History of Present Illness

A 50-year-old, G3P2, with history of breast cancer presents to the office with severe hot flashes. Three years ago, she had right invasive ductal carcinoma that was estrogen and progestin receptor positive and Her2Neu negative. She was treated with breast conserving therapy and radiation. She is currently taking tamoxifen for endocrine therapy. She reports that she has hot flashes that occur frequently during the day and wake her up in the middle of the night and affect her sleep. Because of lack of sleep, she has less concentration at work. She has tried nonpharmacological methods of treating her symptoms, including dressing in layers, wearing loose-fitting clothes, using a portable fan, and keeping her window open at night, but her hot flashes continue to be severe and distressing to her. She also reports using black cohosh, which has not helped.

Her medical history is significant only for her breast cancer, with a surgical history that includes lumpectomy with sentinel lymph node biopsy. She has no known drug allergies. Her only medication is tamoxifen, which she has been taking daily for the past three years. She continues to have regular periods and denies any irregularities in menstruation. She denies genitourinary symptoms.

Physical Examination

General appearance

Well-developed, well-nourished woman

Temperature

37.0°C

Pulse

80 beats/min

Blood pressure

110/72 mmHg

Respiratory rate

16 breaths/min

Oxygen saturation

100% on room air

Height

65 inches

Weight

130 lb

BMI

21.6 kg/m²

GYN

Normal external female genitalia. Normal vaginal mucosal. Parous cervix with no cervical lesions or cervical tenderness. Small anteverted uterus with no tenderness. No adnexal tenderness or masses palpated.

How Would You Manage This Patient?

This patient has severe vasomotor symptoms that are distressing and affecting her daily activities. She has a history of breast cancer and is currently on tamoxifen for treatment. Premenopausal women who undergo treatment for breast cancer are at increased risk of experiencing vasomotor symptoms due to the lower levels of estrogen from antiestrogen treatment. She has tried conservative measures such as wearing loose clothing, dressing in layers, and cooling with a portable fan, but her hot flashes are still bothersome. The patient does not have any genitourinary symptoms of menopause, which can also be associated with the treatment of breast cancer.

Due to her history of hormone receptor positive breast cancer, the patient was counseled on different nonhormonal medical treatments, including cognitive-behavioral therapy, exercise, and avoidance of triggers and alcohol, for her severe hot flashes. In addition, she was started on Effexor 37.5 mg daily. She was counseled that if she did not feel improvement of her symptoms to increase her dose after one week to 75 mg daily. The patient returned in three months and reported improvement of her symptoms on 37.5 mg daily. She was counseled to continue Effexor at this dose, and after 1–2 years to stop the medication to see if her hot flashes continue to be as bothersome.

Treatment of Hot Flashes in Breast Cancer Survivors

Breast cancer is the most common cancer in women in the United States, with a lifetime risk of one in eight (12.5 percent). In 2017, there were an estimated 252, 710 new breast cancer patients and approximately 3.1 million women currently living with breast cancer [1]. Hot flashes, a common symptom of all menopausal women (up to 80 percent), are even more common among breast cancer survivors, who are 5.3 times more likely than women in the general population to experience them [2]. Breast cancer survivors, especially those using tamoxifen, have more severe hot flashes that the general population. Thus, it is important to discuss this topic with women surviving breast cancer.

Hot flashes often begin in the perimenopausal period, and are described as a sudden sensation of intense heat felt in the face and upper body that are often recurrent and last from thirty seconds to five minutes. Hot flashes can vary in duration, frequency, and severity. They can be associated with perspiration, increases in heart rate, palpitations, and anxiety. Hot flashes which occur at night, also known as night sweats, can affect sleep. Hot flashes causing sleep deprivation can contribute to mood changes and/or irritability and can adversely affect quality of life. There have been many different proposed grading scales for the severity of hot flashes, and they are generally classified as mild, moderate, or severe. Mild hot flashes are noticeable but do not interfere with daily activities, while moderate hot flashes interfere somewhat with daily activities, and severe hot flashes are distressing and affect daily activities. Risk factors for hot flashes include sex, age, obesity, decreased physical activity, and smoking. Studies show hot flashes are more frequently reported by African American women and least reported by Asian women [3]. This could be due to cross-cultural perception, which may affect how hot flashes are reported by these women, or biologic differences.

