Menopausal hormone therapy and menopausal symptoms Zain A. Al-Safi, M.D., and Nanette Santoro, M.D. Division of Reproductive Endocrinology and Infertility, University of Colorado, Aurora, Colorado

A majority of women will experience bothersome symptoms related to declining and/or fluctuating levels of estrogen during their menopausal transition. Vasomotor symptoms, vaginal dryness, poor sleep, and depressed mood have all been found to worsen during the menopausal transition. While vasomotor symptoms gradually improve after menopause, the time course can be many years. Vaginal dryness does not improve without treatment, while the long-term course of sleep and mood deterioration is not clearly defined at this time. A small minority of women have vasomotor symptoms that persist throughout the remainder of their lives. These common menopausal symptoms all improve with estrogen treatment. Over the last 10 years, we have witnessed a dramatic reduction in enthusiasm for menopausal hormone therapy, despite its high efficacy relative to other treatments. We have also seen the emergence of sound, evidence-based clinical trials of non-hormonal alternatives that can control the common menopausal symptoms. Understanding the natural history of menopausal symptoms, and the risks and benefits of both hormonal and non-hormonal alternatives, helps the clinician individualize management plans to improve Use your smartphone quality of life. (Fertil SterilÒ 2014;101:905–15. Ó2014 by American Society for Reproductive to scan this QR code Medicine.) and connect to the Key Words: Menopause, hormone therapy, vasomotor symptoms, vulvovaginal atrophy Discuss: You can discuss this article with its authors and with other ASRM members at http://


omen nowadays spend more than a third of their lifetime beyond the menopausal transition (1). With the progressive aging of the population, the proportion of women who are menopausal is expected to continue to rise (2). Thus, reducing the burden of menopauserelated health conditions and improving overall quality of life become increasingly important. Declining and/or fluctuating levels of estrogen are associated with the menopausal transition and may result in bothersome symptoms. Those menopausal symptoms that have been shown to be associated with the onset of the menopausal transition and to improve with hormones are vasomotor symptoms, vulvovaginal atrophy/dyspareunia, sleep disturbance, and adverse

mood (3–6). This review will focus on the common menopausal symptoms, along with hormonal and nonhormonal treatments targeting these conditions. Throughout this review, we will be referring to the Stages of Reproductive Aging Workshop þ10 staging system (7) for various stages of reproductive aging (Fig. 1).

VASOMOTOR SYMPTOMS Vasomotor symptoms (VMS), commonly known as hot flashes/ flushes and night sweats, are sudden episodes of intense heat that usually begin in the face or chest and spread throughout the body, accompanied by sweating and flushing that typically last 1 minute to 5 minutes (8). Although

Received December 2, 2013; revised and accepted February 18, 2014; published online March 6, 2014. N.S. reports stock options with Menogenix and investigator-initiated grants from Bayer, Inc. Z.A.A.-S has nothing to disclose. Reprint requests: Zain A. Al-Safi, M.D., Division of Reproductive Endocrinology and Infertility, University of Colorado School of Medicine, 12631 East 17th Avenue, Mail Stop B-198, Aurora, Colorado 80045 (E-mail: Fertility and Sterility® Vol. 101, No. 4, April 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. VOL. 101 NO. 4 / APRIL 2014

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night sweats are sometimes considered unusually intense hot flashes that occur at night, it is not clear that they differ in their pathophysiology or treatment from less intense hot flashes. It is believed that hot flashes and night sweats interrupt sleep, as women frequently subjectively cite VMS at night as the source of this sleep disturbance (8), however, some laboratory studies do not support this notion (9). Between 60% to 80% of women will experience VMS at some point during their menopausal transition (3). The frequency and severity of VMS peak in the late perimenopause and early postmenopausal years, with large ethnic and racial variation in prevalence, frequency, and severity of symptoms (3). African-American women are most likely to report VMS and are also more likely to describe them as bothersome (10), whereas women of Asian background (Japanese and ChineseAmerican) are least likely to report VMS, and are less likely to describe them as bothersome (3, 10). These racial/ethnic differences in VMS in the Study of Women's Health Across the 905



The Stages of Reproductive Aging Workshop þ 10 staging system for reproductive aging in women. (Taken from Harlow. STRAW þ 10: staging reproductive aging. Fertil Steril 2012.) Al-Safi. Menopausal symptoms and hormone therapy. Fertil Steril 2014.

