• Development and Reproduction
• /
• v.13 no.4
• /
• pp.207-215
• /
• 2009

Numerous factors can affect the activities of hypothalamus-pituitary-gonad (HPG) hormonal axis, resulting in alteration of reproductive capacity or status such as onset of puberty and menopause. Soon after the finding of leptin, a multifunctional hormone secreted from adipocytes, a close relationship between reproduction and body energy balance have been manifested. Ghrelin, another multifunctional hormone from gastrointestinal tract, is an endogenous ligand of growth hormone secretagogue receptor (GHSR), and is thought to be a counterpart of leptin in the regulation of energy homeostasis. As expected, ghrelin can also modulate the reproductive capacity through the modulation of activities of HPG axis. This paper summarizes the current knowledge on the discovery, gene structures, tissue distribution and roles of ghrelin and GHSRs in mammalian reproduction in particular modulation of reproductive hormone secretion in HPG axis. Like POMC gene expression in pituitary gland, preproghrelin gene can generate a complex repertoire of transcripts which further undergo alternative splicing and posttranslational modifications. Concerning the roles of preproghrelin gene products in the control of body physiology except energy homeostasis, limited knowledge is available so far. Several lines of evidence, however, show the interplay of ghrelin between metabolism and reproduction. In rat and human, the distribution of ghrelin receptor GHSRs (GHSR1a and GHSR1b) has been confirmed not only in the hypothalamus and pituitary which were originally postulated as target of ghrelin but also in the testis and ovary. Expression of the preproghrelin gene in the brain and gonads was also verified, suggesting the local role (s) of ghrelin in HPG axis. Ghrelin might play a negative modulator in the secretions of hypothalamic GnRH, pituitary gonadotropins and gonadal steroids though the action on pituitary is still questionable. Recent studies suggest the involvement of ghrelin in regulation of puberty onset and possibly of menopause entry. It is now evident that ghrelin is a crucial hormomal component in 'brain-gut' axis, and is a strong candidate links between metabolism and reproduction. Opposite to that for leptin, ghrelin signaling is likely representing the 'hunger' state of body energy balance and is necessary to avoid the energy investment into reproduction which has not a top priority in maintaining homeostasis. Further researches are needed to gain a deep insight into the more precise action mechanism and role of ghrelin in reproduction, and to guarantee the successful biomedical applications.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.4
• /
• pp.2401-2406
• /
• 2013

From January 1, 2008 to March 31, 2010, 101 patients with stage II-III breast cancer were enrolled in this study and subjected to an anthracycline-based neoadjuvant chemotherapy regimen with or without docetaxel. Surgery was performed after 2-6 cycles of chemotherapy, and the clinical response was determined by pathological and histochemical assessments. The clinical response rate, as indicated by complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), were 6.9, 52.5, 36.6, and 4.0%, respectively. A multivariable correlation analysis indicated that the overall clinical response rate correlated with the number of metastatic lymph nodes, number of chemotherapy cycles, and vessel invasion status. Importantly, the CR rate was only associated with the number of chemotherapy cycles. Nonparametric tests failed to detect a correlation between HER2 or Topo $II{\alpha}$ status and clinical response to neoadjuvant chemotherapy in these patients. When they were stratified by HER2 or HR status, for HER2-positive patients the CR rate was associated with vessel invasion and Topo $II{\alpha}$ status. Based on our findings, we propose that HR, HER-2 and Topo $II{\alpha}$ are not putative predictive biomarkers of chemotherapy outcome for breast cancer patients. Topo $II{\alpha}$ expression level was only inversely correlated with CR rate among HR-positive patients. Importantly, the achievement of CR was largely related to the number of chemotherapy cycles.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.14
• /
• pp.6055-6059
• /
• 2015

