leptin and Uterine-Neoplasms

Leptin is a protein hormone synthesized and secreted by adipose tissue and also probably in other organs and systems in human body. It has multiple functions such as to regulate feed intake and energy balance, gonadal regulation, action in the hypothalamo-pituitary-gonadal axis, regulates the metabolism of the fetal-placental unit in the pregnancy, fertility and reproductive systems, actions in the endometrium, mammary gland with corresponding influences on important physiologic processes such as menstruation, pregnancy and lactation. In the gynecologic surgery the serum leptin concentration is also modified. The knowledge of serum leptin concentration in the oncological diseases is going-up. Leptin is modified in the choriocarcinoma, Meigs' syndrome and other tumors. A better understanding of regulatory mechanisms will have direct clinical significance, as leptin has been proposed to impact on those causes of human perinatal morbidity and mortality that are associated with abnormalities of fetal maturity and development, general concept growth, trophoblast endocrinology, and placental sufficiency. Further investigations in this area will be necessary to improve new knowledge and a better understanding of the actions about this hormone.

Topics: Energy Metabolism; Female; Fertility; Fetal Diseases; Fetal Organ Maturity; Genital Diseases, Female; Humans; Hydatidiform Mole; Hypothalamo-Hypophyseal System; Leptin; Meigs Syndrome; Placenta; Polycystic Ovary Syndrome; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Receptors, Leptin; Reproduction; Uterine Neoplasms

To test if treatment with GnRH analogue, which leads to a significant reduction in myoma volume, changes expression of leptin genes and gene coding leptin receptor isoforms in uterine myomas and in the surrounding unaltered myometrium.. Using RT-PCR, expression of leptin genes and leptin receptor genes was studied in myomas and in the surrounding myometrium in women with uterine myomas, untreated or treated with GnRH analogue. In the randomly selected cases presence of leptin protein and of leptin receptor proteins was examined also by Western blotting.. Expression of leptin genes was demonstrated both in myomas and in the surrounding myometrium, and a similar pattern of expression was found for leptin receptor isoforms. The results of RT-PCR were confirmed by Western blotting, which documented the identical distribution of leptin proteins and leptin receptor proteins in studied tissues. Treatment with GnRH analogue had no effect on the expression pattern of studied genes.. The results of the present study on the administration of GnRH analogue to females with myomas suggest that no direct or immediate inter-relationship exists between expression of leptin genes in uterine myomas on one hand and estrogen, progesterone and leptin levels in the blood on the other. Expression seems to be of a more durable nature but factors that induce such expression remain unknown.

Topics: Adult; Blotting, Western; Case-Control Studies; DNA Primers; Female; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Leptin; Middle Aged; Myoma; Myometrium; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uterine Neoplasms

The purpose of the present study was to investigate changes in serum leptin levels during GnRH agonist therapy. Twenty regularly menstruating women with uterine leiomyomas were enrolled. These subjects were given GnRH agonist (leuprorelin acetate, 3.75 mg) monthly for 4 months. Serum leptin and estradiol (E2) levels were measured at the two time points of day 1 or 2 of the menstrual cycle and the end of GnRH agonist therapy. Weight, total body fat mass, percentage of body fat, and total body lean mass were measured by whole body scanning with dual-energy X-ray absorptiometry. The ratio of serum leptin levels to total body fat mass (leptin-fat mass ratio), and the ratio of serum leptin levels to total body lean mass (leptin-lean mass ratio) were calculated. All subjects became amenorrheic after the initial administration of GnRH agonist. Baseline E2 levels were 45.4 +/- 21.0 pg/mL, which significantly decreased after GnRH agonist therapy (13.3 +/- 4.2 pg/mL, p<0.01). Baseline leptin levels were 8.7 +/- 8.1 ng/mL, which did not differ from the values after 4 months of GnRH agonist administration (8.9 +/- 6.8 ng/mL). Total body fat mass significantly increased from 20.0 +/- 10.4 to 21.0 +/- 9.4 kg (p<0.05), while total body lean mass significantly decreased (34.5 +/- 4.2 kg to 33.3 +/- 3.9 kg, p<0.01). However, leptin-fat mass ratio after GnRH agonist therapy did not differ from the baseline values (0.39 +/- 0.16 ng/mL/kg vs 0.38 +/- 0.16 ng/mL/kg). Hypogonadism does not have a major impact on circulating leptin levels.

