Lower doses of HRT may be more effective and with fewer side effects. At a symposuim held on October 25, 2000, a panel of experts discussed the role of reduced HRT doses in the management of menopause.
This program was supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories.
Maintaining Bone Health: Optimizing HRT Dosing
"Standard combination therapy in this country is 0.625 milligrams of conjugated equine estrogens - or its equivalent - in combination with 2.5 milligrams of medroxyprogesterone acetate," said Robert R. Recker, MD, Director of the Osteoporosis Research Center and Professor of Medicine, Creighton University School of Medicine, Omaha, Nebraska. "There is evidence, largely anecdotal, that lower doses may be as effective but with fewer side effects, translating into improved compliance and long-term benefit. However, the minimum effective dose of estrogens combined with progestins for preventing bone loss is currently unknown."
A randomized, placebo-controlled clinical trial investigated the effects of 3.5 years of treatment with 0.3 mg/day of conjugated equine estrogens (CEE) plus 2.5 mg/day of medroxyprogesterone acetate (MPA) combined with calcium and vitamin D on bone mineral density (BMD) in women over 65. Endpoints assessed included BMD of the hip, spine, and radius, whole bone mineral content (BMC), and markers of bone turnover (e.g. alkaline phosphatase, osteocalcin, hydroxyproline).
Low-dose HRT in conjunction with vitamin D and calcium significantly increased hip and spine BMD (2.0% and 5.1%, respectively) and total body BMC (3.1%), and prevented forearm bone loss. In contrast, no gains were noted for the placebo group, who received only calcium and vitamin D. There were also significant and expected changes in the bone formation and resorption markers. A comparison of studies investigating BMD in postmenopausal women indicates that the low-dose regimen used in the current study results in gains in BMD that are comparable to those reported for the most commonly prescribed CEE/MPA regimens. Bone- sparing results shown for this low-dose regimen also compare favorably to other antiresorptive agents, such as the bisphosphonates and raloxifene.
In summary, continuous HRT with 0.3 mg/day of CEE and MPA, coupled with calcium and vitamin D, may be the lowest effective dose for preventing osteoporosis in postmenopausal women over 65 years.
Low-Dose CEE/MPA with Calcium and Vitamin D Over 2.5 Years Will:
o Increase spine BMD 5.1%
o Increase total body BMC 3.1%
o Increase hip BMD 2.0%
o Prevent forearm bone loss
The Effect of Lowering HRT Doses on Vasomotor Symptom Relief
"Vasomotor symptoms are often the most distressing aspect of menopause," said Valerie Montgomery Rice, MD, Associate Professor in the Reproductive Endocrinology and Infertility Division in the Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City. "We now have data to support that lowering doses of hormone replacement therapy (HRT) can provide relief of these symptoms and other factors associated with menopause."
The first year of the Women's HOPE (Health, Osteoporosis, Progestin, Estrogen) Study investigated the effects of lower doses of conjugated equine estrogen (CEE) alone and continuously combined with different doses of medroxyprogesterone acetate (MPA) on vasomotor symptoms, vaginal atrophy, endometrial histology, and metabolic factors in 2,805 postmenopausal women. After the women met the criteria for the initial screen, they were randomized to receive 1 of 8 treatments: CEE 0.625 mg per day; CEE 0.625 mg/MPA 2.5 mg/day; CEE 0.45 mg per day; CEE 0.45/MPA 1.5 mg/day; CEE 0.45/ MPA 2.5 mg/d; CEE 0.3 mg per day; CEE 0.3 mg/MPA 1.5 mg/day; or placebo. All groups received a calcium supplement; vasomotor symptoms were analyzed by daily frequency and severity (1=mild, 2=moderate, 3=severe) of hot flashes. Vaginal atrophy was assessed by vaginal maturation index (VMI).
For women who recorded taking study medication and who presented with moderate-to-severe hot flashes at baseline (efficacy-evaluable population), vasomotor symptoms - both number and severity - were reduced from baseline within 3 weeks for all active treatment groups. This reduction persisted for 13 cycles, the entire study period. For the CEE alone groups, CEE 0.625 mg was more effective than lower doses (CEE 0.45 mg, CEE 0.3 mg) in reducing the frequency and severity of hot flashes. For the CEE/MPA groups, the reduction in vasomotor symptoms was similar between the lower doses (CEE 0.45/MPA 2.5; CEE 0.45/MPA 1.5, and CEE 0.3/MPA 1.5) and the most commonly prescribed dose (CEE 0.625/MPA 2.5). This suggests that adding MPA to the lower dosages of conjugated estrogen acts synergistically to lower the number and severity of hot flashes over the 12-week period and over the 13-cycle period.
