Different cardiovascular effects of progestins according to structure and activity

Nath, Anita; Sitruk-Ware, Régine

doi:10.1080/13697130902905757

Cited by 40 publications

(34 citation statements)

References 17 publications

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“…Addition of progestogen is needed with estrogen for HRT in women with an intact uterus even if the dose of estrogen is low since it has been reported that endometrial hyperplasia and endometrial cancer occurred in women with an intact uterus when ultralow dose estrogen alone was used (80). Progestogens, such as medroxyprogesterone, levonorgestrel and norethisterone acetate, which are older progestogens, have androgenic activities (81). Estrogen has favorable effects on insulin sensitivity, blood pressure and lipid metabolism, but androgenic activities of progestogens have unfavorable effects on these favorable effects of estrogen.…”

Section: Effects Of Testosterone-derived Progestogens In Womenmentioning

confidence: 99%

Androgen in postmenopausal women

et al. 2012

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Dynamic changes in circulating estradiol level, including increase at menarche and decrease at menopause, occur in a woman's lifetime. Circulating estradiol levels decrease drastically during the menopausal transition, though the levels differ among races. It has been reported that estradiol levels in both Japanese and Chinese women were lower than those in Caucasians, Hispanic and AfricanAmericans (1).Based on data obtained in a previous study (2), we re-analyzed data for 169 healthy men and 252 healthy women aged from 40 to 85 years in the population-based study with addition of data for premenopausal women. Change in circulating estradiol in women from the menopausal transition to postmenopause is characterized as follows : high estradiol level in premenopausal women is drastically decreased and estradiol level in postmenopausal women is significantly lower than that in agematched men. Mean estradiol levels were shown to be 20.1 pg/ml in men and 6.1 pg/ml in postmenopausal women (Figure 1). This dynamic decrease in REVIEW Androgen in postmenopausal women

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Section: Effects Of Testosterone-derived Progestogens In Womenmentioning

confidence: 99%

Androgen in postmenopausal women

et al. 2012

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“…The increased risk of coronary disease and stroke associated with medroxyprogesterone acetate (MPA) treatment observed in several large hormone replacement therapy trials (16, 50) is one likely reason why positive effects of progestins have not been investigated extensively. However, progesterone has divergent and often opposite effects to those of MPA on cardiovascular functions that are probably partially related to its antiandrogenic and antimineralocorticoid activities, which are not shared by MPA (20,35,60). Treatment with progesterone causes vasodilation and lowers blood pressure in normotensive as well as in hypertensive patients, including those with pregnancy-induced hypertension (35,40,48,51).…”

mentioning

confidence: 99%

“…However, progesterone has divergent and often opposite effects to those of MPA on cardiovascular functions that are probably partially related to its antiandrogenic and antimineralocorticoid activities, which are not shared by MPA (20,35,60). Treatment with progesterone causes vasodilation and lowers blood pressure in normotensive as well as in hypertensive patients, including those with pregnancy-induced hypertension (35,40,48,51). Improvements of cardiovascular functions such as decreased coronary artery hyperactivity and lower blood pressure have also been reported in primates and other animal models after progesterone treatment (2,19,45,49).…”

