What’s New in Menopause Management

Leslee L. Subak, MD

Professor of Obstetrics, Gynecology & Reproductive Science

University of California, San Francisco

Objectives

• Define the menopause transition

• Review menopausal symptoms

• Evidence-based treatments for vasomotor and vaginal symptoms

• How to use and stop using hormone therapy

Stages of Reproductive Aging

Age: young ~45-50 yo ~ >50 yo

Stage: Reproductive Menopause Transition Postmenopause

regular cycles irregular/missed cycles no menses >12 moregular ovulation intermittent anovulation anovulationfertile less fertile infertile

E2 50-200pg/ml same or maybe higher 0 -15 pg/mlT 400 pg/ml same same

FSH 10 mIU/ml same or higher >100 mIU/mlLH 10 mIU/ml same or higher >100 mIU/ml

Age: young ~45-50 yo ~ >50 yo

Stage: Reproductive Menopause Transition Postmenopause

regular cycles irregular/missed cycles no menses >12 moregular ovulation intermittent anovulation anovulationfertile less fertile infertile

E2 50-200pg/ml same or maybe higher 0 -15 pg/mlT 400 pg/ml same same

FSH 10 mIU/ml same or higher >100 mIU/mlLH 10 mIU/ml same or higher >100 mIU/ml

Soules, NIH Consensus Conference, Fertil Steril, 2001Soules, NIH Consensus Conference, Fertil Steril, 2001

Definitions

• Perimenopause - several years before and 1 year after menopause

– Early menopause transition– Late menopause transition

• Menopause –cessation of menstruation – End of ovulation and cyclic bleeding– End of fertility and need for birth control– Positive experience for many women

Marker of agingMarker of aging

What Happens at Menopause?

• “Cessation of menses”– end cyclic bleeding– end of ovulation and fertility– marked (retrospectively ) by final

menstrual period

• Changes in hormones– estrogen, progesterone, FSH, LH, GnRh

• Positive experience for many women

• Aging• Aging

What Symptoms are Related to Menopause?

• Many reported by middle-aged women

• Few associated with menopause transition– Hot flushes and night sweats– Vaginal dryness that can cause dyspareunia– Trouble sleeping– Depressive symptoms

• Other common symptoms may be related to aging, stress, other symptoms

Nelson, Evidence Report #120, 2005Nelson, Evidence Report #120, 2005

Problems Peri-Postmenopause

• Abnormal uterine bleeding

• Vasomotor symptoms

• Genital atrophy

• Decrease in skin collagen

• Rapid bone loss

• Increase in coronary heart disease

• Increase in Alzheimer’s disease

Prevalence and Risks Factors for Hot Flushes

Risk Factors†

– Surgical menopause– African-American,

Latina– Higher BMI– Cigarette smoking

Hot Flushes*Hot Flushes*

% ofwomen

% ofwomen

*Gold, Am J Epidemiol, 2000†Randolph, J Clin Endocrinol Metab, 2004*Gold, Am J Epidemiol, 2000†Randolph, J Clin Endocrinol Metab, 2004

Thermoregulation in Women without Hot FlushesThermoregulation in Women without Hot Flushes

Thermoregulation

controlled by anterior hypothalamus and local vascular factors

Thermoregulatory null zone

Core body temperature (CBT) above threshold results in vasodilation, sweating and heat release

CBT below threshold results in vasoconstriction, shivering and heat conservation and production

Thermoregulation in Women with Hot Flushes

Altered

thermoregulation

Narrowed thermoregulatory null zone

CBT at which women with hot flushes vasodilate and sweat is 0.3 degrees C lower

than premenopausal women or women without flushes.

Etiology of Hot FlushesEtiology of Hot Flushes

Etiology of Hot Flushes

• Hot flush is a heat release mechanism– But occurs at normal core body temp

• Not simply estrogen deficiency– E2 in women with and without flushes similar

– other women with low, high or variable estrogen levels do not flush

• Abnormality of hypothalamus related to– CNS adrenergic or serotonergic

neurotransmission?

