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New study on Progesterone
Peer Review on Natural Bio-Identical HRT
Women and Estrogen/Progesterone
Bio-identical progesterone does not have the negative clinical effects associated with progestins
1) Murray JL. Natural Progesterone: What Role in Women’s Health Care. Women Health Primary
Care 1998: 1 (8): 671-687
A review article written by a professor of family medicine at the University of Kansas. "Natural
progesterone is often promoted as an alternative to synthetic progestins for two reasons: It appears to
have fewer side effects in many women. It may have more benefit for lipid profile enhancement,
osteoporosis prevention, and the treatment of menopausal symptoms, premenstrual syndrome and
endometriosis.
2) Barentsen R. Progestogens: Pharmacological Characteristics and Clinically Relevant Differences.
Eur Menopause J 3(4) 266-271, 1996
The author is associated with the Department of Obstetrics and Gynecology at the Free University
Hospital Amsterdam, The Netherlands. "For continuous combined HRT the use of C21-progestogens
or micronized progesterone is preferred on theoretical grounds, Medroxyprogesterone acetate
(Provera) exhibits an unfavorable effect on HDL when continuously administered at a dose of 2.5
mg.
PMS symptoms are associated with high levels of estradiol
3) Seippel L.Luteal phase estradiol relates to symptom severity in patients with premenstrual
syndrome. J Clin Endocrinol Metab 998, 83(6): 1988-92
Conducted at the University hospital of Norrland, Sweeden, Department of Obstetrics and
Gynecology. The study showed high levels of luteal phase estradiol and LH were related to the
severity of negative premenstrual symptoms.
PMS is associated with lower levels of progesterone
4) Rapkin AJ, Morgan M. Progesterone metabolite allopregnanolone in women with premenstrual
syndrome. Obstet Gynecol, 90(5): 709-14 1997 Nov
Conducted at UCLA School of Medicine, Department of Obstetrics and Gynecology. The study
showed lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase of women with
PMS as compared to controls. The lower level could contribute to the genesis of various mood
symptoms of the disorder, such as anxiety, tension, and depression.
Transdermal progesterone is clinically effective and concentrated in target tissue.
5) Chang KJ, Lee TTY, et al. Influences of Percutaneous Administration of Estradiol and
Progesterone on Human Breast Epithelial Cell cycle in Vivo. Fertil Steril 1995; 63: 785-91
Conducted at Taiwan University Hospital, double blind, placebo controlled, randomized study.
Conclusion: Percutaneous exposure to progesterone reduced estradiol induced proliferation of
normal breast cells in vivo. The study also showed increased concentration of progesterone in breast
tissue despite normal serum levels, with percutaneous administration.
6) Leonetti HB. Transdermal progesterone cream for vasomotor symptoms and postmenopausal
bone loss. Obstet Gynecol 1999;94:225-8
Conducted at Temple University, a double blind, randomized placebo controlled study. The study
showed improvement or resolution of vasomotor symptoms (hot flushes) in 83 % of the treated
group, compared to 14% of the placebo group. All women in the treatment group used transdermal
natural progesterone.
Prevention of heart disease is not an indication for estrogen replacement
7) Dr. Jacques E. Rossouw, lead project officer of the Women’s Health Initiative.
Published interview in Ob.Gyn. News, April 15, 1998
"Long-term estrogen replacement therapy is being ardently prescribed to prevent heart disease with
no evidence for these presumed benefits. 66% of physicians who prescribe hormone replacement
therapy do so at least in part to prevent coronary artery disease- an indication that is unproved and
unacceptable"
Bio-identical progesterone protects against coronary vasospasm in primates
8) Miyagawa K, Rosch J, et al. Medroxyprogesterone (Provera) interferes with Ovarian Steroid
protection against Coronary Vasospasm . Nature Medicine 1997; (3): 324-327
Conducted at the Oregon Regional Primate Research Center. "Coronary vasospasm in response to
pathophysiological stimulation without injury showed that progesterone plus estradiol protected but
medroxyprogesterone plus estradiol failed to protect, allowing vasospasm.
