ISSUES IN CLINICAL PRACTICE
| THERAPEUTIC USES OF TESTOSTERONE IN WOMEN —Norman A. Mazer, MD, PhD, Associate Professor of Medicine,
Boston University School of Medicine, Section of Endocrinology, Diabetes, and Nutrition, and Director, Androgen
Clinical Research Unit, Boston Medical Center, Boston, MA
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| Testosterone production in women: healthy young women produce ≈300 µg/day (≈5% of amount produced by
healthy men); 50% of testosterone comes from ovaries (in premenopausal women) and 50% comes from adrenal glands;
production regulated by luteinizing hormone (LH) and corticotropin; levels decrease during fourth and fifth decades of
life (30s and 40s), but do not decrease substantially during menopause or perimenopause (ie, decrease in testosterone related
to age but not specifically to menopause); pathways—estrogen provides negative feedback for hypothalamic-pituitary-ovarian
axis; cortisol provides negative feedback for hypothalamic-pituitary-adrenal axis; ovaries and adrenal
glands produce testosterone and androgen precursors (converted peripherally), but testosterone does not stimulate negative
feedback in brain
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| Androgen deficiency in women: oophorectomy—without estrogen to inhibit pituitary secretion of LH and FSH, these
hormones accumulate at high levels in blood; testosterone declines by ≈50%; adrenal dysfunction—testosterone declines
by ≈50%; pituitary dysfunction—greatest effect on production of testosterone; study showed 40% of women had
undetectable levels
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 | Pharmacologic causes of androgen deficiency: adrenal suppression—corticosteroid treatment (eg, for asthma, rheumatoid
arthritis) suppresses adrenal production of testosterone; study showed similar results in healthy young women taking exogenous
corticosteroids (dexamethasone); ovarian suppression—oral contraceptives (exogenous estradiol or ethinyl estradiol)
suppress secretion of LH, resulting in decreased production of estrogen and androgens
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| Aging: population data (premenopausal women, 20-50 yr of age) show steady decline in dehydroepiandrosterone (DHEA;
primarily effect of diminished adrenal function); decline in testosterone stops (and may slightly reverse) after menopause
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| Other causes of decreased production of androgens: premature ovarian failure; HIV infection; opioid use in treatment of
chronic pain
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| Actions of testosterone in women: stimulates pubertal development (voice lowering, body hair, and genital development);
increases sexual function (involved with arousal and orgasm); stimulates muscle development and strength, bone
density (possibly due to conversion to estrogen), and erythropoiesis; affects energy levels, cognitive function, and feeling
of well-being (natural antidepressant in men); stimulates production of oil and sweat; involved with hair loss (rare in
women); associated with down-regulation of autoimmune response (eg, DHEA beneficial in women with lupus); stimulates
activity of lacrimal and meibomian glands (lubricate eyes); may protect breast tissue (observational study suggests
that addition of testosterone to estrogen therapy reduces risk for breast cancer compared to estrogen alone)
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| Diagnosis of androgen definiency: cardinal symptoms—dysphoric mood or diminished sense of well-being; persistent,
unexplained fatigue; changes in sexual function (eg, decreased libido, sexual receptivity, and pleasure); bone loss;
decreased muscle strength; changes in cognition and memory; measurement of testosterone—no standardized lower
limit to define deficiency in women; assays less accurate at levels that occur in women; free testosterone (focus of therapy)
difficult to measure directly; women of reproductive age considered androgen-deficient if free testosterone in lower
quartile of normal range; total testosterone less useful measure because of wide variation in sex hormone binding globulin
(SHBG) levels; androgen status best assessed by equilibrium dialysis measurement or calculated free testosterone; relative
deficiency occurs when free testosterone <3.5 pg/mL; absolute deficiency occurs when free testosterone <1.3 pg/
mL (often seen in oophorectomized women)
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| Treatment: no treatment approved by Food and Drug Administration (FDA) for female sexual dysfunction, but androgens
commonly used; esterified estrogens and methyltestosterone (eg, Estratest)—testosterone derivative, acts on androgen
receptor and may increase bioavailability of estrogen by lowering level of SHBG; intramuscular injections—testosterone
ester peripherally converted to testosterone; formulations developed for men; 25 mg given every 4 wk typically increases
testosterone production to twice normal physiologic level in women; DHEA—oral formulation available without prescription;
50-mg dose raises testosterone by ≈25 ng/dL and has effects on lipoproteins, cholesterol, and SHBG; compounded
testosterone creams and gels—variable formulations and doses; ≈10% of drug absorbed
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| Testosterone transdermal system (investigational): patch applied twice weekly; formulations available in 150-
µg/day and 300-µg/day doses; pharmacokinetics—study with 11 oophorectomized women with no exogenous estrogen
and low total testosterone at baseline; testosterone rose to upper level of normal range, then leveled off during 4
days of treatment ( quickly fell after patch removed); similar pattern seen in free testosterone levels
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| Phase 2 trial: 75 surgically menopausal women, 31 to 56 yr of age with low testosterone and impaired sexual function not
relieved by estrogen therapy (receiving oral conjugated equine estrogen); double-blind 3-way crossover design looked at
effects of placebo and testosterone (150 µg/day and 300 µg/day); treatment associated with increase in total and free testosterone
(total testosterone elevated, partly due to increase in SHBG caused by oral estrogen therapy) and increase in
