The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells

Ghatge, Radhika P; Jacobsen, Britta M.; Schittone, Stephanie A.; Horwitz, Kathryn B.

doi:10.1186/bcr1340

Cited by 59 publications

(61 citation statements)

References 72 publications

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“…MPA has a longer half-life than progesterone and can be administrated orally (Ghatge et al, 2005). The oral bioavailability of MPA was low, which was estimated to be 5 to 15% (Fotherby, 1996).…”

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confidence: 99%

“…Researches from Women's Health Initiative Trial indicated that the addition of MPA to conjugated equine estrogens significantly increased the risk of breast cancer (Rossouw et al, 2002;Chlebowski et al, 2003) in HRT. Prescriptions for MPA declined dramatically (Hersh et al, 2004;Wood et al, 2007) thereafter, and the reasons for increased breast cancer risk were under intense investigation (Ghatge et al, 2005;Wood et al, 2007;Otto et al, 2008). A recent study suggested that MPA underwent metabolic activation to reactive species that were genotoxic (Siddique et al, 2006).…”

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confidence: 99%

“…In the Unite States, MPA is the most common HRT progestin in use (Ghatge et al, 2005;Singh, 2007;Otto et al, 2008) and one of the most popular oral conceptive among adolescent girls (Cromer et al, 2004). In large doses, MPA is used in adjuvant endocrine therapy to treat endometrial cancer and breast cancer (Ghatge et al, 2005). MPA was an immunosuppressant, and its potential to treat a number of inflammatory conditions was in clinical trial (Adis International Ltd., 2003).…”

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confidence: 99%

“…1), a synthetic progesterone analog, was used in conception and hormone replacement therapy (HRT) by millions of women worldwide (Ratchanon and Taneepanichskul, 2000). In the Unite States, MPA is the most common HRT progestin in use (Ghatge et al, 2005;Singh, 2007;Otto et al, 2008) and one of the most popular oral conceptive among adolescent girls (Cromer et al, 2004). In large doses, MPA is used in adjuvant endocrine therapy to treat endometrial cancer and breast cancer (Ghatge et al, 2005).…”

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confidence: 99%

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Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Liu¹,

Zhao²,

Wang³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Medroxyprogesterone acetate (MPA) is one of the most frequently prescribed progestins for conception, hormone replacement therapy, and adjuvant endocrine therapy. MPA has a low oral bioavailability because of extensive metabolism; however, its metabolism was poorly documented. This study was intended to profile the phase I metabolites of MPA and the cytochrome P450 (P450) isoforms involved. After MPA was incubated with human liver microsomes and the NADPH-generating system, five main metabolites

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Liu¹,

Zhao²,

Wang³

et al. 2008

Drug Metab Dispos

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“…1) is used extensively in conception and hormone replacement therapy. [1][2][3] However, due to its extensive metabolism, MPA usually has low bioavailability. Many side effects 4) are considered to be consequences of the generation of reactive metabolites from MPA.…”

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confidence: 99%

Structure Elucidation of Major Metabolites from Medroxyprogesterone Acetate by P450