Topics: Adult; Antineoplastic Agents, Hormonal; Body Composition; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Leptin; Leuprolide; Longitudinal Studies; Middle Aged; Uterine Neoplasms

Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.

Topics: Adipocytes; Adipokines; Female; Humans; Leiomyoma; Leptin; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta3; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Uterine Neoplasms; Vascular Endothelial Growth Factor A

Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17β-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription.

Topics: Cell Nucleus; Choriocarcinoma; Estrogens; Female; Humans; Leptin; NF-kappa B; Phosphorylation; Placenta; Pregnancy; Receptors, Estrogen; Uterine Neoplasms

The aim of this study was to analyse the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) -2548 G/A (rs12112075) of leptin gene (LEP) and an attempt to evaluate the effect this DNA marker has on endometrial cancer (EC) and uterine leiomyomas (UL).. The study comprised 120 patients treated for endometrial cancer and 90 patients treated for uterine leiomyomas. 90 disease-free individuals were used as controls. In total, 300 patients were investigated in this research.. In this paper we have demonstrated that genotype AG of SNP -2548 G/A of LEP may reduce the risk of developing endometrial cancer, whereas allele A itself may be a risk factor of this malignancy. No association was found between the studied polymorphism and uterine leiomyomas.. -2548 G/A SNP of LEP may play a significant role in the development of EC, however, uterine leiomyomas are not associated with this DNA marker.

Topics: Alleles; Body Mass Index; Case-Control Studies; Endometrial Neoplasms; Female; Genetic Markers; Genotype; Humans; Leiomyoma; Leptin; Middle Aged; Obesity; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk Factors; Uterine Neoplasms

Topics: Adolescent; Adult; Aging; Benzhydryl Compounds; Breast Neoplasms; Child; Disease Susceptibility; Female; Flame Retardants; Humans; Kisspeptins; Leptin; Male; Menarche; Obesity; Phenols; Puberty; Time Factors; Uterine Neoplasms

This study was aimed to understand expressions of the visfatin, leptin, stromal cell derived factor (SDF)-1α, endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) in human uterine leiomyomas (UL) and normal myometrium.. This study investigated expression of visfatin, leptin, SDF-1α, eNOS and VEGF in 23 uterine leiomyoma patients and 10 normal myometrium by RT-PCR and western blot. Messenger RNA transcripts of SDF-1α, eNOS, VEGF and hypoxia inducible factor-1α (HIF-1α) were analyzed according to the size of UL by real-time PCR.. There were no significant differences in expressions of visfatin and leptin between UL compared with normal myometrium. However, expressions of eNOS, SDF-1α and VEGF were significantly higher in both intramural and subserosal UL compared with normal myometrium. The expression of SDF1-α was significantly increased in small UL (<5 cm) compared to the large UL (≥5 cm), whereas the expressions of eNOS, VEGF and HIF-1α were higher in large UL than small UL.. This study shows that expression of SDF-1α, eNOS and VEGF were significantly higher in UL than myometrium with a different expression pattern according to the size of UL. However, expressions of visfatin and leptin had no significant differences between the two groups.

Topics: Adult; Chemokine CXCL12; Female; Humans; Leiomyoma; Leptin; Middle Aged; Myometrium; Nicotinamide Phosphoribosyltransferase; Nitric Oxide Synthase Type III; Uterine Neoplasms; Vascular Endothelial Growth Factor A

