Transdermal natural progesterone cream for postmenopausal women: inconsistent data and complex pharmacokinetics.

Transdermal progesterone cream (PC) is propagated as a possible alternative to hormone replacement therapy (HRT) in the management of menopausal symptoms and treatment of osteoporosis. Nonetheless, considerable concerns were raised regarding the inconsistent results and the credibility of some studies that were not peer-reviewed. Further, the complex nature and diversity of the pharmacokinetics of progesterone led to difficult interpretation of the findings. Given the current best available evidence, using PC for postmenopausal therapy regimens should be considered as an unsubstantiated treatment option, and its clinical applications must be restricted to well-designed interventional trials that assess its efficacy and safety.     

The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss

The effect of percutaneous estradiol alone and combined with natural progesterone on postmenopausal bone loss was studied. A total of 57 women who had experienced a natural menopause 6 months to 3 years previously entered the study. After an initial examination the women were allocated in a blinded pattern to treatment with 3 mg of percutaneous estradiol or placebo. The code was broken after 1 year of treatment, and the women receiving estradiol continued with a cyclic addition of progesterone, whereas those receiving placebo continued with placebo. The women were examined every 3 months during the 2 years of treatment. Measurement of the bone mineral content in the forearms (single photon absorptiometry) and the spine and total skeleton (dual photon absorptiometry) showed a significant decrease of 5% to 7% in the placebo group during the 2 years of treatment, whereas it remained constant in all bone compartments in the estradiol group. Addition of progesterone did not influence the results. Biochemical estimates of calcium metabolism changed toward a premenopausal level in the estradiol group but remained unchanged in the placebo group. We conclude that percutaneous estradiol is effective as preventive therapy of postmenopausal bone loss and that addition of progesterone does not influence bone or calcium metabolism.     

A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group.

OBJECTIVE: To determine the effects of four doses of a 7-day transdermal 17beta-estradiol (E2) delivery system, including 0.025 mg/day, on bone loss in postmenopausal women. METHODS: This was a multicenter, double-masked, randomized, placebo-controlled study of the effects of transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day for the prevention of postmenopausal osteoporosis. Efficacy was evaluated from bone mineral density of lumbar vertebrae L2-L4, radius, proximal femur, and total hip measured with dual-energy x-ray absorptiometry. Serum osteocalcin and urinary pyridinoline and deoxypyridinoline concentrations were measured. RESULTS: At 24 months, E2 doses of 0.025, 0.05, 0.06, and 0.1 mg/day resulted in mean increases in bone mineral density of the lumbar spine of 2.37%, 4.09%, 3.28%, and 4.70%, respectively, and increased bone mineral density of the total hip by 0.26%, 2.85%, 3.05%, and 2.03%, respectively. All increases were statistically significantly greater than placebo, which decreased bone mineral density by 2.49% at the spine and 2.04% at the hip. Consistent and significant improvements in biochemical markers of bone turnover also were noted at various intervals in all treatment groups. The most frequent adverse events were local reactions from the transdermal drug-delivery system, effects of estrogen, and menopausal symptoms. CONCLUSION: Transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day effectively prevented bone loss in postmenopausal women.     

Raloxifene effects on vasomotor and other climacteric symptoms in postmenopausal women