Premarin and Provera do not reduce the risk of recurrent heart attack. It does increase the risk of thromboembolism and gallbladder disease in women
9) Moerman CJ, Witteman JCM, et al. Heart and Estrogen /Progestin Replacement Study. JAMA
1998; 280: 605-613
A multi-center prospective study using Premarin and Provera. This combination did not reduce the
risk of myocardial infarction or other cardiovascular outcome including death. The risk of venous
thromboembolism and gallbladder disease did increase.
Progestins cancel the positive lipid effects of estrogen. Micronized progesterone has no negative lipid effects
10) Writing group of the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart
disease risk factors in postmenopausal women. JAMA. 273: 199-208
A multi-center prospective study that concluded "For these women( with a uterus) micronized progesterone appears to spare the endometrium and to preserve the bulk of estrogen’s favorable
effects on risk factors including HDL-C." Provera essentially canceled the increase in HDL-C seen
with estrogen alone.
Bio-identical Progesterone stimulates osteoblasts
11) Prior JC. Progesterone is a Bone Trophic Hormone. Endocr Rev 1990; 11: 386-398
Discusses bone formation as a process of resorption and new bone formation. While it is firmly
established that estrogen decreases bone resorption, it is equally important to stimulate new bone
formation by stimulating osteoblast function with progesterone.
Progesterone deficiency is associated with increased risk of premenopausal breast cancer
12) Cowan LD, Cardis JA, Tonascia and G.S.Jones. Breast Cancer Incidence in Women with a
History of Progesterone Deficiency. Am J Epidemiology 1981;114:209-17
Conducted at The Johns Hopkins University, followed 1083 women for thirty-three years. The
women with endogenous progesterone deficiency had a 5.4 fold increase in premenopausal breast
cancer. These women also had a 10 fold increase in death from all malignant neoplasms.
Osteoporosis
The works of Lee4,39,40 and of Prior9 in the 1980s and 1990s have brought up for discussion, at the very least, the potential of natural progesterone (not progestins) as key to the prevention and treatment of osteoporosis. Lee39 studied 100 postmenopausal women with height loss and followed 63 of them with dual photon absorptiometry for 3 years. The patients were treated with transdermal progesterone cream, exercise, and dietary interventions, but no exogenous estrogen. Lee reported significant increases in bone density (averaging 15.4%) and showed that those with the lowest density at baseline experienced the greatest improvement during the 3 years.
There are a variety of ways by which progesterone can affect bone metabolism. For example, the hormone appears to stimulate new bone formation.37 Urinary calcium excretion decreases during progesterone administration.
Progesterone also partially antagonizes dexamethasone-induced osteoblast growth inhibition, indicating that it binds to the glucocorticoid receptor in osteoblasts, and thus it may be especially useful in corticosteroid-induced osteoporosis.9 In addition, progesterone appears to increase levels of insulin-like growth factor-1, which promotes bone formation.31
39. Lee JR. Is natural progesterone the missing link in osteoporosis prevention and treatment? Med Hypotheses. 1991; 35:316-318.
40. Lee JR. Osteoporosis reversal with transdermal progesterone. Lancet. 1990;336:1327.
4. Lee JR. Natural Progesterone. The Multiple Roles of a Remarkable Hormone. Sebastopol, Calif: BLL Publishing: 1993.
9. Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev. 1990;11:386-398.
31. Kimzey LM, Gumowski J, Merriam GR, et al. Absorption of micronized progesterone from a nonliquefying vaginal cream. Fertil Steril. 199 1;56:995-996.
PMS
Use of natural progesterone for PMS was popularized in the 1960s after publication of Dalton's groundbreaking work, The Premenstrual Syndrome, in 1964.44 In a subsequent book, this author specifically outlined the use of progesterone for PMS,12 and she later produced further research to support natural progesterone's role in the treatment of PMS.45 Dalton stated that "Progesterone is the treatment of choice for patients with severe symptoms which have resisted other forms of treatment, and for those who are at the end of their tether when first reporting for treatment."12 She also described PMS as an imbalance in the estrogen-progesterone axis; a relative deficiency of progesterone was held responsible for most of the symptoms women experience. Conversely, she stated that an imbalance in the direction of a relative estrogen deficiency gives rise to dysmenorrhea in many women.