Increasingly, placental DNA methylation is assessed as a factor in pregnancy-related complications, yet the transcriptional impact of such findings is not always clear. Using a proliferative in vitro placental model, the effect of DNA methylation loss on gene activation was evaluated at a number of genes selected for being differentially methylated in pre-eclampsia-associated placentae in vivo. We aimed to determine whether reduced DNA methylation at specific loci was associated with transcriptional changes at the corresponding gene, thus providing mechanistic underpinnings for previous clinical findings and to assess the degree of transcriptional response amongst our candidate genes. BeWo and JEG3 choriocarcinoma cells were exposed to 1 μM 5-Aza-2'-deoxycytidine (5-Aza-CdR) or vehicle control for 48 h, and re-plated and cultured for a further 72 h in normal media before cells were harvested for RNA and DNA. Bisulphite pyrosequencing confirmed that DNA methylation was reduced by ∼30-50% points at the selected loci studied in both cell lines. Gene activation, measured by qRT-PCR, was highly variable and transcript specific, indicating differential sensitivity to DNA methylation. Most notably, loss of DNA methylation at the leptin (LEP) promoter corresponded to a 200-fold and 40-fold increase in LEP expression in BeWo and JEG3 cells, respectively (P < 0.01). Transcripts of steroidogenic pathway enzymes CYP11A1 and HSD3B1 were up-regulated ∼40-fold in response to 5-Aza-CdR exposure in BeWo cells (P < 0.01). Other transcripts, including aromatase (CYP19), HSD11B2, inhibin (INHBA) and glucocorticoid receptor (NR3C1) were more moderately, although significantly, affected by loss of associated DNA methylation. These data present a mixed effect of DNA methylation changes at selected loci supporting cautionary interpretation of DNA methylation results in the absence of functional data.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Aromatase; Azacitidine; Cell Line, Tumor; Choriocarcinoma; CpG Islands; Decitabine; DNA Methylation; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Placenta; Pregnancy; Promoter Regions, Genetic; Receptors, Glucocorticoid; TEA Domain Transcription Factors; Transcription Factors; Uterine Neoplasms

Leptin and its receptor (Ob-R) are co-expressed in human placenta suggesting auto- and paracrine mechanisms of the hormone. So far it is unclear, how changes in the placental environment affect Ob-R expression. Hence, the main purpose of the study was to investigate leptin receptor expression and regulation under hypoxic conditions. The influences of hypoxia and leptin on signal transduction and cell proliferation in chorioncarcinoma cell lines as well as primary villous trophoblasts were determined.. We found a time-dependent induction of leptin receptor mRNA and protein in placental cells under hypoxic conditions. In contrast, soluble leptin receptor expression did not change under oxygen deprivation. Leptin treatment neither activated the p42/p44 nor the STAT3 pathway in placental cells, being independent of hypoxic or normoxic conditions. Furthermore, leptin added to the culture medium in high concentrations was unable to interfere with the rate of proliferation.. Our data demonstrate that hypoxia leads to an increase of Ob-R expression in placental cells. Interestingly, leptin-dependent signal transduction and proliferation remained unaffected. A possible role of the soluble leptin receptor in modulating free leptin levels will be discussed.

Topics: Cell Line, Tumor; Cell Proliferation; Choriocarcinoma; Chorionic Villi; Female; Gene Expression; Humans; Hypoxia; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oxygen; Placenta; Pregnancy; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trophoblasts; Up-Regulation; Uterine Neoplasms

Controlled trophoblast invasion is a key process during human placentation and a prerequisite for successful pregnancy. Progesterone is one of the factors to regulate trophoblast invasiveness. Progesterone-induced blocking factor (PIBF) is a progesterone-induced molecule expressed by the trophoblast, and also by tumors. The distribution of PIBF within the first-trimester decidua coincides with sites of trophoblast invasion. Another molecule that has been implicated in the control of trophoblast invasiveness is placental leptin. Leptin inhibits the secretion of progesterone by cytotrophoblast. The aim of this work was to investigate the possible interaction of PIBF and leptins in regulating trophoblast invasion. Paraffin-embedded sections from normal first-trimester placentae, partial moles, complete moles, and choriocarcinomas were reacted with PIBF, leptin, and leptin receptor specific antibodies. PIBF-deficient trophoblast cells were generated using siRNA and leptin receptor was detected on Western blot analysis. The lysates of PIBF-treated cells were used for detecting leptin expression in a protein array. PIBF was expressed in both normal first-trimester villous trophoblast and in partial mole. Compared with this, PIBF expression was markedly decreased in complete mole and absent in choriocarcinoma. Neither leptinR nor leptin were detected in partial mole, whereas both of these molecules were present in complete mole and choriocarcinoma. Leptin receptor expression was upregulated in PIBF-deficient cells, while leptin expression was decreased in PIBF-treated cells. These data suggest that PIBF affects the expression of leptin and its receptor, and that PIBF expression is inversely related to trophoblast invasiveness.

