Biomedical subjects

Esther Eisenberg

Publications and source records attributed to Esther Eisenberg.

8 recordsLinked to original sources

PubMed2006

Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget.

CONTEXT: Endometriosis, the growth of endometrial tissue outside the uterus, is principally an estrogen-dependent disease. In contrast, exposure to progesterone during pregnancy or therapeutically has been shown to provide benefit to some women with this disease. However, recent research suggests that the presence of endometriosis impairs the capacity of the eutopic endometrium to respond to endogenous progesterone. OBJECTIVE: Reduced progesterone responsiveness results in an elevated endometrial expression of matrix metalloproteinases (MMPs) during the secretory phase of the menstrual cycle in women with endometriosis. Although cyclic MMP expression is critical for endometrial growth and remodeling, the failure of progesterone to down-regulate MMPs may impair nidation and promote the invasive establishment of endometriosis. In the current study we examined the ability of a newly developed progesterone receptor (PR) agonist, tanaproget (TNPR), to down-regulate endometrial MMP expression in vitro and regress experimental endometriosis in vivo. SETTING: This study was performed at a university-based medical center. PARTICIPANTS: Asymptomatic volunteers and patients with endometriosis were studied. MAIN OUTCOME MEASURES: We examined the ability of TNPR to down-regulate endometrial MMP expression in vitro compared with that of natural progesterone and two currently marketed synthetic steroidal progestins. Using a human/mouse model of endometriosis, we also tested the in vivo ability of TNPR to regress ectopic lesions established by tissues with reduced progesterone sensitivity. RESULTS: TNPR effectively down-regulated MMP expression in vitro and induced significant reduction of lesions in mice with disease established by tissues from endometriosis patients. CONCLUSION: Given the positive preclinical pharmacological profile of TNPR that has recently been reported, additional development of this compound for the treatment of endometriosis is warranted.

Adolescent↗

PubMed2005

Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis.

OBJECTIVE: To discuss the role that reduced endometrial responsiveness to progesterone (P) might play in the pathophysiology of endometriosis. DESIGN: A review of experimental evidence regarding the failure of P to regulate the expression of matrix metalloproteinases (MMPs) in the endometrium of patients with endometriosis. CONCLUSION(S): Progesterone and locally produced differentiation factors act cooperatively to reduce MMP expression by maternal endometrial cells within the pro-inflammatory micro-environment of early pregnancy. Our in vitro studies with normal human endometrium demonstrate that prior P exposure not only down-regulates MMP expression, but also limits the ability of locally produced proinflammatory cytokines to stimulate expression of these enzymes. In contrast, endometrial tissues from women with endometriosis demonstrate an altered response to P, allowing a continuous expression of MMPs throughout the secretory phase. Although the factors that influence the loss of P sensitivity in the endometrium of patients with endometriosis have not yet been defined, alterations in cell-cell communication seem to contribute to dysregulated MMP expression. Specifically, proinflammatory cytokines produced by epithelial cells oppose stromal cell responses to P, inhibiting production of key differentiation factors necessary for cell-specific MMP regulation. The resulting loss in normal MMP regulation enhances the invasive capacity of endometrial tissue, promoting ectopic establishment in an experimental model.

Endometriosis↗

PubMed2005

Reduced expression of progesterone receptor-B in the endometrium of women with endometriosis and in cocultures of endometrial cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

OBJECTIVE: To analyze endometrial progesterone receptor (PR) expression in women with endometriosis compared with disease-free women and to assess the impact of in vitro 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on PR isotype expression. DESIGN: Controlled laboratory study. SETTING: University medical center. PATIENT(S): Healthy volunteers and women with surgically diagnosed endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Analysis of in vivo PR-A and PR-B expression in endometrium from women with and without endometriosis. The impact of in vitro TCDD exposure on PR-B/PR-A ratio and cell-specific matrix metalloproteinase (MMP) expression was also determined. RESULT(S): The PR-B/PR-A ratio was lower in endometrial tissues from women with endometriosis compared with normal tissues. A similar ratio was induced in normal stromal cells cocultured with epithelial cells and exposed to TCDD. Disruption of stromal PR expression following TCDD exposure was associated with a failure of P-mediated down-regulation of both stromal-specific pro-MMP-3 and epithelial-specific pro-MMP-7. CONCLUSION(S): Our data suggest that reduced progesterone (P) sensitivity in the endometrium of women with endometriosis may be related to an altered pattern of PR expression. The ability of TCDD to selectively down-regulate stromal PR-B expression and increase MMP expression in both stromal and epithelial cells suggests that exposure to this toxin may negatively impact P-mediated cell-cell communication in the human endometrium.

Adult↗

PubMed2005

Endometrial biology and the etiology of endometriosis.

Two recent studies reported in this issue of Fertility and Sterility have explored important issues regarding the understanding and diagnosing of endometriosis. These studies emphasize the complexity of endometriosis and underscore the different roles of clinicians and translational scientists in exploring this disease.

Endometriosis↗

PubMed2005

Beyond screening: identifying new barriers to early onset group B streptococcal disease prevention.