Nation (SWAN) persisted even after controlling for key factors like body mass index, estradiol level, hormone use, smoking, education and economic strain (difficulty paying for basic necessities) (3). Obesity has been found to be a key risk factor for perimenopausal, but not postmenopausal, VMS. Women with higher abdominal adiposity, particularly subcutaneous adiposity, are more likely to report VMS in the early and late perimenopause (11). Smoking has also been associated with VMS, while other health behaviors such as dietary composition, has weaker and less consistent associations (3). While unadjusted data from SWAN showed association of VMS with lower physical activity scores, no such association existed after adjustment for other factors (3). Women who experience premenstrual symptoms are at a higher risk for VMS when they traverse the menopause (3). VMS have been associated with all aspects of perceived sleep disturbance that contribute to the subjective complaint of poor sleep. These include falling asleep, staying asleep, and early morning awakening (5). Quality of life can be negatively affected by VMS, yet remarkably little is known about their pathophysiology (12). 906

The main factors thought to influence VMS occurrence and severity include reproductive hormones, particularly estradiol, inherent thermoregulatory process within the individual, and genetics (13–18). Reproductive hormones are believed to play an integral role as evidenced by the onset of VMS occurring in the context of the dramatic reproductive hormone changes of the menopausal transition and by the therapeutic role of exogenous estrogen in their treatment. Data from Penn Ovarian Aging Study showed that fluctuations of estradiol, decreased levels of inhibin B, and increased FSH levels, were significantly and independently associated with menopausal symptoms (13). VMS are believed to be thermoregulatory heat dissipation events, although the exact mechanisms underlying VMS are not entirely known. The thermoneutral zone in the hypothalamus is narrowed in women with VMS (14). This is believed to be the area of the brain in which core body temperature is maintained without triggering thermoregulatory homeostatic mechanisms such as sweating or shivering. In symptomatic women, small fluctuations in core body temperature can exceed this zone and trigger heat dissipation mechanism, such as sweating VOL. 101 NO. 4 / APRIL 2014

Fertility and Sterility® and peripheral vasodilation (which is experienced as a hot flash). Estrogen appears to widen this thermoneutral zone, thus reducing VMS (15). Finally, studies suggest a possible link between genetic polymorphisms and prevalence and severity of VMS. These involve variants in genes encoding estrogen receptor alpha (16, 17) and single nucleotide polymorphisms involved in the synthesis and metabolism of estrogens, such as those affecting enzymes (like sulfotransferase and aromatase) related to synthesis of and conversion to more or less potent estrogens (18). These polymorphisms may alter sex steroid hormone activity, but it is unknown whether these genetic determinants exert their effects centrally or peripherally (12). Longitudinal studies of the duration of women's experience of VMS have observed a median duration between 5 years to 10 years (19, 20). A small but significant percentage of women still report bothersome hot flashes 8 years after their final menstrual period (21). The identified predictors for VMS duration include earlier menopausal stage at onset of VMS, younger age at onset of VMS, and/ or being African American. They were all associated with longer duration of VMS, while obesity was associated with a shorter duration (20). Emerging data from SWAN have suggested a possible link between VMS and adverse physical health outcomes such as cardiovascular disease (CVD), as persistent VMS have been associated with measures of subclinical CVD indicating higher CVD risk, especially when associated with other CVD risk factors, such as obesity (22, 23). VMS were also linked to lower bone mineral density (24) and higher bone turnover (25). In contrast, other population based studies indicate that hot flashes with night sweats were associated with a reduced risk of death over the following 20 years (26). Further investigation is required to explore the precise nature and reasons for these associations.

VULVOVAGINAL ATROPHY Vulvovaginal atrophy with its symptoms of vaginal dryness, itching, dyspareunia, and irritation, is strongly and consistently linked to estrogen deficiency (27, 28). Similar to VMS, vulvovaginal atrophy is highly prevalent in menopausal and perimenopausal women. One survey study observed a prevalence rate of 45% among a large sample of women over the age of 45, progressing from 4% in early perimenopause to 21% in late perimenopause to 47% by 3 years after the final menstrual period (4). On the other hand, data from the observational cohort of the Women's Health Initiative (WHI) Study indicated a vulvovaginal atrophy prevalence of 27% (29). Among Hispanic women within the SWAN cohort, Central American women reported vaginal dryness more frequently than Puerto Rican/Dominican, South American, or Cuban women (30). Painful urination and frequent urinary tract infections can also occur in association with vulvovaginal atrophy. Unlike VMS, vulvovaginal atrophy does not improve without treatment. Other non-estrogen related etiologies for vulvovaginal complaints need to be ruled out, as various inflammatory conditions of the vulva like contact dermatitis, squamous VOL. 101 NO. 4 / APRIL 2014

hyperplasia, or lichen sclerosis can also cause such complaints (31). Evaluation should include inquiring about the use of exogenous agents like soaps, perfumes, powders, or panty liners, as these may mimic or exacerbate vulvovaginal irritation due to atrophy. Physical examination should include inspection of the vulva for obvious lesions, dermatoses, erythema, or inflammation, as well as signs of vaginal atrophy. Microscopic examination of vaginal smears can be used to assess the vaginal maturation index, which is the ratio of parabasal, intermediate, and superficial squamous cells. Vaginal pH can also be clinically useful to determine hormonal influence (31).

