ISSUES IN MENOPAUSE
| HORMONAL EVALUATION, MENOPAUSE, AND SEXUAL DYSFUNCTION —Michelle P. Warren, MD, Professor
of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New
York, NY
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| Physiology of menopause: age range for perimenopausal transition 35 to 50 yr of age; on average, symptoms start
≈47.5 yr of age; symptoms may begin before cessation of menstrual periods; average duration for transition 3.8 yr; few
ova remain in ovaries; body less responsive to hormones; final menstrual period within 1 yr if woman goes 2 mo without
menstrual period 2 times; increase in pituitary gonadotropins and decrease in inhibin; body struggling to make more
estrogen; anovulation; occasionally heavy bleeding; 60% to 70% of women experience hot flushes; nervousness and irritability
often first signs; debate as to importance of estrogen loss in development of disease, but acceleration of health
problems with onset of menopause; early symptoms—hot flushes, mood, sleep, and cognitive changes; vaginal dryness,
pain with intercourse, vulvovaginal atrophy; primary symptoms—menstrual cycle changes, oligomenorrhea,
amenorrhea, vasomotor symptoms, and vaginal dryness; secondary symptoms—urinary stress and urge incontinence;
psychophysiologic changes; musculoskeletal pains; decreased concentration; decreased libido; sexual dysfunction—
pain with intercourse; decreased arousal during sexual stimulation; decreased frequency; loss of sexual desire; hot
flushes—may continue for years after menopause in percentage of women; data show majority of patients experience
hot flushes around time of last menstrual period or before; small number of patients experience hot flushes for >10 yr or
even remainder of life; quality of life— studies show deterioration; some women have extreme aggravation of underlying
issues experienced before menopause, with significant increase in anxiety; depression—well-documented increase
in incidence of depression during menopausal transition
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| Sexual dysfunction and menopausal transition: study by Dennerstein showed 42% of women reported sexual
dysfunction during early menopausal transition, compared to 88% during late menopausal transition; for happily
married women, loss of intimacy upsetting, and women without partners feel they will never have partner if they
lose interest in sex; survey presented in 1998 showed about two thirds of women reported lack of interest in sexual
arousal and decrease in libido; many women reporting problems may have underlying issues not related to loss of
hormones
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| Role of androgens: adrenal glands and ovaries main sources for androgen production; increased binding of estrogens
and decreased testosterone if protein that binds testosterone bound to sex hormone binding globulin (SHBG);
testosterone affects sexual response, brain, genitalia, bone, and muscle; testosterone decrease related to age; greatest
decline in testosterone in late 20s to early 40s; dehydroepiandrosterone sulfate (DHEAS)—primary hormone secreted
by adrenal gland; unclear function and importance in sexual functioning; increases dramatically at puberty
and decreases with aging; does not appear to be related solely to menopause; 50% of androgens produced by ovary
(testosterone most potent androgen); oophorectomized women—dramatic decrease in testosterone level; relative
risk for nonorgasmic response >2.5, compared to women going through natural menopause; twice risk of worsening
sex life than women going through natural menopause; earlier menopause in women undergoing hysterectomy
(blood flow to ovaries may be compromised); significantly reduced sexual thoughts, desire, arousal, frequency of
activity, pleasure, orgasm, and relationship satisfaction well documented in surgically menopausal women; more
hysterectomies performed in United States than any other developed country; anovulatory bleeding should be controlled
with interventions other than hysterectomy
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| Sexual complaints: loss of sexual desire (hypoactive sexual desire disorder) most common complaint (≈40% of
sexual complaints); sexual pain disorder related to vaginal atrophy; vaginal atrophy and sexual pain with intercourse
if vaginal estrogen not used; female androgen insufficiency associated with decreased bioavailable testosterone
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| Evaluation: medical history important; medical conditions, eg, thyroid disease, hyperprolactinemia, depression, adrenal
insufficiency, associated with sexual dysfunction; antidepressants, corticosteroids, and oral estrogen therapies
can affect sex,ual functioning; oral estrogens cause elevation of SHBG, which decreases bioavailable testosterone;
irradiation, chemotherapy, premature menopause, adrenal insufficiency, chronic SHBG elevation, hypothalamic-
pituitary disorder, drug-related issues, and idiopathic causes of adrenal insufficiency warrant consideration for androgen
replacement; overtreatment or long-term treatment with thyroid hormone can lead to significant elevation
of SHBG; acute onset of sexual dysfunction more likely to reflect acute problems related to changes in hormones;
chronic situation may involve more issues, ie, biologic, interpersonal, psychologic, and sociocultural; successful
outcome dependent on treatment of all issues
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| Managing low sexual desire in menopausal women: studies show no association with testosterone levels in
sexual functioning in women, except in specific groups, eg, oophorectomized women; decline in sexual function
