Fig. 5.1
STRAW stages of reproduction
Vasomotor Symptoms and Other Impactful Issues Related to Menopause
Declining and variable production of estrogen during the menopausal transition (stages −2 to +1 in STRAW-10) is associated with many of the first, most bothersome, and most frequent symptoms of the menopausal transition: hot flushes and night sweats. These symptoms are a consequence of unexpected, episodic, and sudden peripheral vasodilation with increased blood flow to the chest, face, and neck resulting in profuse sweating, heart palpitations, anxiety, and flushing. These symptoms can last anywhere from 1 to 5 min and can occur at night. Such symptoms, when frequent, may disrupt sleep patterns, which if sustained can lead to downstream consequences such as chronic fatigue, sexual dysfunction, and even depression [11]. According to findings from the Study of Women’s Health Across the Nation (SWAN), which assessed menopausal symptoms in 14,906 ethnically diverse women aged 40–55 years residing in the United States, while vasomotor menopausal symptoms (VMS) vary greatly in their frequency and intensity among menopausal women, symptoms typically are most debilitating for 1–2 years, but for some women symptoms may persist for as long as 14 years [18]. Risk factors for VMS include obesity, smoking, depression/anxiety, and low socioeconomic status, in addition to ethnic and genetic factors [31]. Additionally, there is research to show variations of VMS among women of different ethnicities and race: African American women were most likely to report vasomotor symptoms, while Asian women (Japanese and Chinese) were the least likely to report them [31].
With the sustained hypoestrogenic state that characterizes menopause, the severity and frequency of vasomotor symptom will relent in most women, but additional symptoms may develop. These include vaginal dryness, vaginal atrophy, and recurrent urinary tract infections that cause physical discomfort. In addition, weight gain, skin dryness, and facial wrinkles may accelerate and impair one’s self image. Finally, accelerated bone loss and progression of subclinical atherosclerosis associated with hypoestrogenic states can increase the risk of osteoporotic fractures and heart disease with even greater impact on life’s quality and quantity.
Reducing Symptoms: Treatment Options for Women
Supporting a woman’s journey through perimenopause and menopause and working to mitigate the bothersome symptoms are integral to our role as medical providers. Equally important is our ability to discern patterns when symptoms are most troublesome and determine whether any other disease process could be causing or amplifying her symptoms. It is also our role to know about and provide patients with the full spectrum of treatment options, including hormonal and nonhormonal pharmacotherapies, and integrative approaches. Each encounter should thus be viewed as an opportunity to gain insight and knowledge into a woman’s menopausal transition, evaluate her symptom burden and their impact on well-being and quality of life, and assess the personal psychosocial circumstances in which those symptoms are occurring. Understanding her desire for a particular therapy along with her expectations, reservations, and fears about such therapy is also crucial to the optimal selection of an appropriate intervention.
Nonhormonal Pharmacotherapies for Menopausal Hot Flushes
Although they are generally considered less effective than hormonal therapies, a number of nonhormonal therapies for vasomotor symptoms have been in clinical use for some time now. While their efficacy has been proven in clinical trials, it is important to note some of the important limitations of hot flush trials. The most significant is the high placebo response rate in hot flush therapy, with placebo improvement rates reported to be as high as 50 % (Boekhout). Large clinical trials are therefore needed to obtain adequate study power, yet most of the trials on nonhormonal therapies have been relatively small. Secondly, the hot flush diary commonly used to assess hot flushes in clinical trials is mostly subjective and influenced by recall bias, which limits accurate and reliable data capture [28].
One should never forget as well that all pharmacotherapies, including vitamins and supplements, have risks and side effects. It is important therefore for a woman to decide which of those are acceptable in return for a reduction of her vasomotor symptoms. Once a therapy is chosen after a careful, mindful, and individualized analysis, we find it useful to see patients every 6–8 weeks to confirm that treatment goals are being met, to rule out adverse effects, and to make sure the patient is content with her choice of therapy. For all therapies, we discuss the expected 2–3 year duration of treatment and recommend drug-free “holidays” every 6 months to determine whether continued therapy is necessary. We empower women to decide for themselves on the timing of the weaning trials and inform them of the 50 % chance of recurrent symptoms. For some this would necessitate a return to therapy, while for others the symptoms may have become more manageable, and they may consider other approaches. Some of the most commonly used nonhormonal therapies for hot flushes are discussed next.
Selective Serotonin Reuptake Inhibitors/Selective Norepinephrine Reuptake Inhibitors
For those patients troubled by hot flushes in whom estrogen-containing therapy is not an option, either because of a contraindication, unjustifiable risk, or personal preference, consideration should be given to selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs). While their mechanism of action is not completely understood, they are believed to exert their beneficial effects centrally by restoring the balance of neurotransmitters which regulate the hypothalamic thermoregulatory zone, a balance that is often disrupted by declining estrogen levels [25]. Given that SSRIs and SNRIs are useful for management of anxiety and depressive disorders, they are particularly useful in the patient with VMS who also endorses mood changes during the transition. SSRIs that have been studied for VMS management include paroxetine, fluoxetine, citalopram, and sertraline, and they are all generally well tolerated though with some known possible side effects including weight gain and decreased libido, difficulty reaching orgasm, decreased energy, and headaches (http://www.drugwatch.com/ssri/). Table 5.1 shows the effect and dose of various SSRIs and SNRIs that have been studied for minimizing hot flushes [34]. For patients with a history of breast cancer who are on tamoxifen, SNRIs are preferred, as they do not increase the CYP2D6 system [4, 10]. Both venlafaxine (35.5–75 mg/day) and desvenlafaxine (100 mg/day) have been proven useful [10, 25, 32, 36].
