ArticleLiterature Review

IGF-1 in gynaecology and obstetrics: Update 2002

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Abstract

Recent discoveries on endocrine, paracrine and autocrine involvement of insulin-like growth factor-1 (IGF-1) in the proliferation of many tissues raised the attention of its role in reproduction and in the growth of various cancers as well as of benign proliferations. The intention of this article is to focus on IGF-1 in the field of gynaecology. Perimenopausal women who exhibit high IGF-1 and low IGF binding protein (IGFBP) levels, like IGFBG-3, have an increased risk of developing breast cancer. A higher risk for cervical, ovarian and endometrial cancer is related to high IGF-1 levels in post- and premenopausal women. It has been shown that myomas, by far the most common benign uterine tumor in women, grow in the presence of IGF-1, in vitro as well as in vivo. Studies show that IGF-1 is involved in the differentiation of various reproductive tissues, like endometrium and ovarian tissues. Patients suffering from polycystic ovary syndrome (PCO) frequently show insulin resistance accompanied by an increase of IGF-1 in plasma. Plasma IGF-1 levels are higher in cases of severe endometriosis, however, in endometriosis and in PCO IGF levels locally in the endometrium are reduced, what might explain infertility. Recently, it was shown that IGF facilitates the implantation of the human embryo in the endometrium during IVF. Implantation is a paradox where different immune systems have to collaborate to make implantation and survival of the pregnancy possible. IGF seems to be the starter molecule so that the two epithelia can fuse. A disturbance can result in complications during pregnancy i.e. spontaneous miscarriage, preeclampsia as well as defects of the embryo. Therefore, IGF is a useful marker in successful pregnancy as well. A better mechanistic understanding of IGF-1 action on the cellular level not only provides more elegant mechanistic explanations for the scientist, but the practitioner might find it interesting to utilize its diagnostic potential as a marker for various diseases. The relation between systemic IGF levels and local tissue IGF-1 levels has not yet been determined for all conditions.

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... Recent discoveries on endocrine, paracrine and autocrine involvement of insulin-like growth factor-1 (IGF-I) in the proliferation of many tissues raised the attention to its role in reproduction [64]. IGF-I may play a role in regulation of ovulation induction and luteinisation as IGF-I and hCG act synergistically in increasing progesterone secretion of granulosa cells of natural cycles in vitro and are known to stimulate each other's receptor expression [63]. ...
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The influence of the immune system on ovarian physiology has been extensively studied. A large number of studies evaluated the association between different immunological parameters and follicle development, ovulation, luteinization, oocyte quality and fertilization. Numerous cytokines and lymphocyte subpopulations present in the follicular fluid or the surrounding tissue have been evaluated as possible predictors of in vitro fertilization-embryo transfer procedure outcomes. The purpose of this review is to provide a brief summary of the extensive literature dealing with cytokines, lymphocyte subpopulations and immunoglobulins in the follicular fluid and to discuss the possible contribution of cellular and humoral immunity to the reproduction in general.
... The tumor microenvironment has been largely studied as a dynamic system orchestrated by several growth factor as Insulin like Growth Factor-I (IGF-I) (Uchiyama et al, 1993;Chauhan et al, 1996;Dankbar et al, 2000;Gupta et al, 2001). IGF-I functions by autocrine and/or paracrine effect, in physiological and pathological processes, but is also involved in development and progression of several cancers as ovarian cancer (Druckmann, and Rohr, 2002). High levels of free IGF-1 and IGF-1 activity are associated with elevated risk of progression in ovarian cancer (Brokaw et al., 2007). ...
