Hormone Therapy & Menopause Care

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					Hormone Therapy & Menopause Care
Association of Reproductive Health Professionals

Expert Medical Advisory Committee
> > > > > > > > Alan Altman, MD (co-chair) Linda Dominguez, NP Karen Gunning, PharmD Barbara Kass-Annese, NP Robert Langer, MD, MPH Barbara Malat, CPNP, PA-C (co-chair) Joan Tilghman, RN, PhD Susan Wysocki, RNC, NP

Learning Objectives
> Identify two physiological changes associated with menopause > Identify three types of symptoms women commonly experience during perimenopause and menopause > Discuss key findings from the Women’s Health Initiative (WHI) and how these findings should be applied to the treatment of menopausal women

Learning Objectives (continued)
> Describe three effective talking points about menopausal therapy that help patients make informed decisions about hormone therapy > Discuss four basic differences between prescription hormone therapies > Discuss the current data on herbal hormone products > List four requisites for individualizing hormone therapy

Defining Menopause & Perimenopause
A woman’s lifetime

Perimenopause First signs of change

Menopause Diagnosed 12 months retrospectively

NAMS. Menopause Curriculum Study Guide. 2002. Utian, WH. Menopause. 2001.

Two Key Physiological Changes

Loss of primary ovarian follicles

Resulting decrease in serum and tissue estradiol levels

Gruber CJ, et al. N Eng J Med. 2002.

Menopause-related Symptoms
Headache Palpitations Night sweats Insomnia/sleep disturbance

Vaginal dryness Dyspareunia Vaginal itching/burning Urinary frequency, dysuria, urgency

Other Systemic
Fatigue Reduced sexual desire/arousal

Anxiety, irritability and depression
Cognitive difficulties

Backache/ stiffness
Nevin JE, Pharr ME. Prim Care. 2002. Stenchever MA, et al. Comprehensive Gynecology, 4th ed. 2001.

Medical Conditions More Common After Menopause
> Osteoporosis > Atherosclerotic disease

Stenchever MA, et al. Comprehensive Gynecology, 4th ed. 2001. Wenger NK. Brit Med J. 1997.

Fear & Confusion After the WHI & HERS

Overview of HERS
Heart and Estrogen/progestin Replacement Study (HERS) > Secondary prevention in women with CHD > Found CEE with MPA does not reduce MIs > More CHD events in hormone group during Year 1

Coope J. Management of the Menopause and Post-Menopausal Years. 1976. Baumgardner SB, et al. Obstet Gynecol. 1978.; Stampfer MJ, et al. N Engl J Med. 1985.; Wilson PWF, et al. N Engl J Med. 1985.; Hulley S, et al. JAMA. 1998.

Overview of WHI
Women’s Health Initiative (WHI ) > Primary prevention in healthy women > Age 50-79 (mean 63 y) > Post-menopause (mean 12 y) > Treated with CEE with (or without) MPA > Primary outcome rate of fatal or non-fatal MI > E-P arm terminated July 2002 > E-only arm terminated March 2004
Rossouw JE, et al. JAMA. 2002. Anderson GL. Press conference remarks. 2004.

Understanding WHI Results

WHI Results: CHD
E-P arm
HT neither protected nor worsened
Risk of CHD was 24% higher in E-P group

E-only arm

Not statistically significant
39 cases versus 30 cases per 10,000 p-y Time trend existed
Manson JE, et al. N Engl J Med. 2003. WHI Steering Committee. JAMA. 2004. Pradham AD, et al. JAMA. 2002.

No increased risk

WHI Results: Breast Cancer
E-P arm
More invasive breast cancers More total breast cancers

E-only arm

No difference in in situ breast cancers
Invasive cancers larger and more advanced

23% decrease
Approached statistically significant

Time trend existed
Chlebowski, RT. JAMA. 2003. WHI Steering Committee. JAMA. 2004.

WHI Results: VTE
E-P arm
Statistically significant increased risk
Hazard ratio for PE=2.13 8 additional cases of PE per 10,000 person-years Rate also increased

E-only arm

Rossouw JE, et al. JAMA. 2002. WHI Steering Committee. JAMA. 2004.