Women with breast cancer have been reported to have more frequent and more severe hot flashes. One theory explaining this is the rapid estrogen withdrawal from therapies such as chemotherapy and endocrine therapy, surgical removal of the ovaries, or the need to abruptly stop hormone replacement therapy with the diagnosis of breast cancer. Endocrine therapies such as tamoxifen have been shown in women with hormone positive breast cancer to decrease their risk of recurrence by 50 percent. However, tamoxifen has also been shown to be a significant cause of hot flashes among breast cancer patients. There have been many studies in which women have discontinued tamoxifen due to its side effect of vasomotor symptoms despite its efficacy in decreasing breast cancer recurrence [4]. Therefore, it is important to discuss the management of hot flashes in women with breast cancer.

The options for treatment of hot flashes in breast cancer survivors include lifestyle modifications, nonhormonal pharmacologic agents, and alternative and complementary therapy. Hormonal therapy such as estrogen and progestin are not recommended in women with a history of breast cancer due to concerns about an increased risk of recurrence and cancer-related mortality. As a result, it is important to discuss nonhormonal treatment for hot flashes in breast cancer survivors.

Nonhormonal pharmacologic treatment options that have been effective in the treatment of vasomotor symptoms include selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and gabapentin. These medications are not as effective as hormonal replacement therapy but can be a first-line treatment option for breast cancer survivors. The choice of which agent to use should be individualized. SSRIs/SNRIs are the preferred initial medication for the treatment of hot flashes in breast cancer patients due to the variety of evidence for efficacy and provider comfort with prescribing. Depression is common in women with breast cancer and thus an SSRI/SNRI may have added benefit in addition to treating hot flashes in this population. Common side effects of SSRI/SNRI include dry mouth, nausea, constipation, loss of appetite, and loss of libido. These side effects are often dose-dependent. Gabapentin has been shown to improve sleep quality and therefore can be a desirable choice for women with insomnia due to hot flashes. Adverse side effects of this medication include dizziness, drowsiness, headaches, and disorientation.

Paroxetine can affect the metabolism of tamoxifen and thus can affect its efficacy. Although it is the only SSRI/SNRI approved by the US Food and Drug Administration (FDA) for the treatment of hot flashes, it should be avoided in breast cancer patients on tamoxifen because paroxetine is a potent inhibitor of CYP2D6, the enzyme that converts tamoxifen to its active metabolites [5]. First-line SSRIs/SNRIs for the treatment of hot flashes in breast cancer patients on tamoxifen include venlafaxine, citalopram, or escitalopram.

Clonidine is an antihypertensive agent that is an option for the treatment of hot flashes, but its effectiveness is less than that of SSRIs/SNRIs and gabapentin. It can be considered as a second-line approach if SSRIs/SNRIs and gabapentin are contraindicated or not effective. Table 94.1 outlines some nonhormonal pharmacologic agents for the treatment of hot flashes in breast cancer survivors.

Since hot flashes are thought to be triggered by elevation of core body temperature, lifestyle modifications that either lower the core body temperature or prevent the rise in core body temperature have been proposed in the treatment of hot flashes. Some of the lifestyle modifications that are considered are clothing adjustments by dressing in layers that can easily be taken off and natural fibers that allow aeration. Other lifestyle modifications include use of a personal/portable fan, avoidance of triggers such as spicy/hot food or liquids, and avoidance of alcoholic beverages. However, there have not been any clinical trials that show significant decreases in hot flashes with these interventions. The North American Menopause Society (NAMS), while acknowledging that cooling techniques and avoidances of triggers appear risk free, does not recommend this as a form of treatment as it may delay more effective treatment options and there is no current evidence of improvement in hot flash symptoms [5].

Other nonmedical options are exercise, mindfulness-based stress reduction, paced respiration, relaxation, and acupuncture. There have been many randomized control trials that have looked at the effects of exercise and hot flashes. NAMS states that although there are many health benefits of exercise, randomized trials do not provide sufficient evidence to support exercise for treatment of hot flashes. Acupuncture also cannot be currently recommended for the use of hot flashes because of lack of evidence of its efficacy in reducing hot flashes. NAMS does state that cognitive-behavioral therapy has level 1 evidence showing efficacy in alleviating hot flashes and is a relatively risk-free therapy. It encourages women to be educated about this option but recognizes the barriers of time commitment as well as finding a credentialed provider in obtaining this therapy. NAMS also recommends weight loss, although with caution, as it might be beneficial.