44. Dalton K. The Premenstrual Syndrome.Springfield, Ill: Charles C. Thomas; 1964.
45. Dalton K. Trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome. Am J Obstet Gynecol. 1987;156:1555-1556.
12. Dalton K. The Premenstrual Syndrome and Progesterone Therapy. London, England: William Heinemann; 1984.
Sex hormones and headache.
Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Stephen.Silberstein@mail.tju.edu
The normal female life cycle is associated with a number of hormonal milestones: menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex hormones. Menarche marks the onset of menses and cyclic changes in hormone levels. Pregnancy is associated with rising noncyclic levels of sex hormones, and menopause with declining noncyclic levels. Hormonal contraceptive use during the reproductive years and hormone replacement in menopause are therapeutic hormonal interventions that alter the levels and cycling of sex hormones. These events and interventions may cause a change in the prevalence or intensity of headache. The menstrual cycle is the result of a carefully orchestrated sequence of interactions between the hypothalamus, pituitary, ovary, and endometrium, with the sex hormones acting as modulators and effectors at each level. Estrogen and progestins have potent effects on central serotonergic and opioid neurons, modulating both neuronal activity and receptor density. The primary trigger of Menstrually-related migraine (MM) appears to be the withdrawal of estrogen rather than the maintenance of sustained high or low estrogen levels. However, changes in the sustained estrogen levels with pregnancy (increased) and menopause (decreased) appear to affect headaches. Headaches associated with OC use or menopausal hormonal replacement therapy may be related, in part, to periodic discontinuation of oral sex hormone preparations. The treatment of migraine associated with changes in sex hormone levels is frequently difficult and the patients are often refractory to therapy. Based on what is known of the pathophysiology of migraine, we have attempted to provide a logical approach to the treatment of headaches that are associated with menses, menopause, and OCs using abortive and preventive medications and hormonal manipulations. Considerable evidence suggests a link between estrogen and progesterone, the female sex hormones, and migraine. (Silberstein and Merriam, 1997; Lipton and Stewart, 1993; Epstein et al., 1975; Goldstein and Chen, 1982; Selby and Lance, 1960) Although no gender difference is apparent in prepubertal children, with migraine occurring equally in 4p. 100 of boys and girls, (Goldstein and Chen, 1982, Waters and O'Connor, 1971) migraine occurs more frequently in adult women (18p. 100) than in men (6p. 100). (Lipton and Stewart, 1993) Migraine develops most frequently in the second decade, with the peak incidence occurring with adolescence. (Selby and Lance, 1960; Epstein et al., 1975) Menstrually-related migraine (MM) begins at menarche in 33p. 100 of affected women (Epstein et al. , 1975). MM occurs mainly at the time of menses in many migrainous women, and exclusively with menses (true menstrual migraine [TMM]) in some (Epstein et al., 1975). Menstrual migraine can be associated with other somatic complaints arising before and often persisting into menses, such as nausea, backache, breast tenderness, and cramps and like them appears to be the result of falling sex hormone levels (Silberstein and Merriam, 1997; American Psychiatric Association, 1994). In addition, premenstrual migraine can be associated with premenstrual dysphoric disorder (PDD), also called "premenstrual syndrome" (PMS), which is distinct from the physical symptoms of the perimenstrual period and is probably not directly driven by declining progesterone levels (Mortola, 1998). Migraine occurring during (rather than prior to) menstruation is usually not associated with PMS (Silberstein and Merriam, 1997). Migraine may worsen during the first trimester of pregnancy and, although many women become headache-free during the last two trimesters, 25p. 100 have no change in their migraine (Silberstein, 1997). MM typically improves with pregnancy, perhaps due to sustained high estrogen levels (Silberstein, 1997). Hormonal replacement with estrogens can exacerbate migraine and oral contraceptives (OCs) can change its character and frequency
Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury.
Jeanes HL, Wanikiat P, Sharif I, Gray GA.
