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The menopausal woman: The need for an individualized plan of care

Pace, Diane Todd PhD, APRN, FNP-BC, NCMP, FAANP

doi: 10.1097/01.NPR.0000526765.60971.37
Feature: WOMEN'S HEALTH

Abstract: With life expectancy increasing, women will spend one-third of their lives in and beyond menopause. A collaborative discussion with the clinician facilitates informed decision-making and should include evidence-based discussion of physiologic changes, assessment of symptoms and treatment options, review of screening recommendations, and discussion of disease risk-reduction strategies and psychosocial issues.

With life expectancy increasing, women will spend one-third of their lives in and beyond menopause. A collaborative discussion with the clinician facilitates informed decision-making.

Diane Todd Pace is an associate professor/director of special academic programs at the University of Tennessee Health Science Center, College of Nursing, Memphis, Tenn. She is past president of the NAMS.

The author has disclosed the following financial or professional relationships related to this article: Hologic, Pfizer Pharmaceutical, Allergan Pharmaceutical, AMAG Pharmaceuticals, TherapeuticsMD, JDS Therapeutics, and NAMS.

The author would like to acknowledge Curtis Roby, scientific writer at the University of Tennessee Health Science Center, College of Nursing, for his assistance in editing the manuscript.

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In the United States, over 2 million women enter menopause each year. Current estimates suggest 41 million women are currently at menopausal age. By 2020, it is projected the number of U.S. women over age 51 (the average age of natural menopause) will be greater than 50 million.1 Current research findings must be used when making recommendations to patients regarding menopause-related issues.

The North American Menopause Society (NAMS) stresses that menopause provides a unique opportunity for dialogue between women and their clinicians to evaluate and improve health-related practices.2 Engaging in discussion sets the stage for a collaborative effort with the clinician and facilitates informed decision-making among midlife and older women.

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Physiologic changes

Menopause is a normal physiologic event and not a disease. Unless induced through bilateral oophorectomy or iatrogenic ablation of ovarian function (such as chemotherapy or pelvic radiation secondary to illness), it occurs spontaneously as a normal and natural event. The Study of Women's Health Across the Nation (SWAN)—a longitudinal, multiethnic, community-based observational study of women at midlife—has followed over 3,000 women from multiple states and racial/ethnic groups and found that menopause occurs at 52.54 years regardless of racial or ethnic group, age of menarche, or number of lifetime pregnancies.

This age can vary from 40 to 58 and is defined as the final menstrual period (FMP).1 Menopause is confirmed with the retrospective acknowledgment of absence of menstruation for 12 consecutive months. There is no “universal menopause syndrome” across ethnic groups and no absolute clinical biologic markers during menopause transition.3

The Stages of Reproductive Aging Workshop+10 (STRAW+10) has developed a staging system to clearly communicate physiologic changes occurring during the final 10 to 15 years of a woman's reproductive life.3 STRAW+10 criteria divide these times into three broad phases: reproductive, menopausal transition, and postmenopause. Seven stages center on the FMP (stage 0). The menopause transition phase is classified into stages -2 (early) and -1 (late), with variability in menstrual cycle length and increasing levels of the follicle-stimulating hormone. Menstrual variability is normal, and chronologic age does not accurately predict reproductive ability.

Using the STRAW+10 model can improve clinical decision-making by articulating where the woman is in the menopausal continuum. The lack of standardized lab assays has failed to translate research findings into cost-effective clinical tools. Following 12 consecutive months of amenorrhea, follicle-stimulating hormone levels will be greater than 30 mIU/mL with a subsequent reduction in estrogen levels. Baseline testing in menopause transition is seldom necessary and may be financially challenging unless results would affect interventions; the intervention can be initiated based on symptoms present during the encounter.2 Menstrual cycle changes are generally the best predictor of menopause stage. Salivary hormone testing of reproductive hormones has not been found to be valid or reliable and is not indicated for clinical practice.2

Conditions such as thyroid disease, infection, insulinoma, pheochromocytoma, autoimmune disorders, new-onset hypertension, diabetes mellitus, and autonomic dysfunction may cause symptoms similar to those in menopausal transition and should be considered (if necessary) in the differential diagnoses.1 With irregular cycles and fluctuating hormones, it is critical to counsel the woman at midlife that pregnancy is possible until menopause occurs and contraception options should be discussed if appropriate.