Topics: Blotting, Western; Cell Line; Choriocarcinoma; Decidua; Embryo Implantation; Female; Humans; Hydatidiform Mole; Leptin; Placenta; Placentation; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Progesterone; Receptors, Leptin; RNA Interference; RNA, Small Interfering; Suppressor Factors, Immunologic; Trophoblasts; Uterine Neoplasms

Previously, the polymorphism-2548 G/A within the promoter of the leptin (LEP) gene was reported to be associated with overweight and obesity, the factors significantly associated to increased endometrial cancer risk. Leptin has been described to play an important role in signal transduction in endometrial cancer cells indicating that leptin promotes endometrial cancer growth and invasiveness and implicating the JAK/STAT and AKT pathways as critical mediators of leptin action. The aim of the study was to investigate the possible associations of LEP-2548 G/A polymorphism with endometrial cancer and its related traits.. Using PCR with following restriction analysis, we studied 67 endometrial cancer cases (mean age 64.3 +/- 10.3 years) that were enrolled in the study along with 67 controls matched for age, BMI and ethnic origin (mean age 62.1 +/-9.8 years); an additional cohort of 543 healthy individual was recruited to investigate the general population frequencies.. The present study revealed no significant differences between the genotypes or alleles of investigated polymorphism for endometrial cancer risk or its related traits (age of menarche, menopause, number of spontaneous abortions in personal history or waiting time till the onset of the disease) among the groups, thus indicating that the genetic variants of LEP-2548 G/A is not a relevant marker of endometrial cancer risk in this Czech population.. To conclude, the polymorphism LEP-2548 G/A doesn't seem to represent a major genetic marker for endometrial cancer in the studied Czech population; however, it was associated with obesity, which finding is in accordance with previous reports.

Topics: Body Mass Index; Endometrial Neoplasms; Female; Genotype; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Uterine Neoplasms

Leptin, the 16-kDa protein product of the obese gene, was originally considered as an adipocyte-derived signaling molecule for the central control of metabolism. However, leptin has been suggested to be involved in other functions during pregnancy, particularly in placenta. In the present work, we studied a possible effect of leptin on trophoblastic cell proliferation, survival, and apoptosis. Recombinant human leptin added to JEG-3 and BeWo choriocarcinoma cell lines showed a stimulatory effect on cell proliferation up to 3 and 2.4 times, respectively, measured by (3)H-thymidine incorporation and cell counting. These effects were time and dose dependent. Maximal effect was achieved at 250 ng leptin/ml for JEG-3 cells and 50 ng leptin/ml for BeWo cells. Moreover, by inhibiting endogenous leptin expression with 2 microM of an antisense oligonucleotide (AS), cell proliferation was diminished. We analyzed cell population distribution during the different stages of cell cycle by fluorescence-activated cell sorting, and we found that leptin treatment displaced the cells towards a G2/M phase. We also found that leptin upregulated cyclin D1 expression, one of the key cell cycle-signaling proteins. Since proliferation and death processes are intimately related, the effect of leptin on cell apoptosis was investigated. Treatment with 2 microM leptin AS increased the number of apoptotic cells 60 times, as assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, and the caspase-3 activity was increased more than 2 fold. This effect was prevented by the addition of 100 ng leptin/ml. In conclusion, we provide evidence that suggests that leptin is a trophic and mitogenic factor for trophoblastic cells by virtue of its inhibiting apoptosis and promoting proliferation.