Article
The microenvironment, composed of several cellular elements and extracellular matrix, plays an important role in tumor development and metastasis. Thus, the study of these interactions is important for cell targeted therapies fighting against chemoresistant tumor cells. This thesis aims to investigate the role of growth factor IGF-I in the chemoresistance of ovarian cancer cells and myeloid leukemia, present in the microenvironment.As a first step, we demonstrated that drug resistance of ovarian cancer cells gained by host cells (hospicells) is related to the secretion of IGF-I by these cells. We have also demonstrated that IGF-I is involved in the regulation of genes ABC (MDR-1, MRP1, MRP2, and BCRP) via STAT3, Jak2, PI3K et ERK signaling pathways.In myeloid leukemia, we have shown that IGF-I has an effect on cell proliferation. It induces the expression of P-gp protein and chemoresistance of cells sensitive to chemotherapy. We also determined the role of IGF-I in the resistance of leukemic cells in the presence of hospicells. These cells have an in vivo hyperangiogenic activity, related to HIF-1 and VEGF, and inhibit immune responses of T cells by NO production.We determined the crucial role of MMP-9 in resistant cells migration of breast cancer expressing P-gp protein and in the formation of a tubular network, suggesting a link between the expression of P-gp and MMP-9.
... Disturbances in the functioning of the IGFBP/IGF/1GF1R system may lead to the induction of carcinogenesis, which has been demonstrated in various types of malignancies, i.e. breast, prostate, or colon cancer. Both, increased activity of the IGF-1/IGF-1R complex and lowered IGF-BP expression have been mentioned among the promoting factors for neoplastic processes [2] . IGF-1 is believed to exert its mitogenic effect on various cells by stimulating their proliferation and inhibiting their apoptosis via endocrine, paracrine and autocrine mechanisms [1]. ...
Article
Insulin-like growth factor 1 (IGF-1) is a mitogen which plays a key role in regulating cell proliferation, differentiation, and apoptosis. It belongs to the family of proteins also composed of insulin-like growth factor 2 (IGF-2), two types of membrane receptors (IGF-1R and IGF-2R), 6 binding proteins (IGFBP 1-6), hydrolyzing proteases, and reactive molecules binding proteins, which regulate the activity of growth factors. Disturbances in the functioning of IGFBP/IGF/1GF1R can lead to induction of carcinogenesis, which has been demonstrated in breast, prostate or colon cancers. Findings evaluating the role of IGF-1 in endometrial cancer biology are ambiguous and contradictory. Therefore, in the present study, we analyzed the role of IGF-1 in the process of carcinogenesis of endometrial cancer, based on the available literature.
... Activity of IGFBP and related cellular effects of IGF are controlled by specifi c proteases (in particular, by serine proteases and MMP), which augment bioavailability of IGF by hydrolyzing IGFBP to small fragments with diminished affi nity to IGF. The IGF signal system plays important roles in normal performance of the ovaries [7] as well as in the onset and progress of malignant epithelial tumors [5]. All components of this system are expressed in OT cells where they can be viewed as signifi cant factors in prognosis of the disease [8,11,12]. ...
Article
IGF-1, IGF-2, and IGFBP-1,2,3 were assayed in blood serum of patients with malignant ovarian tumors (n=44), borderline ovarian tumors (n=11), and benign ovarian tumors (n=12) as well as in healthy women (n=33). In blood serum of patients with malignant ovarian tumors, the level of IGF-1 was lower and IGFBP-1 was higher than in other groups. In patients with malignant and borderline ovarian tumors, the level of IGFBP-2 was higher than in healthy women and in patients with benign ovarian tumors. There was no correlation between most examined parameters and the clinical and morphological peculiarities of ovarian tumors. The study revealed IGF/IGFBP imbalance in patients with malignant ovarian tumor and showed that IGFBP-2 proved to be a potential diagnostic serological marker w with 90% sensitivity and 90% specificity.
... Importantly, animal studies have not demonstrated embryotoxicity and teratogenicity with insulin detemir exposure. [79] Hod et al. have not detected any difference in the rate of congenital abnormalities between detemir and NPH use ( Table 4, detemir n = 8/142, 5.6%; NPH: n = 8/145, 5.5%). [78] The rate of neonatal hypoglycemia (insulin detemir 18%, NPH insulin 12%, P = 0.22) was comparable between groups. ...
