MPA and postmenopausal coronary artery atherosclerosis revisited

Whether progestins, particularly medroxyprogesterone acetate (MPA), attenuate the cardiovascular benefits of postmenopausal estrogen replacement therapy (ERT) has been controversial for over a decade. Concerns related first to findings that MPA attenuated increases of high density lipoprotein cholesterol (HDLC) concentrations of postmenopausal women compared to conjugated equine estrogen (CEE) alone. That observation was followed by early cynomolgus monkey studies that suggested MPA decreased estrogen's cardiovascular benefits (vascular reactivity and coronary artery atherosclerosis inhibition). In a more recent and larger trial with cynomolgus monkeys, no differences were seen in the coronary artery atherosclerosis protective effect of CEE when MPA was co-administered (HRT). The lack of attenuation of ERTs benefits by progestins has also been seen in at least three studies of carotid artery intima-media thickness (IMT) of postmenopausal women. Additionally, the majority of studies of vascular reactivity of postmenopausal women have not found differences when CEE is given alone or with MPA. Seven observational studies of cardiovascular outcomes of postmenopausal women permit separate consideration of ERT versus HRT use; there is no evidence of attenuation of ERTs benefits by progestin use. In conclusion, it is evident that the current experimental, clinical, and observational data do not provide evidence that progestins attenuate estrogen's cardiovascular benefits.     

Combined effects of female hormones and metabolic rate on ventilatory drives in women

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.     

Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed

Estrogens and selective estrogen receptor modulators (SERMs), such as raloxifene (RAL) and tamoxifen (TAM), acutely relax arteries, but the long-term effects of estrogens and SERMs on vascular reactivity in the mesenteric vasculature have not been well defined. In this study, we used an isolated, perfused mesenteric vascular bed technique to investigate the effect of chronic treatment of estrogens and SERMs on vascular reactivity of the mesenteric bed. Ovariectomized female Sprague-Dawley rats were treated by gavage with vehicle (control, 2-hydroxypropyl-beta-cyclodextrin), ethinyl estradiol, estradiol benzoate, equilin (EQ), TAM, or RAL for 3 wk. EQ and TAM increased vasoconstriction in response to all three vasoconstrictors tested (KCl, norepinephrine, and 5-HT). Ethinyl estradiol increased vasoconstriction in response to KCl and 5-HT, whereas responses to estradiol benzoate and RAL were less consistent. Only EQ (134 +/- 4 mmHg) and TAM (104 +/- 4 mmHg) changed mean arterial blood pressure compared with control (117 +/- 4 mmHg). These data demonstrate that 3-wk gavage treatment with estrogens and SERMs affects vascular reactivity in the mesenteric vascular bed. However, the three formulations of estrogen did not produce equivalent effects, and the effects of the SERMs were different from those of the estrogens.     

Alternative hormone replacement regimens: is there a need for further clinical trials?

PURPOSE OF REVIEW: To review the randomized trials of hormone replacement therapy. RECENT FINDINGS: Studies have shown that conjugated equine estrogen 0.625 mg a day plus medroxyprogesterone acetate 2.5 mg a day increased the risk of cardiovascular events during the first year of treatment in women both with and without coronary heart disease. Conjugated equine estrogen plus medroxyprogesterone acetate also increased the overall risk of myocardial infarction and stroke in women without coronary heart disease, and myocardial infarction or death in women with coronary heart disease, and also increased the risk of breast cancer, cognitive decline and dementia. Unopposed, oral 17B-estradiol increased the risk of stroke during the first 6 months of treatment in women with a previous stroke. Oral 17B-estradiol with or without cyclic progestin had no effect on the progression of atherosclerosis or reinfarction. Transdermal 17B-estradiol plus cyclic progestin was associated with a non-significant increase in coronary heart disease events in women with coronary heart disease. Compared with placebo, cardiovascular events increased in the ongoing estrogen-only arm of the Women's Health Initiative, indicating that unopposed conjugated equine estrogen is unlikely to be cardioprotective. However, oral 17B-estradiol retarded the progression of subclinical atherosclerosis in younger women without coronary heart disease. SUMMARY: Hormone replacement therapy should not be initiated for the primary or secondary prevention of coronary heart disease in women. A trial of 17B-estradiol started at menopause in women without coronary heart disease should be considered.     