SLEEP DISTURBANCES Sleep quality declines with age, but the menopausal transition appears to contribute to this decline in women (32). Virtually all markers of subjective sleep quality seem to be impacted by the process of menopause. Self-reported measures of sleep quality include assessments of sleep latency, sleep duration, and wakefulness (33), while objectively measured sleep quality assesses sleep continuity, duration, and architecture as well as measures of sleep apnea (34, 35). Self-reported poor sleep increases as women traverse the menopause, it was reported in 38% of the 12,603 women who participated in the cross-sectional survey of the SWAN Study (32). As with most menopausal symptoms, severity and prevalence seem to peak during the late menopausal transition, when women are undergoing prolonged amenorrhea (32). Mechanisms through which VMS influence reports of poor sleep are not entirely known. It was found that hot flashes occurring in the first half of the night were associated with more awakenings and arousals than those occurring in the second half, possibly because rapid eye movement sleep, which is more frequent in the second half of the night, suppresses thermoregulation (36). A significant proportion of women find perimenopause as a particularly challenging period of life for preserving good sleep (37). SWAN data indicate that the menopausal transition is related to self-reported sleep difficulty, independent of age (32), indicating that age is not the primary determinant of the perimenopause–sleep relationship. Likewise, it was found that the perimenopause-sleep relationship is not entirely explained by VMS, as subgroup analyses restricted to women without VMS continue to find an association between the perimenopause and poor sleep quality (32). A number of additional variables that were associated with sleep difficulty included psychological (depression, anxiety) symptoms, self-perceived health, quality of life, less physical activity, current smoking and arthritis (32). Prevalence of sleep difficulty increased from premenopause to late perimenopause and plateaued through postmenopause, decreasing slightly in age-adjusted analyses from 45% in late perimenopause to 43% in postmenopause (32). Primary sleep disorders, such as sleep apnea and periodic limb movement disorder were also common at this age group, with 53% of women having either one or both in one cross-sectional study of women who reported disturbed sleep (35), and a lower prevalence in other studies (34). Beyond quality of life, sleep disturbances may increase the risk for developing adverse health conditions such as the metabolic 907

VIEWS AND REVIEWS syndrome and prelude to cardiometabolic disease (38). When evaluating women with sleep disturbances, it is important to exclude other medical (e.g. chronic obstructive pulmonary disease, hyperthyroidism), and psychiatric disorders (e.g. depression, anxiety), or medications (e.g. decongestants) that can contribute to sleep difficulty (39).

MANAGEMENT OF MENOPAUSAL SYMPTOMS Vasomotor Symptoms Lifestyle modifications are an appropriate first step to consider before initiating, or in conjunction with, pharmacologic therapies for VMS. These include avoiding smoking, and moderate alcohol use, as they were associated with VMS (3, 40). Despite limited supporting data, common sense lifestyle solutions such as dressing in layers, maintaining a low ambient temperature, and consuming cool drinks are reasonable measures for managing VMS (41). Aerobic exercise has not been associated with a consistent reduction in VMS (42), however, it favorably affects mood, perceived stress, and body image (19), and also decreases body weight, all of which may render VMS less bothersome. The WHI's dietary intervention trial indicated that weight loss was associated with a decreased prevalence of VMS among postmenopausal women (43). Other non-pharmacologic therapies that have been studied for treatment of VMS and showed possible benefit include paced respiration, a type of slow, deep breathing that requires training (44), clinical hypnosis (45), cognitive behavioral therapy (46), and mindfulness based stress reduction (47). These are summarized in Table 1. Most of these interventions are useful for mild-moderate symptoms as the effect is small and study designs frequently preclude definitive conclusions. These treatments have essentially no harm associated with their use, and thus they are very attractive to patients. Although not widely used at this time due to limited efficacy for severe symptoms, further studies may prove some of these interventions to be effective for the more bothersome VMS. Acupuncture was not shown to have benefit over placebo for VMS in a meta-analysis (48). A similar lack of efficacy was observed for yoga (49) and omega-3 supplementation (50). Other causes of flushing need to be ruled out in these women, such as emotional flushing, autonomic epilepsy, hyperthyroidism, medications (e.g. calcium channel blockers), alcohol related flushing, pheocromocytoma, and carcinoid syndrome (51).