Article
Introduction: Diabetes during pregnancy may lead to maternal, fetal and neonatal complications. In order to limit unwarranted outcomes, strict glycemic control is essential. In the past, human insulin was the only insulin formulation administered in pregnancy. However, insulin analogues have also been used for this indication in recent years. Areas covered: This article reviews the published data regarding the safety of insulin analogue use during pregnancy. We present the qualities, advantages and pitfalls of insulin analogue use in pregnancy compared with human insulin. Insulins lispro, aspart and detemir are safe in pregnant women with type 1 diabetes. Correspondingly, they were reclassified for the treatment of pregnant women with diabetes from category C to category B. For insulin glargine use in pregnancy, most studies are small and retrospective. Yet, no major safety concerns were reported. Insulin glulisine and degludec have not been studied in pregnancy. Expert opinion: Insulin analogues are viable therapeutic options for diabetes in pregnancy, specifically lispro, aspart and detemir. Though data in limited, their safety and efficacy are comparable with human insulin. Remarkably, the analogues are superior to human insulin regarding hypoglycaemia risk. More data, specifically for their use in pregnancies complicated by gestational diabetes or type 2 diabetes, is needed.
... Perimenopausal women with a high IGF-1 serum level and a low IGF-1 binding protein have an increased risk of developing breast cancer. Iodine can inhibit the production of IGF-1 in a dose-dependent manner [5,18]. ...
... Increased estrogen levels associated with the proximity of endometriotic cells may trigger up-regulation of insulinlike growth factor (IGF)-binding proteins in OSE cells, leading to estrogen-induced growth [56]. Moreover, IGF-1 signaling in these cells may be altered by the higher levels of plasma IGF-1 shown in severe cases of endometriosis [57] and the higher levels of IGF-1 in the peritoneal fluid of women with endometriosis [58]. In addition to IGF-1, the peritoneal fluid of women with endometriosis contains significantly higher levels of several other growth factors compared with patients without endometriosis. ...
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Objective: Endometriosis has been suspected of playing a role in the etiology of ovarian cancer. Design: This systematic review addresses the parallels and specific relationship of endometriosis and gynecological cancer regarding risk factors, histological data, genetic alterations, aberrant activation of oncogenic and antiapoptotic pathways, and options in clinical diagnosis. Data sources and eligibility criteria: We have performed a Pubmed search looking for all articles in English, using as key words "endometriosis", "ovarian cancer", "gynecologic cancer", "pathogenesis". Results: The evidence of the published studies suggests that ovarian tumors can arise from more than one potential source, endometriosis being one of these sources. Conclusion: Understanding the mechanism of the development of endometriosis and elucidating its pathogenesis and pathophysiology are intrinsic to the prevention of endometriosis associated ovarian cancer and the search for effective therapies.
... 20 Furthermore, a clinical study also demonstrated that GH administration increased serum levels of IGF-1, resulting in enhanced ovarian function. 22 In addition, IGF-1 and IGFBPs undergo hormonal control and are well known to enhance the mitogenic effects of estrogens. 23 Furthermore, studies have shown that serum IGF-1 levels are lower in postmenopausal women than in premenopausal women and that administration of levonorgestrel (either for contraception or for hormone therapy) decreased IGF-1 messenger RNA (mRNA) but stimulated IGFBP-1 mRNA in the plasma of treated postmenopausal women. ...
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Menoprogen (MPG), a TCM herbal formula improves menopausal symptoms in clinical trials, however its mechanism has remained elusive. Previous studies show that MPG is not directly estrogenic, thus the goal of this study was to investigate the effects of MPG on IGF-1 and IGFBP-1 levels in an aged female rat model of menopause. In a six-armed study, 14-month-old Sprague-Dawley (SD) female rats (n = 8 per arm) were randomly divided into an untreated aged group, an E2-treated aged group (17β-estradiol), and three arms with increasing doses of MPG groups (162, 324, or 648 mg/kg/day). The sixth arm contained four-month-old SD female rats as a normal comparison group. Four weeks after MPG or E2 administration, the animals were sacrificed after blood draws, and then ovarian tissues were excised. The levels of E2 and progesterone (P4) were determined by radioimmunoassay, and serum and ovarian tissue levels of IGF-1, IGFBP-1, and IGF-1 receptor (IGFR) were determined by ELISA. Compared with the normal group, the aged rats had significantly reduced serum levels of E2, P4, and IGF-1 and increased serum and ovarian tissue levels of IGFBP-1. MPG restored serum IGF-1 and IGFBP-1 levels and down-regulated the ovarian levels of IGFBP-1, which were closely related to increases of E2 and P4 levels in the aged rats. No significant differences were observed between the three doses of MPG for either IGF-1 or IGFBP-1. MPG has a direct in vivo effect in aged female rats by positively regulating serum and ovarian IGF-1 and IGFBP-1 levels.
