Management of Common Menopausal Complaints

Alice B. Gibbons, MDSummit Medical Group

February 12, 2014

Vasomotor Symptoms=Hot Flushes

• Estrogen alone or combined with Progesterone, 75% reduction in flashes

• Orally or transdermally, in patches, gels and sprays

• Low dose also effective; Ultra low dose not effective, and not FDA approved

• Risks are thromboembolic disease and breast cancer

Women’s Health Initiative Study, 1999

• Primary focus was heart disease prevention• Average age of study participants was 63• Women had no menopausal symptoms• Women hadsignificant other medical

problems• Maybe estrogen was triggering events in

patients who already had atherosclerosis?• Study ended prematurely

• Synthetic products • Binds to many receptors giving side effects (fluid

retention, acne, weight gain, sugar intolerance)• Can cause anxiety/irritability in central nervous

system• Blunts estrogen’s favorable impact on lipids• Stimulates breast cells• Constricts blood vessel, increases heart disease

• Post WHI 2002:• 50% decline in conventional hormone therapy

prescriptions in first 6 months• Many patients turned to compounded therapy• Many chose alternative therapies• Discontinuation of HT-50% have recurrent

symptoms.• No guidelines on discontinuing abruptly or

tapering

FDA Clearly States

“Other doses of estrogens and progestins and other combinations were not studied in the WHI trials, in absence of data these risks should be assumed to be similar”

Kronos Early Estrogen Prevention Study (KEEPS) @ 2007

• Purpose: to evaluate progression of atherosclerosis which causes heart disease

• Four year trial in women aged 42-58 with a uterus, started on estrogen within 3 years of menopause

• Received one of three treatments with progesterone:

Oral estrogen, Transdermal, or Placebo Brain Research 2013;1514:12-17

North American Menopause Society 2012 Position Statement

• Individualization is of key importance in the decision to use HT and should incorporate the woman’s health and quality of life….as well as her personal risk factors.

• The recommendation for duration of therapy differs for EPT and ET. For EPT, duration is limited by the increased risk of breast cancer associated with 3-5 years of use; for ET a more favorable risk profile during a mean of 7 years of use, allows more flexibility in the duration of use

• Menopause 2012;19(3):257-271

Global Consensus Statement on HRT (2013)

• Key Conclusions• Benefits outweigh risks for women under 60 or

within 10 years of menopause• HRT is effective for symptoms related to

menopause such as hot flashes, sleep, bone health.

• Taking HRT should be individualized and made in consultation with a qualified physician.

• Maturitas 2013;74:391-92.

• Bioidentical (native) Some are FDA approved

• “Natural”- found in nature, derived from pregnant mares urine (thus the name Premarin)

Estrone sulfate (human bioidentical)Equilin sulfate (native to horses)

• Synthetic- made in a laboratory, broken down in stomach to be estradiol

What does it mean to be a bioidentical hormone?

– Derived from plants– Claimed to be similar to human hormones, i.e. acts

like estrogen and progesterone– Sometimes used to treat menopause symptoms– Not from an animal, not synthetic (man-made)

FDA-approved Hormones for Menopausal Symptoms

Type/source Brand name(s) Form Bioidentical?

Estrogens

Conjugated equine estrogens (CEE)/pregnant mares’ urine

PremarinPill No

Vaginal cream No

Synthetic conjugated estrogens/plants Cenestin, Enjuvia Pill No

Esterified estrogens/plants Menest Pill No

17 beta-estradiol/plants    ++Micronized (Particles are made smaller for better absorption)++

