Low-dose Hormone Replacement Therapy Research Articles

Low-dose hormone replacement therapy: effects on bone

Hormone replacement therapy (HRT) is considered the mainstay for postmenopausal osteoporosis prevention. However, at the standard doses, HRT preparations can induce bothersome hormone-related side-effects,in both sequential and continuous combined regimens. Lower-dose HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with verylow rates of unscheduled bleeding. Moreover, low-dose HRT associated with an adequate calcium supplement can spare bone by preventing the increase in bone turnover and the resultant bone loss in postmenopausalwomen. Low-dose regimens may be considered as a starting dose not only in elderly subjects, but also in early postmenopausal women to allow for adjustment to HRT. In older women, these may minimize theoccurrence of side-effects and improve compliance, while preventing the long-term consequences of estrogen deprivation.

Hormone replacement therapy: the benefits in tailoring the regimen and dose

Despite the clear benefits of long-term hormone replacement therapy (HRT), the majority of patients tend to undergo short-term treatment. The cyclical bleedings induced by the sequential progestogen administration are often unacceptable namely in the elderly postmenopausal women. At the standard doses HRT preparations can also induce annoying hormone-related side effects, both in sequential and continuous combined regimens. Lower HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with high rates of amenorrhea. Continuous administration of low doses of progestins is safe for endometrium protection and minimizes progestin-related side effects. Indeed, it has been demonstrated that low dose HRT can prevent the increase in bone turnover and the consequent bone loss in postmenopausal women. The choice of lower HRT dosages can also be useful for the number of potential disadvantages of standard HRT doses, mainly for long-term treatments. Low dose regimens should be considered as a starting dose to minimize the occurrence of side effects, improving compliance and, therefore, HRT effects on the prevention of long-term consequences of estrogen deprivation.

Is low-dose hormone replacement therapy for postmenopausal women efficacious and desirable?

Is low-dose hormone replacement therapy for postmenopausal women efficacious and desirable?

Effects of 15 months of 17β-estradiol and dydrogesterone on systolic cardiac function according to quantitative and Doppler echocardiography in healthy postmenopausal women

Objective: Our goal was to investigate the short-term and intermediate effects of low-dose hormone replacement therapy on echocardiographic parameters of cardiac function in healthy postmenopausal women. Study Design: In a prospective, controlled study 30 healthy postmenopausal women (mean age, 52 ± 3 years) were randomly assigned to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17β-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and thereafter 2 mg 17β-estradiol combined with 10 mg dydrogesterone for a period of 3 months. The control group (n = 15) received no treatment. M-mode, quantitative 2-dimensional, and Doppler echocardiographic measurements were performed at baseline and within the 17β-estradiol phase at 3, 12, and 15 months. Results: After 12 months significant differences in change between the 2 groups were found for left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular mass index, and stroke volume index. These differences were caused by changes in the control group rather than in the hormone replacement therapy group, in which no significant within-group changes were found. All other parameters measured showed no effect. Conclusion: Within 15 months of 17β-estradiol and dydrogesterone treatment no clinically relevant differences were found in the M-mode, quantitative 2-dimensional, and Doppler echocardiographic parameters measured in this study. It is suggested that 15 months of treatment probably is too short a period for detection of direct effects on the heart itself. (Am J Obstet Gynecol 2001;184:910-6.)

Efficacy of Levormeloxifene in the Prevention of Postmenopausal Bone Loss and on the Lipid Profile Compared to Low Dose Hormone Replacement Therapy1

Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of levormeloxifene.

Efficacy of Levormeloxifene in the Prevention of Postmenopausal Bone Loss and on the Lipid Profile Compared to Low Dose Hormone Replacement Therapy

Efficacy of Levormeloxifene in the Prevention of Postmenopausal Bone Loss and on the Lipid Profile Compared to Low Dose Hormone Replacement Therapy

Is low-dose hormone replacement therapy for postmenopausal women efficacious and desirable?

Is low-dose hormone replacement therapy for postmenopausal women efficacious and desirable?