Centre for Cardiovascular Science, University of Edinburgh, UK. h.l.jeanes@sms.ed.ac.uk
OBJECTIVE: Results from recent clinical trials of estrogen and progestogen therapy (EPT) suggest that some progestogens may interfere with the cardiovascular benefits of estrogen (E). The aim of this study was to investigate whether medroxyprogesterone acetate (MPA) modifies the protective effect of E in experimental ischemia-reperfusion (IR) injury in vivo and in vitro in the rat. DESIGN: Ovariectomized female Wistar rats (250-280 g, n = 61) received E, MPA, E and MPA, or placebo subcutaneously. Fourteen days later, hearts were isolated and perfused with Krebs Henseleit for in vitro experiments or left in situ for in vivo experiments. In both cases, the left coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. RESULTS: In vivo E significantly reduced the necrotic zone of reperfused hearts (21.8% +/- 1.7% of area at risk) compared with placebo (42.8% +/- 4.8% area at risk; P < 0.05). This protection was reversed by co-administration of MPA with E (necrotic zone 38.2% +/- 6.1% area at risk). The influence of E on neutrophil infiltration was demonstrated by its ability to reduce myocardial myeloperoxidase activity (0.2 +/- 0.1 U/g tissue) relative to placebo (1.3 +/- 0.5 U/g tissue; P < 0.05). Myocardial myeloperoxidase activity was significantly increased to 1.1 +/- 0.3 U/g tissue in rats receiving E and MPA. However, MPA also reversed the protective effect of E in neutrophil-free buffer-perfused hearts, suggesting that additional mechanisms are involved. CONCLUSION: In this study, we showed that the administration of MPA can inhibit the effects of E that lead to protection of the myocardium from reperfusion injury and that this involves both neutrophil-dependent and neutrophil-independent mechanisms.
The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats.
Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid.
Jrn Endocrinology 2004 Progesterone safer than Progestins
Low Serum Testosterone and Mortality in Male Veterans
Jrn Endocrine related Cancer 2004 ESTRIOL binds to ERbeta tumor suppressor receptor
Bio-Identical HRT NY An Sciences 2005
Pharmacodynamics of Transdermal Delivery
Potential Advantages of Bioidentical HRT
The Lancet 2003 Transdermal safer than oral
Alt Med Review BIO-IDENTICAL ESTRIOL Safety Efficacy
Is brain estradiol a hormone or a neurotransmitter?
Prevention of mammary carcinogenesis by short-term estrogenand progestin treatments
Fournier HRT and Breast Cancer Risk
HRT and CV mortality
Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.
Progesterone and weight loss
Progestin and fat
Pregnancy, progesterone and progestins in relation to breast cancer risk.
Campagnoli C, Abba C, Ambroggio S, Peris C.
Unit of Endocrinological Gynecology, Sant'Anna Gynecological Hospital, Corso Spezia 60, 10126 Torino, Italy. ginendocrinol@oirmsantanna.piemonte.it
In the last two decades the prevailing opinion, supported by the "estrogen augmented by progesterone" hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likelihood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.
Cyclic progestin administration increases energy expenditure and decreases body fat mass in perimenopausal women.
Cagnacci A, De Toni A, Caretto S, Menozzi R, Bondi M, Corradini B, Alessandrini C, Volpe A.
Department of Obstetrics Gynaecology and Paediatrics, Policlinico di Modena, Modena, Italy. cagnacci@unimore.it
OBJECTIVE: The menopause transition is characterized by luteal phase defect anovulatory cycles, and changes in body weight and body composition. Resting metabolic rate (RMR) is increased in the luteal phase of the menstrual cycle. We evaluated whether progestin administration increases RMR and influences body composition of perimenopausal women. DESIGN: Thirty-six perimenopausal women were randomly allocated to receive either calcium (1 g/day) continuously plus the progestin nomegestrol acetate (NOMAc; 5 mg/day for 10 days x month for 12 months) or calcium alone. Body composition, RMR, energy intake, and climacteric and psychological symptoms were evaluated at baseline and after 12 months. In the NOMAc group, body composition and RMR analyses were performed twice during the first month of treatment. One evaluation was performed after almost 8 days of NOMAc adjunct, and an another before or almost 15 days after NOMAc administration. RESULTS: Resting metabolic rate was increased by NOMAc administration of 54.5 +/- 73.8 kcal/24 h (P < 0.01). In women treated with NOMAc, fat mass decreased by 1.2 +/- 0.6 kg (P < 0.001). In comparison with controls, body weight (P < 0.05) and body mass index (P < 0.05) were also reduced after 12 months of therapy with NOMAc. CONCLUSIONS: In perimenopausal women the use of NOMAc increases RMR. During the menopause transition, cyclic NOMAc administration may contribute to reduce negative modification of body composition.
Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury.
Pettus EH, Wright DW, Stein DG, Hoffman SW.
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Progesterone given after traumatic brain injury (TBI) has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3 (C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2 days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP, and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison to vehicle-treated animals. Measures of NFkappaB p50 showed no change after injury or progesterone treatment, and progesterone did not alter the expression of GFAP. The therapeutic benefit of post-TBI progesterone administration may be due to its salutary effect on inflammatory proteins known to increase immune cell invasion and cerebral edema.
Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia.
Institute of Cell Signalling, Queen's Medical Centre, Clifton Boulevard, Nottingham, NG7 2UH, UK.
Gender differences in outcome following cerebral ischemia have frequently been observed and attributed to the actions of steroid hormones. Progesterone has been shown to possess neuroprotective properties following transient ischemia, with respect to decreasing lesion volume and improving functional recovery. The present study was designed to determine the mechanisms of progesterone neuroprotection, and whether these relate to the inflammatory response. Male mice underwent either 60 min or permanent middle cerebral artery occlusion (MCAO) and received progesterone (8 mg/kg ip) or vehicle 1 h, 6 h and 24 h post-MCAO. Forty-eight hours following transient MCAO, structural magnetic resonance imaging revealed a significant decrease in the amount of edematous tissue present in progesterone-treated mice as compared with vehicle. Using real-time PCR we found that progesterone treatment significantly suppressed the injury-induced upregulation of interleukin (IL)-1beta, transforming growth factor (TGF)beta2, and nitric oxide synthase (NOS)-2 mRNAs in the ipsilateral hemisphere while having no effect on tumor necrosis factor (TNF)-alpha mRNA expression. Progesterone treatment following permanent MCAO also resulted in a significant decrease in lesion volume. This was not apparent in mice lacking a functional NOS-2 gene. Thus, progesterone is neuroprotective in both permanent and transient ischemia, and this effect is related to the suppression of specific aspects of the inflammatory response.
Progesterone induces BRCA1 mRNA decrease, cell cycle alterations and apoptosis in the MCF7 breast cancer cell line.
Ansquer Y, Legrand A, Bringuier AF, Vadrot N, Lardeux B, Mandelbrot L, Feldmann G.
INSERM U 481, Faculte de Medecine Xavier Bichat, 75018 Paris, France. yan.ansquer@lmr.ap-hop-paris.fr
BACKGROUND: Inherited mutations of the BRCA1 gene are responsible for hereditary breast and ovarian cancer syndrome. However, little is known of how disruption of BRCA1 functions preferentially increases cancer risk in hormone-dependent organs. We aimed to study whether BRCA1 was regulated by progesterone in the MCF7 breast cancer cell line. MATERIALS AND METHODS: MCF7 breast cancer cells were incubated with 10(-4) or 10(-10) M progesterone for 24 or 48 hours. BRCA1 expression, proliferation and apoptosis were analysed. RESULTS: 10(-4) M progesterone decreased cell proliferation, cell cycle progression and induced apoptosis. In addition, BRCA1 and cyclin A mRNA decreased. In contrast, none of these effects were observed in MCF7 cells incubated with 10(-10) M progesterone. CONCLUSION: The down-regulation of BRCA1 in MCF7 cells incubated with 10(-4) M progesterone seems to be a consequence of cell cycle alterations rather than a direct effect of the hormone on BRCA1.