Topics: Apoptosis; Caspase 3; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Choriocarcinoma; Cyclin D1; Dose-Response Relationship, Drug; Female; Flow Cytometry; G2 Phase; Humans; Leptin; Pregnancy; Protein Isoforms; Receptors, Leptin; Recombinant Proteins; Time Factors; Trophoblasts; Up-Regulation; Uterine Neoplasms

The purpose of this study was to examine the influence of leptin in women with uterine myoma.. In this study, 38 women with myoma uteri and 30 normal women who applied to the Dr Zekai Tahir Burak Woman Health Research and Education Hospital's gynecology clinic were enrolled. Uterine leiomyomas were proved by pathology postoperatively. In all subjects, FSH, LH, E2, prolactin, hemoglobin, hematocrit, blood urea nitrogen, creatinine, fasting glucose, CA125, and leptin were examined, and body mass index (BMI) was calculated. Data were analyzed by Student's t test and Mann-Whitney U test.. Although leptin level was higher in the myomatic women (5.73 +/- 4.08 ng/mL) than in the normal women, there was no statistically significant difference (p = 0.303). Also, no statistical difference in the ratios of leptin/BMI was found in both groups. A significant correlation was found between high E2 level and myoma uteri (p = 0.021). Hemoglobin levels were significantly lower in the myomatic women (p = 0.044). When we compared the leptin levels according to BMI, leptin levels were higher in patients who had BMI > 30 (p = 0.02).. We did not find any significant difference in serum leptin levels between the two groups. But leptin may have an indirect role in the pathogenesis of uterine leiomyoma. So further research is needed to reveal the role of leptin in myoma uteri pathogenesis.

Topics: Adult; Body Mass Index; CA-125 Antigen; Female; Hemoglobins; Hormones; Humans; Leiomyoma; Leptin; Middle Aged; Uterine Neoplasms

In vitro and in vivo studies have linked mast cell (MC) degranulation and activation with angiogenesis and neovascularization. This assumption is partially supported by the close anatomical association between MC and the vasculature and the recruitment of these cells during tumor growth. The aim of this study was to correlate the extent of angiogenesis with the number of MC expressing tryptase and leptin in human leiomyomas.. Tissues from human leiomyomas and control specimens were investigated immunohistochemically, using murine monoclonal antibodies against the endothelial cell marker CD31, leptin, and the MC marker tryptase.. Angiogenesis, measured as microvessel counts, was highly correlated with MC tryptase- and leptin-positive cell counts.. These data suggest that angiogenesis in leiomyomas is correlated to expression of tryptase in MC granules and provide for the first time evidence of a putative role of leptin, also contained in MC secretory granules, in MC-dependent angiogenesis.

Topics: Cell Count; Cell Degranulation; Female; Humans; Leiomyoma; Leptin; Mast Cells; Neovascularization, Pathologic; Tryptases; Uterine Neoplasms

Leptin, the product of the obesity (ob) gene, along with its receptors (Ob-Rs), is expressed in several tissues and organs. Evidence has been provided that leptin, in addition to being involved in obesity development, plays a role in the regulation of the female reproductive system, angiogenesis and tumor growth. Uterine myoma is a rather common disease that develops more frequently in obese than lean women, where plasma leptin concentrations are elevated. RT-PCR and Western blotting showed that leptin was expressed, as mRNA and protein, in several uterine myomas but not in normal myometrium, while leptin receptors were expressed in both tissues. Immunocytochemistry indicated that leptin-immunoreactivity was located in both myometrial cells and blood-vessel walls of uterine myomas. Leptin(22-56), at concentrations of 10(-7) and 10(-6) M, enhanced the proliferative activity of both the normal myometrium and myoma cells in primary culture. Taken together, our findings allow us to suggest that leptin, acting through autocrine-paracrine mechanism(s), may be involved in the development of uterine myomas.

