Role of progestins with partial antiandrogenic effects

Sitruk-Ware, Régine; Husmann, F; Thijssen, J. H. H.; Skouby, Sven O.; Fruzzetti, Franca; Hanker, J. P.; Huber, Johannes; Druckmann, René

doi:10.1080/13697130400001307

Cited by 9 publications

(4 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…observed with combination estrogen plus progestin hormone therapy (46), although some suggest that progestins with high androgenic properties may antagonize the beneficial changes in LDL and HDL induced by estrogen (39,40,46). The previous studies used oral estrogens, which could have a greater influence on lipid concentrations due to first-pass metabolism via the liver than transdermal estrogens.…”

Section: Discussionmentioning

confidence: 99%

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Meendering¹,

Torgrimson²,

Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Meendering JR, Torgrimson BN, Miller NP, Kaplan PF, Minson CT. Estrogen, medroxyprogesterone acetate, endothelial function, and markers of cardiovascular risk in young women. Am J Physiol Heart Circ Physiol 294: H1630-H1637, 2008. First published February 15, 2008 doi:10.1152/ajpheart.01314.2007.-Medroxyprogesterone acetate (MPA) is widely known for its use in combination hormone therapy for postmenopausal women. However, MPA is also commonly used in young women for contraception and treatment of a number of gynecological conditions. Despite its widespread use, the cardiovascular effects of MPA in young women are unclear. Therefore, the purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. We suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHaϩE2), and on day 7 5 mg of MPA was added (GnRHaϩE2ϩMPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHaϩE2, and GnRHaϩE2ϩMPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHaϩE2 than during GnRHa or GnRHaϩE2ϩMPA (P ϭ 0.006). Endothelin-1 was lower during GnRHaϩE2 than GnRHa alone (P ϭ 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1. endothelium; hormones; flow-mediated vasodilation; endothelin-1; progestins THERE IS SUBSTANTIAL EVIDENCE to suggest that estrogens have a cardioprotective influence in women by improving endothelial function (11,14,19,24) and low-density lipoprotein (LDL) concentrations (45) while decreasing concentrations of endothelin-1 (ET-1) (4,26,31,32,56) and homocysteine (9). In contrast, medroxyprogesterone acetate (MPA) has been shown to counteract the beneficial effects of estrogens in animals (1, 52) and in some studies in postmenopausal women (18,44,49). Recently, the estrogen plus MPA arm of the Women's Health Initiative clinical trial was terminated because of a trend toward negative cardiovascular outcomes (37). These findings raise questions about the use of progestins, and specifically MPA, in hormone treatments.In addition to postmenopausal women, premenopausal women are also commonly prescribed MPA. MPA is used in the injectable prog...

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Meendering¹,

Torgrimson²,

Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…However, other progestin‐only contraceptives in our study, such as the injectable contraceptive, were associated with greater blood pressure, highlighting the potentially important role of progestin type. Progestins are synthetic forms of endogenous progesterone and can be derived from either 17‐a‐hydroxyprogesterone or 19‐nortestosterone (Ghatge et al, 2005 ; Oelkers, 1996 ) resulting in wide variation in both progestational and androgenic activity (Sarna et al, 2009 ; Sitruk‐Ware, 2004 ; Sitruk‐Ware et al, 2004 ). High androgenic activity, predominately present in testosterone‐derived progestins, is associated with higher cardiovascular risk (Nath & Sitruk‐Ware, 2009 ; Sitruk‐Ware, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

The effect of non‐oral hormonal contraceptives on hypertension and blood pressure: A systematic review and meta‐analysis