Clinical evidence supporting the rationale for constant oestrogen, intermittent progestogen hormone replacement therapy

Hormone replacement therapy (HRT) effectively relieves vasomotor and other symptoms associated with menopause, yet is underutilised by the majority of menopausal women. Current HRT regimens combine continuous oestrogen with continuous or sequential progestogen in order to achieve the beneficial effects of oestrogen while avoiding the potential for increased risk of endometrial cancer. Uterine bleeding and other adverse progestogenic effects are major reasons for patient noncompliance and early discontinuation of combination HRT, which can ultimately limit the achievement of long-term oestrogenic benefits. A novel constant 17β-oestradiol, intermittent norgestimate regimen has been developed based on theoretical hormone receptor dynamics in an attempt to minimise the hormonal doses needed, thereby potentially reducing the occurrence of adverse effects associated with higher oestrogen and progestogen doses. Clinical trial data with this novel low-dose HRT regimen demonstrate effective relief of vasomotor symptoms in postmenopausal women, acceptable bleeding rates, no endometrial hyperplasia, beneficial effects on lipids, and excellent tolerability. This regimen has the potential to increase long-term use resulting in important clinical benefits.

Low-dose growth hormone (GH) replacement therapy improves vascular reactivity in adults with GH deficiency

Low-dose growth hormone (GH) replacement therapy improves vascular reactivity in adults with GH deficiency

Moderation of the daily dose of HRT: benefits for patients

Introduction: Hormone replacement therapy (HRT) has many benefits yet compliance rates remain low. One of the main reasons for discontinuing therapy is hyperestrogenic side effects which may be dose related, and the initiation of treatment is critical to a patient’s chances of gaining long-term benefits. The introduction of low dose HRT means that physicians have an option to initiate or titrate patients to a low dose. The purpose of this review is to examine current literature on the benefits for patients of low dose HRT. Results: Low dose estrogen (25 mcg/day transdermally or 0.3 mg/day orally) are effective in controlling postmenopausal symptoms, reducing bone loss and reducing cardiovascular risk factors. Low dose therapy is also effective at reducing vasomotor symptoms in highly symptomatic women. In one study, patients on a daily dose of 25 mcg estrogen experienced an 86% reduction in vasomotor symptoms compared to a 55% reduction in patients on placebo. In addition, many adverse events related to estrogens were reduced using a low dose. Conclusion: Compliance with traditional doses of HRT is currently a problem for many women who may stop taking therapy because they experience hyperestrogenic side effects. Low dose HRT is effective at reducing vasomotor symptoms and controlling symptoms even in highly symptomatic women. Hyperestrogenic side effects may be reduced by initiating treatment at the lowest dose and titrating upwards if necessary. This may have benefits for patients in terms of offering effective control of symptoms whilst minimising hyperestrogenic effects.

Extending the treatment boundaries: Zoladex and add-back

Objective: To review the evidence that add-back hormone replacement therapy (HRT) can ameliorate the metabolic consequences of gonadotropin-releasing hormone (GnRH) agonist treatment in women with symptomatic endometriosis. Methods: A review of relevant literature. Results: Early studies suggested that add-back HRT maintained bone mineral density (BMD) without reducing the symptomatic benefit of GnRH treatment. Both high-dose progestogen and low dose progestogen plus cyclical etidronate are effective in maintaining BMD. Standard and low dose HRT add-back may be more effective in relieving the hypo-estrogenic side-effects of GnRH agonist therapy. Randomized controlled studies have shown that both low-dose and standard-dose add-back HRT reduce the side-effects of GnRH agonist therapy, and that this benefit extends to 12 months of treatment. Conclusions: GnRH agonist treatment with add-back HRT seems to offer the hope of improved treatment for women with endometriosis, but the optimum treatment duration and time to start HRT have yet to be defined.

Low-Dose Estrogen Prevents Bone Loss

The side effects of hormone replacement therapy (HRT), such as breast tenderness, vaginal bleeding, and mood changes, limit its long-term use in some cases. To see whether low-dose HRT could prevent bone loss, researchers performed a controlled trial, randomizing 128 healthy but osteopenic white …

Bone density changes in postmenopausal women with the administration of ipriflavone alone or in association with low-dose ERT