... 20 Furthermore, a clinical study also demonstrated that GH administration increased serum levels of IGF-1, resulting in enhanced ovarian function. 22 In addition, IGF-1 and IGFBPs undergo hormonal control and are well known to enhance the mitogenic effects of estrogens. 23 Furthermore, studies have shown that serum IGF-1 levels are lower in postmenopausal women than in premenopausal women and that administration of levonorgestrel (either for contraception or for hormone therapy) decreased IGF-1 messenger RNA (mRNA) but stimulated IGFBP-1 mRNA in the plasma of treated postmenopausal women. ...
Article
Menoprogen (MPG), a traditional Chinese medicine formula for menopause, improves menopausal symptoms; however, its mechanism remains unknown. Previous studies have shown that MPG is not directly estrogenic; thus, the goal of this study was to investigate the effects of MPG on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) levels in an aged female rat model of menopause. In a six-arm study, 14-month-old female Sprague-Dawley rats (n = 8 per arm) were randomly divided into the following groups: untreated aged, 17β-estradiol-treated aged (estradiol [E2]), and three arms with increasing doses of MPG (162, 324, or 648 mg/kg/d). The sixth arm contained 4-month-old female Sprague-Dawley rats as a normal comparison group. Four weeks after MPG or E2 administration, animals were killed after blood draws, and ovarian tissues were excised. Levels of E2 and progesterone (P4) were determined by radioimmunoassay. Serum and ovarian tissue levels of IGF-1, IGFBP-1, and IGF-1 receptor were determined by enzyme-linked immunosorbent assay. Compared with the normal group, aged rats had significantly reduced serum levels of E2, P4, and IGF-1, and increased serum and ovarian tissue levels of IGFBP-1. MPG restored serum IGF-1 and IGFBP-1 levels and down-regulated ovarian levels of IGFBP-1, which were closely related to increases in E2 and P4 levels in aged rats. No significant differences in either IGF-1 or IGFBP-1 were observed between the three doses of MPG. MPG exerts a direct in vivo effect on aged female rats by positively regulating serum and ovarian IGF-1 and IGFBP-1 levels.
... Various causalities can be considered for favorable tumor factors in uterine carcinosarcoma related to tamoxifen use. First, tamoxifen indirectly activates the PIK3CA/AKT/mTOR pathway via estrogen receptor to induce insulin growth factor 1 signaling that is recognized as the oncogenic risk factor for endometrial cancer [19,23,24]. Because gynecologic malignancy with the PIK3CA/AKT/mTOR pathway alteration is known to be associated with better prognosis [25,26], this may be a possible biological plausibility to support a high proportion of early-stage disease in tamoxifen-related uterine carcinosarcoma. ...
... Considerable attention was paid to the study of the prognostic, predictive, and diagnostic values of IGF/IGFBP levels circulating in the peripheral blood of ovarian cancer patients. On the one hand, and rather unexpectedly, the majority of retrospective epidemiological studies demonstrated the decreased IGF-I level in blood serum of ovarian cancer patients as compared with controls [17,24,49]. On the other hand, two prospective cohort studies investigating the relationship between circulating levels of IGF-I and its major serum binding protein IGFBP-3 and ovarian cancer risk [50,51] revealed that while there was no association between the circulating IGF-I or IGFBP-3 levels and the risk of the disease for all 214 women who subsequently developed ovarian cancer, among women diagnosed with ovarian cancer at age 55 years or younger, the relative risk was higher in those with serum IGF-I level, corresponding to middle or top tertiles than in women with IGF-I level in the lowest tertile (OR = 1.8; 95% CI 0.7-4.3 and OR = 2.4; 95% CI 0.9-6.4 ...