Studies of herbal products have been contradictory in their efficacy in improving hot flashes. NAMS states that over-the-counter supplements and herbal therapies (including black cohosh, crinum, dioscorea, dong quai, evening primrose, flaxseed, ginseng, and others) are unlikely to be beneficial in alleviating hot flashes and should not be recommended for the treatment of hot flashes. The American College of Obstetricians and Gynecologists reports that the use of soy products is not advised in breast cancer survivors due to the lack of safety and efficacy in this population [6]. Behavior/lifestyle modifications should not delay other options that have been shown to be more effective for the treatment of hot flashes for breast cancer survivors.

Key Teaching Points

• 
  

  Breast cancer survivors are at an increased risk of developing severe hot flashes and this may affect their ability to continue breast cancer treatments such as tamoxifen.

  
  
• 
  

  Behavior/lifestyle modifications are reasonable treatment options in women with a history of breast cancer because they are minimal risk and cost-effective and may be beneficial, but they should not delay other options that have been shown to be more effective for the treatment of hot flashes for breast cancer.

  
  
• 
  

  SNRIs/SNRIs and gabapentin are effective nonhormonal treatment options for hot flashes in breast cancer survivors and should be considered first-line treatment options. Gabapentin has been shown to improve sleep quality and therefore can be a desirable choice for women with insomnia due to hot flashes.

  
  
• 
  

  Clonidine is an antihypertensive agent that is an option for the treatment of hot flashes, but its effectiveness is less than that of SSRIs/SNRIs and gabapentin. It can be considered as a second-line approach if SSRIs/SNRIs and gabapentin are contraindicated or not effective.

  
  
• 
  

  Due to limited data of efficacy and safety in this population, the use of over-the-counter supplements and herbal therapies is not recommended for the treatment of hot flashes.

History of Present Illness

A 56-year-old female presents to her gynecologist complaining of vaginal dryness and painful intercourse. Her last menstrual period was at age 52. She experienced bothersome vasomotor symptoms for about three years around the time of her final menstrual period, but this has resolved. She is in a monogamous relationship and she and her partner had been having intercourse 1–2 times weekly until about six months ago, when she began to experience a burning, sharp pain, especially with penetration. She reports that her vagina feels very dry and irritated during intercourse, and on a few occasions, she also noted a slight pinkish discharge afterward. These symptoms have persisted to the point of her having to refrain from intercourse. Urinary urgency has also become more of a problem for her. She is very worried about what is causing her symptoms and this problem is straining her relationship with her partner.

Her medical history is significant only for well-controlled hypothyroidism. She has had one cesarean and one vaginal delivery and no other major surgeries. She works for an accounting firm. Her family history is significant for breast cancer (mother) and Alzheimer’s (maternal grandmother). Her medications include levothyroxine and a calcium supplement.

Physical Examination

General appearance

Anxious-appearing woman in no acute distress

Temperature

36.8 C

Blood pressure

118/72

Pulse

78

Respiratory rate

16 per minute

BMI

25 kg/m²

Abdomen:

Soft, non-distended, non-tender

Pelvic examination

Labia minora regressed, pale introitus, urethral eversion. Vaginal rugae significantly decreased, small amount thin yellow discharge. Cervix pale with some petechiae. Vagina admits two digits with some discomfort. The uterus and adnexa normal.

Saline microscopy

Numerous leukocytes and parabasal (immature) cells, few superficial epithelial cells, no lactobacilli, pH=6.0. No clue cells, yeast, or trichomonads seen.

Urinalysis

Negative

How Would You Manage This Patient?

This patient has vulvovaginal atrophy related to the hypoestrogenic state of menopause. This is part of the constellation of symptoms now referred to as the genitourinary syndrome of menopause (GSM) [1]. The patient was unaware that her symptoms were related to menopause, and therefore, patient education was given about the changes that occur in a low-estrogen state. These changes can affect the vulva, vagina, and lower urinary tract, leading to urinary symptoms and dyspareunia from loss of lubrication and elasticity of the vagina, resulting in sexual dysfunction. This counseling helped alleviate some of the anxiety associated with her symptoms.

