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Biomedical subjects

Laura T Goldsmith

Publications and source records attributed to Laura T Goldsmith.

9 recordsLinked to original sources
PubMed2005

Cloning and characterization of a 5' regulatory region of the prolactin receptor-associated protein/17{beta} hydroxysteroid dehydrogenase 7 gene.

Prolactin receptor-associated protein (PRAP) originally cloned in our laboratory was shown to be a novel, luteal isoform of 17beta hydroxysteroid dehydrogenase 7 (17betaHSD7). In this study, we cloned the promoter region of rat PRAP/17betaHSD7 and investigated the mechanisms regulating both basal activity and LH-induced repression of this promoter. Truncated and site-specific mutants of PRAP/17betaHSD7 promoter identified two enhancer regions that contained highly conserved Sp1 binding site and bound Sp1 from nuclear extracts of both corpora lutea and a rat luteal cell line. Repression of PRAP/17betaHSD7 expression and promoter activity by human chorionic gonadotropin/forskolin was localized to a -52-bp proximal segment of the promoter. This region contained a conserved CCAAT site and bound nuclear factor Y; binding of this transcription factor was inhibited by human chorionic gonadotropin in vivo. Furthermore, mutation of the nuclear factor Y site in the -52-bp promoter-reporter construct abolished forskolin-mediated inhibition of the promoter in a rat luteal cell line. In summary, we have identified the promoter elements involved in the basal expression of PRAP/17betaHSD7. We have also found that LH-mediated repression of this gene is at the level of transcription and involves inhibition of nuclear factor YA binding to the CCAAT site within the proximal promoter.

5' Untranslated Regions↗
PubMed2005

Relaxin regulates endometrial structure and function in the rhesus monkey.

The actions of relaxin are highly species specific. The role of relaxin in human endometrial function has not been well understood because of the paucity of in vivo studies in women or in suitable primate models. A model of early human pregnancy was established in ovariectomized, steroid-primed rhesus monkeys. Relaxin exerts dramatic uterine effects in this model, including a pronounced increase in uterine weight and stimulation of endometrial angiogenesis. In addition, relaxin negatively regulates expression of endometrial matrix metalloproteinases (MMP), causing decreased endometrial levels of MMP-1 and MMP-3 proteins and increased protein levels of their endogenous inhibitor, tissue inhibitor of metalloproteinase 1. This results in maintenance of endometrial collagen content. The negative effects of relaxin on MMP expression in the endometrium are in distinct contrast to the positive regulation of MMPs previously shown in fibroblasts from other tissues including the cervix. Relaxin also significantly inhibits endometrial levels of estrogen receptor alpha and significantly inhibits levels of progesterone isoforms B and A. The findings that relaxin stimulates new blood vessel formation while maintaining endometrial connective tissue integrity are consistent with a significant role of relaxin in the establishment and/or maintenance of early pregnancy.

Animals↗
PubMed2005

Mechanisms of relaxin-mediated premature birth.

In women, circulating relaxin is produced by the corpus luteum of pregnancy. The levels of relaxin are predominantly determined by the luteal mass, the number of corpora lutea present. Relaxin levels are highest after ovulation induction, which stimulates formation of many corpora lutea. Elevated relaxin levels in the first trimester of pregnancy are maintained throughout pregnancy and are linearly related to preterm birth. In an in vitro model of late human pregnancy cervix, relaxin increases MMP-1 and MMP-3 and decreases TIMP-1 levels, thus acting as a positive regulator of matrix metalloproteinases. In an in vivo rhesus monkey model of early pregnancy, relaxin decreases cervical collagen content, decreases cervical lumican levels, and stimulates MMP-7 levels. Early effects of relaxin in the uterus include increasing endometrial arteriole number and increasing the number of leukocytes, uterine natural killer cells, macrophages, and neutrophils. These cells release many cytokines which contribute to changes that stimulate and facilitate uterine contractility. If these changes persist in late pregnancy, relaxin may be a mediator of labor. Excess relaxin may produce these changes at an accelerated rate, causing preterm birth.

Animals↗
PubMed2004

Menopause and hypothalamic-pituitary sensitivity to estrogen.

CONTEXT: The onset of human menopause is thought to be caused solely by ovarian failure and oocyte depletion. However, clinical symptoms and certain recent data in perimenopausal women suggest central nervous system involvement. OBJECTIVE: To determine if modifications of hypothalamic-pituitary response to estrogen feedback mechanisms occur in older reproductive-age women as a mechanism of the onset of menopause. DESIGN, SETTING, AND PARTICIPANTS: The Study of Women's Health Across the Nation (SWAN) is a multiethnic observational cohort study of the menopausal transition in 3302 women at 7 US sites. Of the subcohort of 840 women who participated in the Daily Hormone Study between 1997 and 1999, 680 women had evidence of luteal activity. The remaining 160 women (19%) did not have luteal activity and are the subject of this report. MAIN OUTCOME MEASURES: Daily urinary hormone levels of estrogen and progesterone metabolites, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). RESULTS: Three groups of women were studied: those with estrogen increases with an LH surge, those with estrogen increases without an LH surge, and those with neither. There were no differences in age or ethnicity among the 3 groups of women. Women in the third group (no increases) experienced more menopausal symptoms (hot flashes) than did women in the other groups with estrogen increases. In older reproductive-age women, the frequent existence of anovulatory cycles with estrogen peaks, equivalent to those that result in LH surges in younger women, yet in which no LH surges occur, indicates failure of estrogen-positive feedback on LH secretion. In other anovulatory cycles, follicular-phase estrogen levels did not lower LH secretion as occurs in cycles of younger women, indicating decreased estrogen-negative feedback on LH secretion. CONCLUSION: Our findings are compatible with hypothalamic-pituitary insensitivity to estrogen in aging perimenopausal women.