The long-term impact of 2-3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women.
OBJECTIVE: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to investigate the long-term effects of HRT given for a few years on all-cause and cardiovascular mortality and the severity of atherosclerosis. METHODS: This analysis was based on a cohort of 1,458 postmenopausal women (55.8 +/- 6.1 years old) who previously participated in a number of randomized, placebo-controlled, clinical trials assessing the efficacy of 2-3 years of therapy with various estrogen plus progestin combinations for preventing bone loss. Women were followed on average for 9.8 years and came for a follow-up visit. Outcome variables were all-cause and cardiovascular mortality and the severity of atherosclerosis, as estimated by semi-quantitative scoring of vascular calcification in the lumbar aorta on lateral radiographs. RESULTS: A total of 174 women died during the observation period. All-cause mortality was decreased by 30% in the HRT+ group compared with the HRT- group (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.50-0.97) after adjusting for age, body mass index and smoking. Under the same conditions, similar results characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths), which were decreased by 46% (HR 0.54, 95% CI 0.29-0.98, p = 0.045) and 53% (HR 0.47, 95% CI 0.21-1.03, p = 0.062), respectively. Furthermore, the mean severity score of aortic calcification at follow-up was significantly lower in hormone-treated compared to non-treated women (p < 0.0001). CONCLUSION: Women who receive 2-3 years of HRT after menopause do not have increased all-cause mortality, and results of the present study suggest relative cardiovascular benefits compared to those who had not used hormones.
Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.
Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group.
INSERM Cardiovascular Epidemiology Unit U258, Villejuif, France. scarabin@vjf.inserm.fr <scarabin@vjf.inserm.fr>
BACKGROUND: Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk. METHODS: We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999-2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment. FINDINGS: Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3.5 (95% CI 1.8-6.8) and 0.9 (0.5-1.6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4.0 (1.9-8.3). INTERPRETATION: Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.
Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.
Laboratory and Division of Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy. mcutolo@unige.it
Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.
Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.
Unit of Endocrinological Gynecology, Sant'Anna Gynecological Hospital, Corso Spezia 60, 10126 Torino, Italy. ginendocrinol@oirmsantanna.piemonte.it
Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.
Progesterone inhibits human breast cancer cell growth through transcriptional upregulation of the cyclin-dependent kinase inhibitor p27Kip1 gene.
Gizard F, Robillard R, Gervois P, Faucompre A, Revillion F, Peyrat JP, Hum WD, Staels B.
UR545 INSERM, Institut Pasteur de Lille and Faculte de Pharmacie, Universite de Lille II, France.
The effects of progesterone derivatives on breast cancer development are still controversial, probably accounting for their biphasic, opposed effects on mammary cell-cycle regulation. Here, we demonstrate in vitro that the growth-inhibitory effects of progesterone on breast cancer T-47D cells require the transcriptional upregulation of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) gene. A statistical analysis of human tumor biopsies further indicates that p27 mRNA levels correlate to progesterone receptor (PR) levels. Moreover, p27 gene expression is inversely associated with tumor aggressiveness, and is a prognostic factor of favorable disease outcome. Thus, progesterone derivatives selectively activating the p27 gene promoter could be promising drugs against breast cancer progression.
Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury.
