Tissue
Slide 6
Vasomotor symptoms
Hot flashes
Sleep disturbance
Cardiovascular disease
Urogenital atrophy
Osteoporosis
Skin dryness and aging
Brain
Eyes
Vasomotor
Heart
Bone
Consequences of Estrogen Loss on Target Tissue
Key Points
Tissues responsive to specific hormones undergo changes that result in menopausal symptoms
About 40% of menopausal women develop symptoms serious enough to seek medical attention
Reference
Booher DL. Estrogen supplements in menopause. Cleve Clin J Med. 1990;57:
Breast
Colon
Urogenital Tract

7. Patient History
54-yo woman with recurrent menopausal symptoms after discontinuing HT 3 months ago
Increased frequency and severity of hot flushes
Currently 6 to 8 hot flushes a day
1 to 2 soaking night sweats a week
Early morning awakening with fatigue
Reduced sexual interest
Vaginal dryness; pain with intercourse
She stopped HT because of reports that breast cancer incidence has decreased possibly due to reduced use of HRT after WHI findings
Previously she had taken E+P oral therapy for 2 years without problems
This case report is used as a tool to highlight some significant teaching points about patient management
A 54 year ld female is complaining of recurrent menopausal symptoms after stopping hormone therapy about a year ago. She had stopped hormone therapy because she had concerns about the results that were available for the WHI
She has researched alternative therapies n the web and she has made an appointment to discuss salivary testing and bioidentical hormone therapy because she thinks it works better and is safer.
She has previously taken a standard dose of E/P oral therapy for 4 years without any issues.

8. Other info Family History Physical Findings Blood pressure―124/80
Maternal aunt: postmenopausal breast cancer
Maternal grandmother: fractured hip and wrist at age 81, was bedridden
Paternal grandfather: stroke at age 79, died of MI
Physical Findings
Blood pressure―124/80
BMI 29 (overweight)
Breast exam consistent with fibrocystic changes without masses
Pelvic exam – atrophic changes of vagina

9. Lab/Test Results Mammogram, heterogeneous densities
Total cholesterol 225; HDL 45; Trig 150
TSH 3.5
Bone density: LS -1.8, hip -1.5
Pap smear interpreted as “changes consistent with mild atrophy”
Tests ordered included a mammogram, cholesterol, TSH, bone density and pap smear.
The mammogram showed heterogeneous densities with BiRADS 2
The total cholesterol was 219; HDL was 45; Triglycerides were 50
TSH was 3.5
Bone density was LS―1.8 and hip―1.1
Pap smear interpreted as “changes consistent with mild atrophy”

10. Vasomotor Symptom Prevalence
Slide 10
> 75% of women report hot flashes within the 2-year period surrounding their menopause
Primary reason women seek medical treatment
25% remain symptomatic for > 5 years
Prevalence of Hot Flashes
Menopause
Years Before
Years After
Prevalence of Vasomotor Symptoms
Key Points
Main reason women years of age start HRT is relief from vasomotor symptoms
Hot flashes may start much earlier and continue far longer than is commonly recognized by physicians or acknowledged in gynecology textbooks
If it is true that 75% of women experience hot flashes, 15% severely so, then 4-5 million women in the United States are markedly affected
Patterns of hot flashes may change with time – some become less frequent and less intense, but others may continue at hourly intervals well into old age
References
Ettinger B, Pressman A, Silver P. Effect of age on reasons for initiation and discontinuation of hormone replacement therapy. Menopause. 1999;6:
Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci. 1990;592:52-86. 3 2 1 1 2 3
Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.