Topics: Blotting, Western; Cell Proliferation; Dose-Response Relationship, Drug; Female; Gene Expression; Humans; Immunohistochemistry; Leptin; Myoma; Myometrium; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Uterine Neoplasms

Examination of the potential role of leptin in the development of uterine myomas. Expression of the leptin gene and leptin receptor gene was tested in the myometrium of healthy women, and in myomas and the surrounding myometrium of women with benign tumors.. Using RT-PCR, expression of the leptin gene and leptin receptor gene were studied in myomas and in the surrounding myometrium in 30 women with uterine myomas at various phases of the menstrual cycle, and in the myometrium of ten women in a control group. Presence of leptin gene proteins and leptin receptor gene proteins in the women was also examined by Western blotting.. Using RT-PCR, expression of the leptin gene was demonstrated both in myomas and in the surrounding myometrium. In contrast, expression of the gene could not be detected in the myometrium of healthy women. The results were confirmed by Western blotting, which documented the identical distribution of leptin proteins and leptin receptor proteins in studied tissues.. Demonstration of the expression of leptin genes and leptin proteins in uterine myomas and in the surrounding myometrium, and their absence in the myometrium of healthy women suggests the involvement of leptin in the development of uterine myomas.

Topics: Adult; Aged; Case-Control Studies; DNA Primers; Female; Gene Expression Regulation, Neoplastic; Humans; Leiomyoma; Leptin; Middle Aged; Myometrium; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Uterine Neoplasms

Leptin is a hormone involved in the regulation of body weight and sexual maturation. We previously reported that cancer cachexia was associated with reduced or normal levels of leptin. Here we investigate whether leptin levels are related to cachetic or hormonal status. Circulating leptin and its mRNA from adipose tissue were measured in 87 patients with gynaecological and breast cancers and related to tumour, cachexia and hormonal markers. We found that leptin protein increased in patients with these tumours due to higher mRNA levels. In patients with ovarian cancer, the increased leptin levels were associated with higher circulating follicle-stimulating hormone (FSH). The higher leptin concentrations in patients with endometrial and portio tumours were related to an increase in tissue estrogen receptor (ER) and progesterone receptor (PGR) and, only in the postmenopause, to an increase in circulating estradiol. Patients with breast cancer showed enhanced blood plasma concentrations of progesterone and estradiol, and enhanced tissue levels of ER and PGR associated with increased leptin levels. The data from the present study indicate that, in gynaecological and breast cancers, leptin is related to hormonal status but not to cachexia. We suggest that leptin stimulates the production of sexual hormones, important risk factors for these tumours, and we propose leptin as a novel prognostic marker.

Topics: Adipocytes; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Cachexia; Case-Control Studies; Female; Humans; Leptin; Neoplastic Cells, Circulating; Ovarian Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Uterine Neoplasms

To investigate the expression profile of leptin and leptin receptors in gestational trophoblastic diseases (GTDs).. Using immunohistochemical staining on archival paraffin-embedded tissue sections, we studied the expression of leptin and leptin receptor in hydatidiform moles, with gestational age-matched normal first-trimester placenta used as control. A total of 38 cases of hydatidiform moles were studied, including 20 complete moles (CHMs) and 18 partial moles (PHMs). Among them, 10 cases of the CHM group and 8 cases of the PHM group subsequently developed residual trophoblastic disease (RTD). In addition, two cases of choriocarcinoma and three cases of placental site trophoblastic tumor (PSTT) were also studied. Reverse transcriptase-polymerase chain reaction (RT-PCR) was further performed using RNA extracted from frozen tissue (five CHMs, four PHMs and nine normal first-trimester placenta) to study the expression of leptin and individual leptin receptor isoforms at the transcription level.. In all tissue sections, immunostaining signal was shown in the cytoplasmic compartment of cytotrophoblasts and syncytiotrophoblasts, with much stronger staining in the former. Significantly higher immunostaining intensity was shown for both leptin (P < 0.05) and leptin receptor (P < 0.001) in both CHMs and PHMs compared to normal first-trimester placenta. There was no significant difference between those cases subsequently developing RTD and those which did not (P > 0.05). In the choriocarcinoma and PSTT cases, intense immunostaining was found in the tumor cells. RT-PCR revealed that the expression of leptin and all leptin receptor isoforms were significantly higher in both CHMs and PHMs than in normal placenta (P < 0.05).. There is up-regulated expression of leptin and leptin receptor in GTDs. However, there is no obvious correlation with the development of RTD. The exact role played by leptin and its receptors in the pathogenesis of GTDs awaits further investigations.