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Among various auto/paracrine growth-regulating signaling pathways an important role belongs to that of insulin-like growth factors (IGFs) and insulin. IGF-signaling system is actively involved in the regulation of both normal ovarian function and ovarian tumor growth. On the one hand, all members of this system are expressed in malignant ovarian epithelial cells, and the prognostic significance of this expression has been revealed for some of them in ovarian cancer patients in several studies. On the other hand, circulating IGFs/IGFBPs levels have not been undoubtedly associated with ovarian cancer risk or disease progression, but some of them can be regarded as supplementary serological ovarian cancer markers. An important route to the clinical application of IGF-signaling system studies in ovarian cancer is the growing possibility of using specific molecular targeted agents to suppress its growth-stimulating and other activities. However, the introduction of such agents to practical oncology has met serious problems, with the main difficulties resulting from the absence of reliable predictive molecular markers and metabolic side effects due to the tight connection between IGF-signaling and insulin-regulated processes. The prognostic and diagnostic values of various IGF system components and the current state of corresponding molecular targeted therapies development for ovarian cancer are reviewed.
... The pervasive practice of inserting steroids that induce estrogenization into a large segment of our food source, may account for some of the increase in estrogen influence on tissue receptors. 28,29,30 Coelomic (intestinal) metaplasia may explain the abnormal locations where endometrial implants have been found 31 . ...
... In studies in pregnant rats and rabbits with diabetes treated with moderate to high doses of insulin glargine, congenital abnormalities and abortions have been observed but were thought to be caused by hyperglycemia rather than the insulin [50]. Studies in rats and rabbits have not demonstrated embryo toxicity and teratogenicity concerns for insulin detemir [51]. In women with type 1 diabetes, insulin detemir was reported to be as well tolerated and safe as NPH regarding perinatal outcomes [52,53]. ...
... Estudios en animales no mostraron diferencias entre Detemir e insulina humana con respecto a embriotoxicidad y teratogenicidad 30 . Detemir presenta muy baja afinidad por el receptor IGF-1 y muy baja potencia mitogénica 11 . ...
Article
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Insulin analogues have been used in the treatment of diabetes in pregnancy and some of them off-label. To know the efficacy and safety of insulin analogues concerning mother and fetus, a literature review on the subject was carried out. Regarding Glulisine, there are no reports on its use on gestation. On Lispro, there are few randomized studies comparing its use to regular human insulin, however, there are several observational studies, mostly retrospective, that do not reveal an increased risk. On Aspart, research has been done on women with type 1 diabetes during pregnancy with a randomized controlled clinical trial comparing it to regular human insulin; its results were used as a basis for its approval in pregnant women. On Glargine, observational studies have been carried out, but none were randomized controlled. On Detemir, a randomized controlled trial that ended in 2011 was carried out, comparing it to NPH human insulin; its results supported the recent approval by the Federal Drug Administration (FDA) to be used in pregnant women. In conclusion, Lispro and Aspart are the options of fast-action analogues for use during pregnancy when the control of glucose postprandial elevations or the prevention of nocturnal and severe hypoglycemia with human insulin is not possible. The long-lasting analogue Detemir may be used during pregnancy, once it has been approved by national drug regulations. Randomized controlled studies during pregnancy are required for Glargine and cost-efficacy studies for all insulin analogues. Key Words: diabetes, Pregnancy, Insulin analogues
... Insulin-like growth factor-1 is an alkaline single chain polypeptide of 70 amino acids [15] that promotes cell growth, insulin release, immune function, and anabolism, while inhibiting apoptosis and growth hormone actions in vivo [16][17][18][19][20][21]. In recent years, there has been a concerted effect to separate and purify IGF-1 from the natural animal tissues, organs, or body fluids [22][23][24]. ...