– CNS opioids

– peripheral vascular instability

Evaluation of Hot Flushes

• History crucial– Age (mean age 52; 50 in smokers; range 45-60)– Menstrual history (shorter, longer or missed

cycles)

• Physical exam – none needed

• Laboratory tests – generally none needed– FSH > 30pg/ml confirmatory– But FSH often normal in early menopause

transition

Diagnosis of Hot Flushes

• Usually clear from history

• Differential diagnosis– Alcohol consumption– Carcinoid– Dumping syndrome– Hyperthyroidism– Narcotic withdrawal– Pheochromocytoma– Medications - nitrates, niacin, gonadotropin-

releasing hormone agonists, antiestrogens

�Estrogen Relieves Hot Flushes

Greendale (PEPI), Obst Gynecol 1998

conjugated estrogens0.625 mg plus

Placebo

alone MPA(cyc)

MPA(cont)

P(cyc)

in Hot Flushes

Treatment of Hot FlushesEstrogen Daily Dose % in HF

1Oral CEE 0.6250.450.3

947878

2Oral E2 1.00.5

0.25

897972

TD E2 0.053

0.0253

0.0144

968655

1Utian, Fertil Steril, 2001; 2Notelovitz, Obstet Gynecol, 2000;

3Utain, Am J Obst Gyn, 1999; 4Bachmann, Obstet Gynecol, 2007

•Estrogen effective- All preparations- Any route- Dose dependent

• Placebo- 30-50% reduction

Side Effects of Estrogen Treatment

• Breast tenderness • Headache

• Endometrial hyperplasia • Bleeding

*Grady, Obstet Gynecol, 1995*Grady, Obstet Gynecol, 1995

Percent increase in risk of

uterine cancer

Years of Estrogen UseYears of Estrogen Use

Progestin Must be Added to Estrogen to Prevent Endometrial Cancer

• Any progestin effective– Oral, transdermal, or vaginal route– Preparations

• medroxyprogesterone acetate• norethindrone• micronized progesterone

• Side effects– More breast tenderness– Uterine Bleeding– Probable increased risk of adverse events

Approaches to Adding Progestin

• Cyclic/sequential– Estrogen given every day– Progestin added 10 or 14 days/mo (or Q 3-4 mo)– Causes cyclic, menstrual-like bleeding

• Continuous/daily– Estrogen given every day– Progestin given at ½ dose every day– Causes erratic bleeding in the first 6 to 12

months of use; subsequently amenorrhea

• Side effects - more breast tenderness, bleeding, probable increased risk of events

• Estrogen and progestin can be given separately or as combination preparation

Estrogen: Newer Regimens and Preparations

• Lower doses• CE - 0.3, 0.45mg • TD E2 - 0.014, 0.025mg• E2 - 0.25mg

• New routes of delivery• vaginal rings (Estring, Femring)• skin gels (EstroGel)

• Use lowest dose of estrogen adequate to control symptoms

• Dose of progestin related to estrogen

* See handout* See handout

Newer Regimens and Preparations

• Long cycle progestin use− 14 days every 3 to 6 months

• Vaginal gel (Prochieve)

• New combination pills and patches

* See handout* See handout

Bioidentical Hormones

• Hormones identical to endogenous – Often = pharmacy compounding – 17β-estradiol, "plant-derived”, “natural”, – Goal: targeted level of hormones in the body – Limited evaluation of safety and efficacy– Estrone, estradiol, progesterone (available in FDA-

approved manufactured products and as pharmacy-compounded products

– Estriol (available in Europe, not approved in US)– Expected to have the same risks and benefits of

comparable approved drugs – Progesterone may have improved safety profile

Risks and Benefits of Hormone Therapy

• Two decades ago, observational studies suggested that hormone therapy–reduced risk

• fracture• heart disease

– increased risk• breast cancer

• If true, hormone therapy would be beneficial on balance for most women

Grady, Ann Intern Med, 1992Grady, Ann Intern Med, 1992

The Last Decade…

• Evidence from randomized trials

• Alternatives treatments for–fracture prevention–prevention of coronary events–treatment of menopausal symptoms

Women’s Health InitiativeRandomized Trials

• 2 NIH-funded concurrent randomized trials in postmenopausal women–uterus - CE+MPA vs. placebo (16,606)–no uterus - CE vs. placebo (10,739)

• Multiple outcomes

• Planned follow-up 9 years

• Both trials stopped early due to lack of benefit or harm

What did the WHI trials show?

1. No increased risk of breast cancer

2. No decreased risk of CHD

3. Increased risk of VTE

4. All of the above

5. It’s complicated

6. The trials were worthless

WHI Results

WHI E+P1 WHI E only2

CHD events 1.3* 0.9

Stroke 1.4* 1.4*

Pulmonary embolism 2.1* 1.3

Breast cancer 1.3* 0.8

Colon cancer 0.6* 1.0

Hip Fracture 0.7* 0.6*

Death 1.0 1.0

*p-value < .05*p-value < .05

Relative RisksRelative Risks

1Rossouw, JAMA, 20022WHI Steering Committee, JAMA 2004

Adverse Effects of Hormone Therapy

Risk per 1000/yearHarm E+P1 Estrogen2

• CHD + 0.7* -• Stroke + 0.8* +1.2*• Breast cancer + 0.8* -• Pulm. embolus + 0.8*Benefit• Hip fracture - 0.5* -0.6*• Colorectal cancer - 0.6* -