Background: Medication policy development in Thailand is continually promoting rational drug use. Letrozole, an endocrine therapy drug, is usually prescribed for post-menopausal status early and advanced stage breast cancer. After Ministry of Public Health announced Letrozole as compulsory licensed drug in 2009, more breast cancer patients can access to this drug at low cost especially those within universal coverage schemes. To ensure that Letrozole is rationally prescribed, the drug utilization study was conducted. Objectives: The aim of this study was to describe the appropriate use of Letrozole in breast cancer and the relationship between appropriate use and health benefit schemes. Materials and Methods: A retrospective study to evaluate use of Letrozole in breast cancer patients was performed for six months between January - June 2010 in seven regional cancer hospitals, Thailand. All prescriptions of Letrozole were identified from pharmacy dispensing databases and prescription papers. A medical record review was also performed to evaluate appropriate use referring to the drug use evaluation criteria. The approved criterion of this study was referred from the guideline of Thai National Formulary version 2010. Results: There were 681 prescriptions of Letrozole for 254 breast cancer patients with an average age of $58.6{\pm}10.0years$. The patients in universal coverage scheme (UCS), civil servant medication benefit scheme (CSMBS) and social security scheme (SSS) were 77.7%, 18.5% and 8.7% respectively. 10.6% were prescribed Letrozole for the first time. Letrozole were prescribed by oncologists (82.8%). The average number of tablets per prescription was $58{\pm}10$. Calcium supplements were prescribed concomitant with Letrozole for 19.4%. To assess drug use evaluation criteria, 45 prescriptions were excluded because of uncompleted clinical data, 636 prescriptions were evaluated. The study showed 86 prescriptions (13.5%) with inappropriate use including 6 (0.9%) not prescribed for estrogen receptor (ER) and/or progesterone receptor (PR) positive, 31 (4.9%) not prescribed for post-menopausal and 49 (7.7%) not prescribed for an appropriate duration. Appropriate use percentages in different health benefit schemes were similar, 85.7% of CSMBS, 86.4% of SSS and 86.7% of UCS. The relationship between health benefit scheme and appropriate use of Letrozole was not significantly different, ${\chi}^2$ (2, N = 636) = 0.081, p > 0.05. Conclusions: The study showed inappropriate use in breast cancer patients because of non-compliance with duration, menopausal status and hormone receptor requirements. To prescribe appropriate indication did not referred to the appropriate practice along the treatment. Drug use evaluation proved very useful for detecting the sign of inappropriate use and allows immediate feedback to the stakeholder for developing medication policy in the future. Importantly, there was no significantly difference in appropriate use of Letrozole across health benefit schemes.

• Development and Reproduction
• /
• v.10 no.4
• /
• pp.255-261
• /
• 2006

Although some phytoes rogens might have beneficiary rather than adverse effects, most endocrine disrupting compounds(EDCs) are considered to be harmful to human and wildlife health through interfering the endocrine system. Previously we found that prepubertal exposure to genistein(GS), a well-known isoflavone phytoestrogen, could activate the reproductive system of immature female rats resulting precocious puberty. Interestingly, di(2-ethyl hexyl) phthalate(DEHP) exposure brought inverse result, a delayed puberty, in the same experimental regimen. In this study, we examined whether prepubertal exposure to GS or DEHP affect the gene expressions of estrogen receptors($ER\;{\alpha}$ and $ER\;{\beta}$) and LH receptor(LHR) which represent the maturational status of ovary and uterus in immature rats. GS (100 mg/kg/day) was administered daily from postnatal day 25 to the day when the first vaginal opening(VO) was observed, and the animals were sacrificed on the next day(day 32). Similarly, DEHP(l00 mg/kg/day) was administered daily from postnatal day 25 through the day when the first V.O. in control group was observed, and the animals were sacrificed on the next day(day 36). To determine the transcriptional changes in the hormone receptors, total RNAs were extracted from ovary and uterus and were applied to semi-quantitative reverse transcription polymerase chain reaction(RT-PCR). In the GS group, the transcriptional activities of $ER\;{\alpha}$, $ER\;{\beta}$ and LHR in uterus and LHR in ovary were significantly increased when compared to those of control group. In the DEHP group, the transcriptional activities of all the hormone receptors measured were significantly lowered when compared to those of control group. These alteration of the reproductive hormone receptor expressions in ovary and uterus might be represent the phenotypic aspects(secondary sexual characteristics) such as tissue weights and reproductive hormone levels during perinatal period in immature female rats.

