**7. Steroid estrogens and cardiovascular system**

Coronary heart diseases (CHD) is rare, and the incidence of CHD complications is much lower in premenopausal women then in man or postmenopausal women of similar age. After menopause the gender difference is lost and the incidence of CHD complications in women gradually approach that the men. In addition, menopause adversely affects several risk factors for CHD. It allows to assume the important role of estrogens in the protection of body from coronary heart diseases and expediency of their use as HRT medications.

Protective effect of estrogens has been shown in various animal models.

Rats have been used as a model system to study estrogenic effects on plasma lipid levels (**Lundeen et al., 1997**). On the whole this model has a lot of restrictions, first of all the main one is the predominant plasma cholesterol is HDL, not LDL, as it is in human. There are known: mouse models of atherosclerosis (**Hodgin & Maeda, 2002**) on rabbits (**Haarbo & Christiansen, 1996**) and primates (**Adams et al., 1990**). In all cases the main is the evaluation of influence of estrogens on the development of atherosclerotic plaque or lesion. In most cases it was shown the inhibitory activity of estrogens on atherosclerosis development.

Firstly it was postulated that main antiatherosclerotic action of estrogen is caused by the ability to decrease cholesterol level in serum; however in a number of investigations it was shown that this mechanism is not obligatory (**Shavva et al., 1987; Holm et al., 1997**).

At the present time it is postulated that atheroprotective effects of estrogen may be mediated by their nuclear receptors. ERα was found in endothelial cells (**Venkov et al., 1996**), in smooth-muscle cells (**Karas et al., 1994**) and in myocardial cells. A number of authors maintain the opinion about the importance for protective functions both ERα (**Gerard'es** et al, 2006; **Pare at al., 2002**), and ERβ (**Watanabe et al., 2003).** It is impossible to note the

The new area in synthesis of compounds with osteoprotective properties should be noted – the creation of hybrid molecules having steroid and peptide fragments, for example compounds (**Wang et al., 2003**). Such compounds have stronger action in the experiments

Peptidylsteroid **114** has very interesting properties (**Yokogawa et al., 2006**). This hybrid compound during intranasal administration has a potent antiosteoporotic effect without

In the treatment of estrogen-sensitive conditions aromatase inhibitors are to be used sometimes, which triggers estrogen concentration to drop, increasing osteoporosis and cardiovascular disease risk (**Ponzone et al., 2008; Reid, 2009; Gennari et al., 2011**). In each case the decision in using a drug depends on individual features of the patient. Usage combined drugs, which have calcitriol as a part of them, might prove useful to lower

Coronary heart diseases (CHD) is rare, and the incidence of CHD complications is much lower in premenopausal women then in man or postmenopausal women of similar age. After menopause the gender difference is lost and the incidence of CHD complications in women gradually approach that the men. In addition, menopause adversely affects several risk factors for CHD. It allows to assume the important role of estrogens in the protection of

Rats have been used as a model system to study estrogenic effects on plasma lipid levels (**Lundeen et al., 1997**). On the whole this model has a lot of restrictions, first of all the main one is the predominant plasma cholesterol is HDL, not LDL, as it is in human. There are known: mouse models of atherosclerosis (**Hodgin & Maeda, 2002**) on rabbits (**Haarbo & Christiansen, 1996**) and primates (**Adams et al., 1990**). In all cases the main is the evaluation of influence of estrogens on the development of atherosclerotic plaque or lesion. In most cases it was shown the inhibitory activity of estrogens on atherosclerosis development. Firstly it was postulated that main antiatherosclerotic action of estrogen is caused by the ability to decrease cholesterol level in serum; however in a number of investigations it was

body from coronary heart diseases and expediency of their use as HRT medications.

shown that this mechanism is not obligatory (**Shavva et al., 1987; Holm et al., 1997**).

At the present time it is postulated that atheroprotective effects of estrogen may be mediated by their nuclear receptors. ERα was found in endothelial cells (**Venkov et al., 1996**), in smooth-muscle cells (**Karas et al., 1994**) and in myocardial cells. A number of authors maintain the opinion about the importance for protective functions both ERα (**Gerard'es** et al, 2006; **Pare at al., 2002**), and ERβ (**Watanabe et al., 2003).** It is impossible to note the

Protective effect of estrogens has been shown in various animal models.

**HOLeuPheGlyGlyTyrOCCH2O**

**OH**

**H**

**H H**

**OH**

**H**

**H H**

 **114 115** 

side effects in experiments on female ddY mice.

