Managing Menopausal Issues: Options for Therapy

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Managing Menopausal IssuesOptions for Therapy

• Jan Shepherd, MD, FACOG

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Objectives

• Compare and contrast contemporary pharmacologic
  options for HT.
• Compare the pharmacology of oral HT to that of
  transdermal delivery systems.
• Identify options for management of menopausal
  issues with agents other than HT.

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A 52 year-old Caucasian female, LMP 6 months ago,
presents with significant hot flashes interfering
with her daily activities and sleep. She has
read that HT can cause breast cancer and heart
attacks. If you and she decide on HT, what is
your initial choice for therapy?
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Current Options for HT
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Lower-Dose HT

• Effective
• Reduces symptoms
• Protects bone
• Improved acceptance and safety
• Lower rate of breakthrough bleeding
• Fewer side effects
• Requires less progestin
• ? Decreased risk

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Oral Estrogens(in increasing order of potency)

• estrone (Ogen, Ortho-Est)
• estradiol (Estrace, Prefest, Activella,
  Angelique, transdermal/vaginal preparations)
• conjugated estrogens (Premarin, Prempro,
  Premphase, Cenestin, Estratab, Menest, Enjuvia)
• ethinyl estradiol (Femhrt, oral contraceptives)

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Premarin (Conjugated Equine Estrogens
from PREgnant MARes urINe)

• Sodium estrone sulfate - 50-60
• Sodium equilin sulfate - 22.5-32.5
• 17a - dihydro equilin sulfate
• Estradiol sulfate
• 17a - dihydro equilenin sulfate
• Sodium equilenin sulfate

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Novel Delivery Systems

• Estrogen-only and combination patches
• Systemic therapy vaginal ring (Femring)
• Gel, cream, mist
• All contain estradiol
• Provide steady blood levels

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Transdermal vs Oral Estrogen
Oral
Transdermal
Stomach / Intestines
Bloodstream
Liver
Cells of target tissues
Liver proteins

• SHBG
• C-reactive protein? Antithrombin III
• Factors VII, X

? TG
Filer WD, Filer RB. Am Fam Physician.
1994491639-1644.
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Vaginal Preparations

• Minimal blood levels
• Used if vaginal dryness is only symptom
• Preparations
• Premarin cream
• Estradiol cream, tablets (10 µg. lower dose now
  available)
• Estring (3-month low-dose estradiol vaginal ring)

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Progestins

• In increasing order of potency
• Micronized progesterone (Prometrium)
• Norgestimate (Prefest)
• Norethindrone acetate (Aygestin, Activella,
  Femhrt)
• Medroxyprogesterone acetate (MPA, Provera)
• May be associated with less risk of breast
  cancer

Hormone Relative Potency
Progesterone 1.0
19-nor- testosterone 5.6
MPA 8.1
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Continuous Combined Preparations

• PremPro (Premarin Provera)
• Activella (estradiol norethindrone acetate)
• Prefest (estradiol norgestimate)
• Femhrt (ethinyl estradiol norethindrone
  acetate)
• Angeliq (estradiol drospirenone)
• Patches (estradiol norethindrone acetate or
  levonorgestrel)

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A 54 year-old female presents with persistent hot
flashes on PremPro .625. Requests you check a
salivary estriol level and prescribe
bio-identical hormones based on the result.
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Comparison of Pharmaceutical HT with
Bioidentical HT
Characteristic Pharmaceutical HT Bioidentical HT
Molecular structure Similar or identical to human Identical to human
FDA oversight Yes No
Dosage Monitored, accurate consistent Not monitored may be inaccurate inconsistent
Purity Monitored pure Not monitored may be impure
Safety Tested risks known Not FDA tested risks unknown
Efficacy Tested proven Not FDA tested unproven
Scientific Evidence Existent conclusive Insufficient
Potency 67.5 to 268.4 of label in FDA study
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Other Pharmacologic Options

• Statins and other lipid-lowering agents
• Bisphosphonates
• Centrally-acting meds for hot flashes
• Raloxifene a SERM

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60-year old g3p3, LMP age 50. No menopausal
symptoms. At Health Fair, T score -1.5. No
personal or FH of fractures. On HCTZ for bp,
otherwise healthy. Nonsmoker, nondrinker. Ht
54, wt 135. Vitamin D 24 ng/ml. All other
labs normal. How will you manage?
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Treating with Bisphosphonates

• Treat If T score lt -2.5 or lt -1.5 with history of
  fracture
• If T score -1.0 to -2.5 (no fracture), treat if
  FRAX score
• 10-year probability of major osteoporotic
  fracture gt 20
• 10-year probability of hip fracture gt 3
• Re-evaluate at 5 years ? drug holiday if
• Risk factors low
• T score gt -2.5
• Pt agrees to repeat DEXA in 2 years

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http//www.sheffield.ac.uk/FRAX/tool.jsp?country9
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New Denosumab (Prolia)

• Monoclonal antibody against RANKL (cytokine
  leading to formation and activation of
  osteoclasts)
• 60 mg subq q 6 months
• Rapid response, more effective than alendronate
• Rapid loss of effect when stopped
• Adverse events incidence similar to alendronate
• Indicated for osteoporotic pts at high risk of
  fracture

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A 50 year old g1p1, LMP 1 year ago, history of
DVT in pregnancy, presents with severe hot
flashes.
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Medications for Hot Flashes(Off-label)
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• A 54 year old on tamoxifen after lumpectomy,
  radiation, and chemotherapy for ER breast
  cancer presents with severe hot flashes. How
  will you treat?
• What if she presents with only severe vaginal
  dryness/dyspareunia?

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Raloxifene (Evista)

• Antagonist
• Breast
• Endometrium
• Hypothalamus
• Agonist
• Bone
• Liver
• Lipids
• Coagulation factors

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Raloxifene

• Indications
• Prevention and treatment of osteoporosis
• Prevention of invasive breast cancer
• Dosage - 60 mg/day

Only in Postmenopausal women
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Raloxifene - Benefits

• Prevention and treatment of osteoporosis
• 2-3 increase in bone mineral density
• 30-50 reduction in vertebral fracture risk
• 44-71 reduction in invasive breast cancer
• ? incidence of endometrial cancer
• Positive effect on lipid profile
• ? triglycerides, ? LDL, no effect on HDL
• Not shown to ? cardiovascular mortality

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Raloxifene - Risks

• ? DVT/VTE
• ? Risk of stroke
• Cause or increase hot flashes
• No effect on vaginal symptoms
• May cause leg cramps

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Coming Soon TSECS (Aprela)Tissue Selective
Estrogen Complexes

• A SERM (bazedoxiphene) plus conjugated estrogens
• Concept
• Antagonist to estrogens effects on breast and
  endometrium
• Preserves estrogens effects on symptoms and bone
• Additional effects studied
• DVT/PE risk oral estrogen alone
• ? LDL, ? HDL , but ? triglycerides
• No effect on C-reactive protein

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Alternative Therapies

• Acupuncture
• Phytoestrogens
• Soy
• Red clover
• Black cohosh
• Ginseng, ginkgo
• Omega-3 fatty acids
• Vitamin E
• ?
• None proven superior to placebo

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Lifestyle Interventions
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Lifestyle Interventions

• Cooler environment
• Weight loss
• Smoking cessation
• Aerobic exercise

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3 Most Important Health Measures for
Postmenopausal Women

• Weight-bearing exercise
• Low-fat diet rich in fruits and vegetables
• Calcium 1000-1200 mg/day vitamin D 800-1000
  IU/day