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Evidence-Based Reviews


Minding menopause: Psychotropics vs. estrogen? What you need to know now

Psychotropics have become a first-line therapy for hot flashes and depression in perimenopause. Will you be ready when Ob/Gyns call you for help?

Vol. 2, No. 10 / October 2003

Psychiatrists are suddenly viewed as experts in treating menopause-related mood problems because of our expertise with using psychotropics. Practically overnight, the Women’s Health Initiative studies1,2 have made women and their doctors think twice about using estrogen. Instead, many are turning to psychiatric medications that have been shown to improve both mood and hot flashes—without estrogen’s potential risks.

Chances are good that after an Ob/Gyn has tried one or two psychotropics without success or with too many side effects, he or she will ask a psychiatrist to consult for certain patients. How well-prepared are you to assume this role?

If your recall of female reproductive physiology from medical school is incomplete, read on about one approach to a perimenopausal patient with depressed mood. This review can help you:

  • discuss menopause knowledgeably when other physicians refer their patients to you
  • provide effective, up-to-date treatments for menopause-related mood and sexual problems, using psychotropics or hormones, alone or in combination.

Irritable, with no interest in sex

Anne, age 51, has been referred to you for complaints of depressed mood and low libido. She says she has become irritable and snaps easily at her two children and her husband. She has no interest in sex, no urge to masturbate, and has had no sexual intercourse for 6 months.

Table 1

Why mood problems may occur during menopause

Hypothesis

Explanation

Psychodynamic

Onset of menopause is a critical life event and a readjustment of self-concept

Sociologic

Mood changes are caused by changing life circumstances at menopause (‘empty nest,’ aging parents, health changes)

Domino

Depressed mood is caused by hot flashes due to declining estrogen levels, which cause chronic sleep deprivation with subsequent irritability and memory and mood changes

Biochemical

Decreasing estrogen leads to neurochemical changes in the brain (serotonin, dopamine, cholinergic, GABA, norepinephrine)

Anne also complains of fatigue, dry hair and skin, warm flushes, and painful joints. She has no personal or family history of depression. She is not suicidal but states that she really doesn’t want to live anymore if “this is it.”

HOT FLASHES: A SPARK FOR DEPRESSION

Women who experience their first depression after age 50 do not fit the usual DSM-IV diagnostic criteria for depression. The Massachusetts Women’s Health Study3 found that 52% of women who experience depressed mood in the perimenopause have never had a depression before. This study also found a correlation between a longer perimenopause (>27 months) and increased risk of depressed mood. At the same time, women who have had a prior depression are 4 to 9 times more likely to experience depressive symptoms during perimenopause than those who have never had a depression before.4

The increased mood symptoms may be related to psychodynamic, sociologic, or biochemical factors, or they may result from a domino effect triggered by declining estrogen levels (Table 1). Women who experience vasomotor symptoms such as hot flashes are at 4.6 times greater risk for depression than those who are hot flash-free.5

Hot flashes begin on average at age 51, which is also the average age when natural menopause begins. During menopause, most women (82%) experience hot flashes (suddenly feeling hot and sweating during the day), warm flushes (a sensation of warmth or heat spreading over the skin), and night sweats (Table 2). All women who undergo surgical menopause experience hot flashes.

Hot flashes are moderate to severe for 40% of women who experience them and persist for 5 to 15 years. By definition, moderate to severe hot flashes occur 6 to 10 or more times daily, last 6 to 10 minutes each, and are often preceded by anxiety, palpitations, irritability, nervousness, or panic.

A marriage under stress

Anne says that her husband is angry about the lack of sexual intercourse, and she feels the stress in their marriage. She also is worrying about her children leaving for college and about her mother’s ill health.

She scores 20 on the Beck Depression Inventory, which indicates that she has mild to moderate depression. Her menstrual periods remain regular, but her cycle has shortened from 29 to 24 days. She reports experiencing some hot flashes that wake her at night and says she hasn’t had a good night’s sleep in months.

Laboratory tests show FSH of 25 mIU/mL and inhibin B <45 pg/mL. Her estradiol is 80 pg/mL, which is not yet in the menopausal range of 10 to 20 pg/mL. Her thyroid stimulating hormone (TSH) is normal. Her endocrinologic and reproductive diagnosis is perimenopause.