Management options were discussed, including use of a personal lubricant with sexual activity as well as local vaginal estrogen therapy. She was counseled about the options for local vaginal estrogen, which included cream, tablet, and ring formulations. She chose to begin the vaginal tablet and was instructed to use this nightly for 14 days and then to decrease dosing to twice weekly. This patient returned three months later and reported significant improvement in the dyspareunia and that she had been able to resume sexual intercourse. She denied any vaginal bleeding or discharge. She also related that her urinary urgency was better. She was encouraged to continue the treatment twice weekly, cautioning her that failure to do this would cause her symptoms to return. A recommendation for yearly follow-up was given.

Genitourinary Syndrome of Menopause

Symptoms of GSM, which include vaginal dryness, dyspareunia, itching, irritation, urinary frequency and urgency, and leucorrhea, affect 20–45 percent of perimenopausal and postmenopausal women. [1] They are related to the hypoestrogenic state associated with menopause. In contrast to vasomotor symptoms, which tend to improve with time, GSM often worsens without intervention and can lead to significant negative effects on a woman’s sexual health and quality of life, as demonstrated in a number of surveys of postmenopausal women [2]. The timing of onset of these symptoms in the menopausal transition is quite variable, and many symptomatic women do not bring this problem to the attention of their providers unless providers routinely ask their patients about these symptoms.

During the reproductive years, in the presence of endogenous estrogen, the vagina has a well-vascularized, rugated surface that is usually well lubricated in response to sexual stimulation. Estrogen is a dominant regulator of vaginal physiology (alpha and beta receptors) and to a slightly lesser extent vulvar and lower genital tract physiology; therefore, chronically low estrogen levels associated with menopause cause significant physiologic and anatomic changes. These changes are attributable to diminished collagen, elastin, and hyaluronic acid content as well as impaired smooth muscle proliferation and loss of vascularity [2]. These physiologic and anatomic changes are apparent on physical examination.

The diagnosis of GSM can usually be made by history by assessing the patient’s estrogen status (age, last menstrual period, cancer history, surgical history). It is important to ask all perimenopausal and postmenopausal women about symptoms of GSM, as a large percentage of patients are uncomfortable initiating a conversation about these issues with their provider. The history should assess whether the patient has symptoms of GSM and whether these symptoms are a problem and/or affecting her sexuality and quality of life.

Physical examination findings for GSM include small to absent labia minora, constricted introitus, and pale, dry vagina that lacks rugae. The vagina may also be shortened and narrowed. Particular care should be taken in performance of the pelvic examination as atrophic changes can make both the speculum and bimanual examinations painful for the patient, and petechiae and microtrauma may be present. Additional lubricant and a thinner caliber speculum can be helpful. The differential diagnosis includes autoimmune disorders, allergic and inflammatory conditions (e.g., desquamative inflammatory vaginitis, contact dermatitis, lichen planus, and lichen sclerosus), vaginal infections (candidiasis, trichomoniasis), trauma, and vaginismus. Findings on physical examination correlate with symptoms of vaginal dryness, dyspareunia, irritation, itching, and dysuria. Lack of lubrication, vaginal thinning, and loss of elasticity particularly lead to dyspareunia (Table 95.1). However, symptoms do not always correlate with findings on physical examination, with the discrepancy usually related to the sexual activity of the patient, as those who are sexually active tend to be more symptomatic. Other findings consistent with GSM are an elevated vaginal pH >4.5 and a saline microscopy demonstrating few superficial epithelial cells and lactobacilli and numerous parabasal cells and leukocytes. Parabasal or immature cells are smaller and rounder than superficial epithelial cells and have more prominent nuclei.

For some women, a personal lubricant with sexual activity may be all that is needed for treatment. Most over-the-counter lubricants are water- or silicone-based, with the silicone-based versions potentially being safer and more effective. Long-acting vaginal moisturizers can also be used, especially if the patient is bothered by dryness not associated with sexual activity.

If the patient’s symptoms are not improved with the addition of lubrication or her presenting symptoms and physical findings are severe, vaginal estrogen therapy should be prescribed. This local therapy is preferred, especially in the absence of other menopausal complaints such as vasomotor symptoms. Three different delivery systems are currently available: estrogen cream (both estradiol and conjugated estrogens), a 10 mcg vaginal tablet, and an estrogen ring which delivers 7.5 mcg of estradiol per day. Choice of one of these therapies is dictated by patient preference, provider experience, and cost. The vaginal creams are administered with an applicator, which allows for adjustments in dosing. A typical dose is 0.5–1.0 g inserted nightly for 14 days and then decreased to twice weekly. Some patients find the creams to be messy, but the creams do have the advantage of more effective treatment of vulvar and introital symptoms. The vaginal tablet is administered with a disposable applicator. This is also used nightly for 14 days and then decreased to twice weekly for maintenance. The estrogen ring is inserted by the patient and replaced every three months [3, 4, 5].