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Vasomotor symptoms

Although not all women progressing through menopause will experience bothersome symptoms, the most reported (at a rate of 75%) are vasomotor symptoms (VMS).1,2,4 Researchers with a large cross-sectional survey of 2,020 women with moderate-to-severe VMS found these symptoms were negatively associated with psychological well-being in women at midlife.5 Results from SWAN also suggested VMS may be independently associated with an elevation in cardiovascular risk and risk of osteopenia.6-8

The precise mechanism and triggers for VMS are not fully understood. VMS is a global term referring to hot flashes, hot flushes, and night sweats during menopause and is often associated with complaints of heat in the face, neck, and chest. Women usually experience the following cascade of symptoms:

  • increased core body temperature, blood flow to the skin, and heart rate
  • intense feeling of heat with reddening of the upper body
  • increased heart rate peak and skin blood flow peak and sweating
  • chills and shivering.8

Heart rate may increase as much as 7 to 15 beats/minute, and skin temperature may take as long as 30 minutes or more to return to baseline. Night sweats occurring during sleep hours are often associated with excessive perspiration, feeling overheated, and disrupted sleep.1

Recent studies have indicated that women may experience VMS much longer than previously thought. The median total VMS duration is 7.4 years, but some women can experience symptoms as long as 12 years.4 Black women report the longest duration with a median of 10.1 years. The following are also associated with extended duration: younger age at onset of menopause, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at onset of symptoms.4

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Genitourinary syndrome of menopause

As declining estrogen levels occur in the postmenopausal period, changes in the vagina, vulva, and urinary tract also occur. The vagina loses elasticity, shortens, narrows, and may be easily traumatized and irritated with loss of rugae. On exam, surfaces are thin, pale, and dry, and petechiae may be present; the vaginal pH will be greater than 5.0, and parabasal cells replace normal vaginal epithelium. Repopulation with diverse vaginal flora occurs, which may result in urinary tract infections. Vaginal secretions significantly decrease, affecting natural lubrication during sexual stimulation. With all of these changes, many women will also complain of dyspareunia.9

The term vulvovaginal atrophy is frequently used to refer to these changes in the vaginal and vulvar areas. In 2012, however, a panel from several large women's health organizations convened to discuss the need for more acceptable terminology and found that vulvovaginal atrophy did not include the anatomical area of the urinary tract also affected by estrogen deficiency. The panel acknowledged a new term was needed, and the term genitourinary syndrome of menopause (GSM) was adopted.10

Symptoms of GSM should be evaluated by clinicians during the annual/periodic women's exam before the onset of symptoms. Two large studies—the Vaginal Health: Insights, Views, & Attitudes survey and the REal Women's VIew of Treatment Options for Menopausal Vaginal ChangEs (REVIVE) survey—examined the impact these symptoms had on women. Both studies reported that participants with vulvovaginal atrophy complained of having a lower quality of life (QOL), with symptoms having a negative effect on their lives as well as their sexual health.11,12

Most clinicians are reluctant to initiate discussions regarding sexual health or complaints about vaginal discomfort. In the REVIVE survey, although approximately half of the study participants had no discussion about their VVA symptoms with their clinician, 40% expressed their expectation that the provider should initiate this conversation. When these conversations occurred, only 13% of clinicians had initiated them.12 Results from these studies should prompt clinicians to initiate conversations early before the onset of symptoms, informing patients that VVA/GSM is a common disorder experienced by most postmenopausal women due to decreasing levels of estrogen, and if left untreated, will worsen over time. Clinicians should assess for early clinical changes and discuss options for preventing and/or treating this disorder.12

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Management of menopause-related symptoms

Because there is no single menopausal syndrome, individualizing a plan of care for each woman is an important part of preparation to manage menopause transition through the postmenopausal reproductive period. For some women, it will be guiding them toward choices for ensuring a healthy lifestyle, risk reduction, and health promotion. Counseling a midlife woman and any treatment options for symptom interventions should be individualized based on underlying health, risk factors, and symptoms.1

Social, cultural, racial, and ethnic differences; the frequency and severity of menopause-related symptoms; attitudes toward menopause; and knowledge of and attitudes about available therapies all affect the way women respond to recommended plans of care. Respect for these differences, providing evidence-based information, and collaborating will help women make informed treatment choices.