mentioning

confidence: 99%

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Pang

Dong

Thomas

2015

American Journal of Physiology-Endocrinology and Metabolism

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Pang Y, Dong J, Thomas P. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-␣. Am J Physiol Endocrinol Metab 308: E899 -E911, 2015. First published March 24, 2015; doi:10.1152/ajpendo.00527.2014.-Progesterone exerts beneficial effects on the human cardiovascular system by inducing rapid increases in nitric oxide (NO) production in vascular endothelial cells, but the receptors mediating these nongenomic progesterone actions remain unclear. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that progesterone binds to plasma membranes of HUVECs with the characteristics of membrane progesterone receptors (mPRs). The selective mPR agonist Org OD 02-0 had high binding affinity for the progesterone receptor on HUVEC membranes, whereas nuclear PR (nPR) agonists R5020 and medroxyprogesterone acetate displayed low binding affinities. Immunocytochemical and Western blot analyses confirmed that mPRs are expressed in HUVECs and are localized on their plasma membranes. NO levels increased rapidly after treatment with 20 nM progesterone, Org OD 02-0, and a progesterone-BSA conjugate but not with R5020, suggesting that this progesterone action is at the cell surface and initiated through mPRs. Progesterone and Org OD 02-0 (20 nM) also significantly increased endothelial nitric oxide synthase (eNOS) activity and eNOS phosphorylation. Knockdown of mPR␣ expression by treatment with small-interfering RNA (siRNA) blocked the stimulatory effects of 20 nM progesterone on NO production and eNOS phosphorylation, whereas knockdown of nPR was ineffective. Treatment with PI3K/ Akt and MAP kinase inhibitors blocked the stimulatory effects of progesterone, Org OD 02-0, and progesterone-BSA on NO production and eNOS phosphorylation and also prevented progesterone-and Org OD 02-0-induced increases in Akt and ERK phosphorylation. The results suggest that progesterone stimulation of NO production in HUVECs is mediated by mPR␣ and involves signaling through PI3K/Akt and MAP kinase pathways. membrane progesterone receptors; human vascular endothelial cells; rapid progesterone action; nitric oxide; nitric oxide synthase FEMALE REPRODUCTIVE HORMONES are widely considered to have beneficial effects on cardiovascular functions in women. The lower incidence of cardiovascular disease in middle-aged premenopausal women than in men and postmenopausal women has been attributed to the presence of female sex steroids in the circulation (22,27,41,47). Blood pressure is typically lower in women than in men and often drops during pregnancy when circulating levels of estrogens and progesterone are elevated (30,70,71). Furthermore, synthesis of a major regulator of vasodilation, nitric oxide (NO), is greater in women than in men (14). These sex differences in the occurrence of cardiovascular disease are due partly to the well-known beneficial effects of estrogens, which include upregulation of NO production in human endothelial cells (7,18,28,33). Numerous...

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“…The androgenicity, dose and regimen of progestins determine their effect upon the lipid profile as they oppose some of the estrogenic response [13]. Androgenic progestins have shown an adverse effect over total and HDL cholesterol [14]. Natural estrogens such as 17β-estradiol have been favored recently because they increase the HDL level without increasing the VLDL level as is often observed with EE.…”

Section: Lipid Metabolismmentioning

confidence: 99%

Metabolic effects of contraceptive steroids

Sitruk-Ware

Nath

2011

Rev Endocr Metab Disord

114

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Estrogen and progestins have been used by millions of women as effective combined contraceptives. The safety of hormonal contraceptives has been documented by years of follow-up and serious adverse events that may be related to their use are rare in the young population exposed to these agents. The balance between the benefits and the risks of contraceptive steroids is generally positive in particular when comparing to the risks of pregnancy and especially in women with risk factors. The metabolic changes induced by the synthetic steroids used in contraception, such as lipoprotein changes, insulin response to glucose, and coagulation factors have been considered as potential markers of cardiovascular and venous risk. Observations of these effects have led to modifications of the composition of hormonal contraceptive in order to minimize these changes and hence potentially decrease the risks. The synthetic estrogen Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism including estrogen-dependent markers such as liver proteins. This stronger hepatic impact of EE has been related to its 17α-ethinyl group which prevents the inactivation of the molecule and results in a more pronounced hepatic effect of EE as compared to estradiol. Due to its strong activity, administering EE via a non-oral route does not prevent its impact on liver proteins. In order to circumvent the metabolic changes induced by EE, newer products using more natural compounds such as estradiol (E2) and estradiol valerate (E2V) have been introduced. The synthetic progestins used for contraception are structurally related either to testosterone (T) (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to bind more specifically to the progesterone receptor and to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) and the 19-norpregnanes including Nestorone® (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) have been combined with estrogen either EE or E2 or estradiol valerate (E2V). Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type and dose of estrogen associated in a combination and the route of administration. The lower metabolic impact of estradiol-based combinations may result in an improved safety profile, but large surveillance studies are warranted to confirm this plausible hypothesis. So far, the contraindications and warnings for use of current COCs also apply to the estradiol-based COCs.

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Different cardiovascular effects of progestins according to structure and activity

Cited by 40 publications

References 17 publications

Androgen in postmenopausal women

Androgen in postmenopausal women

Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α

Metabolic effects of contraceptive steroids

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