• The Korean Journal of Physiology and Pharmacology
• /
• v.17 no.5
• /
• pp.385-392
• /
• 2013

Vitamin D deficiency is prevalent, primarily due to limited sun exposure, which may be observed in urban areas, or as a result of modern lifestyles. Common myths about vitamin D persist, including that it is mostly obtained from the diet and is only essential for bone and mineral homeostasis. Nonetheless, advances in biomedical science suggest that vitamin D is a hormone that is integral to numerous physiologic functions in most cells and tissues. Therefore, abnormal vitamin D levels may contribute to health disturbances. A number of recent reports on potential associations between vitamin D deficiency and cardiovascular disease have highlighted its role in this system. A focus over the previous decade has been to better understand the mechanisms behind vitamin D regulation and the pathophysiology associated with suboptimal vitamin D levels. Vitamin D deficiency is highly associated with the incidence of cardiovascular diseases, even when considering other well-known risk factors. In this process, the renin-angiotensin system is disrupted, and hypertension and endothelial dysfunction contribute to the risk of cardiovascular disease. Likewise, clinical outcomes upon the normalization of vitamin D levels have been investigated in different patient populations. It makes sense that vitamin D supplementation to improve vitamin D status among vitamin D-deficient individuals could be useful without requiring a sudden lifestyle change. This manuscript provides a brief overview of vitamin D metabolism and the vitamin D receptor. It also summarizes the current clinical research relating to vitamin D supplementation and its effects on hypertension and endothelial dysfunction in cardiovascular medicine.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.9
• /
• pp.5193-5198
• /
• 2013

The glycemic index (GI) and glycemic load (GL) have been considered risk factors for breast cancer, but association studies of breast cancer risk using simple GI and GL might be affected by confounding effects of the overall diet. A total of 357 cases and 357 age-matched controls were enrolled, and dietary intake was assessed using a validated food frequency questionnaire (FFQ) with 103 food items. GI and GL dietary patterns were derived by reduced rank regression (RRR) method. The GI and GL pattern scores were positively associated with breast cancer risk among postmenopausal women [OR (95%CI): 3.31 (1.06-10.39), p for trend=0.031; 9.24 (2.93-29.14), p for trend<0.001, respectively], while the GI pattern showed no statistically significant effects on breast cancer risk, and the GL pattern was only marginally significant, among premenopausal women (p for trend=0.043). The GI and GL pattern scores were positively associated with the risk of breast cancer in subgroups defined by hormone receptor status in postmenopausal women. The GI and GL patterns based on all food items consumed were positively associated with breast cancer.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.15
• /
• pp.6035-6039
• /
• 2014

Background: Substantial evidence from epidemiological studies has suggested that increased levels of calcium may play a protective role against colorectal cancer (CRC). Given the vital role of calcium sensing receptor (CaSR) and parathyroid hormone (PTH) in the maintenance of calcium homeostasis, we explored whether the rs1801725 (A986S) variant located in exon 7 of the CaSR gene and the rs6256 variant located in exon 3 of PTH gene might be associated with CRC risk. Materials and Methods: In this study 860 subjects including 350 cases with CRC and 510 controls were enrolled and genotyped using PCR-RFLP methods. Results: We observed no significant difference in genotype or allele frequencies between the cases with CRC and controls for both CaSR and PTH genes either before or after adjustment for confounding factors including age, BMI, sex, smoking status, and family history of CRC. Furthermore, no evidence for effect modification of any association of rs1801725 and rs6256 variants and CRC by BMI, sex, or tumor site was observed. In addition, there was no significant difference in genotype and allele frequencies between the normal weight (BMI < $25kg/m^2$) cases and overweight/obese (BMI ${\geq}25kg/m^2$) cases for the two SNPs. Conclusions: These data indicated that the CaSR gene A986S variant is not a genetic contributor to CRC risk in the Iranian population. Furthermore, our results suggest for the first time that PTH gene variant does not affect CRC risk. Nonetheless, further studies with larger sample size are needed to validate these findings.