Topics: Choriocarcinoma; Female; Humans; Hydatidiform Mole; Immunohistochemistry; Leptin; Placenta; Pregnancy; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation; Uterine Neoplasms

To analyze the possible involvement of leptin in uterine leiomyomas.. Serum leptin levels, determined by radioimmunoassay, were compared in myomatic (n = 50) and the normal (n = 50) women.. A significant correlation was found between serum leptin levels and body mass index in both the myomatic women (r = 0.76, p < 0.001) and the normal women (r = 0.56, p < 0.001). Serum leptin levels in the myomatic women (9.3 +/- 0.6 ng/mL) were significantly lower (p < 0.001) than those in the normal women (13.6 +/- 1.2 ng/mL). In addition, the ratios of serum leptin levels/body mass index in the myomatic women (0.38 +/- 0.02) were significantly lower than those in the normal women (0.57 +/- 0.04) (p < 0.001). A significant correlation was found between the ratios of serum leptin levels/body mass index and body mass index (r = 0.59, p < 0.001) in the normal women, but not in the myomatic women (r = 0.27, p = 0.061).. The lower plasma leptin levels observed in the women with myomas were independent of body mass index, and unlike the normal women there was no significant up-regulation of leptin production in response to increased adiposity.

Topics: Adult; Body Mass Index; Body Weight; Female; Humans; Leiomyoma; Leptin; Middle Aged; Radioimmunoassay; Uterine Neoplasms

Leptin and glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6m M glucose (LG), proliferation and thymidine incorporation were induced by serum but not by leptin. At variance, at 25m M glucose (HG), proliferation and thymidine incorporation were stimulated by leptin and serum to a comparable extent. HG culturing also enhanced leptin-stimulated insulin receptor substrate 1 (IRS1) and MAPK phosphorylation. Blockage of MAPK activity with PD98059 caused an inhibition of glucose- and leptin-dependent thymidine incorporation. At variance with HG conditions no effects were observed in cells cultured in 6m M glucose upon treatment with PD98059. Neither glucose nor leptin determined a modification in leptin receptors total content. In this study, we provide evidence that in placental cells, leptin, similarly to that observed with insulin, stimulates cell proliferation by inducing the IRS1/MAPK pathway in a glucose-dependent fashion.

Topics: Cell Division; Choriocarcinoma; DNA; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Female; Flavonoids; Glucose; Growth Substances; Humans; Leptin; Mitogen-Activated Protein Kinases; Signal Transduction; Trophoblasts; Tumor Cells, Cultured; Uterine Neoplasms; Viral Proteins

The purpose of this study was to examine the influence of luteinizing hormone-releasing hormone analog goserelin on serum leptin and body composition in women with solitary uterine myoma.. Fifteen women who were regularly menstruating and not obese were included. In all subjects, serum concentrations of leptin, insulin, testosterone, progesterone, and estradiol and body mass index and waist-to-hip ratio were measured before and after 4, 8, and 12 weeks of treatment with goserelin (3.6 mg every 4 weeks). Fat mass and lean body mass were measured by dual energy radiographic densitometry at baseline and after 12 weeks of therapy. Data were analyzed by multiple way analysis of variance and both simple and multiple regression.. The treatment caused a significant regression of myoma. Body weight, fat, and lean mass were unchanged. No changes in plasma leptin (even after correction for fat mass) were noted during the treatment. Plasma estradiol decreased below castrate levels. Plasma progesterone decreased significantly, and testosterone tended to decline during the study. At baseline a highly significant positive correlation was found between serum leptin and fat mass. In a multiple regression analysis, neither the change in fat mass nor any of the hormonal parameters explained the significant portion of variance of plasma leptin during the treatment.. Pharmacologic gonadectomy does not influence plasma leptin concentrations in women if body fat mass is unchanged.