**7. Steroid estrogens and cardiovascular system** 

osteoporosis (**Krishnan et al., 2010).** 

on rats in comparison with sum of action of these compounds.

**H2NLeuPheGlyGlyTyrOCCH2O**

experimental data, showing the cardioprotective activity of estrogens, which is not mediated by nuclear receptors (**Shavva et al., 1987; Karas et al., 2001**).

Estrogens increase vasodilatation and inhibit the response of blood vessels to injury and the development of atherosclerosis, this action is referred to non genomic, this develops maximum after 20 min after estrogen introduction (**Mendelsohn & Karas, 1999**). Fast vasodilatation is possible due to the influence on both calcium-activated potassium ionchannel function (**Ghanam et al., 2000**), and on the synthesis of nitric oxide (the last relaxes vascular smooth muscle and inhibits platelet activation (**Holm et al., 1997; Node et al., 1997**). More detailed ways of non-genomic effects have been considered by **Mendelsohn & Karas (1999**).

Of crucial importance is the influence of agents on hemodynamic functions (**Borissoff et al., 2011**).

One more factor of risk of arising of atherosclerosis and thrombosis is higher content of oxidized lipoproteins, possible mechanism of these diseases have been considered **(Steinberg et al., 1989; Holvoet & Collen, 1994).**

Antioxidant action of estrogens has been widely studied *in vivo* and *in vitro*. Besides its effects on LDL-oxidation (**Maziere et al., 1991; Markides et al., 1998; Ruiz-Larrea et al., 2000; Badeau et al., 2005**), it has reported that estrogens decreased lipid peroxidation in brain homogenates and neuronal cultures (**Vedder et al., 1999; Thibodeau P. et al., 2002**), reduced the superoxide anion production of different cells (**Bekesi et al., 2000**; **Florian et al., 2004).** All these effects may contribute to the beneficial consequences of estrogen replacement on the cardiac and vascular function, bone and mineral metabolism, brain function.

In the experiments on rabbits with hypercholesterinemic diet it was shown that 17 dihydroequilin sulphate and 17-ethynylestradiol significantly reduce atherosclerosis by 35% in the aortic arch and 75-80% in the thoracic and abdominal aorta, in spite of high level of LDL cholesterol (**Sulistiany at al., 1995**). High ration between HDL and LDL level is important but is not absolute parameter in prognosis of cardio-heart diseases risk. Clinical trials of estrone sulphate (at the same time 17-ethynylestradiol has been investigated) in postmenopausal women have shown the significant improvement of this parameter. It is important that the action of estrone sulphate did not result in triglycerides level increasing in contrast to 17-ethynylestradiol (**Colvin et al., 1990**).

Thus, numerous investigations on animal models (we described only few of them) give the evidence about the advisability of application of estrogens for HRT. First clinical trials for using of estrogens with this aim gave optimism, however wide-ranging investigations did not confirm the expectations. In older postmenopausal women with established coronaryartery atherosclerosis, 17β-estradiol had no significant effect on the progression of atherosclerosis (**Hodis et al., 2003**). Moreover, the combination: estrogen plus progestin may increase the risk of CHD (**Manson et al., 2003**). This is very important effect, because the content of triglycerides in blood is the independent factor of risk of cardio-vascular diseases (**Koren et al., 1996**).

This difference is very important because the increased level of triglycerides in blood is the independent factor of risk of cardiovascular diseases (**Koren et al., 1996**).

From other side, main and side effects of any medication depend on/from methods of the introduction into the body. Therefore the positive results obtained during transdermal introduction of estradiol takes attention **(Sumino et. al., 2006)**. Oral estrogens raised triglycerides whilst transdermal estradiol lowered those (**Nerbrand et al., 2004**). The

Approaches for Searching

17808-17814, ISSN 0021-9258

1392-1398, ISSN 0022-2623

1072-8368

8809

0026-895X

ISSN 0039-128X

2003), pp. 419-427, ISSN 0140-6736

of Modified Steroid Estrogen Analogues with Improved Biological Properties 201

An, J.; Ribeiro, R.C.J.; Webb, P.; Gustaffson, J.-Ǻ.; Kushner, P.J.; Baxter, J.D. & Leitman, D.C.