Article
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An enzyme-linked immunosorbent assay (ELISA) was used to detect the content of insulin-like growth factor-1 (IGF-1) in velvet antler water extract. The ELISA was validated with respect to parallelism, recovery, intra-assay variation, and inter-assay variation. The practical working range of detection was estimated to be 0.8 to 200 ng/mL, and the recovery was 96.7% or more. The effect of sample matrix was assessed by serial dilution. The result indicated that this ELISA method is a reliable, safe, and cost-effective tool for determination of IGF-1 content in velvet antler and serum.
... The tumor microenvironment has been largely studied as a dynamic system orchestrated by several growth factor such as insulin like growth factor-I (IGF-I) (1)(2)(3)(4). IGF-I functions by autocrine and/or paracrine effect, in physiological and pathological processes, but is also involved in development and progression of various cancers such as ovarian cancer (5). High levels of free IGF-I and IGF-I activity are associated with elevated risk of progression in ovarian cancer (6). ...
Article
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Interaction between tumor cells and their micro-environment has a crucial role in the development, progression and drug resistance of cancer. Our objective was to confirm the role of Hospicells, which are stromal cells from the cancer microenvironment, in drug resistance and tumor cell growth. We demonstrated that soluble factors secreted by Hospicells activate several genes and upregulate the JAK/STAT signaling pathway in ovarian cancer cell lines. Hospicells express all insulin-like growth factor (IGF) family as detected by gene array, RT-PCR, protein array and immunocytochemistry. While focusing attention on the microenvironment, we considered the role of IGF-I in proliferation and survival of ovarian cancer cells. Indeed, IGF-I is a major regulator of different stages of cancer development. We studied the effect of exogenously added IGF-I on the regulation of ATP-binding cassette (ABC) genes (MDR1, MRP1, MRP2, MRP3, MRP5 and BCRP) in the ovarian cancer cell line OVCAR3 and validated the results obtained using the IGF-IR antagonist picropodophyllin. IGF-I regulates the expression of ABC genes in OVCAR3 cells via the PI3-kinase, MEK and JAK2/STAT3 signaling pathways. The OVCAR3 cell line when co-cultured with Hospicells showed a marked degree of drug resistance. The drug resistance observed could be amplified with exogenous IGF-I. Addition of IGF-IR inhibitor, however, reduced the degree of resistance in these exposed cells. Cells that were treated with anticancer drugs and then exposed to IGF-I showed an increase in drug resistance and, thereby, an increase in cell survival. This observation indicates that drug resistance of OVCAR3 cells increases when there is synergy between OVCAR3 cells and Hospicells and it is amplified when IGF-I was exogenously added. In conclusion, inhibition of IGF-IR and targeting of the JAK2/STAT3 signaling pathway can be a target for ovarian cancer therapy.
... Insulin Detemir. Studies in rats and rabbits have not demonstrated embryo toxicity and teratogenicity concerns for insulin detemir [58]. There has been one large randomised control trial of insulin detemir in pregnancy [59,60] and two small retrospective case series published of 10 and 18 women [61,62]. ...
Article
Excellent glycaemic control is essential in pregnancy to optimise maternal and fetal outcomes. The aim of this review is assess efficacy and safety of insulin analogues in pregnancy. Insulin lispro and insulin aspart are safe in pregnancy and may improve post-prandial glycaemic control in women with type 1 diabetes. However, a lack of data indicating improved fetal outcomes would suggest that there is no imperative to switch to a short acting analogue where the woman is well controlled with human insulin. There are no reports of the use of insulin glulisine in pregnancy and so it cannot be recommended. Most studies of insulin glargine in pregnancy are small, retrospective and include women with pre-existing diabetes and gestational diabetes. There appear to be no major safety concerns and so it seems reasonable to continue insulin glargine if required to achieve excellent glycaemic control. A head-to-head comparison between insulin detemir and NPH insulin in women with type 1 diabetes showed that while fetal outcomes did not differ, fasting plasma glucose improved with insulin detemir without an increased incidence of hypoglycaemia. The greater evidence base supports the use of insulin detemir as the first line long acting analogue in pregnancy but the lack of definitive fetal benefits means that there is no strong need to switch a woman who is well controlled on NPH insulin. There seems little justification in using insulin analogues in gestational diabetes or women with type 2 diabetes where the risk of hypoglycaemia is low.