Introduction and Objectives: Raloxifene, a novel selective estrogen receptor modulator (SERM), is under investigation for the prevention of osteoporosis in postmenopausal women. Like traditional estrogen replacement therapy, raloxifene has beneficial effects on bone and on serum lipids whereas, in contrast to estrogen’s adverse effects in the breast and uterus, raloxifene is an estrogen antagonist in the breast and is nonstimulatory in the uterus. This study examines the effects of raloxifene 60 mg/day compared with placebo on: 1) the incidence of vasomotor symptoms: hot flashes (flushing) and sweating (including night sweats), 2) the severity and time course of hot flashes, and 3) the relation of hot flashes to baseline subject characteristics and study discontinuations. Additionally, the study explores the effects of raloxifene 60 mg/day compared with placebo on other climacteric symptoms that affect the quality of life of postmenopausal women, such as depression, insomnia, mood lability and genitourinary complaints.Methods: Integrated data from five randomized, placebo-controlled studies involving 1,165 healthy, postmenopausal women, with up to 30 months of study drug exposure, were analyzed. The incidence and severity of hot flashes and other climacteric symptoms were compared in patients treated with placebo or raloxifene (60 mg/day) via open-ended, non-directed subject self-assessment questionnaires. Data were analyzed for subgroup-by-therapy interactions using many baseline subject characteristics such as age, body mass index, smoking, alcohol, and years post-menopause, as well as preexisting conditions such as hot flashes, sweating, insomnia, depression, and history of hysterectomy. The overall incidence of other climacteric symptoms were reported as adverse events.Results: The increase in overall incidence of hot flashes in raloxifene-treated (24.6%) and placebo-treated (18.3%) subjects was modest, but statistically significant. However, this difference was significant only during the first 6 months of therapy, raloxifene (20.1%) compared with placebo (14.4%). After 6 months of treatment, there was no statistically significant difference in the incidence of hot flashes between the two treatment groups. The majority of hot flashes in raloxifene-treated subjects were subject-assessed as “mild-to-moderate” in severity (89%). The incidence of hot flashes reported as “severe” did not differ significantly in raloxifene- or placebo-treated subjects. Subgroup analyses revealed the overall incidence of hot flashes to be highest for both raloxifene and placebo-treated subjects, in younger (age < 55 years) women (P = .004), in women who had previously experienced hot flashes (P = .031), and in women having had hysterectomies (P < .001). Within each of these subgroups, there was no statistical difference in the incidence of hot flashes between the raloxifene and placebo groups. Between the two treatment groups, there was no difference in the overall incidence of subject discontinuations from study due to hot flashes. The occurrence of the other common vasomotor symptom, sweating (which includes night sweats), was not statistically different for the raloxifene- or placebo-treated subjects.Genitourinary complaints are often symptoms related to vaginal dryness, such as dyspareunia and decreased libido, as well as other symptoms of vaginitis and leukorrhea. No statistically significant differences occurred for raloxifene- or placebo-treated subjects in reports of these genitourinary symptoms. Similarly, for the other common climacteric symptoms; depression, insomnia, and mood lability, no significant differences in incidence between the raloxifene and placebo treatment groups were observed.Conclusions: Raloxifene (60 mg/day) treatment modestly increased the incidence of hot flashes compared with placebo, however, this difference was only statistically significant during the first 6 months of treatment. There were no differences in the severity of hot flashes between treatment groups, and this symptom did not adversely affect subjects’ study participation. In both the raloxifene and placebo treatment groups, young postmenopausal women (age < 55), those with baseline hot flashes, and those with histories of hysterectomy were most likely to experience hot flashes. Raloxifene therapy did not affect the occurrence of other climacteric symptoms commonly affecting the quality of life of women after menopause.     

A comparison of acupuncture and oral estradiol treatment of vasomotor symptoms in postmenopausal women.

OBJECTIVE: To compare the effects of electro-acupuncture with oral estradiol and superficial needle insertion on hot flushes in postmenopausal women. MATERIAL AND METHODS: Forty-five postmenopausal women with vasomotor symptoms were randomized to electro-acupuncture, superficial needle insertion or oral estradiol treatment during 12 weeks, with 6 months' follow-up. The number and severity of flushes were registered daily and the Kupperman index and a general estimate of climacteric symptoms were completed before, during and after therapy. RESULTS: In the electro-acupuncture group, the mean number of flushes/24 h decreased from 7.3 to 3.5 (ANOVA, p < 0.001). Eleven of the 15 women had at least a 50% decrease in number of flushes (with a mean decrease of 82%). Superficial needle insertion decreased the number of flushes/24 h from 8.1 to 3.8 (p < 0.001). In seven out of 13 women, the number of flushes decreased by at least 50% (mean decrease 83%). In the estrogen group, the number of flushes decreased from 8.4 to 0.8 (p < 0.001). The decrease in number of flushes persisted during the 24-week follow-up period in all treatment groups. The Kupperman index and the general climacteric symptom score decreased, and remained unchanged 24 weeks after treatment in all groups (p < 0.001). Electro-acupuncture decreased the number of flushes/24 h significantly over time, but not to the same extent as the estrogen treatment. No significant difference in effect was found between electro-acupuncture and the superficial needle insertion. CONCLUSION: We suggest that acupuncture is a viable alternative treatment of vasomotor symptoms in postmenopausal women and cannot recommend superficial needle insertion as an inactive control treatment.     