Estrace, others Pill Yes*

Alora, Climara, Esclim, Estraderm, Vivelle, others

Patch Yes

Estrogel Transdermal gel Yes

Estrasorb Topical cream Yes

Estrace Vaginal cream** Yes

Estring Vaginal ring** Yes

Estropipate (modified estrone)/plantsOrtho-Est, Ogen, others Pill No

Ogen Vaginal cream** No

Estradiol acetate Femring Vaginal ring Yes

Estradiol hemihydrate Vagifem Vaginal tablet** Yes

Ethinyl estradiol Estinyl Pill No

Progestins, micronized progesterone Brand Name Form Bioidentical

Medroxyprogesterone acetate (MPA) Amen, Cycrin, Provera Pill No

Micronized progesterone USPPrometrium Pill Yes

Prochieve 4% Vaginal gel Yes

Norgestrel Ovrette Pill No

Norethindrone Micronor, Nor-QD, others Pill No

Norethindrone acetate Aygestin, others Pill No

Combined hormones

CEE and MPA Premphase, Prempro Pill No

Ethinyl estradiol and norethindrone acetate Femhrt Pill No

17 beta-estradiol and norethindrone acetateActivella Pill No

Combipatch Patch No~

17 beta-estradiol and norgestimate Prefest Pill No~

17 beta-estradiol and levonorgestrel Climara Pro Patch No~

– Compounded* bioidentical hormones NOT FDA approved• Considered a dietary supplement• No rigorous testing required

– As a dietary supplement, the burden for the FDA is to prove it is unsafe rather than effective

*Compounded hormone = mixed by pharmacists as prescribed by practitioners

BIEST

• Estradiol- reproductive age

• Estrone-present in menopause

• Estriol-present in pregnancy, very weak

TRIEST

• Estriol not available as single agent tablet in USA, required to have “new drug” application for FDA approval

• No safety studies for Biest or Triest• No studies showing native hormones prevent

bone loss

Popular prescription method• Variable dose over 28 day cycle• Topical Application

Background on Wiley• Author but not a physician• No supporting scientific data

• “Ultrafiltrate” of blood; should be able to measure free hormone available

• Measures deficiencies in order to customize PROBLEMS• No agreement between blood and saliva levels• Saliva levels vary with diet and time of day

(need to measure 5x/day)

Dosing according to symptom response, NOTblood levels. End points:

• Control of vasomotor symptoms (hot flushes)

• Reversal of vaginal atrophy (dryness)• insomnia improvement

FDA has not approved any bioidentical combination product

Failed ≥ one quality tests 34% <2%

Failed Potency analyses 90% .13%

CompoundedProducts

FDA-ApprovedProducts

COMPOUNDED PROGESTERONE for menopausal symptoms

May not protect uterine liningDoesn’t prevent osteoporosis,Doesn’t eradicate symptoms, so why would we use it by itself?

TESTOSTERONE• Patch used for Hypoactive Sexual Desire Disorder• Increase in number of satisfying sexualepisodes from .5 (placebo) to 2.1(testosteronepatch)• May change lipid profile unfavorablyBlood tests inaccurate in women Again, not FDA approved

In patient’s with uterus in place, means taking two products, and therefore, more cost

FDA products more likely to be covered by insurance

Compounded products more expensive overall

Conflict if doctor also selling product

More likely to be offered to economically more advantaged

Women seek it out to restore sexual well-being; may be psychologically more vulnerable

Other Useful Agents-not estrogens-

• Progesterone alone may help hot flashes when used alone, but safety unclear

• Testosterone alone not FDA approved, shows no benefit and has male hormone side effects. When used with HT, improved sexual function scores

• Clonidine- medication to lower BP, not FDA approved for menopause symptoms

• Gabapentin (Neurontin) anti-seizure, 45% effective in studies, not FDA approved

• SSRIs-anti depressants-Paroxetine (Paxil) is ONLY non-hormonal therapy that is FDA APPROVED

•Anti-depressant, not a hormone

•Hot flashes decreased by 55% in Lexapro group, 35% in placebo group

•Women felt that 1.4 fewer hot flushes/day was a meaningful improvement

•Similar result to other drugs in this category-area of exploration

•Strong placebo effect which means non-medical factors were Important

JAMA.2011;305(3):267-274. doi:10.1001/jama.2010.

Selective Estrogen Receptor Modulators (SERMs)Definition:

Synthetic compounds that selectively stimulate or inhibit the estrogen receptors of different target tissues

Estrogen receptors in different target tissues vary in chemical structure

Example: Tamoxifen: inhibits breast tissue, but stimulates uterus Evista: inhibits breast tissue, stimulates bone, neutral on the uterus

New Product Bazedoxifene Negative on the uterus, stimulates bone

Brand New: HT/SERM combination product known as a Tissue Selective Estrogen Complex (TSEC)

Ideally, this combination would have the positive attributes of both drug categories with fewer undesirable side effects.