Medroxyprogesterone acetate attenuates long-term effects of 17beta-estradiol in coronary arteries from hyperlipidemic rabbits

OBJECTIVE: The progestin component in hormone replacement treatment may oppose the effects of estrogen on vascular function. This study examined the effect of long-term treatment with 17beta-estradiol (E(2)) alone and in combination with two progestins on K(+) and Ca(2+)-mediated mechanisms in coronary arteries. METHODS: Watanabe heritable hyperlipidemic rabbits were treated orally with either E(2) (4 mg/day), medroxyprogesterone acetate (MPA) (10 mg/day), norethindrone acetate (NETA) (2 mg/day), E(2)+MPA, E(2)+NETA, or placebo for 16 weeks (n=10 in each group). Coronary arteries were used for mRNA and myograph studies. RESULTS: E(2) increased vasodilatation induced by sodium nitroprusside and decreased vasocontraction induced by potassium. The first but not the latter response was opposed by MPA. The combination of MPA and E(2), but neither compound alone enhanced nimodipine-induced vasodilatation and increased the expression of L-type voltage-gated Ca(2+) channel mRNA. NETA had no opposing effects. Hormone treatment did not affect large-conductance Ca(2+) activated or ATP-sensitive K(+) channels or cGMP-dependent protein kinase mRNA expression. Hyperlipidemia had no effect on vascular reactivity. CONCLUSION: When E(2) is administered with MPA, effects of E(2) on nitric oxide and Ca(2+)-mediated vascular reactivity in rabbit coronary arteries are modulated. The results suggest that the progestin component in hormone replacement treatment may interfere with the supposed beneficial vascular effects of estrogen.     

Comparative contents of mRNAs of sex steroid receptors and enzymes of their metabolism in arterial walls of men

The potential role of estrogens in regulation of metabolism in arteries of men was studied. Contents of mRNAs of sex hormone receptors, of some enzymes of their metabolism, and of some potential markers of the hormone effects were determined by real-time polymerase chain reaction in fragments of 18-54-year-old men's large arteries with and without atherosclerotic lesions. Contents of estrogen receptor alpha (ERalpha) and transferrin receptor mRNAs were significantly different in undamaged fragments of the aorta and of the carotid and coronary arteries. Contents of some mRNAs in the carotid artery and aorta were found to correlate, which suggested a similarly directed regulation of their expressions. The levels of ERalpha and aromatase mRNAs negatively correlated with the blood plasma concentration of estradiol. Levels of steroid sulfatase and aromatase mRNAs were lower and the level of estrogen sulfotransferase mRNA was higher in blood vessel fragments with atherosclerotic lesions than in undamaged fragments. It is suggested that large arteries should be different in sensitivity to estrogens and that atherosclerotic lesions could lead to local suppression of the effect of estrogen on the cells of arteries.     

Nomegestrol acetate and vascular reactivity: nonhuman primate experiments

Prevention of coronary artery disease has been recognized as a major benefit of estrogen replacement therapy (ERT) in postmenopausal women. However, endometrial hyperplasia induced by unopposed ERT has raised important safety concerns. Progesterone or synthetic progestins have been used in combined hormone replacement therapy (HRT) to prevent endometrial cancer risk. Therefore, a major concern has been to ensure that the vascular beneficial effects of estrogens are not opposed when combined with progestins. Nomegestrol acetate (NOMAC) is an orally active progestin widely prescribed for HRT. Its vascular effects were evaluated in two models of coronary vascular reactivity in primates: 1) the paradoxical vasoconstriction to acetylcholine (Ach) coronary infusion after 5 months of mildly atherogenic diet in ovariectomized (OVX) Cynomolgus monkeys and 2) the pharmacologically evoked coronary vasospasm in the OVX Rhesus monkey. In the first model, after 3 months of continuous oral administration in the diet at 0.1 mg/kg/day, E2 prevented the paradoxical response to Ach, alone as well as combined with 0.25 mg/kg/day NOMAC, whereas NOMAC counteracted the endometrial stimulation. In the second model, after one artificial cycle consisting of 28 days of E2 subcutaneous (s.c.) implant and of daily oral gavage with 1 mg/kg/day of NOMAC for the last 14 days, no vasospasm (0 of 11 tested animals) occurred when the complete challenge protocol, including serotonin and the thromboxane agonist U46619, was administered to OVX Rhesus monkeys. In the balanced crossover design, identical artificial cycles with medroxyprogesterone acetate (MPA) at the same dose resulted in 7 vasospasms in 12 animals. In parallel, effective progestative activity was demonstrated by a secretory pattern in endometrial sections obtained at the end of the cycle. In these two nonhuman primate cardiovascular models, NOMAC did not have the negating effects observed with MPA.     

