Case studies and clinical considerations in menopausal management
BEYOND THE CASES: OTHER CHALLENGES IN MENOPAUSAL MANAGEMENT
HT discontinuation, dose reduction in real-world practice
Dr. Thacker: The first case we covered touched on both discontinuation of HT and HT dosage reduction. These are issues that come up often in clinical practice; what lessons does the panel have to share on these issues?
Dr. Gass: I find that there is a small subset of women who are highly symptomatic and are probably always going to be miserable whenever they try to go off HT. For some, if they are highly symptomatic at menopause, they tend to stay that way. They may try to go off, but a year later, they come back and say, “I am just too miserable.”
Dr. McKenzie: In my practice, I have noticed patients who end up staying on higher doses of HT for a long period because they do not tolerate weaning. If you take them down to 0.625 mg of estrogen, their hot flashes resume, so they seem to require 0.9 mg.
Dr. Thacker: I have a very small subset of those women too. I wonder if their metabolism is different; maybe 0.9 mg of conjugated equine estrogens is to them what 0.3 mg is to other women. As women get older, perhaps metabolic changes are one reason that many can reduce their hormone dosage. It is very challenging. I tell my students that it is much easier trying to determine how much thyroid hormone replacement to give a patient than how much estrogen.
When does transdermal estrogen make sense?
Dr. Sikon: I would be interested in the rest of the panel’s views on management of a woman in her early postmenopausal years who is symptomatic and has been on oral HT and is also a smoker. Would you switch her to transdermal estrogen or continue her oral HT and continue aggressive smoking cessation counseling?
Dr. Thacker: Many practitioners think that a smoker cannot take any type of HT because they equate it to oral/hormonal contraceptives, which increase the risk of heart attack in smokers over age 35, but hormonal contraceptives are different in that they involve a much higher dose of hormone. In my practice, the cases when I will offer transdermal estrogen are generally when a patient has gastrointestinal upset, known gallbladder disease, elevated triglycerides, or a prior deep vein thrombosis (DVT), even though I will tell the patient that the HT-associated risks are still possible with transdermal therapies. Many women are inappropriately and inaccurately told that compounded transdermal therapies are “risk free.”
Dr. McKenzie: Transdermal estrogen is also an option for patients who are poor pill takers or are already taking too many pills. Many of my patients are on transdermal estrogen for the convenience that it offers. It is unfortunate that transdermal progesterone cream does not protect the endometrium in all patients; for women with a uterus, an oral progestogen needs to be prescribed. However, two transdermal patches containing progestogens have been shown to be efficacious in protecting the endometrium.
How should a history of DVT affect decision-making?
Dr. McKenzie: What do you do when a patient has a history of postoperative DVT and is already on HT? How many of the panel would discontinue the HT as opposed to continuing it?
Dr. Hodis: If it were a history of spontaneous DVT, I would feel uncomfortable continuing HT. A few years ago, a clinical trial was stopped early because women with a prior spontaneous DVT who were randomized to HT had a substantial increase in DVT incidence relative to those randomized to placebo.5 In the case of provoked or postoperative DVT, it may be a tougher call.
Dr. Thacker: I think that DVT is the greatest risk with HT, even though the media are more focused on breast cancer risk. The risk of breast cancer with estrogen alone is debatable, at least with oral conjugated estrogen, which was associated with a decreased risk in women who had undergone hysterectomy in the Women’s Health Initiative (WHI).6
When I see a woman with a history of DVT in my practice, I check her homocysteine levels and check for factor V Leiden and prothrombin gene mutation. If I find an inherited hypercoagulability disorder, I tell the patient that her risk of DVT with any type of hormone product is not just multiplicative, it is logarithmic. If the patient already requires lifelong anticoagulation, then I am a bit more comfortable with prescribing HT and I usually will try the transdermal route first; however, I always consider nonhormonal treatment alternatives first.
Dr. Gass: The WHI was supposed to have excluded women with a history of DVT, but a few such women were enrolled, and it was demonstrated that they were at higher risk of DVT recurrence if randomized to HT. The majority of DVT episodes in the WHI were spontaneous, not related to surgical procedures.
Dr. Jenkins: I have a patient who had been on low-dose HT for 30 years and underwent lumbar spine surgery. She had a somewhat prolonged recovery, so her lack of mobility and her age clearly increased her risk of DVT. So she was taken off HT and became miserable from the resulting hot flashes and sleep disturbance. We thoroughly discussed the risks and benefits of restarting HT, and because she was taking warfarin, we felt comfortable restarting the HT.
Women with spontaneous DVT are a different case, however, and I have an issue with restarting oral or transdermal HT in those cases. However, if we discuss the data with these patients and document the significant risks of HT in their cases, some may want to accept the increased risk in order to improve their quality of life, and that may be reasonable if they are truly fully informed.
Dr. Thacker: What about a woman who has been on oral contraceptives for several years and has not had a DVT? Is the safe use of oral/ hormonal contraceptives something you take into account, Dr. Gass, in your decision whether to prescribe HT?
Dr. Gass: Yes, that can be reassuring. Twenty-seven percent of EPT participants and 49% of estrogen therapy (ET) participants in the WHI randomized trial had used hormones in the past, so it was as if they were already tested for an early risk of blood clots.7
What role for SERMs (estrogen agonists/antagonists)?
Dr. Thacker: I would like to discuss the use of estrogen agonists/estogen antagonists, formerly known as selective estrogen receptor modulators (SERMs), such as raloxifene. Raloxifene now has an indication for breast cancer prevention as well as for reduction of vertebral fractures. I don’t know if there is adequate recognition among practitioners that SERMs appear to be associated with the same risk of DVT that estrogen is, and a greater risk of fatal stroke.
Dr. Jenkins: I find the lack of hip fracture data with raloxifene concerning, because hip fracture carries the highest 5-year mortality of any type of fracture. Raloxifene therefore is not a first-line agent for bone loss in my practice. But we also have to consider the patient’s risk of breast cancer and whether or not she has been on tamoxifen and now needs an agent to protect her against fracture. The question is whether we should consider starting these patients on raloxifene versus a bisphosphonate.
Dr. Thacker: Dr. Gass, do you think that raloxifene is safe for the endometrium? For years, we did not know the full effects of tamoxifen on the endometrium; it took experience with millions of patients to find out that tamoxifen increases the risk of endometrial cancer.
Dr. Gass: I do think that raloxifene is safer. I use it in my practice primarily for women younger than age 65 who are not yet at high risk for hip fracture but are still concerned about breast cancer. Although this concern diminishes as women age without having developed breast cancer, for younger women, who may see their friends getting breast cancer, it is a major concern. So if a patient is a good candidate for a bone loss agent and also has concern about breast cancer, raloxifene can be a good option, especially since we do not know what the implications are of taking bisphosphonates for 30 years. Questions about that are starting to be raised, so I think it is good to consider a sequential approach for some of these patients. A sequential approach might involve use of HT in a symptomatic menopausal woman, followed by use of raloxifene after the woman no longer has menopausal symptoms but is concerned about spine fracture protection and breast cancer risk reduction, followed by bisphosphonate use as she gets older and is at increased risk for stroke/VTE and for hip fracture.
