menopause and hormone replacement therapy hrt (1)

Menopause-symptom relief and treatment options

Irene Stronczak R.Ph.B.Pharm Hons.National Certified Menopause Practitioner

•Discuss Symptoms of menopause

• Discuss the place in therapy of hormone replacement and bio-identical hormones in menopause

• Discuss dosage, formulations, route of administration, side effects, and contraindications

• Discuss the controversies and appropriate use of hormone replacement therapy

•Discuss patient case studies

OBJECTIVES

HT formulation,route,and timing of initiation produce different effects

• Absolute risks for HT use in healthy women ages 50-59 are low

• HT initiation in older women carries greater risks

• Breast cancer risk increases with EPT beyond 3-5years

• ET can be considered for longer duration of use because it carries a lower risk for breast cancer

NAMS 2012 Position Statement

Hormone therapy—what we know today

3

• HT may reduce total mortality when initiated soon after menopause

• Both ET and EPT may reduce total mortality by 30%

when initiated in women younger than age 60

NAMS position statement. Menopause 2012.

HT & Total Mortality

4

estrogen/progesterone treatment started soon after menopause appears to be safe; relieves many of the symptoms of menopause; and improves mood, bone density, and several markers of cardiovascular risk.

KEEPS Results Give New Insight Into Hormone Therapy-2012

5

6

HT & Coronary Heart Disease / Stroke ET may reduce CHD and coronary artery risk when initiated in younger and more recently postmenopausalwomen without a uterus

• HT is currently not recommended for coronary protection in women of any age

• Both ET and EPT appear to increase ischemic stroke risk and have no effect on hemorrhagic stroke risk

Hulley S, et al. JAMA. 1998;280:605-13; Grady D, et al. JAMA. 2002;288:49-57; Blumenthal RS, et al. Am J Cardiol. 2000;85:1015-7.

The women in HERS were on average 18 years post menopause, suggesting that years since menopause may have an important influence on the cardiovascular effects associated with initiation of CEE/MPA

Cardiovascular risks of CEE/MPA in this population were observed early and did not occur in individuals taking concomitant statin therapy

HERS: Lessons Learned

7

Therapeutic goal is lowest effective estrogen dose,plus appropriate progestogen dose for women with a uterus

•Lower doses have fewer side effects and may have more favorable benefit-risk ratio than standard doses

•All routes of administration of ET can effectively treat menopausal symptoms

•Transdermal ET may be associated with lower risk of DVT, stroke, and MI

•Multiple progestogen options for endometrial protection

NAMS position statement. Menopause 2012.

Dose & Route of Administration

8

9

Lower daily doses typically used with systemic ET: 0.3 mg oral CE 0.5 mg oral micronized 17ß-estradiol 0.014-0.025 mg transdermal 17ß-estradiol patch

Typical lowest doses of progestogen: 1.5 mg oral medroxyprogesterone acetate 0.1 mg oral norethindrone acetate 0.5 mg oral drospirenone 50 mg oral micronized progesterone

HT Starting Dosages

10NAMS position statement. Menopause 2010.

No First-pass Effect

Less of an effect on:

- Clotting factors

- Triglycerides

- C-reactive protein

- Sex hormone-binding globulin

Transdermal v oral route

11

First line therapy for VMS and for patients with conditions:

- High risk of DVT or PTE - High triglyceride levels - Gall bladder disease- Hypertension

2. Need for “steady state” drug release - Daily mood swings

- Migraine headaches - Shift workers

3. Inability to use oral tablets

- Stomach upset- Problems with taking a daily pill

Consider using transdermal estrogen

Transdermal/Topical Transdermal mimics the way the ovaries release

hormones. No first pass metabolism & metabolites formed. Greater chance that hormone gets to target tissue prior to

metabolism Steroids are well absorbed through the skin Transdermal Estradiol when given with or without oral

progesterone, has no detrimental effects on coagulation and no observed increased risk for venous thromboembolism