11. Duration of Hot Flushes After Menopause
Ages 29 to 82 Years
Number of years women report having hot flushes as estimated by a survey of 501 untreated women who experienced hot flushes 2 4 6 8 10 12 14 16 18 20 22 24 28 30 36 41
Hot flushes occur in the vast majority of menopausal women,1-3 with estimates ranging from 68%1 to 93%2 of women. Hot flushes often begin before menopause, tend to peak within 2 to 3 years after menopause, and lessen thereafter.3 But the range of patterns among menopausal women is quite diverse.
Kronenberg3 showed that women can have hot flushes for more than 20 years. In this survey of 501 self-selected postmenopausal women (ages 29 to 82 years), the total duration of flushing ranged from a few months to 44 years after menopause.
Fifty percent of the women in this survey began experiencing hot flushes before menopause, when the menstrual cycle was still regular or just becoming irregular. Most of the remaining women began having episodes within 1 year of menopause, and a small percentage did not begin having them until >2 years after menopause.
Although the majority (60%) of these women experienced hot flushes for <7 years, 15% had hot flushes for >15 years.
The symptoms that can accompany hot flushes (including perspiration and palpitations) contribute to the discomfort, inconvenience, and anxiety associated with vasomotor symptoms, particularly when these episodes occur very frequently and during the night. Thus, the effect of hot flushes on QOL can be quite significant.
Kronenberg3 reported that, for women in Western societies, hot flushes are a chief menopausal complaint that leads women to seek medical treatment, supporting the belief that this symptom represents a significant disruption in QOL.
Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.
Kronenberg F. Ann NY Acad Sci. 1990;592: Used with permission.
1Freedman RR. In: Menopause: Biology and Pathobiology. 2000:
2Thompson B, et al. J Biosoc Sci. 1973;5:71-82.
3Kronenberg F. Ann NY Acad Sci. 1990;592:52-86.

12. Rx Options for Vasomotor Symptoms
For mild VMS
Lifestyle changes (limited efficacy)
Nonprescription remedies—no difference from placebo but no evidence of harm
Dietary isoflavones
Black cohosh-remifemin
Vitamin E
For night sweats
Reduce bedroom temp to 65 degrees F
For patients with mild vasomotor symptoms suggest lifestyle changes and nonprescription remedies.
Nonprescription remedies include dietary isoflavones, black cohosh and vitamin E
INCLUDE VITAMIN E DATA FROM NAMS need to find reference
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:

13. Rx:Moderate-to-Severe Vasomotor Sxs
Estrogen replacement therapy “gold standard”
Greater than 80% decrease in VMS
SSRIs and Gabapentin
early studies show efficacy
50% reduction in frequency and severity of hot flashes
Progestogens- effective at high doses
Limited by side effects-weight gain, bloating, depression
Clonidine (oral or transdermal)-minimal efficacy
For patients with moderate to severe vasomotor symptoms, hormone therapy is the only FDA-approved treatment and is the gold standard.
SSRIs and gabapentin have efficacy in early studies evaluating 14 hot flashes/week
Progestogens are effective but large doses are needed.
Clonidine can be used either orally or with a transdermal patch.
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:

14. Various Doses of CEE Taken Alone or With MPA Relieve Vasomotor Symptoms
0.45/1.5
0.625/2.5
Placebo
0.45/2.5
0.3/1.5
Placebo
0.625
0.45
0.3
In the Women’s HOPE study, hot flushes were analyzed in women who reported at least 7 moderate-to-severe hot flushes on each of the last 7 days of baseline screening or at least 50 total hot flushes during the last 7 days of baseline screening. Participants recorded the number and severity of hot flushes on daily diary cards throughout the screening and study periods.
This graph depicts mean number of hot flushes over a 12-week period for women given unopposed CEE (0.625, 0.45, or 0.3 mg/d), CEE with MPA (0.625/2.5, 0.45/2.5, 0.45/1.5, or 0.3/1.5 mg/d), or placebo.
Data for unopposed CEE groups are shown on the left, and CEE/MPA data are shown on the right.
Within one week of initiating therapy, all treatment groups (including placebo) experienced a significant reduction in number of hot flushes compared with baseline, except for the CEE 0.3/MPA 1.5 group, which decreased from baseline (P < .001) by the end of the second week. By the third week, all CEE and CEE/MPA treatment groups exhibited a significant (P < .001) reduction in mean daily number of hot flushes compared with the placebo group. These differences were maintained throughout the 1-year trial.
Thus, all of the doses of CEE alone or CEE/MPA examined in this study provided significant symptom relief within the first few weeks of use.
The reduction in number of hot flushes was comparable in all CEE/MPA groups.
The results also suggest that the addition of MPA to lower doses of CEE may enhance the relief of vasomotor symptoms seen with CEE alone.
*Adjusted for baseline.
Mean hot flushes at baseline = 12.3 (range 11.3–13.8). Analyses included women who recorded taking study medication and had at least 7 moderate-to-severe
flushes/week or at least 50 flushes per week at baseline.
Utian WH, et al. Fertil Steril. 2001;75: Used with permission.
Utian WH, et al. Fertil Steril. 2001;75:

15. Alternatives to HT Provide Modest Reduction in Vasomotor Symptoms
Placebo (n = 347)
Soy (n = 66)
Clonidine (n = 75)
Fluoxetine (n = 20)
Median Score
Vitamin E (n = 57)
Venlafaxine (n = 45)
Megestrol (n = 74)
This slide includes the results of a cross-study comparison of several similarly conducted placebo-controlled clinical trials on the effects of various therapies on hot flushes in breast cancer survivors.1-7
The studies were all conducted by the same group of investigators, minimizing design variability. Placebo was reported to reduce hot flushes by approximately 25%. The effect of soy was similar to placebo. Clonidine and vitamin E reduced hot flushes slightly more than placebo. However, the improvement in hot flush scores with clonidine was observed in the first week, whereas the benefit with vitamin E was not apparent for several weeks.
The antidepressant venlafaxine was the most effective of the nonhormonal treatments, reducing hot flush scores by approximately 50% to 60%.
NOTE: These data are not from head-to-head trials. In addition, it is likely that patients in these studies may have been taking tamoxifen, which is often associated with increased vasomotor symptoms.
Week
NOTE: These data are not from head-to-head trials; trials were conducted in women with breast cancer.
Loprinzi CL, et al. Lancet Oncol. 2001;2:
1Loprinzi CL, et al. Lancet Oncol. 2001;2:
2Goldberg RM, et al. J Clin Oncol. 1994;12:155-8.
3Barton DL, et al. J Clin Oncol. 1998;16:
4Quella SK, et al. J Clin Oncol. 2000;18:
5Quella SK, et al. Cancer. 1998;82:
6Loprinzi CL, et al. Lancet. 2000;356:
7Loprinzi CL, et al. J Clin Oncol. 2002;20:

16. Urogenital Atrophy
Changes in the urogenital tract are among the most consistent hypoestrogenic features of the menopause
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. Executive Summary. Obstet Gynecol. 2004; 104 (no. 4, supplement): 56s-61s.

17. Efficacy of Low-dose Vaginal Estriol on Vaginal Symptoms
Estriol (1 mg) or placebo administered once daily for 2 weeks, then 2 mg once weekly for 6 months
Variables
Rx Group (n = 44)
Control Group (n = 44)
P-Value*
Before Treatment
After Treatment
Vaginal dryness
Dyspareunia
Urogenital atrophy
100%
86.4%
20.5%
27.3%
84.1%
90.9%
93.2%
< .001
< .01
Before starting therapy, all 88 women had presented with urogenital atrophy ranging from moderate to severe, and most (38 in the treatment group and 37 in the control group) reported symptoms of dyspareunia.
After 6 months, vaginal dryness, dyspareunia, and urogenital atrophy improved in the estriol group compared with the placebo group.
In the treated participants, there were statistically significant increases in mean MUP, MUCP, and mean PTR in comparison with the control participants.
Note that P < .05 is possibly significant for the urodynamic variables.
As noted on the previous slide, this is a controversial topic, as several studies have shown estrogen to have little or no effect on urinary stress incontinence and pelvic floor relaxation2,3; this topic requires further confirmation. A number of studies reporting no effect, such as the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial3, did not use urodynamics to assess outcomes did not use urodynamics to assess outcomes.
*P-value is comparison between the treatment and control groups. Dessole S, et al. Menopause. 2004;11:49-56.
1Dessole S, Rubattu G, Ambrosini G, et al. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause. 2004;11:49-56; 2Grady D, Brown JS, Vittinghoff E, et al. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol. 2001;97:116-20; 3Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: Results from the postmenopausal estrogen/progestin interventions trial. Obstet Gynecol. 1998;92:

18. Menopausal Hormone Therapy
What are the risks?

19. Women’s Health Initiative (WHI) Clinical Trials of HT
>27,000 postmenopausal women randomized
PREVENTION TRIAL - 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
Between 1993 and 1998, over 27,000 postmenopausal women between the ages of 50 and 79 years were enrolled in the WHI HT trials at 40 US clinical centers. Mean age at baseline was approximately 63 years.
In the E+P trial, a total of 16,608 women without prior hysterectomy were randomized to CEE/MPA or placebo.1
In the E-alone trial, a total of 10,739 women with prior hysterectomy were randomized to CEE alone or placebo.2
The primary outcomes for both HT trials were CHD (acute myocardial infarction [MI], silent MI, or CHD death) and invasive breast cancer.
The investigators also designed a “global index” as a summary measure of the overall balance of risks and benefits of HT.1
The global index is an unweighted index defined as the first event for each participant among the following: CHD, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death from other causes.
The conditions included in the global index were those that the WHI investigators had determined to be important aspects of health benefits/risks that might be affected by long-term use of HT.
A variety of other conditions were not part of the global index, including gallbladder disease, diabetes, menopausal symptoms, and cognitive function..
HT = hormone therapy; CHD = coronary heart disease; E+P = estrogen plus progesterone.
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:
Women's Health Initiative Steering Committee. JAMA. 2004;291:
1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:
2Women’s Health Initiative Steering Committee. JAMA. 2004;291:

20. WHI Clinical Trial HRT Arm ERT Arm
Multicenter, randomized, double blind placebo controlled
Mean age: 63.3 years. Intact uterus
Average duration of follow-up: 5.2 years
Regimens: CEE mg/d + MPA 2.5 mg/d (n = 8,506) or placebo (n = 8,102)
ERT Arm
All women had hysterectomy
Average duration of follow up : 6.8 years
Regimen: CEE mg/d (n=5310) or placebo (n=5429)
Primary outcome: Nonfatal MI and CHD death
Primary adverse outcome: Invasive breast cancer
Global index: Summary measure of risks and benefits
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

21. WHI Combined HRT Baseline HRT Placebo Characteristics n=8506 n=8102
Age at screening, yrs*
Prior hormone use, %
Body mass index, kg/m2*
Never smokers, %
Diabetes, %
Hypertension, %
Statin use at baseline, %
Family Hx breast cancer, %
History of MI,† %
History of CABG/PTCA,† %
63.2 (7.1)
26.1
28.5 (5.8)
49.6
4.4
35.7
6.9
16.0
1.6
1.1
63.3 (7.1)
25.6
28.5 (5.9)
50.0
4.4
36.4
6.8
15.3
1.9
1.5‡

22. 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
Overall, the absolute number of cases of clinical disease per 10,000 women per year were low in WHI E+P trial.
The number of cases per year in 10,000 women are shown here for disease outcomes which suggested an increased risk with CEE/MPA (CHD, stroke, invasive breast cancer, PE, and VTE), those where CEE/MPA may have provided benefit (colorectal cancer and hip fractures), and those with neutral outcomes (endometrial cancers and total deaths).
Not shown are numbers for total fractures, which were lower in women using CEE/MPA.
CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; VTE = venous thromboembolism; PE =
pulmonary embolism.
*Risk of CHD in first year was statistically significant; overall risk of CHD was not statistically significant.
Adapted from National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update— Available at: Accessed 6/22/02.
National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: health/women/upd2002.htm. Accessed June 22, 2002.
Manson JE, et al. N Engl J Med. 2003;349:
Wassertheil-Smoller S, et al. JAMA. 2003;289:
Chlebowski RT, et al. JAMA. 2003;289:

23. WHI E Alone: Absolute Risks & Benefits
CEE
Placebo
More Cases in E Group
Fewer Cases in E Group
No Significant Difference in # of Cases
Number per Year per 10,000 Women
As observed in the WHI CEE/MPA trial, the absolute number of cases of clinical disease per 10,000 women per year were low in the WHI CEE-alone trial.
The number of cases per year in 10,000 women are shown here for disease outcomes which suggested an increased risk with CEE/MPA (stroke), those where CEE/MPA may have provided benefit (hip fractures), and those with neutral outcomes (VTE, CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and total deaths).
Not shown are numbers for total fractures, which were substantially lower in women assigned to CEE alone, compared to those assigned to placebo (139 per 10,000 women/year among CEE users vs 195 per 10,000 women/year among those receiving placebo).
Colorectal
Cancer
CHD
Strokes
Breast
VTE
Hip
Fractures
Total
Deaths PE
Women's Health Initiative Steering Committee. JAMA. 2004;291:
Women’s Health Initiative Steering Committee. JAMA. 2004;291:

24. WHI: Relative and Absolute Risk or Benefit of CEE plus MPA at 5.2 Yrs
Cases Risk Ratio Changes/10,000
Outcome HRT Placebo Women
Breast Ca ( ) + 8
MI/CVD ( ) + 7
Stroke ( ) + 8
VTE ( )
PE ( ) + 8
Colon Ca ( ) - 6
Hip Fx ( ) - 5
Vertebral Fx ( ) - 5
Death ( )

25. WHI Results CEE Alone Health Event Risk Ratio vs. Nominal CI
Placebo (6.8 yrs)
CHD (nonfatal MI or death)
Stroke
VTE
Breast Cancer
Colorectal Cancer
Hip Fracture
Global Index

26. Risk of Invasive Breast Cancer in the WHI HT Trials: Absolute risk is small-about 2 additional cases per 1000 women using E+P for 5 yearsACOG -no increase with E HR
Placebo
1.00
E+P1
1.24
95% nCI
95% aCI
E alone2
0.77
0.5
1.0
5.0
2.0
Hazard Ratio
nCI = nominal confidence interval; aCI = adjusted confidence interval.
1Chlebowski RT, et al. JAMA. 2003;289:
2Women's Health Initiative Steering Committee. JAMA. 2004;291:

27. Hazard Ratios from 3 Hormone Therapy Trials
Hazard Ratio (95% C.I.)
JAMA 2004; 291; 1770

28. Relative Risk of Breast Ca
BrCa1,2 mutation 10
Early menarche 1
Late age at birth of first child 2
Benign breast disease
Hormone therapy
Moderate alcohol use
Family history

29. Collaborative Group Reanalysis
HT Use RR
Ever use
1.14*
Current use
1.21*
Current use, 5 years†
1.35*
Past use
1.07
Relative risk of breast cancer similar to WHI E+P
Increasing risk with longer duration of use
The Collaborative Group on Hormonal Factors in Breast Cancer reanalyzed 90% of the worldwide epidemiologic evidence on the relationship between risk of breast cancer and use of HT.
This reanalysis examined 52,705 women with invasive breast cancer and 108,411 women without breast cancer, and included 51 studies from 21 countries.
The main analysis was based on 53,865 postmenopausal women; of these, 17,830 (33%) were HT users.
Results were reported in terms of RR; these values were similar to the HR of 1.26 found in WHI.
The RR for ever-users was 1.14.
The RR for current or recent users was 1.21.
The RR for current or recent users with 5 years of use was (Note that the average duration of use in this group was 11 years.)
The RR for past users was 1.07.
Consistent with the WHI E+P results, the Collaborative Group results suggest that HT use may be associated with a small increase in breast cancer risk compared with the risk among nonusers.
*P < .01 vs never-user. †Average duration of use was 11 years. RR = relative risk.
Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:
Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:

30. Recommendations from the ACOG Task Force on HT
Women should be counseled that the absolute risk of breast cancer for any individual remains relatively low, but study findings indicate that E+P is associated with an increased risk of breast cancer.
Although the risk of breast cancer may be lower for women who take E alone, in women with pelvic organs present, risk for endometrial cancer and ovarian cancer (?) should be considered.
For breast cancer survivors, alternatives to HT should be considered for the treatment of menopausal symptoms.
ACOG Task Force on HT. Obstet Gynecol. 2004; 104 (no. 4, supplement): 106s-117s.