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Management of VMS

The most common reason a woman seeks care from her clinician during menopause transition is for VMS. Once the clinician determines that VMS symptoms are due to menopause, there are many options available for discussion.

Complementary and integrative health. Including options of vitamins, supplements, and prayer, 62% of individuals in the United States use some form of complementary and integrative health as an option for health interventions.2 Herbal products such as black cohosh and soy isoflavones as well as acupuncture have been studied to reduce VMS. NAMS has published an evidence-based position statement discussing various nonhormonal options.13 Guidelines suggest these options can be considered when hormone therapy (HT) is either not an option because of medical contraindications or the woman chooses not to use hormonal or other pharmacologic interventions. Consideration of costs, time, and effort involved as well as potential of adverse reactions; the lack of long-term studies; and potential supplement or herbal product interactions with prescribed or over-the-counter (OTC) medications need to be considered and discussed with the patient.13

Although some of the following options were considered by NAMS as having no validated level of evidence to recommend as effective, some women have found they reduce VMS on an individual basis with few adverse reactions.1,13 In small studies, other measures were found to be effective or had associated lifestyle benefits:

  • exercise
  • cooling techniques (cooling pads and pillows, fans)
  • avoiding triggers (hot drinks, spicy foods)
  • yoga
  • weight loss
  • paced respirations
  • relaxation
  • hypnosis
  • dressing in layers
  • smoking cessation
  • clothing/pajamas or gowns/bedsheets/pillowcases made from wicking fabric.

The National Center for Complementary and Integrative Health provides evidence-based resources along with research results and clinical practice guidelines.14 Because many women purchase OTC supplements to alleviate minor symptoms and these products are not regulated by the FDA, clinicians should have concerns regarding safety, purity, and efficacy, as well as potential for drug/herb interactions and adverse reactions. Women should be queried to identify any supplements they may be taking.

A variety of complementary/alternative approaches for management of VMS (including acupuncture, herbal products, dietary soy, and isoflavone products) have been found to be similar to that of placebo.2 Two specific supplements (black cohosh and Swedish flower pollen extract) have been identified as options for managing VMS.13

In multiple trials conducted on black cohosh with peri/postmenopausal women, the supplement appeared to be effective for some women; however, in randomized controlled trials, the supplement was no different than placebo in reducing VMS.13 In some studies, it has shown no effect on endometrial tissue as demonstrated on ultrasound.13 There have been limited reports of possible hepatotoxicity with use of black cohosh, so a warning statement is included that indicates patients should discontinue if they develop symptoms of liver trouble.13

A proprietary extract from Swedish flower pollen (Relizen), although new to the U.S. market, has been available in Europe since 1999. In several small clinical trials, the supplement was found to have significant reductions in VMS on the Menopause Rating Scale and daily diaries, in providing a nonestrogenic alternative to HT, and in inhibiting the CYP2D6 metabolic pathway used to metabolize tamoxifen.15-18

There are mixed results on the effects of soy-based isoflavones on VMS, showing they are modestly effective. Supplements providing higher proportions of genistein or increased S-equol have been suggested to provide more benefits.19 Isoflavones can be found in a variety of products, including oral supplements, soybeans, soy protein, tofu, and yogurt.19 Recommending the right product and determining if the patient is able to metabolize the supplement to S-equol pose challenges for the clinician. The efficacy of isoflavones on bone and cardiovascular outcomes, although of interest, has not been demonstrated.19

Pharmacologic hormones. Systemic HT is the most effective treatment for moderate-to-severe menopausal VMS, which has been demonstrated in numerous randomized controlled trials over many years.1 Additional FDA indications for the use of systemic HT include prevention of bone loss and VVA/GSM. Deciding which pharmacologic interventions to recommend should be based upon an individualized plan that considers a woman's health status, personal preference, financial considerations, and adverse reactions. Tables listing all government-approved therapies for menopausal symptoms in the United States and Canada are available on the NAMS website (www.menopause.org/docs/default-source/professional/nams-ht-tables.pdf).