Centre for Cardiovascular Science, University of Edinburgh, UK. h.l.jeanes@sms.ed.ac.uk
OBJECTIVE: Results from recent clinical trials of estrogen and progestogen therapy (EPT) suggest that some progestogens may interfere with the cardiovascular benefits of estrogen (E). The aim of this study was to investigate whether medroxyprogesterone acetate (MPA) modifies the protective effect of E in experimental ischemia-reperfusion (IR) injury in vivo and in vitro in the rat. DESIGN: Ovariectomized female Wistar rats (250-280 g, n = 61) received E, MPA, E and MPA, or placebo subcutaneously. Fourteen days later, hearts were isolated and perfused with Krebs Henseleit for in vitro experiments or left in situ for in vivo experiments. In both cases, the left coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. RESULTS: In vivo E significantly reduced the necrotic zone of reperfused hearts (21.8% +/- 1.7% of area at risk) compared with placebo (42.8% +/- 4.8% area at risk; P < 0.05). This protection was reversed by co-administration of MPA with E (necrotic zone 38.2% +/- 6.1% area at risk). The influence of E on neutrophil infiltration was demonstrated by its ability to reduce myocardial myeloperoxidase activity (0.2 +/- 0.1 U/g tissue) relative to placebo (1.3 +/- 0.5 U/g tissue; P < 0.05). Myocardial myeloperoxidase activity was significantly increased to 1.1 +/- 0.3 U/g tissue in rats receiving E and MPA. However, MPA also reversed the protective effect of E in neutrophil-free buffer-perfused hearts, suggesting that additional mechanisms are involved. CONCLUSION: In this study, we showed that the administration of MPA can inhibit the effects of E that lead to protection of the myocardium from reperfusion injury and that this involves both neutrophil-dependent and neutrophil-independent mechanisms.
The long-term impact of 2-3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women.
Alexandersen P, Tanko LB, Bagger YZ, Qin G, Christiansen C.
Center for Clinical and Basic Research, Ballerup, Denmark.
OBJECTIVE: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to investigate the long-term effects of HRT given for a few years on all-cause and cardiovascular mortality and the severity of atherosclerosis. METHODS: This analysis was based on a cohort of 1,458 postmenopausal women (55.8 +/- 6.1 years old) who previously participated in a number of randomized, placebo-controlled, clinical trials assessing the efficacy of 2-3 years of therapy with various estrogen plus progestin combinations for preventing bone loss. Women were followed on average for 9.8 years and came for a follow-up visit. Outcome variables were all-cause and cardiovascular mortality and the severity of atherosclerosis, as estimated by semi-quantitative scoring of vascular calcification in the lumbar aorta on lateral radiographs. RESULTS: A total of 174 women died during the observation period. All-cause mortality was decreased by 30% in the HRT+ group compared with the HRT- group (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.50-0.97) after adjusting for age, body mass index and smoking. Under the same conditions, similar results characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths), which were decreased by 46% (HR 0.54, 95% CI 0.29-0.98, p = 0.045) and 53% (HR 0.47, 95% CI 0.21-1.03, p = 0.062), respectively. Furthermore, the mean severity score of aortic calcification at follow-up was significantly lower in hormone-treated compared to non-treated women (p < 0.0001). CONCLUSION: Women who receive 2-3 years of HRT after menopause do not have increased all-cause mortality, and results of the present study suggest relative cardiovascular benefits compared to those who had not used hormones
Hormone levels and mammary epithelial cell proliferation in rats treated with a regimen of estradiol and progesterone that mimics the preventive effect of pregnancy against mammary cancer.
Swanson SM, Whitaker LM, Stockard CR, Myers RB, Oelschlager D, Grizzle WE, Juliana MM, Grubbs CJ.
Department of Nutrition Sciences, University of Alabama at Birmingham 35294, USA.
Women who bear their first child by their late teens have about half the risk of developing breast cancer relative to nulliparous women. The rat is a good model for studying the role of hormones in breast cancer since, for example, young rats become nearly refractory to mammary carcinogenesis after delivering a litter of pups. Short term administration of estradiol and progesterone (E & P) provides virgin rats protection from mammary carcinogenesis as effectively as pregnancy. The purpose of these studies were twofold: first, to evaluate potential long-term toxicity of the E & P treatments and second, to compare hormone treated rats and pregnant rats with respect to circulating E & P levels as well as mammary epithelial cell proliferation and differentiation. To test for toxicity, rats were treated with E & P (20 micrograms and 4 mg, respectively) or vehicle by s.c. injections 5 times per week for 5 weeks beginning at 40 days of age. The animals were weighed biweekly and sacrificed at 500 days of age when detailed necropsies were performed. No significant difference in weight gain was observed between the two groups nor was any toxicity grossly observable in the hormone-treated rats. Furthermore, there was no increase in the number of spontaneous mammary or pituitary tumors in the E & P treated group relative to controls. To evaluate serum hormone titers and mammary proliferation, rats were treated with steroids or vehicle daily beginning at 65 days of age. At 6 and 24 hours after the 1st, 14th and 35th injection, serum E & P were measured by RIA and mammary epithelial cell proliferation by immunohistochemistry (PCNA). At 6 hours after each injection, E & P levels were 3 to 5 fold those observed late in pregnancy. By 24 hours, however, E & P levels subsided to late pregnancy levels or lower. The mammary epithelial cell proliferation index in either E & P treated or late pregnant rats was 6 to 14%. Histologic sections and wholemounts of mammary glands showed a similar degree of differentiation between rats treated with E & P for 14 days or longer and late pregnant rats. These data further suggest that E & P treatments are a non-toxic means of mimicking the protective effect of pregnancy against mammary cancer and that pregnancy or hormone treatments may achieve this prophylaxis through a differentiation mechanism.