VMI was determined by the proportion of vaginal superficial cells relative to the number of parabasal and intermediate cells in a lateral vaginal wall smear. All of the active treatment groups were associated with an increased percentage of superficial cells. Conjugated estrogen alone groups demonstrated a dose-response effect, with 0.625 mg being the most effective in increasing the percentage of superficial cells. In combination groups, when comparing the most commonly prescribed dose of .625/2.5 to the lower doses, there were no differences in their ability to increase the percentage of superficial cells. "Hopefully, this improvement in VMI will translate to a decrease in vaginal atrophy," Dr. Montgomery Rice observed, "in turn decreasing dyspareunia."
"The clinical implications for the vasomotor portion of the Women's HOPE Study are that lower doses of CEE combined with lower doses of MPA are as effective as currently prescribed doses for the relief of vasomotor symptoms and vaginal atrophy," concluded Dr. Montgomery Rice. "Using lower HRT doses provides clinicians with an important opportunity to increase both initiation and acceptance of therapy in their postmenopausal patients."
Vasomotor Summary
o All lower doses of CEE combined with MPA were similar to CEE 0.625/MPA 2.5 for vasomotor symptom relief
o Results suggest that the addition of MPA to lower doses of CEE is beneficial for relieving vasomotor symptoms
Women's HOPE Study
Purpose:
To examine the effect of lower doses of estrogen alone or estrogen-progestin combinations on vasomotor symptoms, vaginal atrophy, endometrial histology, and metabolic factors
Participants:
2805 healthy postmenopausal women
Endometrial Safety & Improved Amenorrhea Rates with Lower HRT Doses
"Data from the Women's HOPE Study were also used to evaluate endometrial hyperplasia, the surrogate used for endometrial cancer," said David F. Archer, MD, Direc-tor of the Clinical Research Center at the Jones Institute for Reproductive Medicine of
Eastern Virginia Medical School, Norfolk, Virginia. "But what role do lower doses of HRT play in improving endometrial protection while also being associated with reduced bleeding?"
As already noted, the Women's HOPE Study had several arms including conjugated equine estrogen (CEE) alone and with progestin (medroxyprogesterone acetate - MPA). Endometrial hyperplasia rates were < 0.5% for all continuous combined CEE/MPA doses as well as for the lowest dose of CEE alone (0.3 mg/day). Current epidemiologic investigations indicate that low-dose unopposed estrogen in women with a uterus increases their risk for endometrial carcinoma. For this reason, physicians should not use any dose of unopposed estrogen in women with a uterus. Specifically, and not surprisingly, the maximum occurrence of hyperplasia was with the 0.625 milligrams of unopposed conjugated estrogen (approximately 8.0%) and 3.2% for the CEE 0.45 mg group.
Some degree of uterine bleeding or spotting can be anticipated when HRT is administered to
postmenopausal women with a uterus. For most women, the principal reason for discontinuation of HRT in the first year after initiation is the reoccurrence of vaginal bleeding. With cyclic or sequential therapy, the bleeding that occurs is usually regular in terms of the anticipated day of bleeding but reduced in amount and duration. In continuous combined preparations, the bleeding is unpredictable, irregular, and often spotty or light.
In the Women's HOPE Study, self-reported bleeding data were used to assess rates of amenorrhea (defined as the absence of any vaginal bleeding or spotting), both cumulatively and by individual cycles, and rates of "no bleeding" (defined as the absence of vaginal bleeding with or without spotting), also both cumulatively and by individual cycles. "Bleeding" is any episode that required sanitary protection; "spotting" was loss of blood from the vagina that did not require sanitary protection. Data collected were for the efficacy-evaluable population, which included all patients who completed 13 cycles with complete records and who did not miss Ž 3 continuous days or Ž 5 discontinuous days of their study medication in any 28-day cycle.