Topics: Adipose Tissue; Adult; Antineoplastic Agents, Hormonal; Body Composition; Estradiol; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leiomyoma; Leptin; Middle Aged; Progesterone; Testosterone; Uterine Neoplasms

To investigate the effects of total abdominal hysterectomy on circulating leptin levels, 16 pre- and 8 postmenopausal patients with uterine leiomyoma or carcinoma in situ of the uterine cervix were enrolled. Serum levels of leptin and fasting blood sugar (FBS) were determined before (day -7) and after surgery (day +1 and +7). Body mass index (BMI) was recorded at day -7 and +7. Anesthesia duration, surgical duration, hematology, and blood loss during surgery were recorded. Relations of these variables to serum leptin levels were investigated. Serum leptin levels rose from 7.3+/-4.7 ng/mL to 9.3+/-5.8 ng/mL at day +1 (P < 0.01), then decreased to 4.9+/-3.0 ng/mL at day +7 (P < 0.05 vs. values at day -7 and +1). FBS levels also rose from 89.4+/-7.5 mg/dL to 119.3+/-24.0 mg/dL (P < 0.01), then returned to normal at day +7 (96.2+/-9.0 mg/dL). However, there was no significant correlation observed between FBS and leptin levels at each time point (r < or = 0.22). BMI decreased from 22.7+/-3.0 kg/m2 to 21.7+/-2.9 kg/m2 at day +7 (P < 0.001). At day -7 and +7, leptin levels were positively correlatd with BMI (r = 0.79, P < 0.001 and r = 0.71, P < 0.001, respectively). Circulating leptin levels were increased on day one after total abdominal hysterectomy.

Topics: Adult; Blood Glucose; Body Mass Index; Carcinoma in Situ; Female; Humans; Hysterectomy; Leiomyoma; Leptin; Middle Aged; Postmenopause; Premenopause; Uterine Cervical Neoplasms; Uterine Neoplasms

Leptin is important in the regulation of fat mass and body weight. Adipose tissue not only secretes leptin but also serves as a site of action for leptin. This study was designed to examine the relationships among tissue expression of leptin receptors, serum leptin, and body mass index.. Omental adipose tissue and fasting blood samples were obtained from 57 nondiabetic women who underwent surgery for either myoma of the uterus or ovarian cyst. Tissue RNA was extracted using Trizol reagent and serum leptin concentrations were determined with commercial kits. The leptin receptor isoforms in tissues were quantified using real-time Taqman technology.. Three leptin receptor isoforms, Ob-Rb, HuB219.1, and HuB219.3, were found in human omental adipose tissue. The amounts of HuB219.1 and HuB219.3 mRNA relative to that of Ob-Rb were 1314.2 and 16.7, respectively. Higher body mass index was significantly correlated with an increase in serum leptin concentration and a decrease in leptin receptor HuB219.1 isoform in omental fat, even after adjustment for age and menopausal status. There was no direct association between serum leptin concentration and tissue HuB219.1 mRNA level.. HuB219.1 is the major isoform of leptin receptor expressed in human omental adipose tissue. Our findings suggest that the shorter leptin receptor isoforms in human omental adipose tissue might play an important role in body weight control. Further studies on the inter-relationship between leptin concentrations and multiple leptin receptor isoforms are needed to elucidate the exact mechanism of obesity.

Topics: Adipose Tissue; Body Mass Index; Carrier Proteins; Female; Humans; Leiomyoma; Leptin; Omentum; Ovarian Cysts; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Uterine Neoplasms

Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.

Topics: Adipose Tissue; Adult; Amnion; Amniotic Fluid; Choriocarcinoma; Female; Gene Expression; Hormones; Humans; Hydatidiform Mole; Leptin; Obesity; Placenta; Pregnancy; Protein Biosynthesis; Proteins; RNA, Messenger; Trophoblasts; Tumor Cells, Cultured; Uterine Neoplasms

Topics: Adult; Female; Humans; Hydatidiform Mole; Leptin; Obesity; Pregnancy; Protein Biosynthesis; Reference Values; Uterine Neoplasms