Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. Estrogen Deficiency in Adolescents and Young Adults: Impact on Bone Mineral Content and Effects of Estrogen Replacement Therapy Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: A two-year study How many women lose bone mineral density while taking hormone replacement therapy? Results from the Postmenopausal Estrogen/Progestin Interventions Trial. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. Reproductive hormones and skeletal health in young women. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. A randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. Effect of hormone therapy and calcitriol on serum lipid profile in postmenopausal older women: association with estrogen receptor-&agr; genotypes Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner's syndrome and previously normal bone density. Estrogen-plus-progestin use and mammographic density in postmenopausal women: Women's Health Initiative randomized trial. The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. Estrogen plus progestin and the risk of coronary heart disease. A 2‐year Study of Lipid and Lipoprotein Changes in Postmenopausal Women With Tibolone and Estrogen‐Progestin Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. Postmenopausal hormone therapy and change in mammographic density.
Purpose of review Provide evidence -based recent data on oral micronized progesterone ( OMP ) and progestins in menopausal hormonal therapy ( MHT ) . Recent findings Medroxyprogesterone acetate ( MPA ) increases breast cancer acting through the glucocorticoid receptor ; progestins in MHT increase thrombosis more than oral estrogens ; MPA , but not OMP or other progestins , increase monocyte cell endothelium adhesion ; MPA and estradiol (E2)/MPA have negative brain effects , whereas E2/progesterone ( P4 ) has neuroregenerative brain effects . The ‘ window of opportunity ’ cardiovascular disease hypothesis is not supported by a r and omized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness ; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome ;  transdermal estradiol/OMP does not increase venous thromboembolism in observational data . P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor & agr ; genetic effects ;  OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospect i ve cohorts , one population -based . Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day . Summary New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer , venous thromboembolism , cardiovascular system , and brain effects .  OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome .  OMP effectively treats vasomotor symptoms and sleep disturbances , and could safely be used alone for symptomatic menopause CONTEXT In the Women 's Health Initiative trial of estrogen-plus-progestin therapy , women assigned to active treatment had fewer fractures . OBJECTIVE To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial ( September 1993-July 2002 ) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years . INTERVENTION Women were r and omly assigned to receive conjugated equine estrogen , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , in 1 tablet ( n = 8506 ) or placebo ( n = 8102 ) . MAIN OUTCOME MEASURES All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial ( July 7 , 2002 ) ; bone mineral density ( BMD ) , measured in a subset of women ( n = 1024 ) at baseline and years 1 and 3 ; and a global index , developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk . RESULTS Seven hundred thirty-three women ( 8.6 % ) in the estrogen-plus-progestin group and 896 women ( 11.1 % ) in the placebo group experienced a fracture ( hazard ratio [ HR ] , 0.76 ; 95 % confidence interval [ CI ] , 0.69 - 0.83 ) . The effect did not differ in women stratified by age , body mass index , smoking status , history of falls , personal and family history of fracture , total calcium intake , past use of hormone therapy , BMD , or summary fracture risk score . Total hip BMD increased 3.7 % after 3 years of treatment with estrogen plus progestin compared with 0.14 % in the placebo group ( P<.001 ) . The HR for the global index was similar across tertiles of the fracture risk scale ( lowest fracture risk tertile , HR , 1.20 ; 95 % CI , 0.93 - 1.58 ; middle tertile , HR , 1.23 ; 95 % CI , 1.04 - 1.46 ; highest tertile , HR , 1.03 ; 95 % CI , 0.88 - 1.24 ) ( P for interaction = .54 ) . CONCLUSIONS This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women . The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined . When considering the effects of hormone therapy on other important disease outcomes in a global model , there was no net benefit , even in women considered to be at high risk of fracture Because the long-term effects of estrogen replacement in adolescents with ovarian failure and hypothalamic amenorrhea have not been previously studied , we conducted a 2-year study of 35 patients to determine factors contributing to baseline bone density measures ( bone density , bone mineral content , and bone width ) and the response to estrogen therapy . Estrogen-deficient patients were often profoundly osteopenic by single-photon absorptiometry of the radius and dual-photon absorptiometry of the spine , despite estrogen replacement . Variables that were significant predictors of better initial single-photon absorptiometry measurements included increased age , increased body mass index , spontaneous pubertal development , lack of radiation therapy , and lower serum osteocalcin . Patients treated with estrogen/progestin had stable cortical bone mineral content and bone density at the distal one-third of the radius , a slight improvement in bone density at the distal one-tenth of the radius , and an encouraging , but marginal , improvement in the z score ( st and ard deviation from the mean ) of bone mineral content at the distal onetenth . The z scores for cortical bone width and bone density decreased , suggesting a possible relative worsening over time . In untreated estrogen-deficient girls , bone mineral content and bone density decreased ( but not significantly ) ; the z score of cortical bone width showed a significant decrease . Using dual-photon absorptiometry , a history of radiation therapy was found to be a predictor of lower bone density compared with age-matched controls . Estrogen/ progestin therapy did not result in changes in serum levels of lipids and antithrombin HI , weight , or blood pressure . This study suggests that because most adolescent/young adult patients with estrogen deficiency may not achieve normal bone density with current therapy , earlier and more aggressive intervention may be necessary BACKGROUND Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption , but the balance between its long-term risks and benefits remains unclear . Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear . METHODS We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age . An additional 435 women who were prepared to receive a combination of estrogen and progestin  were r and omly assigned to one of the above treatments or open-label estrogen-progestin . The main outcome measure was the change in bone mineral density of the lumbar spine , hip , distal forearm , and total body measured annually for two years by dual-energy x-ray absorptiometry . RESULTS The women who received placebo lost bone mineral density at all measured sites , whereas the women treated with 5 mg of alendronate daily had a mean ( + /-SE ) increase in bone mineral density of 3.5+/-0.2 percent at the lumbar spine , 1.9+/-0.1 percent at the hip , and 0.7+/-0.1 percent for the total body ( all P<0.001 ) . Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density .  Alendronate did not increase bone mineral density of the forearm , but it slowed the loss . The responses to estrogen-progestin were 1 to 2 percentage points greater than those to the 5-mg dose of alendronate . Alendronate was well tolerated , with a safety profile similar to that of placebo or estrogen-progestin . CONCLUSIONS Alendronate prevents bone loss in postmenopausal women under 60 years of age to nearly the same extent as estrogen-progestin OBJECTIVE To assess the effects of hormone therapy on bone mineral density ( BMD ) in the spine and hip of postmenopausal women . DESIGN A 3-year , multicenter , r and omized , double-blinded , placebo-controlled clinical trial . PARTICIPANTS A total of 875 healthy women aged 45 to 64 years recruited at 7 clinical centers . INTERVENTIONS Treatments were ( 1 ) placebo ; ( 2 ) conjugated equine estrogens ( CEE ) , 0.625 mg/d ; ( 3 ) CEE , 0.625 mg/d plus medroxyprogesterone acetate ( MPA ) , 10 mg/d for 12 d/mo ; ( 4 ) CEE , 0.625 mg/d plus MPA , 2.5 mg/d daily ; or ( 5 ) CEE , 0.625 mg/d plus micronized progesterone ( MP ) , 200 mg/d for 12 d/mo . MAIN OUTCOME MEASURES Bone mineral density at baseline , 12 months , and 36 months . RESULTS Participants assigned to the placebo group lost an average of 1.8 % of spine BMD and 1.7 % of hip BMD by the 36-month visit , while those assigned to active regimens gained BMD at both sites , ranging from 3.5 % to 5.0 % mean total increases in spinal BMD and a mean total increase of 1.7 % of BMD in the hip . Changes in BMD for women assigned to active regimens were significantly greater than those assigned to placebo . Women assigned to CEE plus continuous MPA had significantly greater increases in spinal BMD ( increase of 5 % ) than those assigned to the other 3 active regimens ( average increase , 3.8 % ) . Findings were similar among those adhering to assigned therapy , although , among adherent participants , there were no significant differences in BMD changes among the 4 active treatment groups . Older women , women with low initial BMD , and those with no previous hormone use gained significantly more bone than younger women , women with higher initial BMD , and those who had used hormones previously . CONCLUSIONS Postmenopausal women assigned to placebo demonstrated decreased BMD at the spine and hip , whereas women assigned to estrogen therapy increased BMD during a 36-month period . These findings demonstrate that estrogen replacement therapy increases BMD at clinical ly important sites Objective To determine the relationships among bone mineral density changes , bone marker changes , and plasma estrogens in postmenopausal women receiving estrogen replacement therapy .  Design A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens ( 0.3 mg , 0.625 mg , or 1.25 mg ) or placebo daily for up to 24 months . Bone mineral density and bone marker measurements were determined at 6-month intervals ; plasma estrogens were measured in a subset after 12 , 18 , and 24 months . Results Esterified estrogens produced significant increases in bone mineral density ( lumbar spine , hip ) compared with baseline and placebo at 6 , 12 , 18 , and 24 months . Bone markers decreased from baseline with all esterified estrogen doses relative to placebo . Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months ( correlation coefficient range = −0.122 to −0.439 ) . The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin . Mean plasma estrogen levels increased with esterified estrogen dose , and bone mineral density changes correlated positively with plasma estrogen levels . Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. Conclusions Esterified estrogens , at doses from 0.3 mg to 1.25 mg/day , unopposed by progestin , increase bone mineral density of the spine and hip in postmenopausal women .  These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12 , 18 , or 24 months . Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy BACKGROUND The frequency of bone loss among women using postmenopausal hormone therapy is unknown . METHODS We used data from the Postmenopausal Estrogen/Progestin Interventions Trial to address the frequency of bone loss among women using postmenopausal hormone replacement therapy .  Of 701 women r and omized to active treatment ( conjugated equine estrogens alone or in combination with 1 of 3 progestins ) , 538 ( 76.7 % ) were adherent and had replicate bone mineral density ( BMD ) measures at baseline , 12 months , and 36 months . Of 174 placebo-assigned women , 132 ( 75.9 % ) were similarly eligible . Replicate BMD measures were used to calculate within-person measurement errors , which were then used to delineate cut points that defined bone losers with 97.5 % , 95.0 % , 90.0 % , or 75.0 % confidence . RESULTS At the lumbar spine , during the first 12 months , 1.5 % of hormone users lost BMD with 97.5 % confidence , corresponding to a decline of -3 % per year ; during months 12 to 36 , only 0.6 % of treated women lost spinal BMD to this degree . An annual loss of -1 % or more was the criterion for spinal bone loss at the 75.0 % confidence level ; 5.1 % and 8.0 % of hormone users met this criterion in the first year and in months 12 to 36 , respectively . For the total hip , during the first 12 months , 2.3 % of hormone-adherent women lost -3.0 % per year or more , the 97.5 % confidence definition of loss ; 0.4 % were so classified during months 12 to 36 . To be 75.0 % confident of hip BMD loss , a -1.0 % per year decline in BMD was required ; using this criterion , 14.5 % and 11.8 % of hormone users lost total hip BMD between 0 to 12 and 12 to 36 months , respectively . Among hormone-adherent women , at the spine and hip , there was virtually no overlap between women classified as bone losers in the first 12 months and those classified as such in the last 24 months . With 95.0 % certainty , corresponding to an approximate loss of -2.5 % at the spine and hip , 31.3 % and 11.7 % of placebo-adherent women lost spinal BMD in the first 12 and last 24 months , respectively . Parallel figures for the hip were 32.3 % and 7.9 % , respectively . CONCLUSION Bone loss while taking postmenopausal hormones is rare , and bone loss among untreated women is far from universal OBJECTIVES We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate ( MPA ) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infa rct ion , or both . BACKGROUND Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women ; however , women with an intact uterus also take progestin to protect against uterine malignancies . The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown . METHODS Eighteen postmenopausal women ( mean + /- SD age 59+/-7 years ) were given 17-beta-estradiol in single-blinded manner for four weeks ( 1 mg/day for three weeks then 2 mg/day for one week ) . Estradiol ( 2 mg/day ) was then continued , and the patients were r and omized ( double-blind ) for 12 days to either transvaginal progesterone gel ( 90 mg on alternate days ) and oral MPA placebo ( 10 mg/day ) , or vice versa . After another two weeks on estradiol alone , the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment . Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase . RESULTS Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline ( mean difference with 95 % confidence interval [ CI ] : 72 s [ 34 to 110 ] , p = 0.001 ) , and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy ( 92 s [ 35 to 149 ] , p = 0.001 ) ) . Two patients ( 11 % ) were withdrawn while taking estradiol/MPA owing to unstable angina . CONCLUSIONS Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia , as compared with estrogen/MPA . These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration BACKGROUND Up to 3 years of treatment with alendronate , 5 mg/d , prevents  postmenopausal bone loss .  OBJECTIVE To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued . DESIGN R and omized , controlled trial . SETTING United States and Europe . PARTICIPANTS 1609 postmenopausal women 45 to 59 years of age . INTERVENTION Participants were r and omly assigned to receive oral alendronate , 5 mg/d or 2.5 mg/d ; placebo ; or open-label estrogen-progestin . Women in the alendronate groups received alendronate for the first 2 years of the study . Treatment was then continued without change or replaced with placebo for the last 2 years of the study . MEASUREMENTS Annual measurement of bone mineral density . RESULTS By year 4 , the bone mineral density of participants in the placebo group had decreased by 1 % to 6 % ( P < 0.001 ) . Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine ( mean change [ + /-SE ] , 3.8%+/-0.3 % ) , hip ( mean , 2.9%+/-0.2 % ) , and total body ( mean , 0.9%+/-0.2 % ) ( P < 0.001 overall ) . By year 4 , bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo . In years 3 and 4 , bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo . Compared with 5 mg of alendronate per day , estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater . CONCLUSIONS Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss . A residual effect was seen 2 years after alendronate therapy was stopped ; however , continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo OBJECTIVES To investigate the effect of vitamin K2 treatment for a year on spinal bone mineral density ( BMD ) in postmenopausal women , comparing with vitamin D3 hormone replacement therapy and to determine the factors which affect the efficacy of vitamin K2 therapy . SUBJECTS AND METHODS Seventy-two postmenopausal women were r and omized into four groups and treated with respective agents . Before the therapy , 6 and 12 months after the treatment , their lumbar spine BMD were measured by dual energy X-ray absorptiometry . The rates of change in BMD ( delta BMD ) were calculated . Correlations of BMD with age , year since menopause and the initial BMD were determined . RESULTS Vitamin K2 suppressed the decrease in spinal BMD as compared with no treatment group . BMD in women treated with vitamin K2 was inversely correlated with their age ( r = -0.54 ; P < 0.05 ) . CONCLUSIONS Vitamin K2 therapy may be a useful method for preventing postmenopausal spinal bone mineral loss . In addition , the therapy should be started early in postmenopausal period In young women , low estrogen levels complicate a wide variety of diseases , including premature ovarian failure , anorexia nervosa , athletic amenorrhea , prolactinoma , hypopituitarism , and chronic kidney disease . Hypoestrogenemia may also result from therapy with GnRH agonists , glucocorticosteroids , chemotherapy , and especially aromatase inhibitors . All of these situations are associated with bone loss , because estrogen chronically suppresses bone resorption . Several mechanisms are involved : 1 ) estrogen increases osteoclast apoptosis ; 2 ) by suppressing interleukins and proinflammatory cytokine expression in bone marrow cells , estrogen decreases the number of osteoclasts ; 3 ) by inhibiting the production of receptor activator of nuclear factor-κB lig and , estrogen reduces the number and activity of osteoclasts ; and 4 ) by increasing stromal cell/osteoblast cell expression of TGFβ , estrogen inhibits osteoclast activity . Estrogen also has some positive effects on bone formation by acting as a mitogen to cells early in the osteoblast line , reducing apoptosis of osteoblasts , and increasing expression of TGFβ , bone morphogenetic proteins , and IGF-I ( 1 ) . In these pathological conditions , the cause of the bone loss is frequently multifactorial . For example , women with anorexia nervosa also have low IGF levels . Nonspecific factors such as poor diet , reduced exercise , or chronic inflammation may further increase bone resorption . Low estrogen levels are also seen in healthy young women who are using depo-medroxyprogesterone acetate ( DMPA ) for contraception .  Bone loss is a side effect of this medication ( 2 ) . The bone mineral density ( BMD ) decreases at a more rapid rate during the first years of therapy and then continues to decrease at a slower rate ( 3 ) . After 5 yr , the loss is about 6 % ( 0.5 sd ) . The  DMPA effects are worse in teenagers ; combined results from four prospect i ve studies found an average loss of spine BMD of 3.1 % over 2 yr in  DMPA  users compared with a gain of 7.2 % in untreated controls ( 4 ) . A cross-sectional study in this issue by Walsh and colleagues ( 5 ) focused on the age of starting DMPA .  One group aged 18–25 started DMPA before age 20 , and another group aged 35–45 started after age 34 . Each group had matched controls . Importantly , the average use was 37 months in both groups . This avoids the confounding between age and duration of use , which is encountered in other studies . The BMD was significantly lower than controls when DMPA was started in teenagers but not when it was started after age 34 . Estrogen levels were lower in the DMPA users than the non-hormone users and were also lower in the younger women than in the older women . The authors concluded that estrogen levels mediated the effect of DMPA on bone markers because adding DMPA to a regression model reduced the correlation between markers and estrogen . These correlations were not very strong ( r = −0.17 between N-telopeptide and estradiol-treated ) , so this is a tenuous conclusion , but it is bolstered by the findings from two other studies that adding estrogen to DMPA abolishes the negative effect on the skeleton ( 6,7 ) . The age range of the older group of women is underrepresented in most of the previous studies of skeletal effects of DMPA . These results lead to several questions about basic bone biology . How are adolescent bones different from mature bones ? How does DMPA use compare to the natural state of low estrogen seen in healthy lactating women ? Is bone completely restored in these situations ? There are also important clinical questions about potential risk of fractures and the skeletal risks from other forms of contraception BACKGROUND Prospect i ve studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine . OBJECTIVES To determine the effects of unopposed esterified estrogens on bone mineral density , lipid levels , and endometrial tissue structure , and to relate these effects to changes in plasma estradiol levels . METHODS Four hundred six postmenopausal women were given calcium , 1000 mg/d , and r and omly assigned to receive continuous esterified estrogens ( 0.3 , 0.625 , or 1.25 mg/d ) or placebo for 24 months . Bone mineral density measurements and endometrial and laboratory assessment s were conducted every 6 months ; plasma estradiol concentrations were measured after 12 , 18 , and 24 months . RESULTS All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6 , 12 , 18 , and 24 months . Mean plasma estradiol levels increased with esterified estrogens dose , and individual subject bone mineral density changes appeared related to plasma estradiol concentrations . Clinical ly relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily . Lipid changes were dose related and apparent in all groups . CONCLUSIONS Esterified estrogens at doses from 0.3 to 1.25 mg/d , administered unopposed by progestin , produce a continuum of positive changes on bone and lipids . Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities . The 0.3-mg dose result ed in positive bone and lipid changes without inducing endometrial hyperplasia Long-term use of the injectable contraceptive depot medroxyprogesterone acetate ( DMPA , Depo-Provera ) is associated with a reduction in bone mineral density ( BMD ) , particularly in the lumbar spine . The cause of DMPA-associated bone loss is not known , but the relative estrogen deficiency induced by DMPA use could be responsible . We have undertaken a r and omized , double-blind controlled trial of oral estrogen replacement therapy in 38 premenopausal women ( mean age 37 ) with a minimum 2 yr DMPA use who had a below average baseline lumbar spine BMD ( T score < or = 0 ) . Nineteen women were allocated to receive conjugated estrogens ( 0.625 mg/d orally ) and 19 to receive a matching placebo . All continued with regular DMPA injections throughout the study . Areal bone density was measured by dual energy x-ray absorptiometry at the lumbar spine , femoral neck , and total body sites every 6 months for 2 yr ; the main outcome measure being the change in areal BMD at the lumbar spine . At baseline , the two groups were well matched for demographic , anthropometric , and biochemical variables , and for BMD . Twenty-seven subjects completed at least 18 months in the study , and 26 the full 2 yr , with similar numbers dropping out from each group ( mainly for personal reasons ) . In the estrogen-treated group , mean lumbar spine BMD increased 1 % , whereas in the placebo group it fell 2.6 % , over 2 yr . The between group differences were 2.0 % at 12 months ( P = 0.058 ) , 3.2 % at 18 months ( P < 0.01 ) , and 3.5 % at 24 months ( P < 0.002 ) . Differences of lesser statistical magnitude were seen at the femoral neck ( between group differences at 2 yr : 2.7 % , P = 0.24 ) , Ward 's triangle ( 5.0 % , P = 0.055 ) , greater trochanter ( 3.6 % , P = 0.056 ) , total body ( 1.3 % , P = 0.046 ) , legs ( 1.3 % , P = 0.065 ) , and trunk ( 2.0 % , P = 0.029 ) . There were no major adverse events . These data support the view that the likely cause of DMPA-associated bone loss is estrogen deficiency and demonstrate that it can be arrested by estrogen replacement therapy Objective : The aim of this study was to examine the effect of conjugated equine estrogens alone ( ET ) , conjugated equine estrogens + medroxyprogesterone ( EPT ) , calcitriol alone , calcitriol + EPT/ET , or placebo on serum lipid profile and analyze the interaction with estrogen receptor-&agr ; gene single nucleotide polymorphisms ( ESR-&agr ; SNPs ) on the response to therapy . Methods : A total of 489 postmenopausal women older than 65 years were enrolled into a 3-year double-blind , placebo-controlled clinical trial . Results : In both intent-to-treat and complier ( > 80 % adherent ) analysis , there was a significant increase in serum high-density lipoproteins and a significant decrease in serum low-density lipoproteins ( LDLs ) and the LDL/high-density lipoprotein ratio in all hormone treatment groups compared with placebo ( P < 0.05 ) . However , serum triglycerides and very low-density lipoproteins increased in the EPT and ET + calcitriol groups versus placebo ( P < 0.05 ) . ESR-&agr ; SNPs PvuII and XbaI seemed to have a significant effect on the response to treatment . Genotypes containing the p allele showed a significantly greater decrease in serum cholesterol and very low-density lipoprotein than those having the P allele in the ET + calcitriol group ( P < 0.05 ) , and those with the x allele had a significantly greater decrease in serum cholesterol in the hormone therapy + calcitriol group at the end of 3 years versus the X allele , and a greater decrease in serum LDL in alleles x versus the X in the ET + calcitriol group ( P < 0.05 ) . Conclusions : ET with or without progesterone had a favorable effect on lipid profile  in postmenopausal older women , and this was dependent on estrogen receptor SNPs-PvuII and XbaI. However , this interaction with ESR-&agr ; SNPs needs to be confirmed in larger studies OBJECTIVE To determine whether young women with Turner 's syndrome who had normal bone mineral density ( BMD ) before the induction of puberty maintain normal BMD in young adulthood . DESIGN Controlled clinical study . SETTING A private hospital clinical research setting . PATIENTS Young women with Turner 's syndrome in Tanner stage V of puberty with previously normal BMD . INTERVENTIONS Oral conjugated estrogens and progesterone acetate were administered continuously for a mean ( + /-SD ) of 4.1+/-1.0 years . Bone mineral densities and blood sample s were evaluated . MAIN OUTCOME MEASURE(S ) The BMD of the lumbar spine and the femoral neck was determined during young adulthood . The change in BMD over the previous 6 years also was evaluated . Serum concentrations of the carboxy-terminal propeptide of type 1 collagen and of the carboxy-terminal cross-linked telopeptide of type 1 collagen were measured . RESULT ( S ) The BMD of the lumbar spine was reduced significantly in our patients . There was no change in the BMD of the femoral neck or lumbar spine over a period of 6.1 years . Concentrations of the carboxy-terminal propeptide of type 1 collagen were decreased , whereas concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen were increased . CONCLUSION ( S ) Young women with Turner 's syndrome do not attain normal peak bone mass even when estrogen