Non-Hormonal. When menopausal hormone therapy (MHT) is contraindicated (e.g. a history of breast cancer) (Table 2), or by patient preference after counseling on the risks and benefits of MHT, non-hormonal medications can be used to alleviate menopausal symptoms. Trials for these medications provide evidence for efficacy, although they are less effective than estrogen (52), which often makes them suboptimal for the most severely affected women. With the exception of the low-dose paroxetine 7.5 mg for treatment of VMS, non-hormonal alternatives are not approved by the Food and Drug Administration (FDA) for this indication, and thus prescribing them is ‘‘off-label.’’ A list of these medications, with their common doses and side effects is summarized in Table 3. Selective Serotonin Reuptake Inhibitors and Serotonin– Norepinephrine Reuptake Inhibitors. Selective serotonin reuptake inhibitors (SSRIs) have been found efficacious in the treatment of VMS based on a number of randomized clinical trials (53–55). Once initiated, VMS relief usually occurs within a week (53), a far more rapid effect than the relief of depressive symptoms, which usually takes 6 weeks or longer. Paroxetine and fluoxetine are among the first SSRIs that have been used to treat hot flashes. Doses of either 12.5 mg/day or 25 mg/day of paroxetine were studied in a randomized, controlled trial of 165 women who were treated for 6 weeks. Both doses significantly reduced hot flashes composite scores (62.2% and 64.6%) when compared with placebo (37.8%) (53). Paroxetine was recently approved by the FDA in a 7.5 mg formulation for the treatment of VMS. Furthermore, a randomized, placebocontrolled trial of 20 mg fluoxetine administration in 81 breast cancer survivors showed a reduction in hot flashes by 20% in women treated with fluoxetine for 4 weeks when compared to the placebo treated group (54). Escitalopram,

TABLE 2 Contraindications for menopausal hormone therapy. Condition History of breast or endometrial cancer Porphyria History of thromboembolic disease Unexplained vaginal bleeding


Active liver disease Acute cardiovascular disease Immobilization

Nonpharmacologic interventions that have been studied and showed possible benefit for treatment of vasomotor symptoms.

History of coronary artery disease or stroke Hypertriglyceridemia

Intervention Stellate ganglion blockade Paced respiration Clinical hypnosis Cognitive behavioral therapy Mindfulness based stress reduction Al-Safi. Menopausal symptoms and hormone therapy. Fertil Steril 2014.


Reference 109 44 45 46 47

Atypical ductal hyperplasia of the breast Uncontrolled hypertension Active gallbladder disease Migraine headaches

Reason for contraindication May be exacerbated with hormones May be exacerbated with hormones May increase risk for thromboembolism Need to rule out neoplasia, as it may be exacerbated with hormones Estrogen is metabolized in the liver May be exacerbated with hormones May increase risk for thromboembolism May be exacerbated with hormones May increase risk for thromboembolism May increase risk of progression to malignancy May increase risk of cardiovascular disease May be exacerbated with hormones May increase risk of stroke

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TABLE 3 Nonhormonal medications for treatment of vasomotor symptoms. Treatment



7.5 mg/d–25 mg/d


20 mg/d


10 mg/d–20 mg/d


37.5 mg/d, 75 mg/d, or 150 mg/d


Oral dose: 0.025 mg/ twice daily–0.075 mg/twice daily; transdermal dose: 0.1 mg/d 100 mg/d–900 mg/ d in divided doses


Common side effects Nausea, headache, insomnia, and possible sexual dysfunction Nausea, headache, insomnia, and possible sexual dysfunction Nausea, headache, insomnia, and possible sexual dysfunction Nausea or vomiting, dry mouth, anorexia, and possible sexual dysfunction Dry mouth, insomnia, drowsiness, skin reaction with the transdermal skin patch Dizziness, unsteadiness and drowsiness

Al-Safi. Menopausal symptoms and hormone therapy. Fertil Steril 2014.