WHI Results: Stroke
E-P arm
Statistically significant increased risk of ischemic stroke

E-only arm

Slightly increased risk

Hazard ratio=1.44

Wassertheil-Smoller S, et al. JAMA. 2003. WHI Steering Committee. JAMA. 2004.

WHI Results: Osteoporotic Fractures
E-P arm
Statistically significant lower risk Hazard ratio=0.76

E-only arm
Statistically significant reduction in hip fractures

Cauley, JA. JAMA. 2003. WHI Steering Committee. JAMA. 2004.

WHI Results: Colorectal Cancer
E-P arm
Statistically significant decreased risk
Hazard ratio=0.61 Diagnosed cancers more advanced in HT group

E-only arm
No overall reduction Significant age effect with lower rate in 50-59 age group

Chlebowski RT, et al. N Engl J Med. 2004. WHI Steering Committee. JAMA. 2004.

WHI Results: Quality of Life
E-P arm
Subgroup of about 1,500 tested
No significant difference In 574 who were 50-54 and symptomatic, improvement in sleep disturbance No data available (study ended)

E-only arm

Hays J, et al. N Engl J Med. 2003.

WHI Results: Gynecologic Cancers
E-P arm
Rates low
No differences between groups

E-only arm
No data available (study ended)

Anderson GL, et al. JAMA. 2003.

WHI Results: Dementia
E-P arm
In subgroup over age 65, no protective effect seen with HT

E-only arm

Decrease in MMSE scores in HT group
When segmented by age, risk seen only in 75-80 age group
Rapp SR, et al. JAMA. 2003. Shumaker SA, et al. JAMA. 2003. NIH. 2004.

Non-significant trend toward increased risk

Understanding WHI Results
What WHI results do not tell us > Benefits and risks of beginning HT at menopause > Benefits and risks for treatment of menopauserelated symptoms > Use of other doses, formulations, regimens, durations, and routes of administration of HT > Information on events after cessation

Putting WHI Results into Context
> Well-designed study of mostly asymptomatic women distant from menopause > Results have been generalized to other groups and to other HT formulations > Not yet known if findings apply

Lobo RA. Arch Intern Med. 2004.

Translating Results into Clinical Practice
Oral hormone therapy & post-menopausal women

Not for cardio protection

Not for treating CVD

ACOG Guidelines
Not for prevention of cardiac disease or osteoporosis

May be appropriate to treat menopause-related symptoms
Shortest possible duration in smallest effective dose

ACOG. 2004.

NAMS Guidelines
Extended use may be acceptable for some women Do not use for prevention of stroke, CHD, or osteoporosis Use local therapy for vaginal symptoms Use for shortest duration possible

North American Menopause Society. Menopause. 2003.

NPWH Guidelines
Women whose QoL is affected are best candidates Use lowest dose and shortest duration Use local therapy for urogenital symptoms

Women’s choice about duration should be respected

Nurse Practitioners in Women’s Health. 2004.

FDA Guidelines
Effective for treating vasomotor symptoms and vaginal dryness, preventing osteoporosis Use topical therapy for vaginal dryness alone Use as last resort for osteoporosis prevention alone

Use lowest dose and shortest duration possible

Food and Drug Administration. 2004.

Counseling Patients About HT
Each woman must weigh risks and benefits in light of her circumstances
Women must put risks into perspective to make fully informed decision Each woman must clarify her purpose and goal for using HT

Contraindications to Systemic ET
> > > > > > Pregnancy VTE Breast cancer Estrogen-sensitive cancers Liver disease Hypertriglyceridemia

Weighing Risks and Benefits
Provide accurate information Ask: “What are the risks and benefits for you?” Ask: “Do you have concerns about HT?” Discuss lifestyle changes

Understanding Risk
Relative Risk Helps investigators identify causes Absolute Risk
Helps assess impact on an individual

> WHI: 26% increase in breast cancer in E-P arm > This does not mean 26% chance of getting breast cancer
International Food Information Council. 2004. Nurse Practitioners in Women’s Health. 2004. Rossouw JE, et al. JAMA. 2002.

Absolute Risk Quantified by WHI
MI Stroke Breast cancer

Risk or benefit of E-P per 10,000 women
7 more cases 8 more cases 8 more cases

Colorectal cancer Hip fractures
WHI. June 2002 HRT Update. 2002.