Hormone replacement therapy and cardiovascular disease.

A large amount of research continues to be conducted on the mechanisms of hormone replacement therapy (HRT) effects, and the first of the large clinical trials published its results during the past year. In addition to the well known effects on LDL-cholesterol, HDL-cholesterol, and triglycerides, recent studies confirmed that estrogen with or without a progestin lowers lipoprotein (a) concentrations in women (but not in men). In men, estrogen appears to have a similar effect on other lipids and lipoproteins and on plasminogen activator inhibitor-1 as in women. A comparison of estrogen with simvastatin indicated that simvastatin is better at lowering LDL-cholesterol while estrogen is better at raising HDL-cholesterol; when given in combination the additional effects were modest. Estrogen and simvastatin had similar beneficial effects on endothelial function. The estrogen effect on endothelial function may be blocked by medroxyprogesterone, but the data are inconsistent. These studies of intermediate outcomes were put in perspective by the results of a landmark secondary prevention trial of coronary heart disease (CHD). This randomized placebo-controlled trial (Heart and Estrogen/Progestin Replacement Study) of conjugated equine estrogens plus medroxyprogesterone failed to show the anticipated reduction in CHD, and at the same time the threefold increase in venous thromboembolism confirmed that HRT is procoagulant. Therefore, it is still not known whether HRT is a viable option for the prevention of CHD. The preliminary data on selective estrogen receptor modulators are not overly promising, but a definitive trial to test whether raloxifene will reduce CHD is ongoing.     

Progestins and estrogens and Alzheimer's disease

Sex-specific incidence rates for Alzheimer's disease (AD) are higher in women than men. Many fundamental researches and some clinical investigations have reported therapeutic and preventive effects of estrogens on AD. But WHIMS [S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones IIIrd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wabertheil-Smoller, J. Wactawsk-Wende, WHIMS investigators, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women's health initiative memory study: a randomized controlled trial, JAMA 289 (2003) 2651–2662], which used daily continuous hormone replacement therapy (HRT), reported that the hazard ratio of the HRT for probable dementia was 2.05.

Effect of progestins, and continuous (not cyclically) HRT, even only with estrogen should be reconsidered.

In our clinical study, conjugated equine estrogen (CEE) alone showed good changes of psychiatric tests for AD on the 3rd week, but addition of medroxyprogesterone acetate (MPA) or norethindrone since 4th week suppressed these tests. Using human umbilical vein epithelial cell (HUVEC), levonorgestrel (LNG), norethindrone acetate (NETA), MPA increased intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion melocule-1 (VCAM-1) and E-secretin but dienogest (DNG) showed no effect. In vitro flow system, estradiol (E₂), suppressed adhesion of white cell, but LNG, NETA, MPA increased the adhesions. DNG showed less effect.

Non-feminizing estrogen J 861, which has Δ8,9 double bond and straight in its structure and has less effect on sexual organs. J 861 has shown ameliorative effects on central nervous system (CNS) (increasing of cholineacetyltransferase immunoreactive cells in substantia innominata (SI), etc.) like E₂.

More investigations about progestins and estrogens and AD should be done.     