Net bad events +2.0* +0.6

1Rossouw, JAMA, 20022WHI Steering Committee, JAMA 2004 * p < .05

Endocrine Society 2010

Net Effect of Hormone Therapy is HarmRisk is Small for Short-term Use

• No role for prevention

• Estrogen only– 0.6/1000 bad outcomes each year– 3/1000 or 1/300 for 5 years of treatment

• Estrogen plus progestin– 2/1000 bad outcomes each year– 10/1000 or 1/100 for 5 years of treatment

• Timing hypothesis– Possibly no increased CHD risk among

women within 10 years of menopause1

– But other harms still present2 1Rossouw, JAMA, 20072Prentice, Am J Epidemiol, 2009

Hormone related indicators of the risk of breast cancer

ASRM Practice Committee Report 2008

Applying Risks from WHI to Symptomatic Women

• Women in WHI averaged 63 years old

• Women with menopausal symptoms generally 45 to 55

• Disease rates lower in younger women

• Relative risks have less impact

Estimated Risks of Hormone Therapyin Symptomatic Women

• Assume treating women in early 50s

• Unopposed estrogen• .8/10,000 per year of treatment*• 4/10,000 or 1/2500 for 5 years

• Estrogen plus progestin• 1.6/1000 per year of treatment*• 8/1000 or 1/150 for 5 years

Risks are small for individual woman, but major public health impact if millions of usersRisks are small for individual woman, but major public health impact if millions of users

*Grady, NEJM, 2006*Grady, NEJM, 2006

Prevention of Osteoporotic Fractures

• Harms seen in WHI clearly apply– Women in WHI averaged 63 years old– Women treated to prevent osteoporotic fractures

are generally older– Long-term treatment is required

• Estrogen should not be first-line therapy

• Prefer bisphosphonates or other drugs unless contraindications

Hormone Therapy for Hot Flushes

•Given net effect of hormone therapy is harm and purpose is to control symptoms

–Use lowest dose that controls symptoms*–Stop therapy when symptoms resolve*

•Contraindications–Breast cancer or high risk of breast cancer–Deep vein thrombosis or high risk

• Transdermal estrogen probably safer

–Active liver or gallbladder disease

*FDA; American College of Obstetrics and Gynecology; North American Menopause Society

Symptomatic Treatment

•Given that net effect of hormone therapy is harm, treatment should be– lowest dose of

Estrogen and Progestin•TD E2 0.014mg/d • Standard dose Q3-4 mo•oral E2 0.25 mg - MPA 5mg x 14 d

•CEE - 0.3 mg - MPA 10mg x 10 d

- progesterone 200mg x 14 d

- shortest time possible

FDA; American College of Obstetrics and Gynecology; North American Menopause Society

How long do hot flushes last?

1. A few months

2. A few years

3. Average of 8 years

4. Average of 15 years

Natural History of Hot Flushes

• In many women, resolve in a few years

• Mean duration 8 years

• In 10-15%, persist into late life

• Course variable, unpredictable

Hormones for Hot Flashes

• Estrogen +/- progestin very effective– most women with hot flashes are young– hot flashes usually resolve in a few years

• Risk of bad outcomes is small, especially with unopposed estrogen

Endocrine Society 2010

Stopping Hormone Therapy

• Determine if symptoms have resolved–Stop therapy every 6 months to 1 year– If bothersome symptoms, recur – resume

• After 5 years or so on therapy, if still symptomatic, attempt taper

• Dose taper• Day taper

• For severe symptoms, long-term continuation of HT is reasonable

Hot Flushes: Alternatives to Estrogen

Lifestyle Changes

• Lower ambient temperature*

• Dress in layers

• All kinds of other amazing things

*Kronenberg, J Therm Biol, 1992*Kronenberg, J Therm Biol, 1992

Alternative Therapies

• Possibly effective (pilots and small trials)– Paced respiration– Restorative yoga

• Mixed/poor evidence– Acupuncture– Exercise (worsened hot flashes in 1 trial)

• Not effective– Homeopathy– Magnets

Herbs and Supplements

• No benefit– Chinese herbs (so far)– Dong quai– Evening primrose– Ginseng– Red Clover

• No data– Chasteberry– Licorice– Wild yam

• Slightly effective– Vitamin E 800 IU QD

( 1 HF/day)