18 more cases
6 fewer cases 5 fewer cases

Absolute Risk Quantified by WHI
Risk factor Baseline risk Risk per 1,000 women 45 Extra breast cancers --

HT 5 y HT 15 y
Menopause after 54

47 57

2 12

BMI > 31
Lifetime excess alcohol Lack of exercise

72 72

27 27

Huang Z. JAMA. 1997.; LaCroix AZ. Lancet. 1997.; Longnecker MP. Cancer Epidemiol Biomarkers Prev. 1995.; Smith-Warner SA. JAMA. 1998.; Thune I. N Engl J Med. 1997.; WHI. 2002.

Relative Risk of Breast Cancer
Risk factor First pregnancy after age 30 BMI > 29.68 Being college graduate Daily alcohol over 5 g/d Late menopause (>5 y post avg) HT use for 5 y
Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997.

Relative risk of breast cancer 1.48 1.48 1.36 1.16 1.14 1.12

Clarifying Goals or Purpose
Risk/benefit ratio varies based on goals “What is most important among your menopauserelated health concerns?” “Why do you want to start/continue HT?”

Individualizing Hormone Therapy
Requires: > Familiarity > Understanding how to help a woman find the best product and regimen

Types of HT: Estrogens

17 betaestradiol

Conjugated equine estrogens (CEE)

Estrone derivatives

Types of HT: Progestogens



Adams MR, et al. Arteriosclerosis. 1990.; Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997.; Espeland MA, et al. J Clin Endocrinol Metab. 1997.; NAMS. 2002.; Williams JK, et al. J Am Coll Cardiol. 1994.

Types of HT: Progestogens

Synthetic progestogens

Structurally related to progesterone

Structurally related to testosterone

NAMS. Menopause. 2003. King RJ, Whitehead MI. Fertil Steril. 1986. PEPI Investigators. JAMA. 1995.

Progestogens: Possible Side Effects
> Swelling and breast pain more common with MPA > Acne and hirsutism more common with levonorgestrel and norethinedrone > Dizziness and fatigue associated with high-dose progesterone > Metabolic effects differ

NAMS. Menopause. 2003. Mitchell JL, et al. Prim Care. 2003. PEPI Investigators. JAMA. 1995.

Routes of Administration

Slater CC, et al. Menopause. 2001.

Routes of Administration: Differences
> > > > > > > Systemic vs. local effects Even vs. uneven blood levels First-pass metabolism or not Hemostatic effects or not Risk of VTE Effects on procoagulants and lipids Need for concomitant progestogen

Vongpatanasin W. J Am Coll Cardiol. 2003.; Decensi A. Circulation. 2002.; Scarabin PY. Lancet. 2003.; Femring package insert. 2003.; Hemelaar M. Menopause. 2003.

Compounding Pharmacies

Cyclic Estrogen frequency Daily Progestogen frequency Last 10-14 D

Old cyclic Continuous combined Long cycle
Cyclic combined

D 1-25
Daily Daily Daily

D 16-25
Daily 10-14 D q 3-6 m D 1-25

Oral Therapies
Cenestin® Estrace® Menest® Ogen® Premarin®

SCE Estradiol Est. E Estropipate CEE


Oral Therapies
Product Prometrium® Provera® Activella® Estrogen --Estradiol Progestogen Micronized progesterone MPA NETA

Ortho-Prefest® Premphase® Prempro®

Estradiol CEE CEE

NETA Norgestimate (pulsed) MPA (D 15-28) MPA

Transdermal (Patches and Gel)
Product Alora® Climara® Climara Pro® Estraderm® Vivelle® CombiPatch® EstroGel® Estrogen Estradiol Estradiol Estradiol Estradiol Estradiol Estradiol Estradiol Progestogen --Levonorgestrel --NETA --

Vaginal Creams, Tablets, and Gels
Premarin® Estrace® Vagifem® Crinone®*/ Prochieve®*

CEE Estradiol

---Micronized progesterone

Estradiol hemihydrate

*Not labeled by the FDA for menopause-related symptoms

Vaginal Rings and IUS
Product Estring®* Femring®** Mirena®*** Estrogen Estradiol Estradiol -Progestogen --Levonorgestrel

*Local **Systemic ***Intrauterine; Mirena is not labeled by the FDA for menopause-related symptoms

Femring package insert. 2003.