sexual function (frequency of sexual fantasies and masturbation, little placebo effect; significant placebo effect seen on
frequency of sexual intercourse); measure of psychologic well-being increased in dose-responsive manner
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| Phase 3 trials: multicenter study of \>1000 surgically menopausal women with hypoactive sexual desire disorder (persistent
or recurrent deficiency or absence of sexual fantasies, thoughts, desire, or receptivity that is associated with personal
distress); randomized double-blind parallel design compared placebo with testosterone patch, 300 µg/day;
primary end point consisted of number of satisfying sexual activities in 4-wk period; secondary end points consisted of
desire and personal distress scores (assessed by questionnaires); sexual activity increased from 3 to 5 events in active
treatment group (clinically relevant); sexual desire, arousal, number of orgasms, and assessment of pleasure increased;
negative concerns about sexuality, and personal distress related to sexual function decreased; adverse events ≈33%
(mostly related to application of patch; similar in both groups); androgenic adverse effects (eg, acne, hirsutism, hair
loss) also similar in both groups; no clinically significant effects on lipids, lipoproteins, high-density lipoprotein
(HDL), insulin, or glucose
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| Conclusions: well-studied physiologic treatment needed for testosterone replacement in women; investigational patch
appears effective, safe, and well tolerated in oophorectomized women; recruitment for clinical trials—current study at
Boston Medical Center needs surgically menopausal women 21 to 60 yr of age; study seeks to assess effect of testosterone
and estrogen treatment on muscle strength, sexual function, and other aspects of health
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| Questions and answers: measuring testosterone—levels highest in morning (8:00 to 10:00 AM; same as in men), but
surgically menopausal women always have low testosterone; testosterone replacement in reproductively intact
women—recent studies suggest similar effects in naturally menopausal women; studies use estrogen plus progestin and
testosterone; topical testosterone gel in premenopausal women with low testosterone improved sexual function; more research
needed; conversion to estrogen—aromatase pathway converts testosterone to estrogen (theoretic concern in
women for whom estrogen contraindicated); although testosterone replacement increases estradiol in men, low doses
used in women do not appear to increase circulating levels of estradiol (questions remain about effect on breast tissue)
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| REDEFINING THE ANNUAL VISIT —Archana Pradhan, MD, MPH, Assistant Professor, Department of Obstetrics, Gynecology,
and Reproductive Sciences, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical
School, New Brunswick, NJ
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| Testing for human papillomavirus (HPV): guidelines from American College of Obstetricians and Gynecologists
(ACOG)—1) triage all women with atypical squamous cells of undetermined significance (ASCUS) by performing
reflex HPV DNA testing for high-risk HPV types; 2) perform primary testing using combination of cervical cytology and
screening for HPV DNA in women \>30 yr of age; data—following current screening recommendations increases detection
of cervical intraepithelial neoplasia (CIN, stages II and III), high-grade lesions, and invasive cancer, and decreases
false-negative results; women with 2 concurrent negative tests have very low risk for high-grade lesion (can expand interval
for testing)
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| Annual gynecologic examination: expanding interval for traditional pelvic examination does not have to result in
fewer visits; can maintain annual visit schedule by adding appropriate services that improve physician-patient relationship
and allow assessment of general health status; applying recommendations of United States Preventive Services Task
Force (USPSTF) improves quality of care and patient satisfaction and can help build practice (eg, retain patients, increase
appropriate services, improve managed-care contracts); other benefits include personal and professional growth (eg, expanding
scope of practice and developing referral base)
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| Expanding role in general and preventive health: for women who do not have primary care provider, annual gynecologic
examination provides regular contact with health care system (important for health maintenance and detection
of treatable medical conditions); traditional services—clinical breast examination; pelvic examination;
Papanicolaou (Pap) test; mammography; newer additions—smoking cessation; instruction in breast self-examination;
screening for domestic violence and substance use; preventive services—USPSTF rates recommended screenings,
based on evidence and magnitude of net benefit (Grades, A-strongly recommend, B-recommend, C-neutral, D-recommend
against, and I-insufficient evidence)
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| Chlamydia: many women asymptomatic; most common bacterial infection in United States (\>3 million new cases diagnosed
each year); 60% of sexually active women <25 yr of age not screened; recommendations—screen all sexually
active women ≤25 yr of age (speaker screens, regardless of sexual history); assess risk in women \>25 yr of age and
screen if risk factors present
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| Colorectal cancer: fourth most common cancer and second leading cause of death in United States; early detection facilitates
treatment (90% of cases treatable when caught early); 65% of population does not receive appropriate screening
at recommended intervals; recommendations—screen average-risk women ≥50 yr of age, using fecal occult blood
test (every year), colonoscopy (every 10 yr), or combination
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| Heart disease: leading cause of death in United States, with \>500,000 deaths each year; screening recommendations—