Menopausal hormone therapy (HT) in patients with breast cancer.
Batur P, Blixen CE, Moore HC, Thacker HL, Xu M.
Department of Internal Medicine, Section of Women's Health Cleveland Clinic Foundation, Crown Centre II, Independence, OH 44131, USA. baturp@ccf.org
OBJECTIVES: To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer. METHODS: We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users. RESULTS: Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients. Among the 1416 HT users, reoccurrence was noted in 10.0% (95% CI: 8.4-11.6%). Cancer-related mortality occurred at a rate of 2.6% (95% CI: 1.8-3.7%), while overall mortality was 4.5% (95% CI: 3.4-5.8%). Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2-0.7) and 0.3 (95% CI: 0.0-0.6), respectively. CONCLUSIONS: In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of reoccurrence with HT use.
Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women.
Rossi R, Bursi F, Veronesi B, Cagnacci A, Modena MG.
Institute of Cardiology, Policlinico Hospital, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy.
BACKGROUND: C-reactive protein (CRP) represents an independent risk factor for coronary disease and stroke. Because oral estrogens increase CRP levels, with inflammatory and thrombotic consequences, we determined whether the co-administration of a progestin might modify the estrogenic effect on CRP. METHODS: In a non-randomized, non-blinded study, we measured C-reactive protein serum concentrations with high-sensitivity technique (hs-CRP) in 163 healthy postmenopausal women divided into groups as follow: 52 not taking hormones (referent group), and 111 taking hormone replacement therapy (HRT) (42 of whom treated with unopposed estrogen, and 69 with an estrogen/progestin combination). RESULTS: Compared with non-users of hormones, median CRP levels were 66% (95% confidence interval: from 44 to 89%) higher and 112% (95% confidence interval: from 89 to 168%) higher among women using a combined estrogen/progestin regimen and, respectively, among women taking unopposed estrogen [1.54 mg/L in the referent group; 2.56 mg/L in the estrogen/progestin group (P=0.032), and 3.27 mg/L in the unopposed estrogen group (P=0.004)]. Furthermore, there was no difference in CRP distributions between women taking different types of progestins. CONCLUSION: concurrent progestin administration may attenuate estrogen's pro-inflammatory effects, independently on the type of used progestin.
The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth
Theodore Fotsis, Youming Zhang, Michael S. Pepper, Herman Adlercreutz, Roberto Montesano, Peter Paul Nawroth & Lothar Schweigerer
THE formation of new blood vessels (angiogenesis) is critical for the growth of tumours1–3 and is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis4. Recognition of the potential therapeutic benefits of controlling pathological angiogenesis has led to a search for angiogenesis inhibitors. Here we report that 2-methoxyoestradiol, an endogenous oestrogen metabolite of previously unknown function, is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis in vitro. Moreover, when administered orally in mice, it strongly inhibits the neovascularization of solid tumours and suppresses their growth. Unlike the angiostatic steroids of corticoid structure5, it does not require the co-administration of heparin or sulphated cyclodextrins for activity. Thus, 2-methoxyoestradiol is the first steroid to have high antiangiogenic activity by itself. Our results suggest that this compound may have therapeutic potential in cancer and other angiogenic diseases.
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