another SSRI, was found in a randomized controlled trial to be effective in reducing hot flashes when compared to placebo. A dose of 10 mg/day to 20 mg/day for 8 weeks improved women's quality of life and this benefit did not vary by baseline demographic, clinical, mood, sleep, or other symptom variables (55). The most common side effects of SSRIs are nausea, headache, and insomnia. Use of the lowest possible dose may minimize these effects. Ever since the identification of serotonin receptors and transporters in osteoblasts, osteocytes, and osteoclasts (56– 58), concern has been raised that medications that block serotonin reuptake may affect bone metabolism, resulting in bone loss. Data from one longitudinal study showed an association of increased bone loss with SSRI use in older women (mean age, 80 years) (59), while another one using data from the WHI did not observe such an association (60). Finally, data from SWAN showed that SSRI use does not appear to have adverse effects on bone loss during the menopausal transition (61). Venlafaxine is a combined serotonin and norepinephrine reuptake inhibitor (SNRI) that has shown promise in reducing the severity of VMS in symptomatic women. A randomized trial was conducted in 229 women for 4 weeks where women received varying doses of venlafaxine (37.5 mg/day, 75 mg/ day, or 150 mg/day) versus placebo. There was a significant reduction in VMS scores in women receiving all doses of venlafaxine in comparison to the placebo (37%, 61%, and 61%, compared to 27% for placebo) (62). Common side effects included nausea, which is temporary in most cases and largely resolved with time (62). Other side effects include mouth dryness, and anorexia. VOL. 101 NO. 4 / APRIL 2014

The mechanism of action of SSRIs or SNRIs in relieving VMS is not known, it has been hypothesized that temperature increases associated with VMS could be linked to an overloading of serotonin-receptor sites in the hypothalamus (53). SSRIs, especially paroxetine and fluoxetine, must be used with caution in women with breast cancer receiving adjuvant tamoxifen therapy since SSRIs reduce the metabolism of tamoxifen to its most active metabolite, endoxifen, by inhibition of the cytochrome P450 enzyme, CYP2D6, an effect that was not seen with venlafaxine (63). Sexual dysfunction has been reported with SSRIs and SNRIs when used in treatment for depression, ranging from 32.5% in one study (64) to 58–73% in another (65). However, this adverse effect has not been observed in studies assessing the usefulness of lower doses of paroxetine or venlafaxine for treatment of VMS (53, 62, 66). One explanation for this discrepancy, therefore, may be related to dosing. Another explanation may be that the depression requiring treatment with the SSRI or SNRI is the root cause of the sexual dysfunction (67, 68). When sexual dysfunction occurs, management strategies usually include changing to another medication (69), or adding a sexual stimulant such as buspirone (70). Although the reduction is not as large as what is seen with MHT (usually 75% to 80%), the SSRIs result in a modest improvement in symptoms and are acceptable for many women (51), but adverse effects may prohibit their use for others. These therapies may be most useful for highly symptomatic women who cannot take estrogen (52). Clonidine. Clonidine, an a2-adrenergic agonist, may resolve VMS by reducing peripheral vascular reactivity. Data also have shown that clonidine lowers hypothalamic norepinephrine levels (71) and raises the sweating threshold in symptomatic postmenopausal women (72) suggesting a possible central mechanism of action on thermoregulatory centers. Trials of clonidine in doses ranging from 0.025 mg twice daily to 0.075 mg twice daily for the oral dose and 0.1 mg per day for the transdermal dose reported inconsistent results, with approximately half of trials demonstrating significantly reduced hot flash frequency or severity for up to 38% reduction in hot flash frequency compared with 24% for placebo (73). Although most trials met criteria for poor quality, the 3 fair quality trials provided a combined estimate of approximately 1 hot flash per day reduction with clonidine (52). Main adverse effects included dry mouth, insomnia, drowsiness, and skin reaction with the transdermal skin patch. Postural hypotension is also a potential concern with clonidine. Gabapentin. Gabapentin provides another potential nonhormonal therapeutic option for the treatment of VMS. One randomized controlled trial of gabapentin (900 mg/day) demonstrated a 45% reduction in hot flash frequency and a 54% reduction in symptom severity compared with 29% and 31% reductions, respectively, for placebo (74). Another randomized, double-blind, placebo-controlled trial (75) was conducted on 197 women aged 45 years to 65 years, all of whom were menopausal and having at least 14 hot flashes per week. These women were randomized to receive either 909