Arai, S.; Miyashiro, Y.; Shibata, Y.; Kashiwagi, B.; Tomaru, Y.; Kobayashi, M.; Watanabe, Y.;

Azzi, A.; Rhese, P.H.; Zhu, D.-W.; Campbell, R.L.; Labrie, F. & Lin, S-X. (1996). Crystal

Badeau, M.; Adlercreutz, H.; Kaihovaara, P. Tikkanen, M. (2005). Estrogen A-ring

*Molecular Biology*, Vol.96, No.3-4, (August 2005), pp.271–278, ISSN 0960-0760 Bai, Y. & Gugière, V. (2003). Isoform-selective Interactions between Estrogen Receptors and

Bauss, F.; Esswein, A.; Reiff, K.; Sponer, G. & Müller-Beckmann, B. (1996). Effect of 17-

Behl, C.; Skutella, T.; Lezoualch, F.; Post, A.; Widmann, M.; Newton, C. Holsboer, F.

Bekesi, G.; Kakucs, R.; Varbro, S.; Racz, K.; Sprintz, D.; Feher, J. Szekacs, B. (2000). In vitro

Beral, V. & Million Women Study Collaborators. (2003). Breast cancer and hormone-

No.3, (September 1996), pp. 168-173, ISSN 0171-967X

(1999). Estradiol repression of tumor necrosis factor-α transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. *Proc. Natl. Acad. Sci. USA*, Vol.96, No.26, (December 1999), pp. 15161-15166, ISSN 0027-8424 An, J.; Tzagarakis-Foaster, C.; Scharschmidt, T.C.; Lomri, N. & Leitman, D.C. (2001).

Estrogen Receptor β-Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens. *J. Biol. Chem*., Vol.276, No.21 (May 2001), pp.

Honma, S. & Suzuki, K. (2010). New quantification method for estradiol in prostatic tissues of benign hyperplasia using liquid chromatography-tandem mass spectrometry. *Steroids*, Vol.75, No.1, (January 2010), pp. 13-19, ISSN 0039-128X Azcoitia, I.; Doncarlos, L. Garcia-Segura, L. (2002). Estrogen and Brain vulnerability. *Neurotoxicity Res*., Vol.4, No.3, (January 2002), pp. 235-245, ISSN 1029-8428 Azzaoui, K.; Diaz-Perez, M.J.; Zannis-Hadjoupoulos, M.; Price, G.B. & Wainer, I.W. (1998).

Effect of Steroids on DNA Synthesis in an in Vitro replication System: Initial Quantitative Structure-Activity Relationship Studies and Construction of Non-Estrogen Receptor Pharmacophore. *J. Med. Chem*., Vol.41, No.9, (April 1998), pp.

structure of human estrogenic 17-hydroxysteroid dehydrogenase complexed with 17-estradiol. *Nature Struct. Biol*., Vol.3, No.8, (August 1996), pp. 665-668, ISSN

structure and antioxidative effect on lipoproteins. *Journal of Steroid Biochemistry &* 

Steroid Receptor Coactivators Promoted by Estradiol and ErbB-2 Signaling in Living Cells. *Mol. Endocrinol.*, Vol.17, No.4, (April 2003), pp. 589-599, ISSN 0888-

Estradiol-Bisphosphonate Conjugate, Potential Bone-Seeking Estrogen Pro-Drugs, on 17-Estradiol Serum Kinetics and Bone Mass in Rats. *Calcif. Tissue Int*., Vol.59,

(1997). Neuroprotection against Oxidative Stress by Estrogens: Structure-Activity Relationship. *Molecular Pharmacology*, Vol.51, No.4, (April 1997), pp. 535–541, ISSN

effects of different steroid hormones on superoxide anion production of human neutrophil granulocytes. *Steroids*, Vol.65, No.12, (December 2000), pp. 889–894,

replacement therapy in the Million Women Study. *Lancet*, V.362, No.9382, (August

conclusion about propriety of such introduction of estrogens may be done only after wideranging long-term investigations.

The investigations of influence of estrogen receptors modulators, being already in clinical application, on coronary heart system have particular interest. First of them is raloxifen. Raloxifene blocks the sedimentation of redundant cholesterol in aorta in the experiments on rabbits (**Bjarnason et al., 1997; 2001**).

One more new steroid has interesting properties (**Pelzer et al., 20**05), this analogue in the experiments in estrogen-deficient spontaneously hypertensive rats has positive influence on hemodynamic function and inhibits cardiac hypertrophy.
