CASE: COWDEN SYNDROME PRECLUDES USE OF HORMONE THERAPY
A 35-year-old G2P2 woman presented with abnormal uterine bleeding. An endometrial biopsy revealed adenocarcinoma. A total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) was performed. The histologic examination detected an endometrial adenocarcinoma, grade 1/3 with no myometrial or vascular invasion and normal pelvic lymph nodes. Surprisingly, an endometrioid adenocarcinoma of the left ovary also was detected. The patient had a colonoscopy, which demonstrated dozens of ganglioneuromas and hamartomatous polyps of the colon.
Given the detection of tumors in the uterus, ovary, and colon, tissue was tested for Lynch mutations; none were detected. A mutation in the PTEN gene was detected, and a diagnosis of Cowden syndrome was made. Cowden syndrome is caused by an autosomal dominant mutation in the PTEN tumor suppressor gene and is associated with an increased risk of tumors of the breast, thyroid, endometrium, colon, rectum, and kidney.
Following her TAH-BSO, the patient was suffering from insomnia, severe hot flashes, and dry vagina. Her oncologist forbade the use of estrogen or progestins because she believed that Cowden syndrome tumors are estrogen sensitive.
Which nonhormonal options are effective treatments for your patient's symptoms of insomnia, hot flashes, and dry vagina?
Consider sleep hygiene, gabapentin 300 mg nightly, zolpidem 5 mg nightly, or eszopiclone 2 mg nightly
For hypoestrogenic women with sleep problems, three proven interventions are:
- improved sleep hygiene
- gabapentin (Neurontin) prior to bedtime
- gamma-aminobutyric acid type A-receptor agonists, such as eszopiclone (Lunesta) and zolpidem (Ambien).
Interventions to improve sleep hygiene include: keeping the bedroom cool, avoiding naps, exercising daily, sticking to a regular sleep-wake schedule, keeping the bedroom dark and quiet, dimming ambient lighting in the evening, avoiding caffeine after lunch and alcohol late in the evening, stopping smoking, and limiting fluids before bedtime.
Gabapentin is FDA-approved for seizures and postherpetic neuralgia (shingles). The drug also has been used off label to treat diabetic neuropathy, chronic pain, and restless leg syndrome. Clinical trials have shown that gabapentin is also effective for treating insomnia and hot flushes.1,2
In my practice, I prescribe gabapentin 300 mg and instruct patients to take it 1 to 2 hours before bedtime. For some patients, 600 mg of the drug is needed to produce sleep improvement.
The most common side effects of gabapentin are somnolence, drowsiness, dizziness, and a "spacey" feeling. These effects tend to subside after a month of treatment. Gabapentin has a half-life of 5 to 7 hours, which means that a single dose taken prior to bedtime will have an effect throughout the night.
Eszopiclone and zolpidem are FDA-approved to treat sleep problems. An extended-release form of zolpidem (Ambien CR) is also available. Eszopiclone and extended-release zolpidem are approved for long-term use. Generic zolpidem is less expensive than eszopiclone or extended-release zolpidem.
In a trial of more than 400 perimenopausal women who had symptoms of insomnia, eszopiclone 3 mg nightly for 4 weeks significantly improved sleep onset, sleep maintenance, sleep duration, sleep quality, and daytime functioning, compared with placebo.3
In my practice, in order to minimize side effects (see paragraph below), I use either a 5-mg dose of immediate-release zolpidem or a 2-mg dose of eszopiclone.
Warn your patients of side effects
The most commonly reported side effects of these nonhormonal insomnia medications are headache, somnolence, and dizziness. The FDA has recently issued a warning that all drugs taken for insomnia can impair driving and activities that require alertness the morning after use.4 In addition, the FDA recommends that "the bedtime dose of zolpidem be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving."
The recommended dose of immediate-release zolpidem has been lowered from 10 mg to 5 mg. The recommended dose of extended-release zolpidem has been reduced from 12.5 mg to 6.25 mg. The FDA is "continuing to evaluate the risk of impaired mental alertness with other insomnia drugs."
Consider venlafaxine 75 mg daily or gabapentin 600 mg nightly
Estrogen is a highly effective treatment for menopausal vasomotor symptoms. For women with vasomotor symptoms who cannot take estrogen, however, moderately effective alternative treatments are selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentin.
A meta-analysis of seven clinical trials of the SSRI and SNRI antidepressants and three trials of gabapentin provided evidence of the efficacy of these agents for the treatment of vasomotor symptoms.5 In the meta-analysis, placebo treatment resulted in an average 24% reduction in reported vasomotor symptoms. The active treatments resulted in significantly greater reductions in vasomotor symptoms, compared with placebo. Venlafaxine 75 mg daily resulted in a 33% greater reduction in vasomotor symptoms than placebo. Gabapentin 900 mg to 2500 mg daily resulted in a 35% to 38% greater reduction in hot flashes than placebo. Paroxetine (25 mg daily), fluoxetine (20 mg daily), and sertraline (50 mg daily) also were effective. Desvenlafaxine at a dose of 100 mg daily recently has been reported to be effective for the treatment of hot flashes.6