Return of ovulatory cyclicity following an intramuscular injection of medroxyprogesterone acetate (Provera)

Kirton, K. T.; Cornette, James C.

doi:10.1016/0010-7824(74)90130-9

Cited by 65 publications

(19 citation statements)

References 5 publications

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“…Additionally we used medium that was phenol red free, since this has weak estrogenic capacities [28]. Measuring viability of all cell lines, no effects were seen treating with concentrations up to 200 ng ml −1 , which is approximately 10 times higher than physiological plasma levels of progesterone or than levels of MPA that are achieved with contraceptive [29].…”

Section: Resultsmentioning

confidence: 99%

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Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

et al. 2011

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Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the ApcMin/+ mouse, a model for spontaneous intestinal polyposis. PRKO-ApcMin/+mice exhibited no change in polyp number, size or localization compared to ApcMin/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

“…Progesterone plasma concentration is maximally 90 nanomole l −1 (approximately 30 ng ml −1 ) in healthy females. MPA plasma concentrations, 5–20 days after injection of a standard contraceptive dose (consisting of an intramuscular injection of 150 mg MPA) ranges from 10 to 25 ng ml −1 [29].…”

Section: Methodsmentioning

confidence: 99%

Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

et al. 2011

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“…2A–B). While sustained release pellets produced mean MPA serum levels of 64.12 ng/ml (a concentration similar to the levels seen in the second trimester of human pregnancy), the 4 and 1 mg injections of DMPA produced mean serum concentration of 21.37 ng/ml and 10.14 ng/ml, respectively (levels that approximate the peak and maintenance serum concentrations of MPA in women using Depo-Provera® for prevention of undesired pregnancy) [26, 27]. To exclude the possibility that MPA-mediated inhibition of T cell expansion was mouse strain specific, WT female BALB/cJ mice were administered 4 mg DMPA 7 d prior to corneal infection, and such mice showed reduced TG T cell infiltrates comparable to those seen among pretreated ovx and intact B6 mice (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Although prior in vitro studies demonstrated that progesterone or MPA inhibited DC activation, this effect was shown at progesterone concentrations much higher than those achieved by pregnancy or Depo-Provera® injection for prevention of undesired pregnancy [69, 70]. As clinical studies indicate that steady state serum concentrations of MPA range between 0.7–10 ng/ml [26, 27, 71–73], further study is needed to learn if DC activation is impaired at these lower concentrations. In addition to the effects of MPA on virus-specific immunological memory, our study also provides novel elucidation of a mechanism by which progesterone may simultaneously promote tolerance and suppress nonspecific T cell activation in mucosal tissue.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Activation and Memory Cell Development Are Impaired among Mice Administered Medroxyprogesterone Acetate Prior to Mucosal Herpes Simplex Virus Type 1 Infection

Miguel

Hendricks

Aguirre

et al. 2012

The Journal of Immunology

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Epidemiological studies indicate that the exogenous sex steroid medroxyprogesterone acetate (MPA) can impair cell-mediated immunity, but mechanisms responsible for this observation are not well defined. Here, MPA administered to mice 1 week prior to herpes simplex virus type 1 (HSV-1) infection of their corneal mucosa impaired initial expansion of viral-specific effector and memory precursor T cells and reduced the number of viral-specific memory T cells found in latently infected mice. MPA treatment also dampened expression of the costimulatory molecules CD40, CD70, and CD80 by dendritic cells (DC) in lymph nodes draining acute infection, while co-culture of such DC with T cells from uninfected mice dramatically impaired ex vivo T cell proliferation compared to the use of DC from mice that did not receive MPA prior to HSV-1 infection. In addition, T cell expansion was comparable to that seen in untreated controls if MPA-treated mice were administered recombinant soluble CD154 (CD40 ligand) concomitant with their mucosal infection. On the other hand, the immunomodulatory effects of MPA were infection site-dependent, as MPA-treated mice exhibited normal expansion of virus-specific T cells when infection was systemic rather than mucosal. Taken together, our results reveal that the administration of MPA prior to viral infection of mucosal tissue impairs DC activation, virus-specific T cell expansion, and development of virus-specific immunological memory.

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“…The MPA serum concentrations of DMPA-users are reported to be in the range 2.5 to 65 nM a few days after injection and to plateau at about 2.6 nM for about three months thereafter [38], [48], [82], while serum concentrations for injectable NET-EN, in the range of 1.5–59 nM have been reported [83]. The concentration of endogenous P4 in serum of premenopausal women is low during the follicular phase (0.65 nM) but rises to about 80 nM during the luteal phase, and to about 600 nM during pregnancy [37].…”

Section: Discussionmentioning

confidence: 99%

The Injectable-Only Contraceptive Medroxyprogesterone Acetate, Unlike Norethisterone Acetate and Progesterone, Regulates Inflammatory Genes in Endocervical Cells via the Glucocorticoid Receptor

et al. 2014

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Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4–20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.

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Return of ovulatory cyclicity following an intramuscular injection of medroxyprogesterone acetate (Provera)

Cited by 65 publications

References 5 publications

Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

Intestinal Tumorigenesis Is Not Affected by Progesterone Signaling in Rodent Models

Dendritic Cell Activation and Memory Cell Development Are Impaired among Mice Administered Medroxyprogesterone Acetate Prior to Mucosal Herpes Simplex Virus Type 1 Infection

The Injectable-Only Contraceptive Medroxyprogesterone Acetate, Unlike Norethisterone Acetate and Progesterone, Regulates Inflammatory Genes in Endocervical Cells via the Glucocorticoid Receptor

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