Ipriflavone is a synthetic flavonoid that has been shown to exert a direct inhibitory effect on osteoclastic activity and possibly stimulate the osteoblast activity in different experimental models. The aim of the present study was to evaluate the effects of either ipriflavone alone or ipriflavone plus low dose hormone replacement therapy (HRT) in the prevention of postmenopausal bone loss. Patients were randomly allocated to different treatment groups receiving calcium (500 mg/day, control group), continuous HRT (25 or 50 μg/day of transdermal 17β-estradiol) plus medrogestone 5 mg/day for 12 days/month, ipriflavone at the standard dose of 600 mg/day, or finally ipriflavone 600 mg/day plus 17β-estradiol 25 μ g/day plus medrogestone 5 mg/day for 12 days/month. No significant differences in basal levels of biochemical markers of bone turnover or in basal bone mineral density (BMD) values were evident in the different groups. In the control group after 12 months, spine BMD showed a significant (p < 0.05) 3.41% decrease. The pattern of BMD modification was significantly different from controls in the high dose HRT group (+ 1.84%), the ipriflavone group (+ 0.11%), and the combined ipriflavone/HRT group (-0.22%). Conversely, the BMD pattern in the low dose HRTgroup (-0.55%) was similar to that observed in controls. Thus, present results confirm that ipriflavone and 50 μg/day of transdermal 17β-estradiol are effective measures in the prevention of postmenopausal osteopenia. A lower transdermal estrogen dose is unable to increase the antiresorptive effect of ipriflavone and did not exert any further action in the prevention of postmenopausal osteopenia.

Rationale for Estrogen With Interrupted Progestin as a New Low-Dose Hormonal Replacement Therapy

Rationale for Estrogen With Interrupted Progestin as a New Low-Dose Hormonal Replacement Therapy

Rationale for estrogen with interrupted progestin as a new low-dose hormonal replacement therapy.

This review outlines the basic principles of a novel interrupted progestin hormone replacement therapy (HRT) regimen in which estrogen is given continuously but the progestin is administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent receptor down-regulation and allow estrogen to increase estrogen and progestin sensitivity during the progestin-free periods. The reasons for poor patient acceptance of HRT are reviewed. The association of HRT with breast and endometrial cancer is discussed, as are the potential benefits of HRT on the skeleton and the cardiovascular system. Basic research studies in the rat are described that provide supporting evidence for the interrupted progestin regimen. Clinically, we review a pilot study examining symptom control, bleeding rates, and safety of the interrupted progestin regimen as well as preliminary results of the usefulness of this regimen for add-back therapy in GnRH agonist-treated patients. Estrogen and progestin receptor measurements in the rat uterus demonstrate a clear up- and down-regulation in response to estrogen and interrupted progestin but not to the continuous administration of estrogen and progestin or estrogen alone. In addition, we found a significant beneficial effect of a low-dose interrupted HRT regimen on bone mineral content and density in an aged rat model of osteopenia, compared with continuous estrogen and progestin or estrogen alone. These results support the hypothesis that the interrupted progestin HRT increases tissue sensitivity to both estrogen and progestin. Clinical studies demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen-responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance of this new regimen compared to continuous combined HRT.

Hormone Replacement Therapy May Reduce the Return of Endogenous Lead from Bone to the Circulation

Hormone replacement therapy (HRT) in postmenopausal women suppresses the increase in bone resorption expected as circulating levels of endogenous estrogen decline. We tested the hypothesis that bone lead content might remain elevated in women on HRT. Fifty six women who at recruitment were on average 35 years postmenopausal were placed on calcium supplementation. Six months later 33 of these women were prescribed either low dose or moderate dose hormone replacement in addition to the calcium supplementation. After approximately 4 years of hormone replacement, lead content was measured at the tibia and calcaneus by in vivo fluorescence excitation, and lead concentrations were measured in serum, whole blood, and urine. Women not taking hormones had significantly lower lead concentrations in cortical bone compared to all women on HRT (p = 0.007). Tibia lead content (mean +/- SD) for women on calcium only was 11.13 +/- 6.22 microgram/g bone mineral. For women on HRT, tibia bone lead was 19.37 +/- 8.62 micrograms/g bone mineral on low-dose HRT and 16.87 +/- 11.68 micrograms/g bone mineral on moderate-dose HRT. There were no differences between groups for lead concentrations measured in trabecular bone, whole blood, serum or urine. Hormone replacement maintains cortical bone lead content. In women not on HRT, there will be a perimenopausal release of lead from bone.

Hormone replacement therapy may reduce the return of endogenous lead from bone to the circulation.