occurs in menopausal transition associated with decline in estrogen levels; estrogen replacement improves sexual
functioning, particularly in women with symptoms, but not associated with improvement in desire or arousal; estrogen
plus testosterone therapy not recommended (lack of data); diagnosis—made by symptoms and circumstances;
tests (total testosterone and free androgen index) supportive but not diagnostic; estrogen therapy—lower
estrogen level associated with increased prevalence of sexual problems, dyspareunia, and vaginal dryness; vaginal
estrogen cream should be suggested to patient who does not want to take oral or transdermal estrogen; estrogens
have significant impact on vaginal blood flow; effective against vaginal dryness and dyspareunia; SHBG—carrier
protein for estrogen and testosterone; production regulated by estrogen/testosterone balance; significant increase in
SHBG with estrogen use (particularly oral estrogen); little increase with transdermal estrogen (important if concerned
about binding of testosterone in patient with sexual dysfunction)
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| Women’s Health Initiative (WHI) in perspective: showed slight increase in incidence of breast cancer, cardiovascular
(CV) events, and stroke in women on hormone replacement therapy (HRT); most significant adverse
event venous thromboembolism (VTE; 18 per 10 000); study review showed hazard ratio for breast cancer 1.24
(changed from 1.26); review did not show increased risk for CV events in women who started HRT at time of
menopause; no increase in breast cancer or CV events (problems may have been related to progestin); presently,
speaker not willing to state no risk with estrogen alone or problems all due to progestin; breast cancer—no increase
in incidence in women who have never taken hormones; probably takes ≈8 yr of using hormones before increase
in breast cancer seen; speaker counsels patients about using HRT for symptoms for 2 to 5 yr, then
reassessing; CV events—significant increase only in women >20 yr after last menstrual period; HRT should not be
initiated in women ≥63 yr of age
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| Hormone replacement therapy: vaginal rings available for local application; Femring (estrogen) full hormone
replacement ring; vaginal tablet and Estring (estradiol) used as directed do not lead to significant systemic levels
unless patient on aromatase inhibitors; some increase in systemic levels until superficial layer of vagina built up;
adding androgens to estrogen—studies show improvement in libido, mood, and physical energy, but studies used
superphysiologic levels of androgen; estrogen plus methyltestosterone used off-label (approved only for relief of
hot flushes); trial involving estrogen plus methyltestosterone showed significant effect in nonhysterectomized
women with few adverse effects
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| SLEEP DISORDERS AND ANXIETY —Lois E. Krahn, MD, Professor of Psychiatry, Mayo Clinic, Scottsdale, AZ
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| Insomnia: significant overlap between anxiety and mood disorders, especially in perimenopausal transition; hyperaroused
state interferes with patient’s ability to achieve restful sleep; occasional insomnia—defined as 2 nights of
sleeplessness in month; chronic insomnia—trouble sleeping almost every night for 1-mo period; sleep quality drops
sharply at menopause; insomnia most common sleep issue in perimenopausal or postmenopausal period; medical
disorders—50% to 90% of women presenting with depression have insomnia; insomnia risk factor for psychiatric
disorders; puts woman at risk for depression, anxiety, alcohol and drug abuse; persisting insomnia puts woman at risk
of developing anxiety disorder; treatment should focus on resolving sleep and anxiety disorders; proposed
mechanism—hyperaroused state with changes in hypothalamic-pituitary-adrenal (HPA) axis believed mechanism
common to insomnia and mood disorders; research shows dexamethasone suppression test (DST) positive in patients
with depression and patients with insomnia; poor sleepers perceive stressful events as more severe than good sleepers;
daytime stress leads to greater arousal at bedtime and decreased sleep quality; stress-related insomnia increases risk
for depression later in life; sleep disturbance major warning sign of recurrence of major depressive disorder; sleep disturbance
most common refractory symptom in treated major depressive disorder; treatment of anxiety and depression
should include addressing issue of sleep disturbance
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| Generalized anxiety disorder (GAD): affects conservatively ≈6.6% of women (number increases in perimenopause);
nonstop worrying about positive and negative issues; chronic process; often leads to stress-related sleep disturbance;
high risk for depression (80%); antidepressant medication to treat anxiety and depression helpful
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| Panic disorder: affects men and women equally; episodic disorder; symptoms start within 10 min, generally do not
last >1 hr; hyperaroused state; physical and psychologic components; catastrophic thoughts; overlaps with depression;
can lead to change in lifestyle; panic attacks exclusively at night rare; think respiratory event, ie, sleep apnea,
rather than panic disorder, with report of attacks exclusively at night; attacks occur in non-rapid eye movement
(REM) sleep stage, followed by insomnia
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| Posttraumatic stress disorder (PTSD): history of exposure to extraordinary event, eg, trauma, natural disasters;
hyperaroused state; flashbacks, nightmares, difficulty sleeping; considerable overlap with obstructive sleep apnea,