NM23-H2, an estrogen receptor beta-associated protein, shows diminished expression with progression of atherosclerosis

While estrogen receptor (ER) profile plays an important role in response to estrogens, receptor coregulators act as critical determinants of signaling. Although the clinical effects of ovarian hormones on various normal and pathological processes are an active area of research, the exact signaling effects on, for example, the vessel wall, are incompletely understood. Hence, we sought to discover proteins that associate with ERbeta, the isoform that shows upregulated mRNA expression after arterial injury. Using a yeast two-hybrid screen we identified NM23-H2, a multifaceted metastasis suppressor candidate protein, as an ERbeta-associated protein. Although NM23-H2 was immunodetected in arteries from young subjects (27 +/- 6 yr, 14 men and 6 women) with benign intimal hyperplasia, expression was diminished in fatty streaks/atheromas and altogether absent in advanced atherosclerotic lesions. Both nm23-H2 mRNA and protein were expressed by vascular cells in vitro. Treatment with 17beta-estradiol and an ERbeta-selective agonist, diarylpropionitrile, increased protein expression of NM23-H2; an effect that was not seen with an ERalpha-selective agonist, propylpyrazole-triol. Estrogen also prompted nuclear localization of NM23-H2 protein in human coronary smooth muscle cells (SMCs). An in vitro mimic of inflammation decreased the expression of NM23-H2 in SMCs, which was restored on addition of estrogen and dependent on the estrogen receptor. In summary, we report the novel association of NM23-H2 with ERbeta and show for the first time its expression in vascular cells and demonstrate regulation of its expression and localization by estrogen. In that the abundance of NM23-H2 diminishes with both the advancement of atherosclerosis and inflammation, this ERbeta-associated protein may play an important role in mediating the vasculoprotective effects of estrogens.     

Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data

ObjectiveTo review he impact of estrogen-containing feminizing hormone regimens on transgender individuals’ risk for VTE.MethodsWe evaluated VTE risk by screening 1170 relevant studies published from 1994 to 2020, focusing on meta-analysis data.ResultsThe type of oral estrogen, route of administration, patient demographics, and comorbidities may affect the risk of VTE. Venous thrombosis is the most common vascular complication associated with HT.ConclusionConjugated equine estrogens and 17-β estradiol appear to be safer than oral ethinyl estradiol. Transdermal estrogen formulations appear to be the least thrombogenic estrogens. Estrogens used concomitantly with progestins increase the risk of VTE compared to estrogens alone.To date, there are no data to demonstrate the benefit of holding HT prior to vaginoplasty or other gender affirming surgeries. For most young, healthy transgender women, there is little risk of VTE with HT, while older patients with risk factors should be discussed case by case.     

Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats

This study tested the hypothesis that evolution of the metabolic syndrome in obese Zucker rats (OZR) leads to impaired dilator reactivity of cerebral resistance arteries vs. responses determined in lean Zucker rats (LZR). Middle cerebral arteries (MCA) from 17-wk-old male LZR and OZR were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with ACh, sodium nitroprusside (SNP), reductions and elevations in Po2, 5-HT, and increased intralumenal pressure. Vessels were treated with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) to assess the role of superoxide production in altering reactivity, and passive vascular wall mechanics was assessed in each vessel. Vascular superoxide production was assessed in isolated arteries using fluorescence microscopy. Vessel dilation to ACh and hypoxia was impaired in OZR vs. LZR, although responses to SNP were normal. Vessel constriction to 5-HT, elevated Po2, and elevated intralumenal pressure was enhanced in OZR vs. LZR. Fluorescence microscopy demonstrated an increased superoxide production in arteries of OZR vs. LZR, correctable by incubation with tempol. Although treatment of vessels from OZR with tempol improved dilation to ACh and hypoxia, constrictor responses to 5-HT, elevated Po2, and pressure were not altered by tempol treatment. Indexes of vessel wall mechanics were comparable between groups. These results suggest that vasodilator reactivity of MCA of OZR in response to endothelium-dependent dilator stimuli is impaired vs. LZR and that this may represent a reduced bioavailability of signaling molecules due to oxidant scavenging. However, oxidative stress-independent increases in myogenic tone and constrictor reactivity may contribute to blunted dilator responses of cerebral microvessels.     