The pathophysiology of peri- and postmenopausal bone loss

Summary. Changes in sex hormones and bone turnover were studied longitudinally in 31 women aged 47–54 years who were approaching the menopause. Every 6 weeks for 2–3 years, hormones and biochemical estimates of the bone turnover were determined and the bone mass was measured at two forearm sites by single photon absorptiometry. Spinal bone mass was measured every 6 months. The bone turnover was normal in women aged 47–54 years with regular menstruation, whereas the estimates of bone resorption were high in the women with irregular menstruation. In nine women, who reached the menopause during the study, bone resorption increased significantly, whereas bone formation showed only a small increase. When the results of the nine women were combined with those of 50 women, who had passed a natural menopause within the preceding 3·5 years, the bone resorption indices reached their peak within the first postmenopausal year, whereas bone formation increased until 1·5–2 years after the last menstrual cycle. At the ultradistal forearm site the rate of bone loss was maximal (5% per year) immediately after the menopause and subsequently declined, which suggests that trabecular bone is more sensitive than cortical bone to changes in bone turnover. Spinal bone loss was identical in late peri-and early postmenopausal women. We conclude that bone resorption starts to increase during the last perimenopausal years, with a beginning acceleration in bone loss, which then becomes sharp after the menopause. The changes are related to the decline in oestrogens, but other mechanisms may also play a role.     

The pathophysiology of peri- and postmenopausal bone loss

Changes in sex hormones and bone turnover were studied longitudinally in 31 women aged 47-54 years who were approaching the menopause. Every 6 weeks for 2-3 years, hormones and biochemical estimates of the bone turnover were determined and the bone mass was measured at two forearm sites by single photon absorptiometry. Spinal bone mass was measured every 6 months. The bone turnover was normal in women aged 47-54 years with regular menstruation, whereas the estimates of bone resorption were high in the women with irregular menstruation. In nine women, who reached the menopause during the study, bone resorption increased significantly, whereas bone formation showed only a small increase. When the results of the nine women were combined with those of 50 women, who had passed a natural menopause within the preceding 3.5 years, the bone resorption indices reached their peak within the first postmenopausal year, whereas bone formation increased until 1.5-2 years after the last menstrual cycle. At the ultradistal forearm site the rate of bone loss was maximal (5% per year) immediately after the menopause and subsequently declined, which suggests that trabecular bone is more sensitive than cortical bone to changes in bone turnover. Spinal bone loss was identical in late peri- and early postmenopausal women. We conclude that bone resorption starts to increase during the last perimenopausal years, with a beginning acceleration in bone loss, which then becomes sharp after the menopause. The changes are related to the decline in oestrogens, but other mechanisms may also play a role.     

Transition from estrogen-progestin to raloxifene in postmenopausal women: effect on vasomotor symptoms