VIEWS AND REVIEWS gabapentin 900 mg daily or placebo for 4 weeks. Of women assigned to receive gabapentin, hot flash scores decreased by 51% as compared with a 26% reduction in the placebo group, from baseline to week 4. Women randomized to gabapentin reported greater dizziness, unsteadiness and drowsiness at week 1 compared with those taking placebo; however, these symptoms improved by week 2 and returned to baseline levels by week 4. A 2009 meta-analysis confirmed these results (76). Therefore, gabapentin seems to be an effective and well-tolerated treatment for VMS, and may be especially helpful for women whose chief complaint is night sweats and resulting poor sleep. Gabapentin is also effective in treatment of restless leg syndrome (77), a common disorder that might be responsible for poor sleep. A gastroretentive (extended release) form of gabapentin has been studied and shown to be modestly effective in treatment of VMS compared to placebo (78), with lower rates of dizziness and somnolence that decreased throughout the study. The mechanism of action of gabapentin is unclear. Increased activity of neurotransmitters in the hypothalamus as a consequence of up-regulation of the gabapentin binding site from estrogen withdrawal has been proposed (79). Gabapentin might exert its effect on VMS by this mechanism. Menopausal Hormonal Therapy. Estrogen, with or without a progestogen, is the most effective treatment for menopause related VMS and urogenital atrophy (80, 81). Since the publication of the WHI trials results, the last 10 years have witnessed dramatic changes in the approach to the management of menopause. The lack of effectiveness of MHT for long-term cardioprotection and a number of small increases in harms have led to a movement away from this treatment. The most concerning risk of combined estrogenprogestin MHT was a small but increasing risk of breast cancer over time (82). This risk was not present in women who have had a hysterectomy and took estrogen alone (83). A recent analysis of the long-term outcomes of women from the WHI indicates that short-term use of hormones, as given in the WHI, is associated with little increased overall risk (84), and they remain a viable option for symptom relief. Estrogen reduces the severity and frequency of VMS by more than 70%, usually within one month (85). However, estrogen treatment is associated with a small but significantly increased risk of some serious diseases, specifically stroke and venous thromboembolism (VTE) (83, 86). When combined with a progestin, there is an additional increased risk of breast cancer (82), and a marginal risk for increased coronary events, which dissipates over time (87). Breast tenderness and uterine bleeding are among the most common adverse effects; others include nausea and vomiting, headaches, weight change, rash and pruritus, and cholecystitis.

Vulvovaginal Atrophy Until very recently, estrogen was the only effective prescription treatment for moderate to severe symptoms of vulvar and vaginal atrophy (e.g., vaginal dryness, dyspareunia, and atrophic vaginitis) (88). Over-the-counter lubricants and moistur910

izers may be tried, but are seldom beneficial for the more severely affected women. Locally administered estrogen is available as a cream, gel or pill and can be used to relieve vaginal dryness and dyspareunia. In the low doses commonly available, opposing the estrogen with progestin is not necessary; however, endometrial safety should not be assumed and any abnormal vaginal bleeding should be investigated immediately (80). Some clinicians may prefer to conduct ongoing endometrial surveillance when low dose vaginal preparations of estrogen are used for a prolonged period of time, as clinical trial data supporting endometrial safety beyond 1 year are lacking (89). Even though both systemic and local estrogen regimens are FDA approved for treating symptomatic vaginal atrophy, some of the very low dose systemic estrogen regimens may be inadequate for the relief of these symptoms, requiring the addition of local estrogen. However, if MHT is considered solely for the treatment of vaginal atrophy, local vaginal estrogen is advised over systemic estrogen. Lower doses of vaginal estrogen therapy than previously used, with less frequent administration, often yield satisfactory results (90). Estrogen Receptor Agonist/Antagonist. Ospemifene is a novel non-steriodal, non-hormonal estrogen receptor agonist/antagonist, also known as selective estrogen receptor modulator (SERM), which was recently approved by the FDA for use in treatment of dyspareunia related to menopausal vulvovaginal atrophy. A randomized, controlled trial compared oral 60 mg/day of ospemifene to placebo for 12 weeks and indicated significant beneficial changes in the vaginal epithelium and reduction in dyspareunia, with hot flashes as the most frequently reported adverse event that occurred in 6.6% of participants in the ospemifene group (91). In this study, all participants that were randomized had moderate-severe dyspareunia. The percentage of participants, in the intent to treat analysis, reporting no vaginal pain or mild vaginal pain with sexual activity on week 12 was greater in the ospemifene group (38.0%, and 25.1%, respectively) than in the placebo group (28.1% or 19.2%, respectively). Other reported adverse events included urinary tract infection, vaginal discharge, vulvar and vaginal mycotic infections, nasopharyngitis, and headache. All participants in that study were provided with non-hormonal lubricants to be used as needed, with a similar proportions of participants use in the first week of the study, and then the percentage of women using lubricants somewhat decreased for both groups, but more so in the ospemifene group (91). Ancillary studies suggest a possible beneficial effect of ospemifene on bone, reducing bone turnover, as was assessed using urinary markers for bone resorption and formation in one clinical trial (92). Also, animal studies suggested antiestrogenic activity in breast cancer models similar to tamoxifen and raloxifene (93). Further studies will be needed to address these endpoints as well as defining its safety profile for long-term use.

