Binding of oral contraceptive progestogens to serum proteins and cytoplasmic receptor

Juchem, M.; Pollow, K.

doi:10.1016/0002-9378(90)90559-p

Cited by 38 publications

(10 citation statements)

References 22 publications

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“…Synthetic progestins have a longer metabolic clearance rate than endogenous progesterone, with an elimination half-life of between 8 and 24 h [7], and even when plasma levels are negligible progestins still may be active in the brain [15], or may be metabolized into neuroactive steroids [34]. Also, progestins have a higher relative binding affinity for the progesterone receptor compared to endogenous progesterone [23]. The synthetic progestins therefore may continue to have a thermogenic effect, either directly or through their metabolites in women taking oral contraceptives even after 3 days of withdrawal.…”

Section: Discussionmentioning

confidence: 97%

Oral contraceptives alter sleep and raise body temperature in young women

Baker

Mitchell

Driver

2001

Pfl�gers Archiv European Journal of Physiology

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Female reproductive steroids, oestrogen and progesterone, not only affect reproductive function, but also thermoregulation and sleep. Chronic administration of synthetic steroids, as occurs in women taking oral contraceptives, may affect these regulatory systems differently from endogenous oestrogen and progesterone. We therefore investigated body temperature and sleep in ten young women taking oral contraceptives, in the active and placebo phases of the contraceptive pack, and compared them to a group of nine women with ovulatory cycles, in the mid-follicular and mid-luteal phases. Body temperature was raised throughout 24 h in the women taking oral contraceptives in the active phase, and in the naturally cycling women in the luteal phase, compared to the follicular phase. The women taking oral contraceptives in the placebo phase, however, continued to have raised body temperatures, similar to those in the active phase, indicating a prolonged action of synthetic reproductive steroids on body temperature. Sleep also was influenced by the endogenous and synthetic reproductive steroids, but independently of body temperature. The women taking oral contraceptives had more stage-2 non-rapid eye movement sleep in the active phase, both compared to their placebo phase and the naturally cycling women. The naturally cycling women, however, had more slow wave sleep in the luteal phase compared to the contraceptive group of women. Exogenous reproductive steroids therefore influence body temperature and sleep differently from endogenous progesterone and oestrogen.

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Section: Discussionmentioning

confidence: 97%

Oral contraceptives alter sleep and raise body temperature in young women

Baker

Mitchell

Driver

2001

Pfl�gers Archiv European Journal of Physiology

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“…It is well known that some synthetic steroids bind to and/or regulate the production of SHBG, thus affecting endogenous sex steroid bioavailability (53)(54)(55). For example, LNG competes for SHBG binding with an IC 50 value of 16 nM (Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Zhang

Olland

Zhu

et al. 2005

Journal of Biological Chemistry

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Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC 50 value of 0.1 nM, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy (ϳ60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC 50 value of 0.02 nM) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

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“…[23] Not only does SHBG have a strong affinity for progestogens, but it is also a hormone-sensitive protein whose plasma concentration can be increased by estrogens and decreased by androgens and some progestogens. Levonorgestrel was the only one of a number of progestogens tested to have an affinity for SHBG similar to that of these sex hormones.…”

Section: Binding Of Levonorgestrel In Bloodmentioning

confidence: 99%

Levonorgestrel

Fotherby

1995

Clinical Pharmacokinetics

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Published values for the serum concentrations and pharmacokinetic parameters of levonorgestrel after administration of various doses of levonorgestrel alone or with ethinylestradiol are reviewed. Most data apply to oral administration of the gestagen, with the smaller amount of data for other modes of administration, e.g. subcutaneous, intravaginal and intra-uterine administration, also included. There is a large variability among the different studies for both serum concentration and pharmacokinetic parameters and not all of this is due to the large interindividual variability demonstrated in all of the studies. The factors responsible for the inter- and intraindividual variability have not been discovered. Sex hormone binding globulin (SHBG) plays an important role in levonorgestrel pharmacokinetics since: (i) levonorgestrel binds strongly to this protein; and (ii) serum SHBG levels are influenced by a large number of different factors including the administration of levonorgestrel and ethinylestradiol. However, not all of the anomalies in the metabolism of levonorgestrel can be ascribed to its interaction with SHBG.

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Binding of oral contraceptive progestogens to serum proteins and cytoplasmic receptor

Cited by 38 publications

References 22 publications

Oral contraceptives alter sleep and raise body temperature in young women

Oral contraceptives alter sleep and raise body temperature in young women

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

Levonorgestrel

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