OBJECTIVE: To compare vasomotor symptoms after transition from estrogen-progestin therapy to raloxifene 60 mg/d with and without a placebo washout. METHODS: Postmenopausal women currently taking continuous combined estrogen-progestin therapy (conjugated equine estrogen, 0.625 mg/medroxyprogesterone acetate, 2.5 or 5 mg) daily for 5 or more months were enrolled. Women were randomized to 1 of 4 blinded regimens: 1) 12 weeks estrogen-progestin; 2) 12 weeks placebo; 3) 4 weeks placebo, then 8 weeks raloxifene; or 4) 12 weeks raloxifene. For the final 36 weeks, all subjects received raloxifene. Vasomotor symptoms were assessed by patient diaries. RESULTS: A total of 266 women (mean age 57.5) were enrolled. Mean hot flush frequency at baseline was approximately 1 per week in the entire population, with 16% of women reporting hot flushes. Mean frequency and severity of hot flushes during the first 12 weeks of the study were statistically greater in the 3 groups transitioned off estrogen-progestin (range of hot flushes per week: 4 weeks, 11-12; 8 weeks, 18-24; 12 weeks, 13-16), as compared with those continuing estrogen-progestin, with no difference between these 3 groups (P> or =.1). Approximately 50-70% of these women reported hot flushes, generally rated as mild to moderate by participants, after estrogen-progestin discontinuation. CONCLUSION: A large proportion of women discontinuing estrogen-progestin experience hot flushes. Raloxifene does not appear to increase the frequency or severity of vasomotor symptoms in women discontinuing estrogen-progestin more than that observed with placebo treatment after estrogen-progestin discontinuation. Transition from estrogen-progestin to raloxifene with no washout period therefore may be acceptable. LEVEL OF EVIDENCE: I     

Omega-3 versus isoflavones in the control of vasomotor symptoms in postmenopausal women

Determine the efficacy and tolerability of omega-3 fatty acids versus soybean isoflavones in reducing the vasomotor symptoms (VMSs) frequency in postmenopausal women. A randomized, prospective, two-arm study was performed in healthy postmenopausal women aged 45–65. The two arms were: two capsules/day of omega-3 (425?mg of omega-3/capsule) administered orally (n?=?38) and two tablets/day of soybean isoflavones (54.4?mg of isoflavones/tablet) (n?=?30), over 16?weeks. The mean baseline frequency of moderate and severe VMSs per week in the omega-3 group was 24.56 and 23.90, respectively, and 19.65 and 19.51 in the isoflavone group. After 4?months, the reduction in moderate and severe hot flashes with omega-3 was significant (p?p?=?.02) hot flashes after 4?months, but not in moderate hot flashes (p?=?.077). Omega-3 did not demonstrate significant efficacy differences versus isoflavones over time. The use of omega-3 has a beneficial effect on hot flash reduction after 4?months of treatment. This is comparable to the benefits found with soybean isoflavones after 3–4?weeks and after 4?months in severe hot flash women, but higher than those found with soybean isoflavones in moderate symptom women.     

The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women

Objective. To evaluate the effect of red clover isoflavone supplementation over vasomotor and overall menopausal symptoms in postmenopausal women. Methods. One hundred and nine postmenopausal women aged 40 or more were assigned to randomly receive either two daily capsules of the active compound (80?mg red clover isoflavones, Group A) or placebo of equal appearance (Group B) for a 90-day period. After a washout period of 7 days, medication was crossed over and taken for 90 days more. Daily hot flush and night sweat frequency and overall menopausal symptom intensity (Kupperman Index) were measured at baseline, 90, 97 and 187 days. Results. Daily hot flush/night sweat frequency and Kupperman Index values were similar in both studied groups at baseline. All indices significantly decreased after red clover phase in Group A, corresponding, respectively to a 73.5%, 72.2% and 75.4% average decrement. These decrements were significantly higher than those observed for Group B after placebo phase (8.2%, 0.9% and 6.7% respectively). In Group A, after washout and placebo phases all values significantly increased. In Group B, all indices remained similar after placebo and washout phases, however significantly dropping after red clover treatment. These values were also significantly lower than those observed in Group A after placebo phase. No side effects were encountered after treatment with the active compound or placebo. Conclusion. Red clover isoflavone supplementation was more effective than placebo in reducing daily vasomotor frequency and overall menopausal intensity in postmenopausal women.     

Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women.