replacement therapy is begun in adolescence . Their low BMD seems to be due to decreased bone formation and increased bone resorption BACKGROUND Increased mammographic density reduces the sensitivity of screening mammography , is associated with increased breast cancer risk , and may be hormone related . We assessed the effect of estrogen-plus-progestin therapy on mammographic density . METHODS In a racially and ethnically diverse ancillary study of the Women 's Health Initiative , we examined data from 413 postmenopausal women who had been r and omly assigned to receive daily combined conjugated equine estrogens ( 0.625 mg ) plus medroxyprogesterone acetate ( i.e. , progestin ; 2.5 mg ) ( n = 202 ) or daily placebo ( n = 211 ) . We assessed the effect of estrogen plus progestin on measured mammographic percent density and abnormal findings over a 1-year and 2-year period . All tests of statistical significance were two-sided and were based on F tests or t tests from mixed-effects models . RESULTS Mean mammographic percent density increased by 6.0 % at year 1 , compared with baseline , in the estrogen-plus-progestin group but decreased by 0.9 % in the placebo group ( difference = 6.9 % , 95 % confidence interval [ CI ] = 5.3 % to 8.5 % ; P < .001 ) . The mean changes in mammographic density persisted but were attenuated slightly after 2 years , with an absolute increase of 4.9 % in the estrogen-plus-progestin group and a decrease of 0.8 % in the placebo group ( difference = 5.7 % , 95 % CI = 4.3 % to 7.3 % ; P < .001 ) . These effects were consistent across racial/ethnic groups but were higher among women aged 70 - 79 years in the estrogen-plus-progestin group ( mean increase at year 1 = 11.6 % ) than in the placebo group ( mean decrease at year 1 = 0.1 % ) ( difference of the means = 11.7 % , 95 % CI = 8.2 % to 15.4 % ; P < .001 , comparing across age groups ) . At year 1 , women who were adherent to treatment in the estrogen-plus-progestin group had a mean increase in density of 7.7 % ( 95 % CI = 5.9 % to 9.5 % ) , and women in the placebo group had a mean decrease in density of 1.1 % ( 95 % CI = 0.3 % to 1.9 % ) . Use of estrogen plus progestin was associated with an increased risk of having an abnormal mammogram at year 1 ( relative risk = 3.9 , 95 % CI = 1.5 to 10.2 ; P = .003 ) , compared with placebo , that was not explained by an increase in density . CONCLUSIONS Use of up to 2 years of estrogen plus progestin was associated with increases in mammographic density We assessed the associations of eight bone turnover markers ( BTMs ) with baseline and 1-year percentage changes in lumbar spine and hip bone mineral density ( BMD ) of 293 postmenopausal women undergoing treatment with hormone replacement therapy ( HRT ) or placebo  using squared correlation coefficients ( R2 ) . In 239 women assigned to treatment with estrogen alone or with with estrogen plus progestins ( active treatment ) , mean percentage changes for all markers decreased significantly and remained below baseline values through 3 years of study , whereas mean percentage changes for 54 women assigned to the placebo group showed no significant change from baseline in any marker . At baseline , age and body mass index ( BMI ) together accounted for 16 % and 25 % of the variance in spine and hip BMD , respectively . The telopeptide resorption marker , cross-linked N-telopeptide of type I collagen ( NTX ) , alone accounted for 12 % and 8 % of variance , respectively . Another telopeptide , carboxy-terminal telopeptide of type I collagen ( Crosslaps ) , accounted for 8 % and 7 % of variance , respectively . A bone-specific alkaline phosphatase ( BALP-2 ) accounted for 8 % of variance at the spine and 5 % at the hip . No other marker accounted for more than 5 % of total variance at either site ; adding either baseline NTX , Crosslaps , or BAP-2 to regressions containing age and BMI increased R2 values at the spine and hip to about 22 % and 28 % , respectively . In the placebo group , baseline spine BMD accounted for 4 % of the variance in 1-year spine BMD percentage change , whereas baseline values for age and BMI accounted for 1 % and 0 % of the variance , respectively ; none of the three accounted for more than 0 % of hip BMD percentage change ; Crosslaps and NTX contributed 5 % and 4 % to the variance in 1-year spine BMD percentage change , but other markers accounted for < 2 % of variance at the spine . At the hip , another BALP ( BALP-1 ) accounted for 4 % of variance , but no other baseline marker except NTX accounted for more than 1 % of variance . In the active treatment group , baseline values for age , BMI , and spine BMD together accounted for 13 % of the percentage change in spine BMD and for 4 % of the BMD change at the hip . No individual or pair of baseline markers significantly enhanced these R2 values , but addition of 1-year percentage changes in some individual markers did significantly increase it . The largest R2 value was obtained by adding the percentage change in BALP-2 , which increased the R2 in spine BMD percentage change to 20 % and that at the hip to 8 % . Adding baseline and change variables for all eight markers to the regression increased R2 to 28 % at the spine and 12 % at the hip . Restricting the set of analyses to individuals who suppressed marker activity beyond the precision error for the measurement did not improve R2s for the regressions . When baseline marker values were stratified into quartiles , only NTX and osteocalcin showed significant relationships between quartile and change in spine BMD , and these did not reach significance at the hip . When the 1-year change in markers was stratified into quartiles , significant relationships with percentage change in spine BMD were observed only for BALP phosphatases . We conclude that BTMs are not a surrogate for BMD to identify women with low bone mass and that they offer little useful information for predicting BMD changes for individual untreated or HRT-treated postmenopausal women Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems . We conducted a 1-year prospect i ve , r and omized , double-blind trial in 143 postmenopausal osteoporotic women ( mean + /- SD age , 68.4+/-5.0 years ) with at least one prevalent vertebral fractures and low bone mineral density ( BMD ) , comparing groups receiving raloxifene at 60 mg/day ( RLX60 ) or 120 mg/day ( RLX120 ) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D.  