31. Reduction in Fracture Risk With E+P and E Alone in WHI Trial
0.5
1.0
2.0
Hip
Vertebral
Lower Arm/ Wrist
All Fractures
CEE/MPA (95% nCI)
CEE alone (95% nCI)
Although it is FDA-approved for osteoporosis prevention, but not treatment, results from the Women’s Health Initiative (WHI) HT trials provide randomized clinical trial evidence for the efficacy of estrogen used alone (E only) or with a progestin (E+P) in reducing the incidence of hip, vertebral, nonvertebral, and total fractures.1,2
As shown in this slide, E+P used a median of 5.6 years reduced the risk of hip fracture by one third (hazard ratio [HR], 0.67; 95% nominal confidence interval [nCI], 0.47–0.96). E+P also reduced the risk of vertebral fracture (HR, 0.65; 95% nCI, 0.46–0.92), lower arm/wrist fractures (HR, 0.71; 95% nCI, 0.59–0.85), and total fractures (HR, 0.76; 95% nCI, 0.69–0.83).
The graph also shows the risk of fracture reported from the WHI E-only study. After almost 7years of follow-up, the use of E alone reduced the risk of hip fracture by almost 40% (HR, 0.61; 95% nCI, 0.41–0.91), the risk of vertebral fractures by 38% (HR, 0.62; 95% nCI, 0.42–0.93), and the risk of total fractures by 30% (HR, 0.70; 95% nCI, 0.63–0.79).
The reduction in fracture risk demonstrated in the WHI is consistent with the results from previously published observational studies that have shown fracture protection among HT users and randomized trials that have shown significant improvement in BMD in women assigned to HT.
Notably, the reduction in fracture risk in the WHI occurred in a study population not specifically selected for being at increased risk of fracture. Based on BMD measurements in a subgroup of study participants, the majority of women in the WHI (53%–58%) were considered to have low bone mass, and about one third of the women had normal BMD.3 This fracture benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy.
Hazard Ratio
Cauley JA, et al. JAMA. 2003;290: ; Women’s Health Initiative Steering Committee. JAMA. 2004;291:
1Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290: ; 2Women’s Health Initiative Steering Committee. JAMA. 2004;291: ; 3Cauley JA. Endocrinologic and Metabolic Drugs Advisory Committee. US Food and Drug Administration: 2003.

32. WHI Fracture Results: Estrogen Rx prevents Fractures
Women treated with E alone or E+P for menopausal symptoms do not need another antiresorptive agent
Findings of WHI warrant consideration of ERT or HRT in women at high risk of fracture who are unable to tolerate other antiresorptive agents (bisphosphonates or SERMs)
HT is the only osteoporosis therapy that has been shown to prevent fractures in women who did not necessarily have osteoporosis.
Fracture reduction in a low-risk population has not been demonstrated with other agents approved for the prevention and/or treatment of osteoporosis. The fracture benefits of these agents have been achieved in women with confirmed osteoporosis who are at a high risk of fracture.
Thus, the WHI provide robust, randomized, clinical trial evidence that HT reduces the risk of fracture among postmenopausal women. These data provide significant support for the concept that estrogen deficiency is a major pathogenetic factor for osteoporosis in aging women and that intervention with estrogen reduces the impact of all fractures. Clinicians should include this information in their assessment of the overall risk-benefit profile for HT for all women considering treatment.
9/19/2018 9:11:36 AM
ACOG Task Force on HT. Obstet Gynecol. 2004;104 (no. 4, supplement):66s-76s.
AACE Osteoporosis Task Force. Endocrine Practice. 2003;9:

33. Osteoporosis Prevention and Treatment
Bisphosphonates -Alendronate, risedronate, ibandronate
SERMs-Raloxifene
Salmon calcitonin
PTH –Teriparatide (increases bone formation)
Calcium 1200 mg /d in divided doses
Vitamin D intake 800 IU/d
HT is the only osteoporosis therapy that has been shown to prevent fractures in women who did not necessarily have osteoporosis.
Fracture reduction in a low-risk population has not been demonstrated with other agents approved for the prevention and/or treatment of osteoporosis. The fracture benefits of these agents have been achieved in women with confirmed osteoporosis who are at a high risk of fracture.
Thus, the WHI provide robust, randomized, clinical trial evidence that HT reduces the risk of fracture among postmenopausal women. These data provide significant support for the concept that estrogen deficiency is a major pathogenetic factor for osteoporosis in aging women and that intervention with estrogen reduces the impact of all fractures. Clinicians should include this information in their assessment of the overall risk-benefit profile for HT for all women considering treatment.
9/19/2018 9:11:36 AM
AACE Osteoporosis Task Force. Endocrine Pract. 2003;9:

34. Relative Risk of CHD: Nurses’ Health Study (NHS) Versus WHI
Never Users
Placebo
CEE Alone
CEE + MPA
CEE
95% nCI
95% aCI
NHS1
WHI
E+P2
WHI
E Alone3
Results for CHD risk between NHS and WHI were markedly different.
NHS investigators reported that postmenopausal hormone use appears to decrease the risk for major coronary events in women without previous heart disease.1 Results also show that risk for major coronary events among oral CEE users (RR, 0.55; 95% CI, 0.45–0.68) was similar to that for E+P users (RR, 0.64; 95% CI, 0.49–0.85) compared with never-users. NHS investigators did not further delineate between type of progestin, dose, or regimen (sequential vs combined) of the progestin component used by the participants in this study.
In the WHI trial,2 after an average follow-up of 5.2 years, an overall HR for CHD was 1.24 in the CEE/MPA group compared with placebo (95% nCI, 1.00–1.54).
Risk Estimate
1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Grodstein F, et al. Ann Intern Med. 2000;133:933-41;
3Women's Health Initiative Steering Committee. JAMA. 2004;291:
1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Grodstein F, et al. Ann Intern Med. 2000;133:933-4; 3Women's Health Initiative Steering Committee. JAMA. 2004;291:

35. WHI: Effect of CEE Alone on Risk of CHD by Age Group
0.63
50–59 y
0.94
60–69 y
1.11
70–79 y
This slide shows the HRs and 95% nominal CIs for the primary outcome (nonfatal MI or CHD death) by age group.
Although the HRs suggest a differential effect of CEE on CHD risk in younger versus older women in the study, the P value for the interaction did not reach statistical significance (P=.07).
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 = )
P = .07 for interaction with age
Hsai J, et al. Arch Intern Med. 2006;166:
Hsai J, et al. Arch Intern Med. 2006;166:

36. 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
In the WHI E+P study, subgroup analyses were performed to determine whether certain subgroups of women were at particularly high or low risk for CHD (non-fatal MI or death due to CHD) following treatment with E+P.
No significant interaction between age and HT was noted. Similarly, the interaction of years since onset of menopause and CHD associated with postmenopausal HT was nonsignificant although there was a trend for less hazard in patients with more recent onset of menopause.
1.71
>20
Manson JE, et al. N Engl J Med. 2003;349:
Manson JE, et al. N Engl J Med. 2003;349:

37. Conclusions From Randomized, Controlled Trials of HT and CHD
Overall, HT has a null effect on the incidence of CHD
Time since menopause and the presence of CHD risk factors may modify the relationship between HT and CHD risk
Initiation and continuation of HT should be for treatment of menopausal symptoms and not for the prevention of heart disease.
Hsai J, et al. Arch Intern Med. 2006;166:357-65; Grodstein F, et al. J Womens Health. 2006;15:35-44;
Manson JE, et al. N Engl J Med. 2003;349:523-34; Hodis HN, et al. N Engl J Med. 2003;349:535-45;
Hodis HN, et al. Ann Intern Med. 2001;135:939-53; Grodstein F, et al. Ann Intern Med. 2000;133:

38. 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)
0.5
1.0
5.0
2.0
In the WHI E+P trial, VTE occurred in 167 women assigned to E+P and 76 women assigned to placebo, resulting in a 2-fold greater risk of VTE in the E+P group (hazard ratio [HR], 2.06).1
A similar 2-fold increase in risk was observed individually for DVT and PE.1 For all three outcomes, risk was increased in the first year of follow-up and an increased risk was observed over the duration of the trial. Trend analysis of the HR over time was statistically significant (P=.01), indicating that the increased risk of VTE, while still present, diminished over the course of the study.
In the WHI E+P trial, the increased VTE risk associated with HT was greatest in the first year of use.1 The HR for VTE was 4.01 after the first year of follow-up (CI not reported). Thereafter, the annual HRs were 1.97 (Year 2), 1.74 (Year 3), 1.70 (Year 4), 2.90 (Year 5), and 1.04 (Year 6 or later).13 The trend for diminishing risk over time was statistically significant (P=.01).
The results from the WHI E-alone trial are less conclusive with respect to the risk of VTE. The incidence of VTE was greater in women assigned to E alone compared with women assigned to placebo (2.8 vs 2.1 per 1000 person-years).2 However, the HR of 1.33 was not statistically significant.
Analyzed separately, the increased risk of DVT (HR, 1.47) in the E-alone group was statistically significant, but the risk of PE was not (HR, 1.34).2
Considered at face value, these results might suggest that the VTE risk associated with E alone is less than the risk associated with E+P. However, caution is warranted in making direct, head-to-head comparisons of the results from the WHI HT trials because the studies enrolled distinctly different populations who, presumably, had different risk factors for chronic disease at baseline.
Hazard Ratio
1Cushman M, et al. JAMA. 2004;292:
2Women's Health Initiative Steering Committee. JAMA. 2004;291:
1Cushman M, et al. JAMA. 2004;292:
2Women's Health Initiative Steering Committee. JAMA. 2004;291:

39. RISK of VTE/PE with EPT/ET
VTE is an infrequent but well established risk of HT
Risk increases approximately 2-fold with HT use
Greatest risk occurs in the first year of use
Absolute risk remains low in HT users due to the low baseline incidence of VTE in the general, non-hospitalized population
ACOG Task Force on HT. Obstet Gynecol. 2004;104 (no. 4, supplement):118s-27s.

40. Age is an Effect Modifier
NEJM 2003;
348:1836

41. ESTHER Case Control Study of Oral and transdermal EPT -Differential effects on risk of VTE
RX Cases Control OR CT
Oral EPT % %
Transdermal % %
EPT
Scarabin PY, Oger E, Ply-Bureau G ESTHER Study Group Lancet 2003; 362:

42. Risks and Benefits of HT
Numerous areas of uncertain benefit or risk
Sexual function
Mood (depression, anxiety)
Urinary incontinence
Diabetes prevention
Sleep
Skin

43. Mortality Rates in Women with Hysterectomy 50-54 Years of Age, +/- Oophorectomy, +/- ET
Proportion Dead From Specific Condition by Age 80 (%)
Strategy
Proportion Alive at Age 80 (%)
Hip Fracture
Ovarian Cancer
Breast Cancer
Stroke
Coronary Heart Disease
Other
Ovarian conservation, no ET
62.46
3.38
0.47
1.82
2.59
7.57
21.72
Oophorectomy, no ET
53.88
4.96
0.00
1.77
2.47
15.95
20.97
Ovarian conservation, ET
62.75
2.06
3.60
Oophorectomy, ET
62.15
3.17
3.59
7.56
21.71
Prophylactic oophorectomy is often recommended concurrent with hysterectomy for the treatment of benign disease. This study attempted to determine if there is an optimal age for this option.
A Markov decision analysis model was used to estimate the optimal strategy for maximizing survival of women at average risk of ovarian cancer. Inputs into the model included published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, secondary heart disease, hip fracture, breast cancer, and stroke.
Four strategies were compared: ovarian conservation or oophorectomy with or without use of estrogen therapy. Outcome was expressed as proportion of women alive at age 80.
Based on the model, ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy. Estrogen therapy following oophorectomy is as effective as ovarian conservation in terms of survival.
Parker WH, et al. Obstet Gynecol. 2005;106:
ET= estrogen therapy
Parker WH, et al. Obstet Gynecol. 2005;106:

44. Many Options for Menopausal HT
Route of delivery
Transdermal patch
Drops/Oil/Gel
Vaginal ring
Choice of estrogen
Multiple dose ranges
Progesterone vs progestin
?Androgen

45. Patient
54-yo woman with recurrent menopausal symptoms after discontinuing HT 3 months ago. Previously she had taken E+P oral therapy for 2 years without problems
VMS-mean duration/options for rx
Reduced sexual interest- more common after BSO ?testosterone
Vaginal dryness; pain with intercourse-topical rx, low dose patch
Risks of HT-Breast CA (E+P), VTE (E), Stroke (E), Other//Benefits-prevention of DM, Fractures, Colon Ca (with E+P)
Breast cancer incidence has decreased-alternative explanations?-mammography screening is down; use of SERMs; change in ERT- more transdermal, less MPA, lower doses

46. Other considerations Overweight- Recommend diet and exercise
Excess weight increases risk of breast Ca and other chronic diseases
Screen for Type 2 DM
High cholesterol-consider statin use for prevention of heart disease
Aging and risk of VTE- low dose aspirin
Adequate calcium and Vitamin D

47. Patient Resources www.HormoneCME.org www.Hormone.org