HRT: 4 experts chart a new course
To clarify the issues raised by the Women’s Health Initiative, OBG Management asked 4 experts the inevitable: Now what? Here, the physicians discuss the findings and detail how this will affect the way they—and you—treat menopausal women.
Randolph: The mechanism of action of HRT is incompletely understood, a dilemma linked to our limited comprehension of the action of endogenous estrogens and progesterone over the course of a woman’s life span. We are discovering that many compounds have estrogenic and progestational activity. In addition, there are at least 2 specific receptors each for estrogens and progestins in various proportions in many tissues in the body.6 Thus, it is useful to rely as much as possible on good clinical trial data, however limited.
As a general rule, it is always appropriate to prescribe the lowest dose of medicine that alleviates the problem. Most other HRT regimens use different estrogens and progestins than the CEE/MPA given in the WHI, with different potencies and side-effect profiles. Some have a different route of administration, such as transdermal or transvaginal, with varying pharmacokinetics. Each difference has advantages and disadvantages over the CEE/MPA that was studied.
Luciano: The mechanisms by which HRT improves vasomotor symptoms is by binding to central nervous system (CNS) estrogen receptors—and perhaps progestin receptors—and suppressing the activation of the thermoregulatory centers that release catecholamines.7 (Catecholamines are responsible for vasomotor symptoms.) HRT improves vaginal dryness by binding to the estrogen receptors on the vaginal epithelium, promoting both the growth of the squamous epithelium and vaginal blood flow, thus increasing the thickness, vascularity, and lubrication of the vagina. In preventing osteoporosis, HRT decreases the activity of osteoclasts, thereby reducing bone metabolism and bone loss.
A 50-year-old woman with progressively infrequent menstrual periods and significant vasomotor symptoms, including night sweats and vaginal dryness, asks about the advisability of hormone replacement therapy (HRT). I inform her that she is an ideal candidate for HRT as long as she has no contraindications such as a history of thromboembolism, cardiovascular disease, or breast cancer. I also tell her that I will prescribe the lowest effective HRT dose—oral or transdermal—be it Activella, FemHRT, Ortho-Prefest, or Combipatch. My recommendations take into account the patient’s preference for oral or transdermal preparations. If she had compromised hepatic function or digestive disturbances, I would prescribe the Combipatch; if her lipid profile revealed significant hypertriglyceridemia, I would opt for Activella or FemHRT. For women with normal triglycerides but depressed high-density lipoprotein (HDL) cholesterol levels, I suggest Ortho-Prefest.
A 52-year-old woman who had her last menstrual period a year ago is experiencing mild vasomotor symptoms, vaginal dryness, and dyspareunia. She is concerned about her risk of osteoporosis, since her mother suffered a hip fracture in her late 70s and was incapacitated for the rest of her life. In addition, the patient’s sister had breast cancer. The patient has no history of thromboembolic events. Given the mild nature of her vasomotor symptoms and the family history of breast cancer, I advise her that HRT is not indicated. The vaginal dryness and dyspareunia can be treated effectively with local low-dose estrogen. Since this patient’s primary concerns are the risk of osteoporosis and breast cancer, I would perform a bone mineral density (BMD) test at the hip and spine, preferably with dual-energy x-ray absorptiometry (DEXA). If she has osteopenia or osteoporosis, raloxifene would be her best option, as this agent would safely address both her osteoporosis and breast cancer concerns. If her vasomotor symptoms are exacerbated from the raloxifene, I would recommend black cohosh or soy protein. I also encourage weight-bearing exercises, along with a daily calcium intake of 1,500 mg and 400 units of vitamin D. If she cannot tolerate raloxifene, I would consider prescribing a weekly regimen of alendronate (35 mg) or risedronate (35 mg) for osteopenia. For osteoporosis, I would prescribe a weekly course of alendronate (70 mg) or risedronate (35 mg).—ANTHONY LUCIANO, MD
Kaunitz: In the past several years, clinicians and women have begun to focus on the use of lower-dose HRT. This trend likely will be accelerated by the WHI findings. Available data suggest that lower doses of HRT can relieve vasomotor symptoms, prevent osteoporosis, and help with genital atrophy.8 As was noted, the only combination HRT studied by the WHI is CEE/MPA. Based on commercially available formulations, I consider “lower dose” ERT to mean conjugated equine or esterified estrogens (0.3 mg daily); oral estradiol (0.5 mg daily); or transdermal estradiol (0.025 to 0.0375-mg patches).
As for the accompanying progestin in HRT, I would give MPA (2.5 mg daily or less frequently than daily) or norethindrone (0.35 mg daily), which is available as a progestin-only OC. The availability of lowerdose combination estrogen-progestin formulations would certainly facilitate use of this therapy in menopausal women with an intact uterus. The HOPE trial, which assessed lower-dose versions of CEE/MPA, found good efficacy in regard to osteoporosis prevention.9 Hopefully, such formulations will soon become commercially available.