There were no differences among groups in the occurrence of uterine bleeding , thrombophlebitis , breast abnormalities , or increased endometrial thickness ( assessed by ultrasonography ) . As compared with controls , the changes in values over 1 year for RLX60 and RLX120 , respectively , were significant for serum bone alkaline phosphatase ( -14.9 % , -8.87 % ) , serum osteocalcin ( -20.7 % , -17.0 % ) , and urinary C-telopeptide fragment of type I collagen/creatinine ( -24.9 % , -30.8 % ) , markers of bone turnover ; for serum total cholesterol ( -7.0 % for RLX60 ) and low density lipoprotein cholesterol ( LDL ) ( -11.4 % for RLX60 ) and for the LDL/HDL cholesterol ratio ( -13.2 % , -8.3 % ) . BMD increased significantly in the total hip ( 1.66 % for RLX60 ) and ultradistal radius ( 2.92 % , 2.50 % ) . There were nonsignificant trends toward increases over controls in BMD for lumbar spine , total body , and total hip ( for RLX120 ) . Using a > 15 % cutoff definition , raloxifene had no effect on incident fractures , but using a > 30 % cutoff , there was a dose-related reduction ( p = 0.047 ) . We conclude that raloxifene therapy is well tolerated , reduces serum lipids , and does not stimulate the uterus or breasts . It has beneficial effects on bone , although , under the conditions of this study , these appear to be of a smaller magnitude than have been reported with estrogen therapy BACKGROUND Recent r and omized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease ( CHD ) . In this report , we provide the final results with regard to estrogen plus progestin and CHD from the Women 's Health Initiative ( WHI ) . METHODS The WHI included a r and omized primary -prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line . Participants were r and omly assigned to receive conjugated equine estrogens ( 0.625 mg per day ) plus medroxyprogesterone acetate ( 2.5 mg per day ) or placebo . The primary efficacy outcome of the trial was CHD ( nonfatal myocardial infa rct ion or death due to CHD ) . RESULTS After a mean follow-up of 5.2 years ( planned duration , 8.5 years ) , the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits . Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 ( nominal 95 percent confidence interval , 1.00 to 1.54 ; 95 percent confidence interval after adjustment for sequential monitoring , 0.97 to 1.60 ) . The elevation in risk was most apparent at one year ( hazard ratio , 1.81 [ 95 percent confidence interval , 1.09 to 3.01 ] ) . Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy , higher base-line levels of C-reactive protein , other biomarkers , and other clinical characteristics did not significantly modify the treatment-related risk of CHD . CONCLUSIONS Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women , especially during the first year after the initiation of hormone use . This treatment should not be prescribed for the prevention of cardiovascular disease Objective To assess changes in lipid-lipoprotein profile in postmenopausal women taking tibolone and estrogenprogestin  , compared with untreated controls . Methods Sixty-three women were r and omized to take a combined estrogen-progestin preparation ( n = 31 ) or tibolone ( n = 32 ) , and 50 other women acted as controls . Fasting lipid-lipoprotein levels were measured over 96 weeks . Results The controls , who were older and postmenopausal longer than the therapy subjects , exhibited significant decreases in total ( P < .05 ) and low-density lipoprotein ( LDL ) ( P < .001 ) cholesterol and increases in triglyceride ( P < .05 ) and lipoprotein ( a ) ( P < .001 ) over the 96-week period of study . Lipoprotein ( a ) also decreased significantly in both treated groups ( P < .001 ) . Total and LDL cholesterol decreased and triglyceride increased in the estrogenprogestin group , but , compared with controls , these changes were not significant . Total cholesterol decreased in the tibolone group , although decreases in low- and particularly high-density lipoprotein ( HDL ) ( P < .001 ) cholesterol and parallel decreases in apolipoprotein A1 ( P < .001 ) and B ( P < .01 ) were also observed . There was evidence of a reversion phenomenon in apolipoproteins A1 and B in all groups , and in lipoprotein ( a ) with tibolone . Conclusion Some changes accompanying tibolone may be favorable and may counter its adverse effect on HDL cholesterol . Lowering of lipoprotein ( a ) was the only significant change found with estrogen-progestin PURPOSE To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen . SUBJECTS AND METHODS A prospect i ve , r and omized clinical trial was performed in 81 postmenopausal women aged 51.7 + /- 4.4 years ( mean + /- SD ) . They were assigned to one of four groups : Provera 20 mg , Premarin 0.6 mg , Premarin 0.3 mg plus Provera 10 mg , and a placebo . In addition , all women received calcium supplementation , if necessary , to a calcium intake of 1,000 mg/day . We