Table 2

Symptoms of menopause related to decreased estrogen

Brain

Irritability, mood swings, depressed mood, forgetfulness, low sex interest, sleep problems, decreased well-being

Body

Hot flashes, vaginal dryness, painful intercourse, fatigue, joint pain, pain with orgasm, bladder dysfunction

TREATING HOT FLASHES IMPROVES MOOD

Until July 2002, estrogen was standard treatment for controlling hot flashes in patients such as Anne. Then the Women’s Health Initiative trial reported that estrogen’s health risks—heart attack, stroke, breast cancer, and blood clots—exceeded potential benefits during 5 years of therapy. As a result, fewer women want to take estrogen,6 and many Ob/Gyns are advising patients to get through menopause without hormones if they can.

For mild hot flashes—one to three per day—patients may only need vitamin E, 800 mg/d, and deep relaxation breathing to “rev down” the sympathetic nervous system when a hot flash occurs.

For moderate to severe hot flashes—four to 10 or more per day—estrogen replacement is the most effective therapy. Estradiol, 1 mg/d, reduces hot flashes by approximately 80 to 90%.7 Many small studies have shown that patients’ mood often improves as estrogen reduces their hot flashes.8 The recent Women’s Health Initiative Quality-of-Life study, however, reported that estrogen plus progestin did not improve mood in women ages 50 to 54 with moderate-to-severe vasomotor symptoms, even though hot flashes were reduced and sleep may have improved.9

New drugs of choice. Because of estrogen’s effectiveness in controlling hot flashes, some women and their doctors may choose to use it briefly (18 to 24 months). For others, psychotropics are becoming the drugs of choice for mood disorders with moderate to severe hot flashes.

The serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine, 75 or 150 mg/d, has been shown to reduce hot flashes by 60 to 70%.10 A new trial is investigating whether duloxetine—an SNRI awaiting FDA approval—also reduces hot flashes. Other useful agents that have been shown to reduce hot flashes by 50% or more include:

  • selective serotonin reuptake inhibitors (SSRIs) paroxetine CR, 12.5 mg/d to 25 mg/d,11 citalopram, 20 to 60 mg/d, 12 and fluoxetine, 20 mg/d13
  • gabapentin, 900 mg/d.14

For hot flashes and moderate to major depression, try an SNRI or SSRI first (see Algorithm), but consider the possible effects on sexual function. All SNRIs and SSRIs have sexual side effects, including anorgasmia and loss of libido in women and men. Among the psychotropics that improve hot flashes and mood, gabapentin is the only one that does not interfere with sexual function.

Mood improves, but still no libido

You and Ann decide on a trial of the SNRI venlafaxine, 75 mg/d, to treat her hot flashes and depressed mood. Four weeks later, her hot flashes are reduced by 50% in frequency and her mood has improved (Beck Depression Inventory score is now 10). She is feeling much better and wishes to continue taking the antidepressant.

She and her husband attempted intercourse once during the past month, although she wasn’t very interested. She did not achieve orgasm, despite adequate vaginal lubrication, and she did not enjoy the experience. “I still have no libido—zero, or even less,” she says.

TREATING LOW INTEREST IN SEX

Being angry with one’s partner is the number-one reason for decreased sexual desire in all studies. Therefore, consider couples therapy for any woman complaining of loss of interest in sex. In addition, eliminate—if possible—any medications she may be taking that have known sexual side effects, such as SSRIs or beta blockers.

If the patient complains of slow or no arousal, vaginal estrogen and/or sildenafil, 25 to 50 mg 1 hour before intercourse, may be beneficial.15 Other agents the FDA is reviewing for erectile dysfunction—such as tadalafil and vardenafil—may also help arousal problems in women.

Understanding how hormones affect female sexual desire also may help you decide what advice to give Anne and how you and her Ob/Gyn coordinate her care. For example, you might treat her sexual complaints and relationship problems while the Ob/Gyn manages symptoms of the vagina, uterus, and breast.