Sleep Disturbances As far as the role of MHT in treatment of perimenopausal sleep disturbances, it was found that MHT alone might be insufficient intervention for improving sleep quality except in VOL. 101 NO. 4 / APRIL 2014

Fertility and Sterility® postmenopausal women (5). Nonetheless, the clinician may decide, in partnership with the patient, to try empiric MHT along with behavioral methods to improve sleep. Cognitivebehavioral interventions can be very helpful in treatment of insomnia, and improve sleep; these may include sleep hygiene education, stimulus control, and relaxation training. These methods are comparable with or superior to hypnotic medications (39). For some women, the consolation that sleep will improve somewhat after the menopausal transition is sufficient.

MENOPAUSAL HORMONAL THERAPY REGIMENS The symptom relief from MHT is primarily due to the estrogen. A progestin is added to negate the increased risk of endometrial cancer from systemic estrogen use. All women with an intact uterus need to be prescribed an adequate progestin in addition to estrogen. Progestins can be given continuously or in a cyclic fashion. Cyclic regimens are more likely to cause withdrawal bleeding than are continuous regimens (94). The cyclic regimens were theoretically aimed at decreasing the duration of exposure to progestins to mitigate long-term risks associated with MHT, especially breast cancer. However, in the absence of evidence that a cyclic regimen is superior, patient preference seems like the most reasonable approach. The most comprehensive data on breast cancer risk with combined estrogen-progestin come from the WHI (82). It should be

recognized that medroxyprogesterone acetate was given continuously and it is possible but not proven that other regimens of progestins would have a different breast cancer risk profile. Progestins may be administered orally, transdermally, or vaginally. The use of a levonorgestrel-containing intrauterine system has also been advocated to minimize systemic exposure to progestins while providing endometrial protection, with one small study reporting equivalent endometrial protection compared to a systemic progestogen (95). Longterm data, however, are lacking. Vaginal progesterone and the progestin-containing intrauterine system are FDA approved for premenopausal women but not for postmenopausal women. The type of progestin is also being investigated to determine whether the breast cancer risks of combined estrogen and progestin MHT can be mitigated. Micronized progesterone has been suggested to be safer than medroxyprogesterone acetate used in the WHI trials, based on observational data (96, 97). Estrogen dose and routes of administration also vary in regard to their risks. Lower doses are associated with less adverse effects like breast tenderness or uterine bleeding, and may have a more favorable benefit-risk ratio than standard doses. Transdermal estrogen is preferred to the oral route, as the latter is subject to first-pass hepatic metabolism which promotes prothrombotic hemostatic changes in factor IX, activated protein C resistance, and tissue-plasminogen activator (98). Furthermore, observational data from the Estrogen and Thromboembolism Risk (ESTHER) Study, a

TABLE 4 Menopausal hormone therapy preparations. Preparation Estrogen Oral 17 b-Estradiol Ethinyl estradiol Conjugated estrogen Transdermal 17 b-estradiol patch 17 b-estradiol gel 17 b-estradiol spray 17 b-estradiol emulsion Vaginal 17 b-estradiol vaginal cream Conjugated estrogen vaginal cream 17 b-estradiol vaginal tablet 17 b-estradiol vaginal ring Progestogen Oral Medroxyprgosesterone acetate Norethindrone acetate Drospirenone Micronized progesterone Transdermal Norethindrone acetate Levonorgestril

Starting dose


0.5 mg/d 2.5 mcg/d 0.3 mg/d–0.45 mg/d

1 tablet/d 1 tablet/d 1 tablet/d

0.014mg/d–0.0375 mg/d 0.25 mg/d or 0.75 mg/d

1 patch twice/wk 0.25 g gel daily 1.25 g gel daily 1spray daily 2 foil-laminated pouches/d

1.53 mg/d 8.7 mg/d 0.2 mg (2 g of cream)/d 0.3125 mg (0.5 g of cream)/d 10 mcg/d 2 mg/ring (7.5 mcg/d) or 12.4 mg/ring (50 mcg/d) 1.5 mg/d–2.5 mg/d

2 g–4 g daily for 2 wk, then taper to maintenance dose of 1 g 1 to 3 times/wk 0.5 g daily for 21 d on and 7 d off or twice/wk 1 tablet/d for 2 wk, then 1 tablet twice/wk 1 ring/90 d