With the use of a double-blind, randomized, dose-ranging design, we tested during an 18-month period the degree of protection against postmenopausal bone loss afforded by micronized 17 beta-estradiol in dosages of 0.5, 1.0, and 2.0 mg. All subjects received supplementation to ensure a minimum of 1500 mg calcium daily. Fifty-one subjects completed at least 1 year of follow-up bone density measurements by quantitative computed tomography and by single- and dual-photon absorptiometry. In the placebo group spinal trabecular bone density decreased 4.9% annually (p less than 0.001), whereas in those taking micronized 17 beta-estradiol bone density tended to increase (annual increases of 0.3% in the 0.5 mg micronized 17 beta-estradiol group, 1.8% in the 1.0 mg micronized 17 beta-estradiol group, and 2.5% in the 2.0 mg micronized 17 beta-estradiol group). After completing the double-blind phase, 41 subjects completed an additional 18 months of follow-up while taking 1.0 mg micronized 17 beta-estradiol. During this time one third of the subjects were randomly assigned to discontinue calcium supplements. Among those who previously received placebo, trabecular bone density increased 4.3% annually, whereas among those who had used micronized 17 beta-estradiol, trabecular bone density response was inversely related to the dosage previously used. Additionally and independently, the level of calcium intake showed a statistically significant correlation with the change in spinal trabecular bone density (r = 0.37, p = 0.02). We conclude that micronized 17 beta-estradiol has a continuous skeletal dose-response effect in the range of 0.5 to 2.0 mg and that calcium intake positively modifies the skeletal response to 1.0 mg micronized 17 beta-estradiol.     

Prevention of postmenopausal bone loss and treatment of osteoporosis

Osteoporosis is now recognized as an increasingly prevalent disorder throughout the world. Fragility fractures and their subsequent short- and long-term complications are the adverse outcomes of this disease that is essentially silent until fractures occur. Given that the presence of one fragility fracture is an important predictor of the risk of subsequent fractures, prevention of the first fracture is critical whenever possible. Two key elements in fracture prevention that are discussed in this article are the attainment of optimal peak bone mass and the prevention of bone loss at menopause, with the major focus on the prevention of postmenopausal bone loss.     

The effect of hormone replacement therapy on postmenopausal bone loss.

Eighty-four postmenopausal women who were randomly allocated to one of four groups, completed a 1 year follow-up. The first group (n = 20) received 0.625 mg/day conjugated estrogens cyclically (CE; 25 days/month). The second (n = 23) received 0.625 mg/day of CE continuously, and the third (n = 17) received 50 micrograms/day of transdermal 17 beta-estradiol cyclically (24 days/month). All these groups also received 2.5 mg of medroxiprogesterone acetate sequentially for the last 12 days of hormone replacement therapy, while the fourth group (n = 24) constituted a treatment-free control group. Dual photon absorptiometry was carried out before therapy and was repeated after 1 year. Serum calcium, phosphate and osteocalcine levels, and the urinary calcium/creatinine and hydroxyproline/creatinine ratios, were measured prior to treatment and 6 and 12 months thereafter. All treatment groups showed an increase in bone mineral content. This increase was higher in the continuous CE treatment group (4.4%, P less than 0.05) and in transdermal group (7.1%, P less than 0.01). Concomitant biochemical effects at 6 and 12 months, reduction in urine calcium and hydroxyproline, reduction in blood calcium, phosphate and osteocalcine, were compatible with the observed effects on bone mineral.     

Relation of estrogen and bone loss in postmenopausal women

Seventy-six women were divided into three groups: child-bearing age (A), premenopausal (B) and postmenopausal (C). In addition 14 cases were randomly chosen from group C (0-5 years after menopause) for estrogen treatment (5 micrograms ethinylestradiol daily for one month). Serum levels of sex steroids and alkaline phosphatase (ALP) were determined as an index of bone formation. Ratios of fasting urinary calcium to creatinine (Ca/Cr) and of hydroxyproline to creatinine (Hyp/Cr) were taken as indexes of bone resorption. Radial bone mineral content (BMC) was measured by single photon absorptiometry. In group C serum ALP Ca/Cr and Hyp/Cr were increased by 20%, 31% and 33%, and the respective values were reduced by 11%, 33% and 24% after estrogen therapy. In group C there was a significant lowering of radial BMC as well as serum E1 and E2 levels.     