Kalenga

Dumanski

Metcalfe

et al. 2022

Physiological Reports

View full text Add to dashboard Cite

Oral contraceptives (OC) are associated with increased risk of hypertension and elevated blood pressure (BP). Whether non‐oral hormonal contraceptives have similar associations is unknown. We sought to investigate the effect of non‐oral hormonal contraceptive (NOHC) use on the risk of hypertension and changes in BP, compared to non‐hormonal contraceptive and OC use. We searched bibliographic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) until August 2020. Studies reporting risk of hypertension or changes in systolic and diastolic BP with NOHC use compared with either non‐hormonal contraceptive or OC use. Abstract screening, full‐text review, data extraction, and quality assessment were completed in duplicate. For studies reporting dichotomous outcomes, we reported results as relative risk with 95% confidence intervals (CI). A random‐effects model was used to estimate pooled weighted mean difference and 95% CI of change in BP. Twenty‐five studies were included. A lower incidence of hypertension was observed with injectable contraceptive use compared to non‐hormonal contraceptive and OC use, although it was unclear if this was statistically significant. Compared to non‐hormonal contraceptive use, injectable contraceptive use was associated with increased BP (SBP: 3.24 mmHg, 95%CI 2.49 to 3.98 mmHg; DBP: 3.15 mmHg, 95%CI 0.09 to 6.20 mmHg), the hormonal intra‐uterine device use was associated with reduced BP (SBP: −4.50 mmHg, 95%CI −8.44 to −0.57 mmHg; DBP: −7.48 mmHg, 95% −14.90 to −0.05 mmHg), and the vaginal ring was associated with reduced diastolic BP (−3.90 mmHg, 95%CI −6.67 to −1.13 mmHg). Compared to OC use, the injectable contraceptive use was associated with increased diastolic BP (2.38 mmHg, 95%CI 0.39 to 4.38 mmHg). NOHC use is associated with changes in BP which differ by type and route of administration. Given the strong association between incremental increases in BP and cardiovascular risk, prospective studies are required.

show abstract

“…There are majorly three types of PR LBD ligands: agonists, antagonists and SPRMs. P4 and other progestins, though have different pharmacological profiles and effects (Sitruk-Ware, 2004; Sitruk-Ware et al, 2004), they generally activate the functional gene expressions, repress estrogen induced endometrial proliferation, and inhibit the endometrial mitogenic effects of estrogens (Vegeto et al, 1993; Kraus et al, 1995; Schindler et al, 2003). Another type of PR LBD ligands, the SPRMs, such as asoprisnil (DeManno et al, 2003), would in some case bring the partial agonism as observed in clinical trials and animal tests (Elger et al, 2000; Spitz, 2003; Chwalisz et al, 2005a,b).…”

Section: Introductionmentioning

confidence: 99%

Ligand Binding Induces Agonistic-Like Conformational Adaptations in Helix 12 of Progesterone Receptor Ligand Binding Domain

Zheng

Xia

2019

Front. Chem.

View full text Add to dashboard Cite

Progesterone receptor (PR) is a member of the nuclear receptor (NR) superfamily and plays a vital role in the female reproductive system. The malfunction of it would lead to several types of cancers. The understanding of conformational changes in its ligand binding domain (LBD) is valuable for both biological function studies and therapeutically intervenes. A key unsolved question is how the binding of a ligand (agonist, antagonist, or a selective modulator) induces conformational changes of PR LBD, especially its helix 12. We applied molecular dynamics (MD) simulations to explore the conformational adaptations of PR LBD with or without a ligand or the co-repressor peptides binding. From the simulations, both the agonist progesterone (P4) and the selective PR modulator (SPRM) asoprisnil induces agonistic-like helix 12 conformations (the “closed” states) in PR LBD and the complex of LBD-SPRM is less stable, comparing to the agonist-liganded PR LBD. The results, therefore, explain the partial agonism of the SPRM, which could induce weak agonistic effects in PR. We also found that co-repressor peptides could be stably associated with the LBD and stabilize the LBD in a “semi-open” state for helix 12. These findings would enhance our understanding of PR structural and functional relationships and would also be useful for future structure and knowledge-based drug discovery.

show abstract

Role of progestins with partial antiandrogenic effects

Cited by 9 publications

References 72 publications

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

The effect of non‐oral hormonal contraceptives on hypertension and blood pressure: A systematic review and meta‐analysis

Ligand Binding Induces Agonistic-Like Conformational Adaptations in Helix 12 of Progesterone Receptor Ligand Binding Domain

Contact Info

Product

Resources

About