0.1 mg/d 0.25 mg/d 100 mg/d–200 mg/d

Daily in combination preparations or 14 d/mo; 1.5 mg with 0.3 mg of conjugated estrogen combination Daily in combination preparations or 14 d/mo Daily 100 mg/d continuously or 200 mg/d for 12 d/mo

0.14 mg/d 0.015 mg/d

1 patch twice/wk 1 patch/wk

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VIEWS AND REVIEWS multicenter case-control study of thromboembolism among postmenopausal women, demonstrated an odds ratio for venous thromboembolism in users of oral estrogen to be 4.2 (95% CI, 1.5–11.6) and 0.9 (95% CI, 0.4–2.1) for transdermal estrogen, compared to nonusers (86). This approach has been endorsed by the American College of Obstetricians and Gynecologists, as gynecologists were recommended to take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy (99). Various MHT regimens with dose ranges are summarized in Table 4.

NEWER TREATMENT MODALITIES Tissue Selective Estrogen Complex Tissue selective estrogen complex (TSEC) is a combination of estrogen and a SERM. In an attempt to mitigate the adverse effects from combining a progestin with estrogen, specifically breast cancer, TSECs were developed so to retain the efficacy of estrogens in treating menopausal symptoms and preventing osteoporosis while ensuring tissue safety via the non-stimulating effects of a SERM on the uterus and breast (100). Bazedoxifene is a SERM that acts as an estrogen receptor antagonist in the endometrium and on breast cancer cells treated with estrogen, but acts as an estrogen agonist on bone (101). A combination conjugated estrogen 0.45 mg and 20 mg bazedoxifene tablet has been recently approved by the FDA for the treatment of menopausal symptoms and the prevention of osteoporosis in non-hysterectomized women, and was found effective in reducing VMS frequency and severity, as well as sleep parameters when compared to placebo (100). It can be an alternative to conventional combined estrogenprogestin therapy. Its efficacy and safety have been evaluated in randomized controlled trials (102, 103), but long-term data are lacking.

DURATION OF MENOPAUSAL HORMONAL THERAPY AND FOLLOW-UP The duration of MHT should be based on a woman's symptoms, preferences, and her benefit-risk profile. The North American Menopause Society has indicated that extending estrogen-progestin therapy with the lowest effective dose is acceptable if it is determined that the benefits of menopausal symptom relief outweigh the risks. Women at high risk of fracture, for whom alternate therapies are not appropriate or cause unacceptable adverse effects, may also choose to continue with MHT (80). Women who continue MHT well beyond their menopause should be well aware of the potential benefits and risks and have ongoing clinical supervision (80). It is still agreed upon that providers should prescribe the lowest dose of MHT for the shortest duration needed to manage menopausal symptoms. For combined estrogen and progestin, the duration is limited by a cumulative risk of breast cancer. This increased risk becomes detectable by 3 years to 5 years of use (104, 105). Estrogen only therapy has a more favorable safety profile. When observed over 7 years of 912

use and over 6 years of follow up, a significant decrease in breast cancer was observed (84), allowing more flexibility in duration of use. Thus, because symptoms can remit over time, periodic weaning is recommended to assess the need for MHT. There is no documented schedule for periodic weaning that has been shown to be better than others. Annual to biannual withdrawal has been recommended.

DISCONTINUATION OF MENOPAUSAL HORMONAL THERAPY VMS have an approximately 50% chance of recurring when MHT is discontinued, independent of age and duration of use (106, 107). Bone resorption accelerates when MHT is discontinued, and vulvovaginal atrophy should be expected to recur. Other risks and benefits return relatively rapidly to baseline, with the exception of breast cancer, which persists somewhat longer (a few years) (108).

CONCLUSION Menopausal symptoms are better understood than ever before, as we have accumulated a number of cohorts of longitudinal data to elucidate their natural history. We have a wider repertoire of agents for successful treatment. The choice of a particular modality should be guided by the patient's risk profile, other symptoms and preferences. Although hormones are overall the most effective for treatment of menopausal symptoms, some patients may choose non-hormonal treatments or they may be contraindicated. The available non-hormonal therapies can be individualized based on their primary mode of action, for example a woman with hot flashes and restless leg syndrome as her primary complaints and doesn't wish to take hormones, gabapentin would be a first choice, or a hypertensive woman who has vasomotor symptoms and estrogen is contraindicated, may benefit from clonidine. We have also accrued substantial knowledge about the risks of MHT which can be mobilized to derive new agents that avoid or mitigate these risks.




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Menopausal hormone therapy and menopausal symptoms.

A majority of women will experience bothersome symptoms related to declining and/or fluctuating levels of estrogen during their menopausal transition...
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