Results indicated that cumulative amenorrhea rates after 13 cycles were higher for women treated with lower doses of CEE, both alone (0.3 ~ 82%; 0.45 ~ 89%) and combined (0.3/1.5 ~ 90%, 0.45/1.5 ~ 80%) than those treated with the most commonly prescribed dose (CEE 0.625/MPA 2.5 ~ 70%). The improvements in amenorrhea with lower doses were most significant during the earlier cycles (1 through 6) of therapy. For all CEE/MPA groups, the rates of amenorrhea by cycle increased with duration of treatment. "Interestingly," noted Dr. Archer, "the incidence of spotting and/or bleeding reached 30 to 35% in the first cycle of placebo use, indicating that many women perceive light spotting or even one day or so of bleeding as not significant enough to report it to their physician or health care provider. This underreported clinical finding is captured in the database in a prospective clinical trial." In general, the treatment emergent adverse events, including breast discomfort, were reported less frequently in the lower-dose groups as compared to the higher-dose group.
"These findings demonstrate," concluded Dr. Archer, "that lower doses of HRT provide sufficient endometrial protection and a more favorable bleeding profile than currently prescribed doses. As a result, these factors may encourage more women to initiate and continue HRT."
Amenorrhea Rates
o Postmenopausal women may obtain more favorable bleeding profiles with lower-dose continuous combined regimens such as 0.45 mg/1.5 mg or 0.3 mg/ 1.5 mg CEE/MPA
o Increased amenorrhea rates and fewer side effects with lower doses of HRT may aid in initiating and sustaining therapy in newly menopausal women
Changes in Lipoproteins & Carbohydrate Metabolism with Lower HRT Doses
"Beginning at the time of menopause, cardiovascular disease is the leading cause of death in older women," said Rogerio A. Lobo, MD, Chairman, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons; and Director, Center for
Reproductive Sciences and Sloane Hospital for Women at Columbia-Presbyterian Medical Center, New York City. "Therefore, it is extremely important to know what regimens have an impact - beneficial or adverse - on various metabolic parameters."
A substudy was conducted in 749 patients (28%) of the 2,673 postmenopausal women that evaluated metabolic effects of lower HRT doses in the Women's HOPE Study. The beneficial effects on high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol of the most commonly prescribed CEE/MPA regimen, 0.625 mg/2.5 mg/day, were also observed in the lower-dose groups, either alone or combined. In particular, the percent changes in HDL- and LDL-cholesterol in the CEE 0.45 and 0.45/MPA 1.5 groups were similar to those observed in the CEE 0.625 mg and 0.625/MPA 2.5 groups.
"Estrogen is related to increasing triglycerides from baseline," continued Dr. Lobo, "and, in general, MPA attenuates this response." In this study, the increase from baseline in triglycerides with CEE 0.625 mg and CEE 0.625/MPA 2.5 mg was blunted in the lower-dose groups, except for the CEE 0.45 mg group.
Lp(a), putatively another independent risk factor for cardiovascular disease, links together APO B and apo A-1, which is like plasminogen, thus linking together the coagulation and lipoprotein cholesterol factors. After one year, Lp(a) was significantly lower compared to baseline and the placebo group in the two CEE 0.45mg/MPA groups and the CEE 0.625/MPA 2.5 mg group. Minimal changes in carbohydrate metabolism were observed for all groups.
After one year, there were also beneficial changes in the coagulation parameters. Fibrinogen, plasminogen activated inhibitor (PAI)-1, and antithrombin III were significantly reduced from baseline in all of the active treatment groups except CEE 0.3/MPA 1.5. The decrease from baseline in protein S activity was dose related, with the CEE 0.3/MPA 1.5 group demonstrating the least reduction. The CEE/MPA regimen containing 0.45 mg/1.5 mg induced improvements in coagulation and fibrinolytic measures that were most similar to those observed with CEE 0.625/MPA 2.5. These results suggest that lower doses of CEE/MPA result in improved HDL- and LDL-cholesterol, beneficially affect fibrinogen and PAI-1, and have minimal impact on carbohydrate metabolism.
"Lower doses of CEE/MPA appear to improve a variety of characteristics of menopause," summed up Dr. Lobo. "Specifically, they relieve vasomotor symptoms, provide endometrial protection, and result in improved bleeding and metabolic profiles."
Lipoproteins and Carbohydrate Metabolism
o Lower doses of CEE alone and CEE/MPA produce favorable lipid profiles and do not adversely impact carbohydrate metabolism
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