Estrogens↗
PubMed2004

Relaxin regulation of endometrial structure and function in the rhesus monkey.

Despite the documented importance of the protein hormone relaxin in reproduction in various mammalian species, the role of relaxin in human reproduction is poorly understood, largely because of the lack of studies in women or in suitable non-human primate models. Here we describe the establishment of a non-human primate model of early human pregnancy and its use in defining the actions of relaxin. Results demonstrate that relaxin exerts dramatic uterine effects including pronounced increase in uterine weight and stimulation of endometrial angiogenesis and resident endometrial lymphocyte number. In addition, relaxin decreases endometrial levels of matrix metalloproteinases 1 and 3 and increases levels of their endogenous inhibitor, tissue inhibitor of metalloproteinase 1, resulting in maintenance of endometrial collagen content. Relaxin significantly inhibits endometrial levels of estrogen receptor alpha, but not beta, and of progesterone receptor isoforms A and B. The findings that relaxin stimulates new blood vessel formation and increases cytokine-containing lymphocyte number while maintaining endometrial connective tissue integrity are consistent with a significant role of relaxin in the establishment and/or maintenance of early pregnancy.

Animals↗
PubMed2004

Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis.

OBJECTIVE: To perform a systematic review of the literature to determine whether singleton pregnancies resulting from IVF-ET/GIFT are at higher risk for preterm birth (<37 weeks). DESIGN: Literature search and systematic review. SETTING: Medical school. INTERVENTION(S): A MEDLINE search (1965-2000) was performed using the terms "premature labor," "infertility," "pregnancy complications," "gonadotropins," "pregnancy outcome," "preterm delivery," and "in vitro fertilization." Criteria for inclusion were English language, original research article, study patients conceived using IVF-ET (with or without intracytoplasmic sperm injection) or GIFT, pregnancy outcome reported compared with a control group (e.g., naturally conceived singletons at their hospital or a national reference), and prematurity clearly defined. Incomplete articles (e.g., abstracts), reports of other studies, and studies that failed to separate multiple from singleton gestations were excluded. MAIN OUTCOME MEASURE(S): Summary of relative risks of preterm birth. RESULT(S): Twenty-seven articles met all inclusion/exclusion criteria and were analyzed by meta-analysis. The random-effects summary relative risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT was 1.98 (95% confidence interval, 1.77-2.22). CONCLUSION(S): The risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT is twice that of natural conceived pregnancies.

Confidence Intervals↗
PubMed2002

Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells.

Extensive evidence demonstrates pronounced effects of relaxin on the differentiation of human endometrial cells in vitro. In vivo data in rhesus monkeys suggest a role for relaxin in the development of endometrial vascular architecture. In women, pregnancy can be established and maintained in the absence of circulating relaxin. Thus, local synthesis by the endometrium is necessary if relaxin plays a physiological role in human endometrial function. Although relaxin protein and the prorelaxin C peptide have been localized to human endometrium, no data for relaxin synthesis have been provided to date. We therefore assessed relaxin mRNA and protein levels in cultured, defined human endometrial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to demonstrate the presence of relaxin mRNA in human stromal and glandular epithelial cells. Secretion of the protein into the media of cultured cells of both types was also detected. Relaxin stimulated the expression of vascular endothelial growth factor in glandular epithelial and stromal cells that were isolated from tissue that had been taken during the secretory phase of the cycle. Relaxin inhibited the expression of procollagenase from both glandular epithelial cells, with a more marked inhibition demonstrated from cells that were isolated from tissue that had been taken during the secretory phase, and from stromal cells. These data demonstrate that human endometrial cells synthesize relaxin, and they support the concept that relaxin fosters endometrial conditions that are required for implantation in women.

Cells, Cultured↗
PubMed2002

Age-related changes in the regulation of luteinizing hormone secretion by estrogen in women.

Despite the many studies that have been conducted using both primate and human models to understand the control of the menstrual cycle, there are many aspects of the hormonal dynamics of the menstrual cycle that are not understood. This Minireview summarizes the changes in estrogen regulation of luteinizing hormone (LH) secretion that occur throughout life in women from the time of maturation of the hypothalamic-pituitary axis resulting in the occurrence of the LH surge during puberty, through the reproductive years, to the changes in the regulation of the LH surge during premenopause and, subsequently, menopause.

Aging↗