Ossein-hydroxyapatite compounds for preventing postmenopausal bone loss. Coadjuvant use with hormone replacement therapy

OBJECTIVE: To evaluate whether the addition of an ossein-hydroxyapatite compound (OHC) may improve the effect of hormone replacement therapy (HRT) on postmenopausal bone loss. STUDY DESIGN: Of the 118 recent surgically postmenopausal women initially selected for this open study, 96 completed one-year follow-up. Patients were allocated into four groups. The first group received 50 micrograms/d of transdermal 17-beta estradiol continuously (group E, n = 23), the second received 3.32 g/d of an OHC every day (group OHC, n = 23), the third received 50 micrograms/d of transdermal 17-beta estradiol continuously plus 3.32 g/d of the OHC every day (group E-OHC, n = 26), and an additional 24 women were used as untreated controls (group C). Bone mass, assessed by dual x-ray absorptiometry, was measured prior to and at the end of treatment. Samples, including serum calcium, phosphate and osteocalcine level, were collected before therapy and during the 6th and 12th treatment months. RESULTS: All treatment groups showed an increase in bone mineral content. This increase was higher in the E-OHC group (4.7%, P < .01). Concomitant biochemical effects at 6 and 12 months were compatible with the observed effects on bone mineral. CONCLUSION: The combined regimen of OHC and HRT increased vertebral bone mass in postmenopausal women to a greater extent than did OHC or HRT alone, suggesting that this drug combination may be useful in the management of postmenopausal bone loss.     

Effect of estrone sulfate on postmenopausal bone loss

Estrogen replacement therapy confers many beneficial effects to postmenopausal women, such as slowing the rate of bone loss and decreasing the risk of coronary artery disease. This multicenter, placebo-controlled study evaluated the lowest effective daily dose of estrone sulfate (0.3, 0.625, or 1.25 mg) combined with 1000 mg elemental calcium supplementation for preventing bone loss in the immediate supplementation for preventing bone loss in the immediate postmenopausal period. Spinal bone mineral density was measured using quantitative computed tomography. Compared with baseline, bone mineral density increased significantly (P less than .05) after 12 months of 0.625 mg daily (+ 1.9%) or 1.25 mg daily (+ 2.5%). The difference between the 0.625-mg and 1.25-mg doses was not statistically significant. Estrone sulfate administration (0.625 and 1.25 mg) produced significant changes in various lipid measurements at both the 6- and 12-month observation points. The prevalence rates for adverse events were comparable among the estrone sulfate groups and the placebo group. Estrone sulfate 0.625 mg daily, combined with 1000 mg elemental calcium supplementation, was the minimum effective dosage to prevent loss of spinal bone mineral density in postmenopausal women over a 12-month period.     

Two new combinations of estrogen and progestogen for prevention of postmenopausal bone loss: long-term effects on bone, calcium and lipid metabolism, climacteric symptoms, and bleeding.

Bone mass, calcium and lipid metabolism, climacteric symptoms, bleeding, blood pressure, and weight changes were studied in 62 healthy postmenopausal women at 3-month intervals throughout 2 years of treatment with continuous estradiol valerate (2 mg) plus cyproterone acetate (1 mg), sequential estradiol valerate (2 mg) plus levonorgestrel (75 micrograms), or placebo. During the 2 years of the study, bone mineral content of the distal and ultradistal regions of the forearm (measured by single-photon absorptiometry) remained unchanged in the hormone groups, whereas bone mineral content at these sites decreased by 5 and 6%, respectively, in the placebo group. Bone mineral density in the spine (measured by dual-photon absorptiometry and dual-energy x-ray absorptiometry) increased by 3-4% in the hormone groups and decreased by 2% in the placebo group. Biochemical estimates of bone turnover (serum alkaline phosphatase and fasting urinary calcium/creatinine) decreased significantly to premenopausal levels in the hormone groups, but remained unchanged in the placebo group. Serum concentrations of total and low-density lipoprotein cholesterol were significantly reduced by 5-10% (P less than .05-.01) in the estradiol + cyproterone acetate group and by 10-15% (P less than .001) in the estradiol valerate + levonorgestrel group. There were no significant changes in high-density lipoprotein cholesterol in the hormone groups. Virtually no changes were observed in the placebo group. Climacteric symptoms and hot flushes were significantly reduced in both hormone groups compared with the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)