Health Canada approved Estradiol for women Testosterone for men

Delivery System-creams and gels

“It remains possible that transdermal estradiol with progesterone which more closely mimics the normal physiology and metabolism of endogenous sex hormones may provide a different risk-benefit profile”

writing group for WHI July 2002

Conclusions of WHI

ET alone 1.29 (1.02-1.65)

ET+ other progestin 1.69 (1.50-1.9)

ET+ progesterone 1.00 (0.83-1.22)

ET+ dydrogesterone 1.16 (0.94-1.43)Estrogen in combination with micronized progesterone = no increased risk Ref: Fournier 2008

Breast cancer risk and progestogen selection

No clear indication that longer HT duration improves or worsens the benefit-risk ratio

HT effects on long-term risks have not been studied in perimenopausal women

Thus, findings from RCTs of postmenopausal women should be extrapolated with caution for younger women

Duration of HT Use


(cont’d)

Extending HT use is acceptable: For women well aware of potential

risks and benefits With lowest effective dose For prevention of further osteoporosis-related

fracture and bone loss when alternate therapies are inappropriate or benefit-risk ratio is unknown

With clinical supervision

HT Duration of Use (cont’d)


Moderate to severe vasomotor symptoms have been documented in 42% of women aged 60 to 65 years. Thus, many women will continue to have vasomotor symptoms after age 65, and these symptoms can disrupt sleep and adversely affect health and quality of life.Provided that the woman has been advised of the increase in risks associated with continuing HT beyond age 60 and has clinical supervision, extending HT use with the lowest effective dose is acceptable under some circumstances, such as for the woman who has persistent bothersome menopausal symptoms and for whom her clinician has determined that the benefits of menopause symptom relief outweigh the risks

The North American Menopause Society Statement on Continuing Use of Systemic Hormone Therapy After Age 65-2015

18

Use of HT should be individualized and not discontinued solely based on a woman’s age.

• Progestogens alone or low-dose oral contraceptives can be offered as alternatives for the relief of menopausal symptoms during the menopausal transition

•E.g.,Oral progesterone 200mg nightly day14-28 of cycle SOGC Clincal Practice Guideline, January 2009, JOGC

Progestogens in the Menopause Transition

19

Mood changes Insomnia-60% Headaches Hot flashes-80% Memory problems Aches and pains Fatigue Decreased libido Bloating Night sweats Skin changes Vaginal dryness Heart palpitations Bone changes Abnormal uterine bleeding

Signs and symptoms of hormone imbalance in patients

Regulates body temp Improves insulin sensitivity Increases basal metabolic rate Increases blood flow Improves sleep Maintains skin collagen Decreases risk of cataracts Increases bone density Decreases LDL,increases HDL Increases mood and energy Decreases wrinkles Decreases homocysteine Increases serotonin formation Decreases depression,anxiety,pain sensitivity

Functions of estrogen

Progesterone Helps the body use estrogen Prevents and treat symptoms of estrogen excess

or deficiency (i.e. vasomotor symptoms) Natural antidepressant Prevents endometrial overgrowth Has receptors in almost every cell of the body Progesterone is needed not only for its balancing

effect on uterine tissue, but also its effect on the breast tissue, heart, brain, bones and its balancing effect on other hormones.

Functions of progesterone

Relief of symptomsGrowth and repairPrevention of memory lossHeart health-improved lipid profilePrevention of osteoporosisQuality of lifeMaintenance of skin healthNeurotransmitter balancePrevention of urogenital atrophy

WHY REPLACE?

Response to widely publicized results from 2002 WHI52% stopped HRT-25% restarted for symptom relief

Suspicion of traditional medicine Dislike of big Pharmaceutical companies Perception it’s a safer alternative “Natural” is equated with safer Wider and more aggressive advertising, via internet and other

media-Oprah phenomenon Patient preference for alternative medicine. Patients still symptomatic on commercial HR products

Why the Surge in Prescriptions for Bioidenticals from Patient P.O.V.?