Alleviates hot flushes (estrogen)Treat vaginal dryness (estrogen)Protect against bone loss (both)Would not stimulate the uterus (serm)Does not require Progesterone (serm)

Duavee is expected to be available in February 2014

Estrogen with Bazedoxifene

Alternative Therapies for Menopausal Hot Flushes

• Phytoestrogens-plants substances with estrogenic biologic activity-no benefit, not detrimental, not studied well

• Vitamins-limited data; Vitamin E (800 IU) effect was one less hot flush/day

• Acupuncture-no benefit over placebo• Reflexology-no benefit over foot massage• Exercise-no significant improvement in hot flushes, but sense

of well-being• Decrease alcohol and caffeine-slight benefit• Placebo alone can have significant impact on flushes

• Good Manufacturing Practices (GMPs)-companies must comply

• US Pharmocopeia (USP)• National Sanitation Foundation (NSF)• ConsumerLab-manufacturer can pay to have

product tested and listed on website (Consumerlab.com)

• Although there is some supervision of this industry, not sufficient data to support use for menopause symptoms

Generally, no overall benefit

Possible benefit,no benefit, or inconclusive

Hormonal Treatment of Vaginal Dryness and Painful Intercourse

• Local therapy in form of creams, rings, and vaginal tablets (Estring, Estrace, Vagifem…)

• Local therapy does not require progesterone to protect uterine lining

• May actually help urinary symptoms• Patients with previous history of breast cancer often

eligible for vaginal estrogen after consultation with oncologist

Vaginal Lubricants

• Lubricants reduce friction and pain related to dryness during sex

• Moisturizers trap moisture and provide long term relief- may reduce irritation, improve acid-base balance

Ospemifene (Osphena) for Vaginal Dryness

• Oral product, SERM category of drug• Estrogen receptor stimulant on vaginal tissue• Does not stimulate the uterine lining• FDA approved for treatment of moderate-to-severe

dryness causing painful sex• Side Effects: hot flushes, vaginal discharge, excessive

sweating• Benefit: easy to take tablet

Even though FDA approved; Note large boxed warning

Sleep Hygiene Sleep only as much as you need to feel refreshed the next day•Maintain a regular sleep and wake pattern 7 days a week.•Avoid napping during the day; it can disturb the normal pattern of sleep and wakefulness•Avoid stimulants, such as caffeine, nicotine and alcohol, too close to bedtime.•Exercise can promote good sleep. Vigorous exercise should be taken in the morning or late afternoon. A relaxing exercise, like yoga, can be done before bed to help initiate a restful night’s sleep.•Food can be disruptive right before sleep; stay away from large meals close to bed time.

More Sleep Hygiene• Associate your bed with sleep and sex only. It is not a good idea to use your bed

to watch television, listen to the radio or read.• Make sure that the sleep environment is pleasant and relaxing. The bed should

be comfortable and the room should not be too hot, too cold or too bright.• Establish a relaxing bed time routine. Try to avoid emotionally upsetting

conversations and activities before trying to go to sleep.• Do not take your problems to bed. If necessary, plan some time earlier in the

evening for working on your problems.• If you are unable to sleep, do not try harder and harder to fall asleep. Instead,

turn on the light, leave the bedroom and do something different, like reading a boring book. Do not engage in stimulating or productive activity. Return to bed only when you are sleepy. Get up at your regular time the next day no matter how little you slept.

• Do not look at clock, turn it awaySource; Modified from the Thoray M Sleep hygiene; a new era CPAP therapy.

Arlington (VA): National Sleep Foundation; 2003.

• More specific binding to JUST progesterone receptors

• Mild diuretic• Mild sedative effects (helps sleep)• No effect on lipids• Does not stimulate breast• Relaxes blood vessels, decreases plaque

formation

Legal History:

1994 2008 2010

Dietary SupplementalHealth & Education Act

FDA EnforcementAction

Dietary Supplement FullImplementation & Enforcement Act