Managing Menopausal Issues:Managing Menopausal Issues:Options for TherapyOptions for Therapy

Jan Shepherd, MD, FACOGJan Shepherd, MD, FACOG

ObjectivesObjectives

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

Current Options for HTCurrent Options for HT

Fertil Steril 2001;75:1065.Fertil Steril 2001;75:1065.

Lower-Dose HTLower-Dose HT

• Effective– Reduces symptoms– Protects bone

• Improved acceptance and safety– Lower rate of breakthrough bleeding– Fewer side effects– Requires less progestin– ? Decreased risk

Oral EstrogensOral Estrogens((in increasing order of potencyin 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)

PremarinPremarin (Conjugated Equine Estrogens (Conjugated Equine Estrogens from PREgnant MARe’s urINe)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 SystemsNovel 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 EstrogenTransdermal vs Oral Estrogen

Bloodstream

Oral

Liver

Liver proteins SHBG C-reactive protein Antithrombin III Factors VII, X

Cells of target tissues

Transdermal

Stomach / Intestines

Filer WD, Filer RB. Am Fam Physician. 1994;49:1639-1644.

TG

Vaginal PreparationsVaginal 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)

ProgestinsProgestins

• 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

PotencyProgesterone 1.0

19-nor- testosterone

5.6

MPA 8.1

* J Clin Onc 2008;26:1260-8.* J Clin Onc 2008;26:1260-8.

Continuous Combined PreparationsContinuous 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 A 54 year-old female presents with persistent hot flashes on with persistent hot flashes on PremPro .625. Requests you PremPro .625. Requests you check a salivary estriol level and check a salivary estriol level and prescribe “bio-identical” prescribe “bio-identical” hormones based on the result.hormones based on the result.

Comparison of Pharmaceutical HT Comparison of Pharmaceutical HT with “Bioidentical” HTwith “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

Santen, R. J. et al. J Clin Endocrinol Metab 2010;95:s1-s66.Santen, R. J. et al. J Clin Endocrinol Metab 2010;95:s1-s66.

*Potency 67.5% to 268.4% of label in FDA study

Other Pharmacologic OptionsOther 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 60-year old g3p3, LMP age 50. No menopausal symptoms. At Health menopausal symptoms. At Health Fair, T score -1.5. No personal or Fair, T score -1.5. No personal or FH of fractures. On HCTZ for bp, FH of fractures. On HCTZ for bp, otherwise healthy. Nonsmoker, otherwise healthy. Nonsmoker, nondrinker. Ht 5’4”, wt 135nondrinker. Ht 5’4”, wt 135##. . Vitamin D 24 ng/ml. All other labs Vitamin D 24 ng/ml. All other labs normal. How will you manage? normal. How will you manage?

Treating with BisphosphonatesTreating 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

NewNew – Denosumab (Prolia®) – 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. *J Bone Miner Res 2009;24:153-61.

A 50 year old g1p1, LMP 1 year A 50 year old g1p1, LMP 1 year ago, history of DVT in pregnancy, ago, history of DVT in pregnancy, presents with severe hot flashes. presents with severe hot flashes.

Medications for Hot FlashesMedications for Hot Flashes(Off-label)(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®)Raloxifene (Evista®)

• Antagonist– Breast– Endometrium– Hypothalamus

• Agonist– Bone– Liver

• Lipids• Coagulation factors

RaloxifeneRaloxifene

• Indications*– Prevention and treatment of osteoporosis– Prevention of invasive breast cancer

• Dosage - 60 mg/day

*Only in Postmenopausal women

Raloxifene - BenefitsRaloxifene - 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 - RisksRaloxifene - Risks

DVT/VTE

• ↑ Risk of stroke

• Cause or increase hot flashes

• No effect on vaginal symptoms

• May cause leg cramps

Coming Soon Coming Soon – TSECS (Aprela®)– TSECS (Aprela®)Tissue Selective Estrogen ComplexesTissue 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 TherapiesAlternative Therapies

• Acupuncture• Phytoestrogens

– Soy– Red clover

• Black cohosh• Ginseng, ginkgo• Omega-3 fatty acids• Vitamin E

None proven superior to placebo

Lifestyle InterventionsLifestyle Interventions

Lifestyle InterventionsLifestyle Interventions

• Cooler environment

• Weight loss

• Smoking cessation

• Aerobic exercise

3 Most Important Health Measures 3 Most Important Health Measures for Postmenopausal Womenfor Postmenopausal Women

• Weight-bearing exercise

• Low-fat diet rich in fruits and vegetables

• Calcium 1000-1200 mg/day & vitamin D 800-1000 IU/day