sleepwalking, and parasomnias; treatment should target anxiety as well as sleep disorder
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| Psychotherapy for insomnia: cognitive behavioral therapy (CBT)—effective; decreases time person awake after
sleep onset; more effective than medications alone; combination of CBT and medications highly effective; can also
address anxiety and catastrophic thinking; can help reduce dosage and duration of use of hypnotics used to treat
sleep disorder; other behavioral tools—yoga, relaxation tapes, sleep restriction, “reassociation” of bed with sleep,
improved sleep habits, restriction of caffeine use in afternoon and evening
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| Newer hypnotics: more beneficial than benzodiazepines; zaleplon (Sonata)—half-life 1 hr; appropriate for patient
who awakens in middle of night; zolpidem (Ambien), eszopiclone (Lunesta), and ramelteon (Rozerem)—slightly
longer half-life; designed to be used with initial insomnia; benzodiazepine receptor agonist (works on γ-aminobutyric
acid [GABA] receptor); no effect on anxiety; ramelteon—melatonin (MT)1 and MT2 receptor agonist; not
controlled substance; no evidence of misuse or overuse; half-life ≈4 hr; Ambien CR, Lunesta, and Rozerem—can be
used long-term, unlike Ambien and Sonata
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| Benzodiazepines: speaker opines temazepam (Restoril) best benzodiazepine because of half-life; 7.5-mg dose
appears as effective as 15-mg dose (previous lowest dose); better tolerated and less likely to cause residual daytime
sleepiness
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| Sedating antidepressants: mirtazapine (Remeron), trazodone (Desyrel), and doxepin; downside is loss of ability
to adjust dose of antidepressant relative to sleep medicine; risk for weight gain with mirtazapine and doxepin (consider
tailoring therapy by using another antidepressant to treat mood disorder or anxiety)
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| Antihistamines: not recommended; limited efficacy; patient develops tolerance over time
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| Sleep issues in context of anxiety disorders: screen for presence of other sleep disorders, eg, snoring, breath
holding, restless leg syndrome; recommend patient seek psychotherapy; multiple factors contribute to disrupted
sleep, eg, chronic pain, snoring bed partner, thyroid disease, urinary frequency; perimenopause—increase in obstructive
sleep apnea (likely related to hormonal shift); data show severity of anxiety strongly associated with severity
and frequency of hot flushes after adjusting for hormonal status and smoking; may explain why venlafaxine
and paroxetine effective for hot flushes
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Educational Objectives
| The goal of this program is to educate the listener about the effect of menopause on sexual functioning and about insomnia
as a risk factor for anxiety and depression. After hearing and assimilating this program, the clinician will be
better able to:
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 | 1. Identify women transitioning to menopause.
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| 2. Discuss the role of androgens in sexual functioning.
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| 3. Counsel women about the use of hormones for the treatment of menopausal symptoms.
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| 4. State the primary mechanism responsible for sleep disorders and the risk factors for insomnia.
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| 5. Treat patients with insomnia.
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Discussed on This Program
Diphenhydramine HCl [several trade names]
Doxepin HCl [Sinequan, Sinequan Concentrate, Zonalon]
Estrogen, vaginal [Estrace Vaginal Cream, Estring, Femring, Ogen Vaginal Cream, Premarin Vaginal Cream]
Eszopiclone [Lunesta]
Mirtazapine [Remeron, Remeron SolTab]
Ramelteon [Rozerem]
Temazepam [Restoril]
Trazodone HCl [Desyrel, Desyrel Dividose]
Venlafaxine HCl [Effexor, Effexor XR]
Zaleplon [Sonata]
Zolpidem tartrate [Ambien, Ambien CR]
Suggested Reading
Dennerstein L et al: Hypoactive sexual desire disorder in menopausal women: a survey of Western European
women. J Sex Med 3(2):212, 2006; de Paula FJ et al: The benefits of androgens combined with hormone replacement
therapy regarding to patients with postmenopausal sexual symptoms. Maturitas [Epub ahead of print], 2006;
Freeman EW et al: The role of anxiety and hormonal changes in menopausal hot flashes. Menopause 12(3):258,
2005; Kuppermann M et al: Effect of hysterectomy vs medical treatment on health-related quality of life and sexual
functioning: the medicine or surgery (Ms) randomized trial. JAMA 291(12):1447, 2004; Taylor DJ et al: Insomnia
as a health risk factor. Behav Sleep Med 1(4):227, 2003.
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. Warren is on the Advisory Board of Wyeth and the Speakers’ Bureau of Wyeth, Merck &
Co., Inc, Novartis, and Warner Chilcott. Dr. Warren also serves as a consultant for Duramed Pharmaceuticals, Ferring
Pharmaceuticals, Vela Pharmaceuticals, Inc, and Xenon Pharmaceuticals, Inc.
Dr. Warren was recorded at Female Sexual Dysfunction and Health 2006, sponsored by Columbia University College of
Physicians and Surgeons, held April 22, 2006, in New York, NY. Dr. Krahn was recorded at the Mayo Clinic Menopausal
Medicine: Care for the Mature Female, sponsored by Mayo Clinic College of Medicine, held March 2-4, 2006, in
San Diego, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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