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Male & Female HRT Risks, Successes, the Future?
Teresa Bailey, PharmD, BCPS, BCACP, FCCP
June 2015
Objectives
 Explain the association of testosterone therapy with mortality, myocardial infarction,
and stroke in men with low testosterone levels.
 Discuss the potential benefits of hormone replacement therapy in women
 Discuss the pros and cons of dehydroepiandrosterone for peri- and postmenopausal
women.
Pathophysiology
 Menopause
o Loss of ovarian function leading to a state of permanent amenorrhea
o Ovaries no longer able to respond to pituitary stimulating hormones, so estrogen levels
are low and production of FSH and LH increases dramatically.
o Average age of onset-51.4 years
o Onset unaffected by: race, socioeconomic status, alcohol consumption, age of
menarche, or age of last pregnancy. Cigarette smoking may accelerate onset up to 2
years because of gametotoxic effects of cigarette smoke on steroid hormone
metabolism by liver.
o Premature menopause-loss of ovarian function before the age of 35 years due to
ovarian surgery, endocrinologic, autoimmune disorders
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Estrogen and Progestin Therapy
Benefits and Risks of Estrogen and Progestin Therapy (Ann Intern Med 1992;117(12):10381041)
Benefits
Estrogen
1. Relieves genitourinary atrophy
Thinning of hair of the mons and
shrinkage of the labia minora
Atrophy of vulva leads to pruritus and pain
Vaginal pH 4.55  68 creating a
favorable environment for bacterial
colonization
Loss of lubrication  dyspareunia
Recurrent episodes of urinary frequency
and urgency with dysuria
2. Relieves vasomotor instability
Occurs in 75%–85% of women.
Occurs usually within 12–24 months after
the last menstrual period.
Increased skin temperature, nausea,
dizziness, headache, palpitations,
diaphoresis, night sweats.
3. Osteoporosis-Reduction of hip fractures by
25%. Reduction of vertebral fractures by
50%. Estrogen reduces rate of resorption
but does not restore bone loss.
Progestin
1. Decrease risk of estrogen-induced
irregular bleeding, endometrial
hyperplasia, and carcinoma
2. Protection against breast carcinoma
3. Enhancement of estrogen prophylaxis
of osteoporosis
4. Lowers LDL cholesterol by 11% and
increases HDL cholesterol by 10%.
However, was not shown to lower
coronary heart disease based on HERS
trial.
5. Increase in life expectancy
6. Insomnia and fatigue
7. Mood changes
8. Sexual function
Risks
Estrogen
1. Endometrial cancer by unopposed estrogen.
Duration of estrogen use dependent; eightfold for 10–20 years of use.
Recommended not to use in women with a
history of endometrial cancer.
2. Breast cancer with unopposed estrogenuncertain. May increase slightly (25%)
among women who take estrogen for
1020 years. Recommended not to use in
women with a history of breast cancer.
3. Increased risk of cardiovascular outcomes.
(See WHI trial).
4. Adverse effects: bloating, headache, breast
tenderness (5–10%)
5. Unpredictable uterine bleeding with
unopposed estrogen (35–40%)
Progestin
1. Adverse effects: bloating, weight gain,
irritability, depression. (Dose related)
2. Unpredictable endometrial bleeding with
continuous estrogen/progestin during
first 8–12 months (30–50%)
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Contraindications of HRT
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Undiagnosed abnormal genital bleeding
Known, suspected, or history of breast cancer
Known or suspected estrogen-dependent neoplasia
Active DVT, PE, or a history of these conditions
Active arterial thromboembolic disease (stroke and MI), or a history of these conditions
Known anaphylactic reaction or angioedema to estrogens/progestins
Known liver dysfunction or disease
Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
Known or suspected pregnancy
Efficacy on Coronary Artery Disease (JAMA 1998;280:605-613) WHI Trial: Efficacy on Coronary
Artery Disease (NIH News Release NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased
Breast Cancer Risk, Lack of Overall Benefit. www.nhlbi.nih.gov/new/press/02-07-09.htm)
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Objective: HRT alter risk for coronary heart disease in postmenopausal women with established
coronary disease
Methods
o R, DB, PC, 20 US center. Follow-up x 4.1 years
o N=2763 women < 80 years old with established coronary disease
o Treatment: Prempro 0.625/2.5 QD versus placebo
Results
o Baseline characteristics similar
o Cardiovascular Outcomes
Outcomes
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Primary CHD events
29% increase
Stroke/TIA
41% increase
Deep vein thrombosis
50% increase
Breast cancer
26% increase
Hip fracture
33% decrease
Any fracture
24% decrease
Colorectal cancer
37% decrease
Longer duration of use  greater  in relative hazards in nonfatal MI and CHD death
Hormone Therapy for Preventing Cardiovascular Disease in Post-menopausal Women. Cochrane
Review 2015
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19 studies reviewed
N = 40,410 post-menopausal women
For primary or secondary prevention of cardiovascular disease events
Results
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No protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial
infarction, angina, or revascularization
Increased risk
 Stroke (NNH = 165)
 Venous thromboembolism (NNH = 118)
 Pulmonary emboli (NNH = 242)
 Greater risk when taking > 10 years
Benefits and Risks of Estrogen and Progestin Therapy Ann Intern Med. 2013;158:47-54.