Following the abrupt termination of the Women's Health Initiative (WHI) trial in 2002, systemic HT use dropped by as much as 80% among U.S. women.20 Even though more than 18 years of data since the WHI have added to clinical knowledge of the risk/benefit balance of prescribing hormones in the postmenopausal period, many women continue to be fearful of accepting a prescription for HT, and many clinicians remain confused by the changing evidence base. However, there continues to be literature published interpreting data from the WHI, helping clinicians understand the risks, benefits, and effectiveness of HT. A recent manuscript reporting on 18 years of cumulative follow-up from the WHI received national media attention. Among postmenopausal women, HT with conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (for a median of 5.6 years or with CEE alone for a median of 7.2 years) was not associated with risk of all-cause, cardiovascular, or cancer mortality.21

In 2016, the Revised Global Consensus Statement on Menopausal Hormone Therapy, which was endorsed by seven scientific and medical societies, agreed that menopausal HT “...is the most effective treatment for VMS associated with menopause at any age, but benefits are more likely to outweigh risks if initiated for symptomatic women before the age of 60 years or within 10 years after menopause.”22 The statement corroborates the recently published 2017 HT position statement of the NAMS, which was endorsed/supported by 33 professional organizations.23 This evidence-based statement moves from previous recommendations of “the lowest dose for the shortest period of time” to individualizing the plan for each woman based on “the most appropriate type, dose, formulation, route of administration, and duration of use of hormone therapy...based on the unique risks of the woman, age or time from menopause, and goals of therapy.”23

Many prescription therapies have been approved by the FDA to manage menopausal symptoms, including estrogens available in oral, transdermal, and topical formulations. All routes of administration can effectively treat menopausal symptoms; oral estrogen is the most widely used.1 Transdermal routes may offer advantages and disadvantages compared with oral, especially observational data showing a positive effect through a lower risk of deep vein thrombosis (DVT).1,24

There is no first-pass hepatic effect with transdermal therapy; therefore, there is no significant increase in triglycerides or C-reactive protein. For patients with metabolic syndrome or hypertriglyceridemia, a transdermal product might be a better option. Multiple transdermal regimens are available, but there is no consensus and insufficient evidence to recommend any one.1

Although there are many prescribing regimen options, with each having advantages and disadvantages, the continuous-combined regimen is predominately prescribed in North America.1 Clinicians providing supervision should be alert to the need for special endometrial monitoring that might be necessary in the presence of breakthrough vaginal bleeding persisting for more than a few months after initiating HT or if there is continued concern regarding the rationale for the onset of bleeding.1

Generally, no evaluation is required for the woman who may experience a short, self-limiting episode of bleeding soon after discontinuing estrogen-progestogen therapy. However, the presence of unexplained vaginal bleeding in menopausal women creates a high level of suspicion of endometrial cancer and requires assessment to exclude malignancy. It can be evaluated through transvaginal ultrasonography and/or endometrial biopsy as appropriate. When initially assessing via ultrasonography, an endometrial thickness of 5 mm or greater or the inability to visualize the endometrium adequately requires endometrial sampling. Further evaluation is also required if there is persistent uterine bleeding—even in the presence of a prior benign endometrial biopsy.1

In women with a uterus, when administering estrogen, coadministration of progestogen is required due to increased risk for endometrial hyperplasia/cancer with treatment of unopposed estrogen.23 Multiple combination formulations are available. Additionally, an oral micronized progesterone may be an option to provide the lowest dose of concomitant dosing with estrogen. This medication often causes somnolence and should be dosed at bedtime; it should be avoided in women who have a peanut allergy.23

A product approved by the FDA in 2013 contrasted the need for combination of progestogen with estrogen for endometrial protection. The tissue-selective estrogen complex combines 0.45 mg CEE with 20 mg bazedoxifene, a selective estrogen receptor modulator, for the treatment of VMS and prevention of osteoporosis among women with a uterus.23 In women who have had a hysterectomy, the addition of a progesterone/progestogen or CEE with bazedoxifene is not needed.1,2,23

Local vaginal estrogen is recommended as the best intervention when only vaginal symptoms are present.1,2,23 Available in multiple formulations, estrogen may be used as long as needed to treat or prevent GSM. Organizations, including NAMS, do not recommend routine use of progestogen for endometrial protection given the very low dose of vaginal estrogen and minimal to no systemic absorption. However, clinicians should follow up on any reported spotting or bleeding.1,2,9,23 Because of the minimal to no systemic absorption, women who are survivors of endometrial or breast cancer may be considered candidates for treatment with vaginal estrogen therapy if nonhormonal options are not successful. Decisions should involve an oncologist.1,2,23