Bio-identical hormones have a chemical structure identical to human hormones but are chemically synthesized from yams or soy and are identical in composition to human hormones, such as progesterone, estriol,testosterone and estradiol.

Natural – neither artificial nor pathologic They look and behave just as our own natural hormones do. They

will act at our cell receptors and break down in our cells (metabolize) exactly the same way as the estrogen and progesterone naturally made inside our body have always done.

Non-bioidentical hormones are not structurally identical to human hormones and may either be chemically synthesized, such as MPA, or derived from a nonhuman source, such as CEE.

Bioidentical Hormones=Bioequivalent

Chemical substitution with a pharmaceutical drug, only mimics some hormonal functions

Ingredients-50%E1,0.5% E2, 40% Horse equilins While some estrogens are from a natural

source, such as equine urine, they are not considered bioidentical because many of their components are foreign to the human body.

Synthetics- Premarin

Progesterone is the same hormone that is produced and circulates in your body Vital to pregnancy

Progestins are synthetically produced molecules that produce the same effects on the endometrium as progesterone Do not have the same structure May not function the same as progesterone in other

tissues Harmful in pregnancy

Progesterone vs. Progestins

27

Evidence Oral medroxyprogesterone (MPA) and estrogen

Increased incidence of breast cancer versus estrogen alone Increased heart disease

Counteracts the vasodilatation of estradiol Increase in blood clots, C-reactive protein MPA speeds the growth of arterial smooth muscle cells,

whereas progesterone slows this growth Norethindrone did not have the same effect Oral micronized progesterone (Prometrium®)

Produces sedating byproducts Stabilizes and protects the endometrium from estrogen Had less breakthrough bleeding than with MPA Same incidence of uterine cancer between MPA and

progesterone Premarin® alone increased stroke and clots

Progesterone vs. Progestins

28

Side effects- Increased weight Fluid retention Depression Breast tenderness Acne Insomnia Vasospastic Increases LDL

Provera is not progesterone

Prometrium Crinone, Estrace, Divigel, Estradot,Climara

Pro,Oescilim,Estalis Estrogel, Androgel, Testim,Androderm Estring, Vagifem,Estragyn Ovestin-Estriol (OTC, Europe)

Cortef Cytomel (T3) Synthroid (T4)

Patented/Conventional Bio-identical Hormones

Compounded Estrone Estradiol Estriol Progesterone Testosterone DHEA Cortisol T3 T4

Methods of delivery Oral Topical

Creams Gels

Sublingual drops, troches Vaginal/mucous membrane

Cream Suppository

Pellets SQ injection

Bio-identical Hormones

Estrone (E1): Second strongest estrogen Converted from estradiol & released from adrenal glands Main estrogen in menopause-converted from androstenedione in

adipose tissue,liver and skinEstradiol (E2): Strongest estrogen Mainly made from the ovary Formed by testosterone aromatization Primary estrogen in menstrual cycleEstriol (E3): Weakest estrogen, end metabolite of estrogen pathway Dominant in pregnancy Considered possibly protective from more potent proliferative

effects of E1 and E2

Bio-identical Estrogens

Pharmacy compounding – defined by both Ontario College of Pharmacy and Pharmacy industry; its core is the “triad” relationship between the patient, her physician, and the pharmacy which prepares a prescription for that patient only upon receipt of a valid prescription

All pharmacies licensed and inspected-OCP Specialized training All drugs used have certificate of analysis- USP Leave out colourants,additives Provide technical help and expertise on dosing guidelines

Pharmacy compounding

History and symptoms may not be enough Every patient is biochemically unique Get baseline for follow up and optimal balance and treatment Low normal may not be optimal for health Many labs do not have ‘age specific ranges’ FSH-does not measure estrogen Blood: Estradiol,FSH,free and total testosterone

Thyroid Panel -free T4,TSH, free T3, Saliva: estradiol , progesterone, testosterone,

DHEAS, and Cortisol 24 hour Urine

Testing-why test?