Hormone replacement therapy (HRT) in postmenopausal women suppresses the increase in bone resorption expected as circulating levels of endogenous estrogen decline. We tested the hypothesis that bone lead content might remain elevated in women on HRT. Fifty six women who at recruitment were on average 35 years postmenopausal were placed on calcium supplementation. Six months later 33 of these women were prescribed either low dose or moderate dose hormone replacement in addition to the calcium supplementation. After approximately 4 years of hormone replacement, lead content was measured at the tibia and calcaneus by in vivo fluorescence excitation, and lead concentrations were measured in serum, whole blood, and urine. Women not taking hormones had significantly lower lead concentrations in cortical bone compared to all women on HRT (p = 0.007). Tibia lead content (mean +/- SD) for women on calcium only was 11.13 +/- 6.22 microgram/g bone mineral. For women on HRT, tibia bone lead was 19.37 +/- 8.62 micrograms/g bone mineral on low-dose HRT and 16.87 +/- 11.68 micrograms/g bone mineral on moderate-dose HRT. There were no differences between groups for lead concentrations measured in trabecular bone, whole blood, serum or urine. Hormone replacement maintains cortical bone lead content. In women not on HRT, there will be a perimenopausal release of lead from bone.

Treatment of menopause: A simple and inexpensive treatment of menopause: prophylaxis of post-menopausal bone loss

Relatively few women elect to receive classical hormone replacement therapy (HRT), and others discontinue treatment because of side-effects or fear of complications. This report presents the results of a long-term study of a low-dose step-down HRT protocol and discusses its potential benefits.

9 Endometriosis: Medical therapy

The management of women with endometriosis is complex and necessitates individualization of patient care. The most commonly used medical therapies are danazol, GnRH agonists, medroxyprogesterone acetate and gestrinone. Studies to date have shown these drugs to have equal efficacy in terms of reduction in laparoscopic score and relief of symptoms. However, their side-effects make them unsuitable for long-term use. The addition of low dose hormone replacement therapy to GnRH agonist regimens may allow prolonged use but the current cost of these agents is high. Low dose oral contraceptive pills deserve further investigation. The role of medical treatment for women with endometriosis and infertility is controversial. There is no place for hormonal therapy in such women with stage I or II disease. When expectant management fails, gamete intrafallopian transfer offers excellent results. For those with stage III or IV disease, surgery is preferable with adjunctive medical therapy in selected cases. If pregnancy does not ensue, in vitro fertilization and embryo transfer are the next line of management, and results are optimized by prior medical therapy and aspiration of endometriomas. Major advances have been made in the medical management of endometriosis. However, current treatment strategies are ineffective in eliminating the disease in most women. New approaches are required in both basic and clinical research in order to finally eradicate this often devastating disease.

The chemoprevention of breast cancer by reducing sex steroid exposure: perspectives from epidemiology.

Mitogenesis is a major driving force in neoplastic development. Blocking the effect of breast cell mitogens by reducing the actual exposure of the breast to these mitogens is an obvious strategy for breast cancer prevention. The ovarian hormones, estrogens and progesterone, are major effective (direct or indirect) breast cell mitogens. A woman's exposure to ovarian estrogens and progesterone is drastically reduced by the use of combination-type oral contraceptives (COCs), but the synthetic estrogen and progestogen in the COCs effectively replace ovarian estrogens and progesterone, so that breast cell exposure to these hormones is not decreased. Doses of estrogen and progestogen in modern COCs are close to the minimum attainable while still retaining both contraceptive efficacy and ovarian suppression (so that endogenous estrogen and progesterone do not add to the dose of estrogen and progestogen from the COC). Considerably lower effective breast cell exposure to estrogen and progestogen can, however, be achieved by using a gonadotropin-releasing hormone agonist (GnRHA) to suppress ovarian function and compensate for the resulting hypoestrogenemia with low-dose hormone replacement therapy. Compared to modern COCs, estrogen exposure can be reduced by approximately 60%, and progestogen dose by more than 80%. Such a contraceptive is predicted to reduce lifetime breast cancer risk by more than 50% if used for 10 years. The possibility that a practical contraceptive could achieve such a major benefit is shown by the dramatic decline in the incidence of both ovarian and endometrial cancer in young women in the U.S. over the last 3 decades--a direct result of COC use.