BACKGROUND: Group B streptococcal infections remain an important cause of morbidity and mortality in newborns. METHODS: Neonatal group B streptococcal cases were identified by active surveillance in 4 urban Tennessee counties. Medical records of mothers of cases and a sample of other pregnant women with live births from the same population were reviewed to determine whether the screening or risk-based approach was used for prevention of early onset group B streptococcal disease and to assess other factors affecting preventability of cases. RESULTS: During 1998 and 1999, 43% of women underwent prenatal group B streptococcal screening. County of residence was the only factor independently associated with not being screened [odds ratio, 7.85; 95% confidence interval (4.69, 13.16)]. Ten affected babies were born to screened mothers (0.40 per 1000). In 9 of these 10, problems were identified: mothers had positive screening cultures but did not receive optimal intrapartum antibiotics (n = 3 of 4); mothers had negative screening cultures (n = 4); and mothers were screened, but the results were unknown, and intrapartum antibiotics were not given (n = 2). CONCLUSIONS: Challenges to implementation of group B streptococcal screening and prophylaxis include insufficient screening, suboptimal intrapartum antibiotics, disease despite negative screening cultures and timely communication of screening results at delivery. An awareness of such problems may lead to supplemental measures to further reduce group B streptococcal disease.

Adult↗

PubMed2002

Progesterone-mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatory-like environment: a regulatory system altered in endometriosis.

The human endometrium exhibits regular cycles of growth, differentiation, and breakdown in response to changing levels of ovarian steroids. Following the tissue loss and repair processes of menstruation, rising levels of estradiol initiate a development-like process leading to a complete restructuring of the endometrial surface. In contrast, while under the predominate influence of progesterone, proliferation declines as cell-specific differentiation prepares the endometrium for pregnancy over a 5- to 6-day period. In the absence of nidation, steroid support is lost; the endometrial surface begins a complex process of tissue breakdown and bleeding, producing a viscous mixture of cellular debris within a bloody menstrual effluent. Although most of the menstrual fluid exits the body, reflux of some material occurs in most women, providing a poorly understood opportunity for ectopic endometrial growth and establishment of the disease endometriosis. The cyclic restructuring of the endometrium requires numerous matrix metalloproteinases (MMPs) that mediate normal and pathological tissue turnover throughout the reproductive tract. The expression of multiple MMPs facilitates degradation of extracellular matrix during growth-related remodeling as well as tissue breakdown at the time of menstruation. However, these enzymes are absent during the early and mid-secretory phase and the suppression of endometrial MMPs remains important to maintaining the integrity of the endometrium during the highly invasive events required to establish a normal hemochorial placenta. Several research groups have suggested that steroid-mediated expression and action of MMPs during the menstrual cycle may provide a key mechanistic link between endometrial turnover and the invasive processes necessary for establishment of endometriosis.

Endometriosis↗

PubMed2002

Paracrine mediators of endometrial matrix metalloproteinase expression: potential targets for progestin-based treatment of endometriosis.

The endometrial lining of the human uterus is a highly specialized, steroid-sensitive tissue. Throughout the reproductive years, the endometrium undergoes dramatic cycles of growth, differentiation, and breakdown under the influence of ovarian steroids. In response to changes in steroid exposure throughout the menstrual cycle, the endometrium produces an array of bioactive growth factors and other cytokines that are critical components of paracrine communication. For example, cell-cell communication via paracrine factors directs the expression of matrix metalloproteinases (MMPs), enzymes that mediate tissue remodeling during the menstrual cycle. The disease endometriosis is thought to occur as a consequence of retrograde menstruation, and MMPs appear to contribute to the establishment and progression of ectopic endometrial growth in the peritoneal cavity. Although the risk for developing endometriosis is linked to a woman's steroid exposure, locally produced paracrine factors can modify steroid action on multiple gene targets, including the MMPs. Estrogen-associated growth factors as well as inflammatory cytokines are potent stimulators of MMP expression and may contribute to the ability of endometrial fragments to invade the peritoneal surface and establish ectopic sites of growth. In contrast, paracrine factors associated with progesterone action during early pregnancy inhibit MMP expression and prevent ectopic endometrial growth in an experimental model. For example, locally produced retinoic acid and transforming growth factor-beta (TGF-beta) act in concert with progesterone to suppress MMPs, while enhancing expression of MMP inhibitors (TIMPs) during endometrial differentiation. Targeting pregnancy-associated factors that inhibit endometrial-specific MMP expression and action may enhance the effectiveness of progestin-related treatments for endometriosis.

Endometriosis↗

PubMed2002

Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.

The cyclic expression of matrix metalloproteinases (MMPs) by human endometrium has been suggested to play a role in the invasive process necessary to establish endometriosis. The ability of progesterone exposure to inhibit endometrial MMP-3 and MMP-7 expression requires the local action of TGF beta and may also be linked to the local production of retinoic acid by stromal cells. A continuous expression of several MMPs in endometriotic lesions has been reported, indicating a failure of progesterone or locally produced factors to suppress these enzymes. To address cell-specific MMP regulation associated with endometriosis, we examined expression of MMP-3 and MMP-7 mRNA in eutopic endometrium and endometriotic lesions acquired during the secretory phase of the menstrual cycle. We examined the in vitro regulation of MMP-3 and MMP-7 protein in similar tissues. We also examined the in vitro regulation of MMP secretion by progesterone, retinoic acid, and TGF beta in endometriosis tissues relative to the establishment of experimental disease. Our studies indicate that either eutopic or ectopic tissue from women with endometriosis exhibit patterns of altered MMP regulation in vivo. A lack of responsiveness to progesterone was demonstrated in vitro, associated with a failure to suppress MMP expression and an enhanced ability of the tissue to establish experimental endometriosis. However, in vitro treatments with retinoic acid and TGF beta restored the ability of progesterone to suppress MMPs in vitro and prevented the establishment of experimental disease.

Adolescent↗