Chen

Jiangwei

Yang

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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835Medroxyprogesterone acetate (17a-acetoxy-6a-methylpregn-4-ene-3,20-dione; MPA, Fig. 1) is used extensively in conception and hormone replacement therapy.1-3) However, due to its extensive metabolism, MPA usually has low bioavailability. Many side effects 4) are considered to be consequences of the generation of reactive metabolites from MPA.5) Although extensive research has been done on the metabolic pathways of MPA, our current understandings of MPA metabolism are still very limited. 6,7)We recently reported metabolism studies of MPA in human liver microsomes (HLMs), in minipig liver microsomes (PLMs) and in rat liver microsomes.8) The aims of these studies were to identify the enzymes responsible for MPA metabolism and to compare potential species differences.8) We obtained and purified three major mono-hydroxy MPA metabolites (namely M-2, M-3, M-4). However, due to the very small sample amount and instrument limitations, their structures were only speculated as 6b-, 1b-, and 2b-hydroxy MPA. Since structures of these metabolites are critical in understanding biological transformation of MPA by P450, it is vital to know their structures unambiguously. In addition, definitive structural information will enable these metabolites to serve as standard compounds or as basis for structure elucidation of further metabolites, without having to chemically synthesize authentic compounds which may be very difficult. Here we report the rigorous structural elucidation for these three metabolites using extensive NMR techniques and molecular modeling. These studies confirmed the previous structural assignments, and provided complete NMR chemical shift information for all the metabolites that may serve as reference standards for further studies of MPA metabolism by P450 enzymes. ExperimentalGeneration and Purification of the Three Major Mono-hydroxy Metabolites All chemicals were purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Preparation and characterization of liver microsomes, generation and HPLC purification of the three major mono-hydroxy metabolites from MPA (M-2, M-3, M-4) were described in details in our previous report. 8) Briefly, MPA (200 mM) was incubated with PLMs (1.0 mg/ml) and NADPH-generating system (1 mM NADP ϩ , 10 mM glucose-6-phosphate, 1 unit/ml of glucose-6-phosphate dehydrogenase, and 4 mM MgCl 2 ) for 60 min at 37°C. PLMs was selected because it resembled HLMs in MPA metabolism and because it's cheaper than HLMs.8) The incubation system was scaled up to 500 ml to generate adequate metabolites. Approximately 5%, 3%, and 5% of MPA was converted to M-2, M-3, and M-4, respectively under these conditions. After protein precipitation by methanol, the reaction mixture was centrifuged at 9000ϫg for 10 min. The supernatant was extracted with ethyl acetate and the organic layer was dried in vacuo. The residue was re-dissolved in ethyl acetate and separated by preparative TLC (Silica gel, 20ϫ20 cm, 2 mm, Merck), which was developed by chloroform-acetone (9 : 1, v/v). 9) MPA and its metabolites were moni...

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Sex and age influence gonadal steroid hormone receptor distributions relative to estrogen receptor β‐containing neurons in the mouse hypothalamic paraventricular nucleus

Contoreggi

Mazid

Goldstein

et al. 2021

J of Comparative Neurology

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Within the hypothalamic paraventricular nucleus (PVN), estrogen receptor (ER) β and other gonadal hormone receptors play a role in central cardiovascular processes. However, the influence of sex and age on the cellular and subcellular relationships of ERβ with ERα, G‐protein ER (GPER1), as well as progestin and androgen receptors (PR and AR) in the PVN is uncertain. In young (2‐ to 3‐month‐old) females and males, ERβ‐enhanced green fluorescent protein (EGFP) containing neurons were approximately four times greater than ERα‐labeled and PR‐labeled nuclei in the PVN. In subdivisions of the PVN, young females, compared to males, had: (1) more ERβ‐EGFP neurons in neuroendocrine rostral regions; (2) fewer ERα‐labeled nuclei in neuroendocrine and autonomic projecting medial subregions; and (3) more ERα‐labeled nuclei in an autonomic projecting caudal region. In contrast, young males, compared to females, had approximately 20 times more AR‐labeled nuclei, which often colocalized with ERβ‐EGFP in neuroendocrine (approximately 70%) and autonomic (approximately 50%) projecting subregions. Ultrastructurally, in soma and dendrites, PVN ERβ‐EGFP colocalized primarily with extranuclear AR (approximately 85% soma) and GPER1 (approximately 70% soma). Aged (12‐ to 24‐month‐old) males had more ERβ‐EGFP neurons in a rostral neuroendocrine subregion compared to aged females and females with accelerated ovarian failure (AOF) and in a caudal autonomic subregion compared to post‐AOF females. Late‐aged (18‐ to 24‐month‐old) females compared to early‐aged (12‐ to 14‐month‐old) females and AOF females had fewer AR‐labeled nuclei in neuroendrocrine and autonomic projecting subregions. These findings indicate that gonadal steroids may directly and indirectly influence PVN neurons via nuclear and extranuclear gonadal hormone receptors in a sex‐specific manner.

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The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells

Cited by 59 publications

References 72 publications

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Structure Elucidation of Major Metabolites from Medroxyprogesterone Acetate by P450

Sex and age influence gonadal steroid hormone receptor distributions relative to estrogen receptor β‐containing neurons in the mouse hypothalamic paraventricular nucleus

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