used single- and dual-photon absorpiometry , metacarpal radiogrammetry , and computed axial tomography to measure bone mineral density in the total skeleton , spine , radius , and metacarpal . RESULTS Women receiving placebo  lost bone at all sites ( p less than 0.01 ) . The Provera-treated group showed no change in total body calcium , but there were decreases in radial density ( p less than 0.01 ) , metacarpal cortex ( p less than 0.01 ) , and spine density ( p less than 0.01 ) . The Premarin-treated group had an increase in spine density and total body density ( p less than 0.05 ) , but a decrease in radial density ( p less than 0.05 ) . The Premarin-plus-Provera group showed no change in spine density , total body calcium , or radial density but had a decrease in metacarpal cortex ( p less than 0.01 ) . CONCLUSIONS Compared to placebo , Provera reduced the rate of loss in cortical areas of the skeleton , but not in the spine , which contains more trabecular bone . In contrast , Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton . The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone , suggesting that there may be a synergistic effect of this hormone combination on bone . Serum cholesterol levels decreased with Provera , Premarin , and the combination of both , whereas levels of serum triglycerides increased with Premarin treatment , decreased with the Provera regimen , and were unchanged with the combination therapy . Provera does not adversely affect the lipid profile CONTEXT Greater mammographic density is associated with increased breast cancer risk and reduced diagnostic mammographic sensitivity and may be seen with estrogen/progestin therapy ( EPT ) . The effects of testosterone therapy on mammographic density in postmenopausal women not on EPT are not known . OBJECTIVE Our objective was to compare effects of two doses of the testosterone transdermal patch ( TTP ) with placebo in postmenopausal women without concomitant EPT on mammographic density  over 52 wk . DESIGN We conducted a r and omized , double-blind , placebo-controlled , parallel-group , multinational trial . PATIENTS Patients included 279 postmenopausal women participating in a testosterone and sexual function study with paired mammograms for baseline and 52 wk/exit . INTERVENTIONS Patients were r and omized to placebo , TTP 150 microg/d , or TTP 300 microg/d , stratified by menopause type ( natural or surgical ) . MAIN OUTCOME MEASURES Change from baseline to wk 52 in the percentage of dense tissue ( PD ) on digital mammograms . RESULTS A total of 250 women with paired mammograms for study baseline and wk 52 were included in the primary analysis . Mean age was 54.6 yr , baseline body mass index was 27.5 kg/m(2 ) , and 78 % were naturally menopausal . There were no baseline differences between groups . Mean changes from baseline ( + /-SEM ) in PD for placebo , TTP 150 microg/d and TTP 300 microg/d were small ( 0.05 + /- 0.16 , 0.06 + /- 0.19 , and 0.21 + /- 0.17 % ) and not significantly different . There were no statistically significant differences from placebo for total dense or nondense area and no significant relationships between hormone levels and PD after adjustment for body mass index . CONCLUSION TTP therapy over 52 wk appears to have no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women not using EPT BACKGROUND Mammographic density is an independent risk factor for breast cancer . Postmenopausal hormone use is associated with an increase in mammographic density , but the magnitude of the density increase is unknown . METHODS Baseline and 12-month mammograms were obtained for 571 ( 65 % ) of the 875 women , aged 45 - 64 years , who were enrolled in the Postmenopausal Estrogen/Progestin Interventions Trial and r and omly assigned to receive placebo , daily conjugated equine estrogens at 0.625 mg/day ( CEE ) , daily CEE and medroxyprogesterone acetate ( MPA ) at 10 mg/day on days 1 - 12 ( CEE+MPA-cyclic ) , daily CEE and MPA at 2.5 mg/day ( CEE+MPA-continuous ) , or daily CEE and micronized progesterone ( MP ) at 200 mg/day on days 1 - 12 ( CEE+MP ) . We analyzed digitized mammograms to determine the percentage of the left breast that was composed of dense tissue ( i.e. , mammographic percent density ) . Linear regression analysis was used to examine the effects of treatments on the change in mammographic percent density between baseline and 12 months , before and after adjustment for possible confounders . All statistical tests were two-sided . RESULTS The adjusted absolute mean changes in mammographic percent density over 12 months were 4.76 % ( 95 % confidence interval [ CI ] = 3.29 % to 6.23 % ) , 4.58 % ( 95 % CI = 3.19 % to 5.97 % ) , and 3.08 % ( 95 % CI = 1.65 % to 4.51 % ) for women in the CEE+MPA-cyclic , CEE+MPA-continuous , and CEE-MP groups , respectively . Each of those absolute mean changes was statistically significantly different from the adjusted absolute mean change in mammographic percent density for women in the placebo group , which was -0.07 % ( 95 % CI = -1.50 % to 1.38 % ) . CONCLUSION Greater mammographic density was associated with the use of estrogen/progestin combination therapy , regardless of how the progestin was given , but not with the use of estrogen only
CONCLUSION Estrogen with an osteoblast P4R-acting progestin ( EPT ) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET .
OBJECTIVE To assess whether progesterone ( P4 ) or osteoblast P4 receptor-acting progestin ( P ) contributed to estrogen ( E ) therapy-related  increased areal bone mineral density ( BMD ) in r and omized controlled trials ( RCT ) with direct r and omization to estrogen ( ET ) or estrogen-progestin ( EPT ) therapy .