Estradiol Can be used alone Compounded into SR capsules,

transdermal, topical & vaginal creams-topical 50-500mcg daily

Start low go slow Priming may be necessary higher dose for

1/12 then decrease

Bio-Identical + Compounded Hormone Replacement

Estriol Blocks the more potent effect of

Estradiol at the receptor Can be given orally-many studies Given alone can help improve urinary

incontinence & vaginal dryness0.05-0.5% vaginal cream 0.5-1g daily x1/12 then prn

Bio-Identical Compounded Hormone Replacement

Bi-Est Estriol/estradiol combination Compounded cream or capsules Offers the benefit of estradiol and the

protective effect of estriol Strength in mg and ratio of the two

estrogens Example: Bi-Est 1.25mg 80:20 = 1.0mg estriol

+ 0.25mg estradiol


Progesterone Topical and oral (Prometrium→) Usual topical dosage is 20-100mg OD-BID, daily Peri menopause cycle days 14- 28 ,or 2 steps day 1-14,day 15-28 Menopause continuous(stop for at least one day) or cycle Oral doses range from 100-400mg daily 1% cream=10mg/g 1g=1/4tsp Progesterone metabolites may cause a tranquilizing effect SOGC does not recommend progesterone cream to provide

endometrial protection Maintain endometrial stripe on U/S<4mm Expect 1-2 periods if starting cyclic progesterone within 6 months of

menopause May cause increase in testosterone


Testosterone: ↑ sense of wellbeing and libido Helps maintain vaginal mucosa, skin

elasticity, muscle mass & heart health Compounded into creams or gels Range 0.05-1%=0.5-10mg Testosterone/ml


Vaginal lubricants

•May be recommended for subjective symptoms

•Do not reverse vaginal atrophy

Are non-physiological

•Give temporary symptom relief, often followed by vaginal irritation

Vaginal Moisturizers and Lubricants

40

• Polycarbophil gel is effective for symptoms of vaginal atrophy

• Improve lubrication

Do not reverse vaginal atrophy

• Are useful for women who cannot take hormones

vaginal moisturizers

41

Restore urogenital physiology

- > Estrogen therapy lowers vaginal pH, thickens the epithelium, increases blood flow, improves vaginal

lubrication- Alleviate symptoms

• > Most women will obtain substantial relief from their symptoms after about 3 weeks of treatment

Some women may require 4–6 weeks before adequate improvement is observed

Principles of local estrogen therapy (supported by NAMS and SOGC)

42

1. Start treatment early,before atrophic changes have occurred. 2. Continued treatment is needed to maintain the benefits. 3.All local estrogen preparations are effective. 4.Patient preference will usually determine the treatment that is used. 5.Additional progestin is not indicated when appropriate

low- dose, local estrogen is used. If estrogen is ineffective or undesired, vaginal lubricants and

moisturizers can relieve symptoms due to dryness.

7.Itisessentialthathealthcareprovidersroutinelyengagein open and sensitive discussions with postmenopausal women to ensure that symptomatic atrophy is detected early and managed appropriately.

IMS Key Treatment Recommendations

43

Dehydroepiandrosterone (DHEA) is an androgen derivative that is available in Canada by prescription only[ It has been evaluated intravaginally for effectiveness in treating VVA and is thought to exert an effect through the androgen and estrogen receptors.The 12-week trials showed improvements in VMI and vaginal pH at 2 dosesV3.25 mg and 13 mg, once daily. It also significantly improved the most bothersome symptoms.