Low-dose vaginal estrogen therapy is considered to have a lower risk profile than systemic hormone therapy, due to the very small changes in serum levels of estrogen. Of concern is the effect of unopposed estrogen on the endometrium and risk of endometrial cancer in patients with an intact uterus. Current evidence suggests that the administration of low-dose vaginal estrogen is safe for the endometrium; however, long-term data are lacking. Concomitant use of a progestogen is not currently recommended [3, 4]. If, however, a patient using one of these therapies reports any vaginal bleeding, this should be promptly evaluated with a transvaginal ultrasound and/or endometrial biopsy. In women with a history of estrogen-dependent breast cancer, the American College of Obstetricians and Gynecologists recommends that nonhormonal therapies be recommended first, but in those patients with more severe symptoms, data do not show an increased risk of cancer recurrence in patients prescribed low-dose vaginal estrogen. The tablet and the ring are preferred over the creams because there is less variability in dosing and potentially less systemic absorption. The patient’s oncologist should be consulted before initiating treatment [6].

Vaginal estrogen therapy for GSM remains the gold standard but other therapies are now available. The selective estrogen receptor modulator (SERM) ospemifene is approved for the treatment of moderate-to-severe dyspareunia. It is a 60 mg oral tablet taken daily. It is not recommended that this be used in breast cancer patients due to lack of data in this population. As a SERM, ospemifene has the potential to increase the risk of venous thromboembolism and can increase vasomotor symptoms. Long-term data on endometrial safety are lacking. Another alternative therapy, recently approved by the FDA for the treatment of dyspareunia associated with menopause, is prasterone, otherwise known as dehydroepiandrosterone. This comes as a daily vaginal insert. Its efficacy was demonstrated in two placebo-controlled clinical trials. Prasterone is felt to exert its effects through stimulation of both testosterone and estrogen receptors [1]. Finally, a CO₂ laser procedure has been marketed for the treatment of vulvovaginal atrophy and dyspareunia. Used in the office setting, it involves three short procedures spaced six weeks apart. Research has demonstrated that the laser stimulates collagen synthesis but studies are small and of short duration and lack a control arm. More data on efficacy and safety need to be collected before embracing this new and expensive technology [5].

Vulvovaginal atrophy may occur in hypoestrogenic states other than natural menopause. Surgical removal of both ovaries, for example, in the case of a patient with a BRCA mutation who has risk-reducing bilateral salpingo-oophorectomy can cause abrupt onset of these symptoms. Cancer treatments (chemotherapy and radiation) and the use of GnRH agonists can result in early menopause (though sometimes temporary) and GSM. Patients with hypothalamic amenorrhea such as in cases of anorexia nervosa or hyperprolactinemia in the postpartum state can also be symptomatic. In these often younger patients with dyspareunia, there may be a higher level of distress in reaction to their impaired sexual function [1]. Aromatase inhibitors used as adjuvant therapy for breast cancer are especially associated with vulvovaginal atrophy.

Key Teaching Points

1. 
   

   1. It is important to ask all perimenopausal and postmenopausal women about GSM as a large percentage of patients are uncomfortable initiating a conversation about these issues with their provider.

   
   
2. 
   

   2. GSM often worsens without intervention, as opposed to vasomotor symptoms, which tend to improve with time, and can lead to significant negative effects on a woman’s sexual health and quality of life.

   
   
3. 
   

   3. Physical examination findings for GSM include small to absent labia minora, constricted introitus, pale and dry vagina that lacks rugae, and shortening and narrowing of the vagina.

   
   
4. 
   

   4. Care should be taken in performing a pelvic examination, and there may be petechiae and microtrauma.

   
   
5. 
   

   5. Vaginal estrogen therapy for GSM remains the gold standard, and low-dose vaginal estrogens can be safely used without a progestogen.

   
   
6. 
   

   6. Nonestrogen alternatives are emerging, including the SERM ospemifene and prasterone, otherwise known as dehydroepiandrosterone.

   
   
7. 
   

   7. Therapies for GSM must be continued indefinitely in order to maintain the therapeutic effects.