• Radiation Oncology Journal
• /
• v.26 no.1
• /
• pp.65-73
• /
• 2008

Purpose: Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Materials and Methods: Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor(ER), progesterone receptor(PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. Results: There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history(4/14) and bilateral breast cancers(3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2-associated cancers demonstrated more expression of ER-negative(19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors(negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was not a prognostic factor. Conclusion: Breast cancer that occurs in women with a germline BRCA1 or BRCA2 mutations have recognizable immunohistochemical features, which may be useful in identifying individuals that are more likely to carry germline mutations. Although the BRCA1/2 mutation status was not a prognostic factor in Korean women with early-onset breast cancer, more cases with a longer follow-up period are needed for further study.

• Radiation Oncology Journal
• /
• v.33 no.4
• /
• pp.301-309
• /
• 2015

Purpose: To identify prognostic factors for disease progression and survival of patients with extracranial oligometastatic breast cancer (EOMBC), and to investigate the role of radiation therapy (RT) for metastatic lesions. Materials and Methods: We retrospectively reviewed the medical records of 50 patients who had been diagnosed with EOMBC following standard treatment for primary breast cancer initially, and received RT for metastatic lesions, with or without other systemic therapy between January 2004 and December 2008. EOMBC was defined as breast cancer with five or less metastases involving any organs except the brain. All patients had bone metastasis (BM) and seven patients had pulmonary, hepatic, or lymph node metastasis. Median RT dose applied to metastatic lesions was 30 Gy (range, 20 to 60 Gy). Results: The 5-year tumor local control (LC) and 3-year distant progression-free survival (DPFS) rate were 66.1% and 36.8%, respectively. High RT dose (${\geq}50Gy_{10}$) was significantly associated with improved LC. The 5-year overall survival (OS) rate was 49%. Positive hormone receptor status, pathologic nodal stage of primary cancer, solitary BM, and whole-lesion RT (WLRT), defined as RT whose field encompassed entire extent of disease, were associated with better survival. On analysis for subgroup of solitary BM, high RT dose was significantly associated with improved LC and DPFS, shorter metastasis-to-RT interval (${\leq}1month$) with improved DPFS, and WLRT with improved DPFS and OS, respectively. Conclusion: High-dose RT in solitary BM status and WLRT have the potential to improve the progression-free survival and OS of patients with EOMBC.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.12
• /
• pp.7445-7449
• /
• 2013

Background: Breast cancer (BC) is the one of the most common cancers in women. It is also a leading cause of death. Unfortunately, some patients initially present with distant metastases and are diagnosed with stage IV disease that is nearly always, by then, incurable. This retrospective analysis investigated the risk factors for stage IV BC that may underlie such late presentation. Materials and Methods: In all, 916 patients with BC who visited the medical oncology polyclinic of eight different centres in Turkeybetween December 2011 and January 2013 were analysed. Results: A total of 115 patients (12.6%) presented with stage IV disease. In univariate analysis; to comparing these with patients at other stages, no statistical difference was found for median diagnosis age or age at menarche (p=0.611 and p=0.820), whereas age at menopause and age at first live birth were significant (p=0.018 and p=0.003). No difference was detected in terms of accompanying diseases, use of oral contraceptives and hormone replacement therapy, smoking, alcohol consumption and the rate of family history of BC between the patients (p=0.655, p=0.389, p=0.762, p=0.813, p=0.229, p=0.737). However, screening methods were employed less often, the rate of illiteracy was higher, and the rate of other cancers was higher in patients with stage IV BC (p=0.022, p=0.022, p=0.018). No statistical difference was observed between the patients in terms of tumour histopathology, and status of oestrogen receptor, progesterone receptor, or human epidermal growth factor-2 receptor (p=0.389, p=0.326, p=0.949, p=0.326). Grade 3 tumours were more frequent in patients with stage IV disease (p<0.001). On multivariate analysis, risk factors for stage IV breast cancer at the time of presentation were found to be age at first live birth and educational level (p=0.003 and p=0.047). Conclusions: Efforts should be made to perform mammography scans, in particular, at regular intervals through national training programs for all women, particularly those with family histories of breast and other types of cancer, and to establish early diagnosis of BC long before it proceeds to stage IV. Additionally, women's education had better be upgraded. In order to make women aware of BC, national education-programmes must be organised.