Herbal Products for Menopause Relief

Carroll DG. Am Fam Physician. 2006. Ma J, Drieling R, Stafford RS. Menopause. 2006.

Herbal Products: Do They Work?
> > > > > Black cohosh Red clover Dong quai Soy Evening primrose seed oil

Carroll DG. Am Fam Physician. 2006.; Low Dog T. Am J Med. 2005. NIH/NCAM. 2005.; Newton KM, et al. Ann Intern Med. 2006. Pockaj BA, et al. J Clin Oncol. 2006.

> Estratest® and Estratest® HS indicated for vasomotor symptoms if estrogen alone ineffective > Testosterone has also been used to improve sexual function
– Not FDA-approved for this use 2003. Estratest and Estratest HS package insert. 2004.

Selective Estrogen Receptor Modulators
> Mediate effects through estrogen receptor binding > Activate certain estrogenic pathways and block others > Not indicated for menopause-related symptoms > Can cause hot flashes from estrogen receptor blockade

Evista package insert. 2001.

Requirements of Individualized Care
Gathering specific health-related information Providing accurate, patient-specific HT information Supporting informed decision making Addressing ongoing health needs

Case 1: Mary S.
> > > > > Final menstrual period 18 months ago at age 49 Healthy with no CHD risk factors Hot flashes daily Herbal remedies not helping “Terrified of those hormone drugs”

Case 1: Recommended Management
> Symptomatic with no contraindication > Candidate for systemic HT, not local HT > To decide on route, consider her preference, medical history, other factors > Progestogen needed if oral, transdermal, or systemic vaginal therapy is chosen

Case 2: Zelda K.
> > > > 60 years old 8 years postmenopausal Has never taken HT Severe dyspareunia, urinary urgency, and frequency X 1 year > Does not want oral HT, because friend had DVT on it

Case 2: Recommended Management
> > > > Severe genitourinary symptoms No vasomotor symptoms Candidate for vaginal estrogen Could use cream, tablet, or locally acting ring (Estring)

Case 3: Ann P.
> 56 years old > Was taking oral HT for vasomotor symptoms > Internist told her to stop HT > Off HT several months > Vasomotor symptoms gone but sexual desire low > Wants to restart HT > No contraindications to systemic HT

Case 3: Recommended Management
> Provider should ask about sexual function, relationship, and pharmacological issues to clarify cause > Low sexual desire may be related to low hormone levels > May be candidate for restarting HT, possibly with androgen

Case 4: Terri O.
> > > > 48 years old Perimenopausal Menses generally regular Experiencing hot flashes, mood swings, and fatigue > Requests HT > Had DVT on oral contraceptive at age 35 > No other medical problems

Case 4: Recommended Management
> HT should not be used during perimenopause > OCs contraindicated > Could use estrogen augmentation with patch > Does not need progestogen – menses still regular > Needs progestogen challenge if no menses X 3 months > Before any form of HT is started, possibility of pregnancy should be investigated, as appropriate

Case 5: Katherine W.
> 54 years old > Post hysterectomy without oophorectomy > Recent severe vasomotor symptoms and forgetfulness > Afraid of HT > Family physician told her recent studies showed “HT causes breast cancer” > Healthy, no contraindications to HT

Case 5: Recommended Management
> Candidate for oral or non-oral systemic HT > Does not need progestogen > Provider should educate about actual risks associated with HT > HT could be used for a short time, then gradually reduced to avoid estrogen withdrawal symptoms

Case 6: Debra R.
> 58 years old > Has taken oral HT for 4 years > Vasomotor symptoms and vaginal dryness have returned over past 3 months

Case 6: Recommended Management
> If adherence not an issue, relapse likely because of increased SHBG caused by oral estrogen > Options include adding androgen or changing to non-oral estrogen

Recommendations for Further Study
> HT using other routes of administration, hormone components, and regimens > Comparison of “bio-identical” products > Use of androgens alone or with HT > Factors that affect patient adherence > How patients make decisions about HT > Optimal regimens for discontinuing HT

> Patients and providers have been confused about HT as a result of the WHI and HERS data > Understanding study results and limitations helps providers counsel women to make informed decisions about HT > Individualization of therapy is essential for women who decide to use HT

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