• Mixed/poor evidence– Black cohosh– Phytoestrogens

% Reduction

• Estrogens 55-95%

• Tibolone 1.25 - 5mg* 80-95%

• Megestrol 20 mg BID 75%

• MPA 20 mg BID 75%

�Other Hormones

* Not available in the US* Not available in the US

• Placebo 30-50%• Placebo 30-50%

% Reduction

• Antidepressants 50-65%- citalopram (celexa) 30mg:1- trial -

- Escitalopram (lexapro) 20 mg: 1+ trial +

- Fluoxetine (prozac) 20-30mg:1+/1- trial +/-

- Paroxetine (paxil) 12.5-25mgCR/20 mg:2 + trials ++

- Venlafaxine (effexor) 37.5-75 mg:1+/1? trial +/-

• Gabapentin 300-2400 mg: 4+ trials 50%

• Clonidine mixed evidence 30%

�Other Drugs

• Placebo 20-50%• Placebo 20-50%

Treatment of Hot Flushes

• Mild symptoms–Lifestyle change–Tolerance

• Moderate symptoms–Low dose estrogen+/-progestin–Paroxetine or gabapentin

• Severe symptoms–Moderate dose estrogen +/- progestin

• Taper and/or stop as symptoms improve

Case 1

Ms. HF could try lifestyle changes or non-hormone treatment, but she likely needs hormone therapy (unless contraindicated)

- Give estrogen alone if no uterus• Prefer estradiol? Transdermal?

- Add a progestin if she has a uterus

- Lowest dose that relieves symptoms

- Try stopping every 6 months

Ms. HF could try lifestyle changes or non-hormone treatment, but she likely needs hormone therapy (unless contraindicated)

- Give estrogen alone if no uterus• Prefer estradiol? Transdermal?

- Add a progestin if she has a uterus

- Lowest dose that relieves symptoms

- Try stopping every 6 months

Menopausal Vaginal Symptoms

• Vaginal symptoms–Dryness - Discomfort– Itching - Dyspareunia

• Prevalence–30% in early menopause–50% in late menopause

• Unlike hot flushes, symptoms generally do not resolve

Etiology of Vaginal Symptoms

• Changes in symptomatic women–Epithelial cells more immature–Decreased blood flow and secretions–Hyalinization of collagen–Fragmentation of elastin–Vaginal fluid less acidic (pH > 6.0)

• Enteric organisms proliferate

• Etiology – estrogen deficiency?

Evaluation of Vaginal Symptoms

• Pelvic examination–Pallor, dryness, decreased rugosity of

vaginal mucosa (vaginal atrophy)–Rule out other causes of symptoms

• infection• trauma

• Laboratory evaluation - none

Treatment of Vaginal Symptoms

• Estrogens – 80 to 100% effective–Vaginal preparations preferred (HANDOUT)

• Provide low systemic dose of estrogen• Generally few side effects• Do not need added progestin*

–Systemic estrogen less effective• Might be adequate, esp. if also needs treatment

for hot flushes

*Suckling, Cochrane Database Syst Rev, 2003

Treatment of Vaginal Symptoms

• Vaginal moisturizers–Replens (other brands not tested)–Bioadhesive polycarbophil-based–As effective as estrogen vaginal cream†

• Vaginal lubricants –Astroglide, etc. –Short-acting lubricants–Use prior to intercourse to relieve

dyspareunia

*Suckling, Cochrane Database Syst Rev, 2003† Nachtigall, Fertil Steril, 1994

Case 2

• Ms VA will probably get relief by using either a vaginal estrogen or a moisturizer such as Replens–Estrogen cream or tablet daily for 2

weeks, then 2-3 times/week

–Replens 3 times/week

Summary

• Hot flushes and night sweats–Treat based on severity of symptoms–Hormones most effective treatment

• Risk for adverse events is small • Use lowest effective dose• Stop when symptoms resolve

• Vaginal symptoms–Vaginal estrogen or Replens

• Depressive symptoms–Treat as for depression

Case 1

• Ms HF: A 51 yo lawyer with frequent hot flushes, night sweats, and trouble sleeping

• Symptoms are “ruining her life”

• Last menstrual period 6 months ago

What would you suggest?

1. Wear layers, keep the windows open – the symptoms will resolve with time

2. Estrogen (with a progestin if she has a uterus)

3. Anti-depressant

4. Gabapentin

5. More tofu in her diet

Case 2

• Ms VA: A 60 yo photographer complaining of vaginal dryness, itching and dyspareunia

• Symptoms are “ruining her sex life”

• Last menstrual period age 49

What would you suggest?

1. Estrogen cream

2. Vaginal moisturizer

3. Vaginal lubricant

4. Just give it up