Transcript Hormone Replacement Therapy October, 2003

Managing Menopausal Issues:
Options for Therapy
Jan Shepherd, MD, FACOG
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.
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?
Current Options for HT
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
Fertil Steril 2001;75:1065.
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)
Premarin
(Conjugated Equine Estrogens
from PREgnant MARe’s urINe)
•
•
•
•
•
•
Sodium estrone sulfate - 50-60%
Sodium equilin sulfate - 22.5-32.5%
17α - dihydro equilin sulfate
Estradiol sulfate
17α - dihydro equilenin sulfate
Sodium equilenin sulfate
Novel Delivery Systems
• Estrogen-only and combination patches
• Systemic therapy vaginal ring (Femring)
• Gel, cream, mist
• All contain estradiol
• Provide steady blood levels
Transdermal vs Oral Estrogen
Oral
Transdermal
Stomach / Intestines
Bloodstream
Liver
Cells of
target tissues
Filer WD, Filer RB. Am Fam Physician. 1994;49:1639-1644.
Liver proteins
 SHBG  TG
 C-reactive protein
 Antithrombin III
 Factors VII, X
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)
Progestins
• In increasing order of
potency
– Micronized progesterone*
(Prometrium)
– Norgestimate (Prefest)
– Norethindrone acetate
(Aygestin, Activella,
Femhrt)
– Medroxyprogesterone
acetate (MPA, Provera)
Hormone
Relative
Potency
Progesterone
1.0
19-nortestosterone
5.6
MPA
8.1
* May be associated with
less risk of breast cancer
* J Clin Onc 2008;26:1260-8.
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)
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.
Comparison of Pharmaceutical HT
with “Bioidentical” HT
Characteristic
“Bioidentical” HT
Pharmaceutical 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
Santen, R. J. et al. J Clin Endocrinol Metab 2010;95:s1-s66.
Other Pharmacologic Options
•
•
•
•
Statins and other lipid-lowering agents
Bisphosphonates
Centrally-acting meds for hot flashes
Raloxifene – a SERM
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 5’4”, wt 135#.
Vitamin D 24 ng/ml. All other labs
normal. How will you manage?
Treating with Bisphosphonates
• Treat If T score < -2.5 or < -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 > 20%
– 10-year probability of hip fracture > 3%
• Re-evaluate at 5 years  drug holiday if:
– Risk factors low
– T score > -2.5
– Pt agrees to repeat DEXA in 2 years
http://www.sheffield.ac.uk/FRAX/tool
.jsp?country=9
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
*J Bone Miner Res 2009;24:153-61.
A 50 year old g1p1, LMP 1 year
ago, history of DVT in pregnancy,
presents with severe hot flashes.
Medications for Hot Flashes
(Off-label)
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?
Raloxifene (Evista®)
• Antagonist
– Breast
– Endometrium
– Hypothalamus
• Agonist
– Bone
– Liver
• Lipids
• Coagulation factors
Raloxifene
• Indications*
– Prevention and treatment of osteoporosis
– Prevention of invasive breast cancer
• Dosage - 60 mg/day
*Only in Postmenopausal women
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
Raloxifene - Risks
•
•
•
•
•
 DVT/VTE
↑ Risk of stroke
Cause or increase hot flashes
No effect on vaginal symptoms
May cause leg cramps
Coming Soon – TSECS (Aprela®)
Tissue Selective Estrogen Complexes
• A SERM (bazedoxiphene) plus conjugated estrogens
• Concept
– Antagonist to estrogen’s effects on breast and
endometrium
– Preserves estrogen’s effects on symptoms and bone
• Additional effects studied
– DVT/PE risk = oral estrogen alone
–  LDL,  HDL , but  triglycerides
– No effect on C-reactive protein
Alternative Therapies
• Acupuncture
• Phytoestrogens
– Soy
– Red clover
• Black cohosh
• Ginseng, ginkgo
• Omega-3 fatty acids
• Vitamin E

None proven superior to placebo
Lifestyle Interventions
Lifestyle Interventions
•
•
•
•
Cooler environment
Weight loss
Smoking cessation
Aerobic exercise
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