HOW TESTOSTERONE AFFECTS SEXUAL DESIRE

Testosterone is the hormone of sexual desire in men and women. Other female androgens include androstenedione, androstenediol, 5 α-dihydrotestosterone (DHT), dihydroepiandrosterone (DHEA), and its sulfate (DHEA-S). Premenopausal women produce these androgens in the ovaries (25%), adrenal glands (25%), and peripheral tissues (50%).

Average daily serum testosterone concentrations decline in women between ages 20 and 50. Lower levels are also seen with estrogen replacement therapy or oral contraceptives, lactation, anorexia nervosa, and conditions that reduce ovarian function. Women who undergo total hysterectomy with bilateral oophorectomy experience a sudden 50% loss of testosterone and an 80% decline in estradiol.16

Regularly menstruating women in their 40s and early 50s can have very low testosterone levels—at least 50% lower in the first 5 to 7 days of their cycles—than they had when they were in their 30s.17 The percentage of women reporting low libido increases with age until menopause, from 30% at age 30 to about 50% at age 50. Then the rate declines to 27% in women age 50 to 59.18 After natural menopause, luteinizing hormone (LH) continues to stimulate the ovarian hilar cells and interstitial cells to produce androgens, which is why many women at age 50 have adequate testosterone levels to sustain sexual desire.

Oral estrogen replacement therapy reduces bioavailable testosterone by 42% on average, which can induce androgen deficiency in a menopausal woman. 19 The increased estrogen inhibits pituitary LH and decreases stimulation of the androgen-producing cells in the ovary.20

Female androgen deficiency. A number of papers have been published on female androgen deficiency syndrome (FADS).21 Its diagnosis requires symptoms of thinning pubic and axillary hair, decreased body odor, lethargy, low mood, diminished well-being, and declining libido and orgasm, despite adequate estrogen but low levels of testosterone and DHEA.

TREATING TESTOSTERONE DEFICIENCY

Benefits of replacement therapy. Replacing testosterone in women with FADS can improve mood, well-being, motivation, cognition, sexual function related to libido, orgasm, sexual fantasies, desire to masturbate, and nipple and clitoral sensitivity. 22 Muscle and bone stimulation and decreased hot flashes are also reported.23 Women with androgen deficiency symptoms and low testosterone at menopause should at least be considered for physiologic testosterone replacement.

Risks of replacement therapy. Androgen replacement therapy does carry some risks, which need to be discussed with the patient. Testosterone may lower levels of beneficial HDL cholesterol, so get the cardiologist’s clearance before you give testosterone to a woman with heart disease or an HDL cholesterol level <45 mg/dL.

Algorithm Managing mood and libido problems during perimenopause



A meta-analysis of eight clinical trials found no changes in liver function in menopausal women taking 1.25 to 2.5 mg/d of methyl testosterone. Liver toxicity has been reported in men using 10-fold higher testosterone dosages.24

At the normal level of testosterone, darkening and thickening of facial hair are rare in light-skinned, light-haired women but can occur in dark-skinned, dark-haired women. Increased irritability, excess energy, argumentativeness, and aggressive behavior have been noted if testosterone levels exceed the physiologic range.

Controlled, randomized studies are needed to assess the effects of long-term use (more than 24 months) of testosterone replacement in women.

Challenges in measuring testosterone levels. Serum free testosterone is the most reliable indicator of a woman’s androgen status, but accurately measuring testosterone levels is tricky:

  • Only 2% of circulating testosterone is unbound and biologically active; the rest is bound to sex hormone-binding globulin (SHBG) or albumin.
  • In ovulating women, serum testosterone levels are higher in the morning than later in the day and vary greatly within the menstrual cycle.
  • Levels of androgens and estrogen are highest during the middle one-third of the cycle—on days 10 to 16, counting the first day of menstrual bleeding as day 1.25
  • Oral contraceptives also decrease androgen production by the ovary and can result in low libido in some women.26

Tests developed to measure testosterone levels in men are not sensitive enough to accurately measure women’s naturally lower serum concentrations, let alone the even lower levels characteristic of female androgen or testosterone deficiency. New measurements and standardization of normal reference ranges have been developed for women complaining of low libido.27

Continued...
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