Intravaginal DHEA

44

1 Several selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) decrease the frequency and severity of vasomotor symptoms in postmenopausal women.2 The SSRI paroxetine is the first nonhormonal medication to be government approved for the treatment of vasomotor symptoms. The approved dose (paroxetine 7.5 mg) is lower than the doses of paroxetine approved for the treatment of depression.3 Although randomized, controlled trials demonstrate efficacy greater than placebo for other SSRIs and SNRIs, including venlafaxine and escitalopram, and other doses of paroxetine, these formulations are not currently approved for the treatment of vasomotor symptoms.4 Some SSRIs and SNRIs inhibit the cytochrome P450 enzyme system and may render tamoxifen less effective.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS

45

Applying Hormone CreamsGeneral Tips Absorption is better in moist skin than dry

Shower and pat dry, then apply Absorption is better in thin skin than thick

Apply to soft skin (inner forearm, inner thigh) Apply to a large area Rub in well Consider a 3-5 day break for progesterone every month to decrease

tolerance

Location Testosterone may cause hair growth on the inner thigh Progesterone on the breast may decrease the tissue density Estrogen on the breast can cause proliferation .: avoid Hormone creams applied to the abdomen will be absorbed to the

liver

Compounded BHT may be just as effective as commercial HT

BHT may be safer and as effective as synthetics-although non human not as bad as we thought

Compounded BHT should be just as safe as commercial HT Research often puts all HRT together ,regardless of type or

dosage form used Research supports use of BHRT Topical estrogen over oral estrogen Avoid synthetic progestins More research needed to support optimum dosing and

testing of compounded creams

The Likely Bottom Line on BHRT

All hormones are designed to work together Use same hormones as body produces Be informed and educated Develop a partnership with the pharmacist If one hormone is deficient it affects actions of all

other hormones-thyroid Cortisol Determine each patients needs and goals-stress

nutritional deficiencies Follow up and testing needed One size does not fit all

SUMMARY

Valuable option – Not the Holy Grail Individual pharmacies should produce

consistent product Studies on compounded BHRT usually

terrible-more becoming available Studies by Big Pharma often skew data Too many people who are involved don’t

know enough (public & professionals)

My perspective on Compounded BHRT

44 yo female Pmh-tah,b/o 2006 Rx-ogen3mg daily,oxycocet prn, c/o insomnia,low libido,low energy,25lb weight gain,night

sweats,hot flashes,mood swings,migraine headaches, Labs-free testosterone,<0.5,estradiol 49 Tx-Prometrium 100mg po hs,testosterone 5mg topically,Bi-est

1.5mg daily topically f/up estradiol 107,free T 5

sleep improved,weight decrease,mood better,d/c Ogen,night sweats rare,hot flashes one every 2-3 weeks,no headaches,’DID NOT THINK THIS WOULD WORK”

Patient case

20 August 2006

Patient Case Study

KE 34 yo female 5’3” 140lbs Symptoms-

– Insomnia, weight gain, anxiety, hot flashes, painful intercourse, mood swings

– Goals & priorities-I want to feel as good as I possibly can without synthetic hormones

Medical hx-TAH BSO hypothyroid, interstitial cystitis, endometriosis, arthritis

Medications-Thyroxine, Premarin

Vitamins-Multivitamin Lifestyles-

– Exercise-Pilates, walking, outdoor sports

– Smoking-quit 1994(8yrs)– Alcohol-social– Caffeine-occasionally

Family hx- mother ovarian cancer, diabetes (uncles)

20 August 2006

Lab Results & Treatment Recommendations

28/05/05-– TSH=6.00,E2=389,DHEA-S=2.4– Restart thyroxine

11/09/05-– Free T <1,Total T=4.7,P=1.09– Tx-testosterone 1.0% 1ml daily– Progesterone 200mg daily

9/01/06-– E2=107,TSH=3.35,free T=4.0

Pt reports a world of difference ,lost 12lbs,no naps ,less joint aches ,some breast tenderness

Decrease Premarin to 1 every other day

02/02/06-– E2=79,free T=4.9,P=41.4

07/04/06-– Pt c/o skin breakouts– Decrease T to every other day, add

saw palmetto 2 x a week

22/06/06– Pt c/o some decreased libido– TSH=2.17,E2=138,P=12.5,Free T=2.0– Replace Premarin with Biest (80/20)

1.0mg bid topically, Testosterone 1% 1.0ml daily/alternating with 0.5mls

Health & Medicine

menopause and hormone replacement therapy hrt (1)