Table 5.1
Results of the efficacy of escitalopram, paroxetine, sertraline, citalopram, and fluoxetine, conducted using the random-effect Bayesian method (total residual deviance = 18.87)
Comparison | Mean effect | 95 % CI | Probability treatment is best | Rank |
|---|---|---|---|---|
Placebo | Reference | – | 0 | – |
Escitalopram | −2.05 | −4.82 to 0.62 | 61 % | 1 |
Paroxetine | −1.23 | −2.39 to −0.12 | 18 % | 2 |
Sertraline | −0.83 | −3.44 to 1.64 | 16 % | 3 |
Citalopram | −0.54 | −2.00 to 0.83 | 3.4 % | 4 |
Fluoxetine | −0.14 | −1.55 to 1.30 | 0.9 % | 5 |
Results of mixed treatment comparison comparing the efficacy of escitalopram, paroxetine, sertraline, citalopram, and fluoxetine, conducted using the random-effect Bayesian method (total residual deviance = 18.87) | ||||
Comparison | Mean effect | 95 % CI | Probability treatment is best | Rank |
Placebo | Reference | – | 0 | – |
Escitalopram | −2.05 | −4.82 to 0.62 | 61 % | 1 |
Paroxetine | −1.23 | −2.39 to −0.12 | 18 % | 2 |
Sertraline | −0.83 | −3.44 to 1.64 | 16 % | 3 |
Citalopram | −0.54 | −2.00 to 0.83 | 3.4 % | 4 |
Fluoxetine | −0.14 | −1.55 to 1.30 | 0.9 % | 5 |
Escitalopram vs. citalopram | 1.511 | −1.55 to 4.58 | – | − |
Escitalopram vs. fluoxetine | 1.914 | −1.11 to5.06 | − | − |
Escitalopram vs. sertraline | 1.225 | −2.44 to 4.89 | − | − |
Escitalopram vs. paroxetine | 0.82 | −2.06 to 3.82 | − | − |
Citalopram vs. fluoxetine | 0.4 | −1.02 to 1.92 | − | − |
Citalopram vs. sertraline | −0.29 | −3.32 to 2.57 | − | − |
Citalopram vs. paroxetine | −0.69 | −2.47 to 1.14 | − | − |
Fluoxetine vs. sertraline | −0.69 | −3.64 to 2.12 | − | − |
Fluoxetine vs. paroxetine | −1.09 | −2.94 to 0.70 | − | − |
Sertraline vs. paroxetine | −0.40 | −3.11 to 2.46 | − | − |
Currently, however, the only FDA-approved SSRI for mitigation of hot flush symptoms is low-dose (7.5 mg) paroxetine.
Gabapentin
Gabapentin, a medication used primarily as an anticonvulsant, has also been shown to decrease vasomotor symptoms. Its mechanism is also not entirely known but believed to involve central and peripheral GABA neurotransmission. While less effective than hormone therapy, gabapentin at doses up to 300 mg three times a day is well tolerated [25]. Its major side effects are sedation, headache, and edema. While others have expressed increase concern of suicide on gabapentin, pharmacoepidemiologic studies have shown no drug effect was detected in the nonpsychiatric populations, while significant reductions in suicide attempt rates were seen for bipolar disorder, major depressive disorder, and other psychiatric disorders [16]. In our experience, this medication is most useful in patients who wish to avoid estrogen therapy and whose primary bothersome symptom is night sweats. A randomized trial found nonsuperiority of gabapentin 2400 mg compared with conjugated equine estrogens (0.625 mg/day), but at this dosage the side effects can become limiting [33].
Clonidine
Clonidine (0.1 mg/day) is an antihypertensive, which had been used for VMS management in the 1970s for patients with breast cancer [25, 32]. It is a centrally acting α-2 adrenergic agonist, which has been theorized to exert its beneficial anti-VMS effects by reducing norepinephrine release and restoring homeostatic function in the thermoregulatory zone of the hypothalamus. Clonidine causes modest improvements in hot flush symptoms although the side effects of large symptom burden including mouth dryness, constipation, itchiness, drowsiness, and difficulty in sleeping can be limiting in its use. This can be a good agent of choice for women who have a preexisting condition of hypertension and contraindications to taking other medications.
Integrative Approaches for Treating Menopausal Hot Flushes
Acupuncture
Acupuncture studies are ongoing in the treatment of hot flushes; however there is promising evidence for its efficacy. Part of the efficacy of acupuncture in improving hot flushes is based on the changes in levels of β-endorphins and other neurotransmitters during acupuncture, potentially affecting the thermoregulatory center in the hypothalamus [2]. A recent meta-analysis of 12 studies with 869 patients using acupuncture therapy for VMS showed significant reductions in both severity and frequency of hot flushes, with effects lasting up to 3 months. Acupuncture also resulted in lasting improvements in psychological, somatic, and urogenital subscale scores [8]. In our clinical practice, the points we most commonly use are St-36, Sp-6, CV-4, LI4, PC-6, GV-20, Lr-3, and Ht-6, although some variability does occur as we individualize each session. In our practice, acupuncture sessions are typically scheduled weekly or bi-weekly, and patients start noticing the benefits after 2–3 sessions, with hot flush intensity improving before hot flush frequency. Sessions last roughly 30 min.
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