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Treatment Algorithm of Menopause
Pharmacotherapy: A Pathophysiologic Approach, 9e
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey
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Conjugated Estrogens/Bazedoxifene (Duavee)
• Indications
o Treatment of moderate/severe vasomotor symptoms associated with menopause
o Prevention of osteoporosis in postmenopausal women with a uterus
• Bazedoxifene: SERM
o Reduces risk of endometrial hyperplasia
• Dose: 0.45 mg/20 mg daily
• Similar precautions to estrogen/progestin
• Amenorrhea at 1 year: 83-88%
Bioidentical Hormones
 “Natural” identical to hormones in the body
 Claim to be safer than prescription hormones
 Patient and provider testimonies
 Estradiol -More stimulating to breast
 Estrone -Stimulating to breast
 Estriol -More active on vagina, cervix, and vulva; Least stimulating to breast
 Side Effects
o May have less side effects than synthetic estrogens
o Breast tenderness/fullness, edema, headaches
 Dosage
o Estrace 1 mg daily
o Estraderm patch 0.05 mg twice weekly
o Estrone 10%, estradiol 10%, estriol 80%
o Estriol cream 0.5mg/gram
Testosterone for peri and postmenopausal women. Cochrane Database of Systematic Reviews 2005
• Whether testosterone is safe and effective to add to HRT for postmenopausal women
• 35 trials (4768 participants)
• Variety of testosterone formulations
• Duration was six months (range 1.5 to 24 months)
• Results
o Sexual function scores improved
o Number of satisfying sexual episodes increased
o Adverse effects
 HDL cholesterol levels decreased
 Hair growth and acne increased
DHEA
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Purported Use
o Anti-aging, anti-cancer, anti-obesity, cholesterol, arthritis, fatigue, diabetes, Alzheimer’s,
AIDS, osteoporosis
Mechanism of Action
o Adrenal steroid that is precursor to other steroids (estrogen, androgen)
o Has no estrogenic and androgenic effects
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NEJM 1999;341:1013-20.
o Randomized, double-blind, placebo, crossover
o 24 women with adrenal insufficiency
o DHEA 50 mg QAM x 4 months
o Steroid and sex hormones
 DHEA, androstenedione, testosterone, dihydrotestosterone increased to normal
levels*
 Estrone and estradiol: no change
o Serum Lipids
 Total cholesterol and HDL: decreased*
 LDL and triglycerides: no change
o Well-being
 90-Item Symptom Checklist for depression, anxiety, obsessive-compulsive,
hostility*
 Multidimensional Mood Questionnaire improved*
 Hospital Anxiety and Depression Scale improved*
o Sexuality
 Frequency of sexual thoughts*
 Degree of sexual interest*
 Level of mental satisfaction with sex*
 Level of physical satisfaction with sex*
DHEA for Women in the Peri- or Postmenopausal Phase. Cochrane Review 2015
Evaluate the safety and efficacy of DHEA to women with menopausal symptoms in the peri- or
postmenopausal phase
o 28 trials
o N = 1,273 menopausal women
o Compared to placebo
 No improvement of quality of life
 Increased androgenic side effects (acne)
 Unclear whether DHEA affected menopausal symptoms
 Improved sexual function
 Similar results with oral or topical
o Insufficient data to compare to HRT
Dehydroepiandrosterone supplementation in elderly men: a meta-analysis study of placebocontrolled trials.J Clin Endocrinol Metab. 2013 Sep;98(9):3615-26
o 25 studies (1353 elderly men)
o Mean duration 36 weeks
o Results
 No effect of DHEA supplementation in comparison with placebo
 Lipid and glycemic metabolism
 Bone health
 Sexual function
 Quality of life
Contraindications/Precautions
o Breast, uterine, or ovarian cancer
o Prostate cancer
o Pregnancy/Lactation
o Liver impairment
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o Diabetes (increased insulin resistance)
o Hyperlipidemia (decreased HDL)
o Polycystic ovary syndrome may worsen
Drug Interactions
o Aromatase inhibitors
 Anastrozole, exemestane, letrozole
 DHEA may interfere
o Corticosteroids (suppress DHEA production)
o Fulvestrant [Faslodex] (DHEA may interfere)
o Tamoxifen (DHEA may interfere)
o CYP 3A4
 Triazolam concentrations increase
o Insulin may decrease DHEA effectiveness
Side Effects
o Dose related
o Masculinization in females
o Voice deepening
o Insomnia
o Hirsutism or hair loss
o Oily skin/acne
o Menstrual irregularities
o Headaches
o Insulin resistance
o Hepatic dysfunction
o Abdominal pain
o Hypertension
o Mania
o Long-term side effects are unknown
o Study duration 1-2 yrs
Testosterone Deficiency
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Other terminology
o Androgen Deficiency Syndrome
o Hypogonadism
o Male Menopause
Total testosterone level < 300 ng/dL
Typically 1% decline/year after 30 years old
20% men > 70 years old: hypogonadism