screen all women ≥45 yr of age for lipid disorders; screen women <45 yr of age when risk factors present; note—
screening especially important for women who do not have primary care providers
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| Aspirin use: data show benefit in women at increased risk for coronary heart disease; risk factors include age, hypertension,
smoking, high cholesterol, low HDL, and diabetes; aspirin therapy shown to reduce risk for stroke (not necessarily
myocardial infarction [MI]) in women 45 to 65 yr of age; therapy associated with decreased risk for MI in women
\>65 yr of age; potential adverse effects of aspirin therapy influence decision to treat (risk factors include age, osteoporosis,
and risk for falls)
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| Osteoporosis: 50% of women who live to 85 yr of age experience ≥1 osteoporotic fracture; risk factors include age \>65
yr, low body weight, and absence of estrogen therapy; recommendations—bone density scans for all women \>65 yr
of age and for younger women at high risk for fractures
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| Obesity: body mass index (BMI) quantifies obesity and facilitates discussion with patients; tools available for easy calculation;
include in medical chart; patients with BMIs between 25 and 29 considered overweight; patients with BMIs ≥30
considered obese; counseling patients—increased BMI associated with arthritis, high blood pressure, diabetes, and heart
disease; most effective weight-loss strategies have nutritional and educational components; obese patients need referral
and treatment
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| Others: questionnaires assess domestic violence and alcohol use; most states have government-funded intervention programs
for tobacco cessation
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| Summary: adding appropriate health screenings and sending annual reminder letters can increase percentage of returning
patients, even after implementing new guidelines for Pap test; annual visit can provide comprehensive health care, especially
to those patients who do not have primary care providers; developing checklist and systems, and using ancillary
staff to provide instructions and information, improves efficiency and minimizes time needed for screening; follow-up
visits appropriate for addressing identified problems; letters sent before follow-up can inform patient of health status and
options for treatment
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Educational Objectives
| The goal of this activity is to inform the clinician about the effects of testosterone deficiency in women and about current
guidelines for preventive gynecologic and general health care. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Discuss the function and regulation of testosterone in healthy women.
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| 2. Identify women at risk for testosterone deficiency and list the associated symptoms.
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| 3. Select treatment options for women with testosterone deficiency.
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| 4. Summarize screening recommendations from the United States Preventive Services Task Force and appropriately
apply them to clinical practice.
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| 5. Educate women about general health issues, including cancer, heart disease, and obesity.
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Suggested Reading
Burger HG, Papalia MA: A clinical update on female androgen insufficiency – testosterone testing and treatment
in women presenting with low sexual desire. Sex Health 3:73, 2006; Buring JE: Aspirin prevents stroke but not MI
in women; vitamin E has no effect on CV disease or cancer. Cleve Clin J Med 73:863, 2006; Denberg TD et al: Effect
of a mailed brochure on appointment-keeping for screening colonoscopy: a randomized trial. Ann Intern Med
145:895, 2006; Gross CP et al: Relation between Medicare screening reimbursement and stage at diagnosis for
older patients with colon cancer. JAMA 296:2815, 2006; Hayes SN: Preventing cardiovascular disease in women.
Am Fam Physician 74:1331, 2006; Kotz K et al: Estrogen and androgen hormone therapy and well-being in surgically
postmenopausal women. J Womens Health (Larchmt) 15:898, 2006; Mason A et al: Undetectable salivary testosterone
in young women with premature ovarian failure. Clin Endocrinol (Oxf) 64:711, 2006; Mather SP et al:
Early non-invasive diagnosis of cervical cancer: beyond Pap smears and human papilloma virus (HPV) testing. Cancer
Biomark 1:183, 2005; Mazer NA et al: Transermal testosterone for women:a new physiological approach for
androgen therapy. Obstet Gynecol Surv 58(7):489, 2003; Mazer NA: Testosterone deficiency in women: etiologies,
diagnosis, and emerging treatments. Int J. Fertil Womens Med 47(2):77, 2002; Nijhuis ER et al: An overview of innovative
techniques to improve cervical cancer screening. Cell Oncol 28:233, 2006; Somboonporn W: Testosterone
therapy for postmenopausal women: efficacy and safety. Semin Reprod Med 24:115, 2006; Supervia A et al:
Effect of smoking and smoking cessation on bone mass, bone remodeling, vitamin D, PTH and sex hormones. J Musculoskelet
Neuronal Interact 6:234, 2006; Terebelo S: Practical approaches to screening for domestic violence.
JAAPA 19:30, 2006; Wierman ME et al: Androgen therapy in women: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab 91:3697, 2006; Wolf JL: Uniquely women’s issues in colorectal cancer screening.
Am J Gastroenterol 101(Suppl3):S625, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Mazer is a former employee of Watson Laboratories; Dr. Pradhan is an investigator for Duramed.
Dr. Mazer was recorded at the 9th annual Practical Issues in Obstetrics, Gynecology and Women’s Health, presented
by Boston University School of Medicine, and held November 4, 2006, in Boston, MA; Dr. Pradhan was recorded at
the 21st annual Issues and Controversies in Obstetrics and Gynecology, held November 9-11, 2006, in Lake Buena
Vista, FL. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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