Given that the risks and benefits are lower in women under age 60 and less than 10 years from menopause, there may be concern for extended use of HT in older women. However, many women will continue to have VMS beyond age 65, with these symptoms continuing to negatively affect health and QOL.4 Given these data, NAMS created an evidence-based statement supporting extended use of HT for women beyond age 65, provided they have been advised of the increase in risks and have clinical supervision.25 Furthermore, the NAMS 2017 position statement identifies as level III data that the recommendation using the Beers Criteria published by the American Geriatric Society on potentially inappropriate medications for older adults to routinely discontinue systemic HT in women age 65 and older is not supported by data.23

For women who have persistent bothersome symptoms and where it has been determined that the benefits of menopause symptom relief outweigh the risks, extending HT may be acceptable and should be individualized and not discontinued solely based on a woman's age. Consideration should be made of personal preferences and balanced with ongoing benefits and risks with decisions to continue HT for preventive and/or QOL purposes.23,25 This decision should be discussed and an informed decision made jointly by the patient and the clinician. Initiating HT after age 60, however, is not recommended without significant consideration of risks and benefits.23

Recurrence of VMS is approximately 50% when HT is discontinued, independent of age and duration of use.1 Tapering or abruptly discontinuing HT in one randomized controlled trial had a similar impact on VMS, neither preventing nor minimizing the reappearance of symptoms.26 Anecdotally drawn from clinical experience, tapering the dose until full discontinuation and occasionally using a supplement or nonhormonal pharmacologic option during tapering has resulted in successful discontinuation (see Estrogen therapy/estrogen-progestogen therapy: Adverse reactions and contraindications).

Counseling women regarding breast cancer and associated risks with HT is a complex issue. There appears to be more flexibility in the duration of taking estrogen alone. An increased risk of breast cancer was seen with 3 to 5 years of estrogen-progestogen therapy use in the WHI, whereas no increased risk of breast cancer was seen with 7 years of estrogen therapy use, allowing for more flexibility in duration of estrogen therapy use in women without a uterus.2 When the data with estrogen plus progestogen are reviewed, this increase in breast cancer is considered rare (eight additional cases/10,000 women/year of therapy with oral, daily, continuous, combined, CEE/medroxyprogesterone acetate).2 The article reporting the 18-year cumulative follow-up on the WHI provides new data on the effect of HT on cancer mortality, especially breast cancer mortality. This topic has long caused concerns for patients and clinicians about HT administration, resulting in a reluctance to prescribe and/or for women to take HT. The new, long-term data showed cancer mortalities were almost identical between hormone users and nonusers, showing that all-cause cancer mortality was not affected by HT use in long-term follow-up.21

The risk of venous thromboembolism (VTE) increases with oral HT; however, a meta-analysis of studies has found no increased risk of stroke in women under age 60 or less than 10 years from menopause who initiate HT. Although data from randomized controlled trials are lacking, observational studies suggest that lower-dose oral/transdermal therapy has less effect on risk of VTE.23

Custom-compounded bioidentical HT. There are many well-tested, brand-name bioidentical hormone products approved in the United States and Canada.2 The term bioidentical hormones describes hormones structurally identical to those produced by a woman's ovaries during the reproductive years. This term is now typically used to describe custom-made HT formulations.2 The compounding pharmacy mixes hormones based on a prescription customized for the individual patient, often based on blood or salivary hormone levels. These products typically contain one or more hormones (estradiol, estrone, estriol) in differing amounts in addition to other ingredients to create a cream, gel, lozenge, tablet, spray, or skin pellet.2,23 Compounding pharmacies are regulated by state pharmacy boards with little oversight by the FDA. Because of the lack of quality control and regulatory oversight of compounding pharmacies with concerns regarding product purity, efficacy, and safety, NAMS and other organizations recommend using FDA-approved HT products.21,23

There may be occasional appropriate use for custom-compounded bioidentical HT when the patient requires a specific dose, ingredient, or route of administration not commercially available or due to an allergy. In that case, documentation in the medical record should validate the reason for the prescription with appropriate counseling by the patient's clinician.2,23