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Signs/symptoms
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Benefits
o Improved libido
o Improved mood and cognition
o Reduced fat mass
o Increased lean body mass
o Increased body muscle strength
o Increased aerobic endurance
o Improved insulin resistance in DM
o Increased BMD
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Potential Risks
o Acne
o Male pattern baldness
o Gynecomastia
o Worsen sleep apnea (excessive doses)
o Stimulate BPH symptoms
o Affect metastatic prostate and breast cancers
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Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with
Low Testosterone Levels. JAMA 2013:310:1829-1836
o Retrospective, cohort study
o 23,173 male veterans underwent coronary angiography and had testosterone level checked
o Testosterone level 300 ng/dL
o Rx for testosterone gel (1%), patch (63%), or injection (36%)
o Association between TT with all-cause mortality, myocardial infarction, stroke
o N = 8,709 men with Testosterone level < 300 ng/dL with or without CAD
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Primary endpoint
 Combined end point of time to all-cause mortality or to hospitalization for MI or
ischemic stroke
 HR = 1.29 (CI, 1.05-1.58)
 Regardless of presence of CAD
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AUA Position Statement
o Potential for misuse of testosterone for non-medical indications, such as body building or
performance enhancement
o Testosterone therapy appropriate treatment for hypogonadism after full discussion of potential
adverse effects
o Testosterone therapy in the absence of hypogonadism not appropriate
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Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59
o Treatment of androgen deficiency with testosterone
o Men with sexual dysfunction
o Patients with chronic illness and low testosterone levels
o Glucocorticoid-treated men
o Older men with low serum testosterone concentration-not recommended
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Conclusion
o Risks may outweigh the benefits for
 Estrogen/progestin therapy
 Testosterone replacement therapy
 DHEA
o Studies lacking
 Bioidentical hormones
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Appendix. Products and Dosing of Estrogens and Progestins for Hormone Replacement
Oral Estrogen Products
Generic Name
Conjugated estrogens, natural source
Synthetic A
Synthetic B
Conjugated estrogens/medroxyprogesterone acetate
Conjugated estrogens/medroxyprogesterone acetate
Brand Name
Premarin
Cenestin
Enjuvia®
Prempro
Premphase
Dose
0.03–1.25 mg/da
0.625 mg/2.5 mg/day
0.625 mg/d for 14 days, then 0.625 mg/5
mg per day for 14 days
Estrace
generics
Esterified estrogens
0.3–1.25 mg/da
Menest
Estropipate
0.75–6 mg/da
Ortho-Est
generics
Estradiol/norgestimate
One daily
Prefest
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Estradiol/norethindrone acetate
One daily
Activella
Mimvey
generics
Ethinyl estradiol/norethindrone acetate
One daily
Femhrt 1/5
Jintelli
a
May administer continuously or cyclically with 3 weeks of daily estrogen followed by 1 week off.
Estradiol
Vaginal Estrogen Products
Generic Name
Micronized estradiol
Conjugated estrogens
Estradiol
Estradiol
Brand Name
Estrace
Dose
One dose daily x 2 weeks, then ½ dose daily x
2 weeks, then one full dose 1–3 times/week for
3 weeks
1.25–2.5 mg daily for 3 weeks
One ring Q 3 months
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Premarin
Estring
Femring
Vagifem
Transdermal Estrogen Products
Generic Name
Estradiol patch
Estradiol patch 0.014 mg
Estradiol dot patch 0.0375mg, 0.05 mg,
0.075 mg, 0.1 mg
Estradiol/norethindrone acetate
Estradiol emulsion
Estradiol gel
Estradiol gel packet
Estradiol gel
Estradiol spray
One vaginal tablet twice weekly
Brand Name
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Alora
Climara
generics
Menostar
Vivelle Dot
Minivelle
Combipatch
Estrasorb
EstraGel
Divigel
Elestrin
Evamist
Dose
0.05–0.1 mg patch twice weekly
0.014 mg patch weekly
One patch twice weekly
One patch twice weekly
Apply 3.48 g to skin daily
Apply 1.25 g daily
Apply 1 packet daily
Apply 1-2 pumps daily
Apply 1-3 sprays daily
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Oral Progestin Products
Generic Name
Medroxyprogesterone acetate
Norethindrone Acetate
Progesterone
Brand Name
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Provera
Cycrin
generics
Aygestin
generics
Prometrium
generics
Dose
5–10 mg daily for 5 to 10 days
2.5–10 mg daily for 15 days
100mg 2 daily for 12 days
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Dosing and Products of Testosterone Replacement. Colquitt CW, Robertson GL. Testosterone
Deficiency. US Pharm 2012;37:34-8.