Progestins and cardiovascular risk markers

Several risks are attributed to progestins as a class-effect; however, the progestins used in hormone replacement therapy (HRT) have varying pharmacologic properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones, do not exert any androgenic effect and, hence, have no negative effect on the lipids. On the other hand, the 19-nortestosterone derivatives and even some 17-hydroxyprogesterones have a partial androgenic effect, which may explain some of the negative effects observed on surrogate markers of cardiovascular risk. The relevance of the lipid changes induced by sex steroids has been questioned, and studies in the female cynomolgous monkey have not shown a direct relationship to atherosclerosis. Results suggest that estrogens (E) have antiatherogenic effects and that P does not reverse the beneficial effect of estradiol. Also, sex hormones modulate the vasomotor response of the main arteries. E preserves the normal endothelium-mediated dilation of coronary arteries, and P does not reverse this potential cardioprotective mechanism. In the same animal model, the addition of cyclic or continuous medroxyprogesterone acetate (MPA) to E inhibited vasodilatation by 50%, while nomegestrol acetate did not diminish the E-induced vasodilatation. Not all progestins act similarly on vasomotion or affect cardiovascular risk factors in the same way. Progestins, such as MPA or norethisterone acetate (NETA), exert a partial detrimental effect on the beneficial actions of estrogens with regard to lipid changes, atheroma development, or vasomotion. In contrast, progesterone itself does not have this inhibitory effect on lipid changes and vascular reactivity in animal models or on exercise-induced myocardial ischemia in humans. Nonandrogenic molecules of P itself and of derivatives, such as 19-norprogesterones, would appear neutral on the vessels. Several ongoing randomized controlled trials of HRT are focusing on primary or secondary prevention of coronary heart disease. Unfortunately, most of these large trials have selected the same HRT regimen for their study design. Further studies with other treatment regimens are thus needed and should consider the various steroids used in different countries.     

Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women.

Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine levels in 145 postmenopausal and premenopausal Chinese women living in Hong Kong. We also investigated the effect of hormone-replacement therapy (HRT) with estrogen or estrogen combined with progestin on plasma lipoprotein profile and homocysteine concentrations in those individuals. Postmenopausal women displayed significantly higher plasma levels of total cholesterol, LDL-cholesterol and apoB as well as higher plasma homocysteine levels than that of premenopausal women. HRT with either estrogen (17beta-estradiol or conjugated equine estrogen) alone or estrogen combined with progestin for 3.5-4.5 years significantly improved the lipoprotein profile in postmenopausal women by decreasing the levels of total cholesterol (12-20% reduction), LDL-cholesterol (26-29% reduction) and apoB (21-25% reduction). In women treated with 17beta-estradiol or conjugated equine estrogens their plasma levels of apoAl were significantly elevated (18% elevation) as compared to non-users. HRT also reduced plasma concentrations of homocysteine (13-15% reduction). In conclusion, we found that long-term HRT was associated with improvement in plasma lipoprotein profile and a reduction in homocysteine concentration in postmenopausal women. These results support the notion that the improvement of lipoprotein profile and a reduction in homocysteine concentration may contribute to the beneficial effect of HRT on cardiovascular risk.     

Production of free estrogens and estrogen conjugates by the preimplantation equine embryo

In vitro production of free estrogens and estrogen conjugates by intact Day 12.5, 13.5 and 14.5 equine embryos was measured at 2-h intervals over a 24-h culture period. Production of free estrogens was higher for Day 14.5 than Day 12.5 embryos. Differences in production of conjugated estrogens were not significant, but a trend toward increased production with increased age of embryo was apparent. No trend toward increased free and conjugated estrogen production per cell was observed with age. Embryo diameter and number of cells increased with age but varied considerably within groups. The amount of free and conjugated estrogens measured in blastocoelic fluid did not decrease over the 24-h culture period, suggesting that estrogens detected in culture medium were produced by the embryo and not the result of leakage of maternal estrogen from the blastocoele. The results of this study support previous results that estrogen production increases with development of equine embryos. This increase in estrogen production appears to be more closely associated with the diameter of the embryo, and hence its number of cells, than with increased intracellular steroidogenic activity.     

Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle

Estrogens can either relax or contract arteries via rapid, nongenomic mechanisms involving classic estrogen receptors (ER). In addition to ERα and ERβ, estrogen may also stimulate G protein-coupled estrogen receptor 1 (GPER) in nonvascular tissue; however, a potential role for GPER in coronary arteries is unclear. The purpose of this study was to determine how GPER activity influenced coronary artery reactivity. In vitro isometric force recordings were performed on endothelium-denuded porcine arteries. These studies were augmented by RT-PCR and single-cell patch-clamp experiments. RT-PCR and immunoblot studies confirmed expression of GPER mRNA and protein, respectively, in smooth muscle from either porcine or human coronary arteries. G-1, a selective GPER agonist, produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro. This response was attenuated by G15, a GPER-selective antagonist, or by inhibiting large-conductance calcium-activated potassium (BK(Ca)) channels with iberiotoxin, but not by inhibiting NO signaling. Last, single-channel patch-clamp studies demonstrated that G-1 stimulates BK(Ca) channel activity in intact smooth muscle cells from either porcine or human coronary arteries but had no effect on channels isolated in excised membrane patches. In summary, GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens.     

The preclinical biology of a new potent and selective progestin: trimegestone

Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.     

Biological effects of hormone replacement therapy in relation to serum estradiol levels

OBJECTIVE: Tissues in various parts of the body have different sensitivities to estradiol. However, it is very difficult to measure the serum estradiol levels precisely in women receiving oral conjugated equine estrogen, which is a mixture of estrogens. In the present study, we precisely measured the serum levels of estradiol in postmenopausal women undergoing hormone replacement therapy (HRT), and we clarified the relationships between serum estradiol levels and the effects of HRT on the Kupperman index, bone mineral density (BMD), serum gonadotropin, lipid metabolism and unscheduled bleeding as the clinical endpoints. METHODS: Sixty-eight postmenopausal or bilaterally ovariectomized women, aged 30-64 years, who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly assigned to two groups: one group of 34 patients who received oral administration of 0.625 mg conjugated equine estrogen (CEE, Premarin, Wyeth) and 2.5 mg medroxyprogesterone acetate (MPA, Provera, Upjohn) every other day, and another group of 34 patients who received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. All subjects were re-classified into three groups according to the serum estradiol level after 12 months of treatment: (1) low estradiol group (<15 pg/ml, n = 25); (2) middle estradiol group (> or =15 and <25 pg/ml, n = 27), and (3) high estradiol group (> or =25 pg/ml, n = 16). We examined the relationships between serum estradiol level and the effects of estradiol on the Kupperman index, BMD, serum gonadotropin levels, lipid profile and unscheduled bleeding in these three groups. Results: Results obtained by using our newly developed high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA) system clearly showed that the effects on each tissue in postmenopausal women receiving oral CEE and MPA is closely related to estradiol level. The effects of HRT on BMD, serum gonadotropin levels and lipid profile were shown to be clearly dependent on the serum estradiol levels, while the effect of HRT on the Kupperman index was independent of the serum estradiol level. Furthermore, it was also found that a very low concentration of estradiol (<15 pg/ml) was sufficient to suppress the serum LH and FSH levels and to relieve vasomotor symptoms, and that the minimum concentration of estradiol required to increase BMD was 15 pg/ml. On the other hand, the level of estradiol required to reduce total cholesterol, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (Apo B) was found to be more than 25 pg/ml, while the level required to increase high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) was at least 15 pg/ml. The incidence of unscheduled bleeding was also lower in the low estradiol group than in the other estradiol level groups. CONCLUSION: These results suggest that the different clinical endpoints have different response thresholds and thus reflect tissue sensitivity to estradiol levels achieved by HRT.     

Progestins and progesterone in hormone replacement therapy and the risk of breast cancer

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.