Pharmacologic: Nonhormonal. Nonhormonal options may be considered because of contraindications or the woman's personal choice; most are not approved by the FDA for managing VMS but may be effective. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, although most often used to treat depression and/or anxiety, are used for managing VMS. Venlafaxine, desvenlafaxine, paroxetine, escitalopram, and citalopram have provided relief in symptomatic menopausal women.13 Low-dose paroxetine mesylate (7.5 mg/d), although not at a dose high enough to treat behavioral health issues, has FDA approval for managing VMS.27 Adverse reactions may include nausea, weight gain, drowsiness, and sexual dysfunction.13

Gabapentin, used FDA off-label, (300 mg three times per day) may also be effective in reducing VMS, but adverse reactions of dizziness and disorientation may make the drug undesirable for some patients.13 For women who have difficulty sleeping (especially due to night sweats), gabapentin might be an option due to its adverse reaction of somnolence. Pregabalin is effective in relieving VMS but has not been studied as well.13

Clonidine, a centrally acting alpha-2 adrenergic agonist often used for the treatment of hypertension, may also be effective in reducing VMS. While studied more extensively in the 1970s to 1990s with mixed results, a study in 2000 using clonidine for patients on tamoxifen therapy showed a reduction in VMS in postmenopausal women with breast cancer.28 Used infrequently due to adverse reactions of insomnia, dry mouth, constipation, and drowsiness, it may be a good choice for patients with hypertension who are also experiencing VMS.

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Resources

Clinicians can conduct risk stratification and personalized risk assessment on patients through MenoPro, a free smartphone app released by NAMS.29 The app is based on the Menopause Decision-Support Algorithm to determine which patients are appropriate candidates for hormonal pharmacologic interventions or candidates for nonhormonal options. The app includes an assessment of symptoms, evaluates the presence of contraindications, and considers age/time since menopause.

The app also considers cardiovascular risk incorporating patient data: smoking status, systolic BP, medication, presence/absence of diabetes mellitus, and total/high-density lipoprotein cholesterol levels. The app includes links to other resources, including breast cancer, osteoporosis, and cardiovascular screening tools, along with various NAMS resources. A self-assessment section is available for women to share a summary with their clinicians. Additionally, the National Association of Nurse Practitioners in Women's Health has a free app (the NPWH Well Woman Visit app) with multiple components dedicated to women's healthcare. Launched in August 2017, a special segment is dedicated to management of the menopausal woman. The app is available for Apple and Android devices.

A plan of care should be based upon the woman's concerns, values, preferences, needs, and desires after considering the health risks and benefits for all interventions. Clinicians have the potential to enhance the patient's sense of well-being not only regarding menopause but toward healthy aging.

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Estrogen therapy/estrogen-progestogen therapy: Adverse reactions and contraindications1

Adverse reactions

  • Breast tenderness
  • Nausea
  • Bloating
  • Headache
  • Irregular vaginal bleeding or spotting
  • Peripheral edema
  • Dizziness
  • Mood changes with progestogen therapy

Contraindications

  • Active liver disease
  • Active or recent arterial thromboembolic disease
  • Current/past breast cancer
  • Known hypersensitivity
  • Known or suspected estrogen-sensitive malignant conditions
  • Active or previous history of DVT or pulmonary embolus
  • Undiagnosed genital bleeding
  • Untreated endometrial hyperplasia
  • Suspected or diagnosed pregnancy
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REFERENCES

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2. Shifren JL, Gass MLNAMS Recommendations for Clinical Care of Midlife Women Working Group. The North American Menopause Society recommendations for clinical care of midlife women. Menopause. 2014;21(10):1038–1062.
3. Harlow SD, Gass M, Hall JE, et al Executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012;19(4):387–395.
4. Avis NE, Crawford SL, Greendale G, et al Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175(4):531–539.
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        18. Goldstein S, Espie M, Druckmann R. Does Relizen, a non-hormonal treatment for vasomotor symptoms, inhibit the CYP2D6 enzyme system. Menopause. 2014;9:52–53.
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        26. Haimov-Kochman R, Barak-Glantz E, Arbel R, et al Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study. Menopause. 2006;13(3):370–376.
        27. Sebela Pharmaceuticals Inc. Brisdelle prescribing information. 2017. http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204516s005lbl.pdf.
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        Keywords:

        bioidentical hormone therapy; estrogen therapy; genitourinary syndrome of menopause; hormone therapy; hot flashes; hot flushes; menopausal hormone therapy; menopause; vasomotor symptoms

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