... Its elevated concentration in follicle fluid contributes, together with insulin, to increased androgenesis, as well as to premature ovarian follicle atresia. The reciprocal effect of insulin-like growth factor (IGF- 1) strengthens the above mentioned symptoms [14]. Moreover, the studies showed that the increased concentration of testosterone in blood of women with PCOS is also affected by decreased production of SHBG (sex hormone binding globulin) by the liver, caused by inhibiting activity of insulin [19]. ...
Article
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Background: PCOS (polycystic ovary syndrome) is called a pathology of the XX century and affects at least 10-15% women of childbearing age. The therapy involves pharmacotherapy of hormonal imbalance, as well as the change of lifestyle, including the diet. Objective: Performing the quantitative assessment of components of diets of women with PCOS, comparing the results with current dietary standards for Polish people and defining dietary requirements for the patients. Material and methods: The study was performed on 54 women of childbearing age (average age 26.03± 5.52) with PCOS syndrome diagnosed according to on the Rotterdam criteria. Anthropometric measurements of the patients were made and BMI and WHR calculated. Quantitative assessment of women’s diets was performed based on the analysis of 3-day food diaries and food records taken from the previous 24h with the interview method. The data were introduced to a dietary software DIETA 5.0, calculating the average intake of the energy, nutrients, vitamins, minerals, cholesterol and dietary fibre. The obtained results were compared to Polish dietary guidelines. Results: Examined group was characterized by increased waist circumference (98.71± 13.6 cm) and an average WHR was 0.92± 0.08. An increased average value of BMI was also shown (28.91± 5.54 kg/m2). The patients consumed, on average, 1952.5±472.7 kcal daily, and the risk of insufficient intake of protein was determined in 36.7% of examined women. The highest risk of deficiency in minerals in women with PCOS was related to calcium (634 mg), potassium (3493 mg) and magnesium (250.1 mg), whereas with reference to vitamins deficiency as much as 70% of tested women were at risk of insufficient intake of folic acid, 36.7% of them - vitamin C, and 26.7% - vitamin B12. The average consumption of vitamin D was at the level of 3.4 μg. Test group was characterized by excessive average consumption of total fat (50%), SFA (70.4%) and saccharose (50%). The percentage of people with excessive average intake of cholesterol was at the level of 40.74%. As much as 83.3% patients consumed too low amounts of dietary fibre in their diets (<25g). Conclusions: In diet therapy of women with PCOS there should be higher intake of folic acid, vitamins D and C, cobalamin, dietary fibre and calcium. The consumption of total fats, saturated fatty acids and cholesterol should be reduced, as through facilitating the development of diabetes and cardio-vascular diseases, they affect the dysfunction of ovaries. The diet of some of the patients should be also supplemented by potassium, magnesium and zinc. The introduction of a properly balanced diet should be the key in the treatment of women with PCOS diagnosed according to Rotterdam criteria.
... On the other hand, PCOS women with normal androgen levels tend to be less exposed to serious metabolic problems [8]. However, they have a greater predisposition to the occurrence of some types of cancer [9,10]. This predisposition seems to be caused by an excessive inflammation that includes higher TNF-alpha concentration [11]. ...
... Research has shown that the increase in IGF-I in patients with PCOS is correlated with insulin resistance; furthermore, these patients are at a higher risk of developing breast, cervical and ovarian cancer [8]. The lack of a hormonal balance which causes disruptions between the hypothalamus pituitary gland and ovaries is also one of the causes of PCOS [9]. ...
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Objectives: An increase in IGF-I and TNF-α may be a cardioprotective effect. To examine the relationships between IGF-I and TNF-α and test the anthropometric and biochemical parameters before and after a low-glycemic index reduction diet using a correlation matrix. Material and methods: Twenty-two women diagnosed with PCOS according to Rotterdam's criteria were eligible for this study, which analysed the results before and after a three months dietary intervention. Body composition measurements were determined by bioimpedance and performed twice, along with the labelling of lipid, carbohydrate and hormonal profiles. IGF-I and TNF-α were also determined in the serum. Results: Before dietary intervention, a significant correlation was observed. A correlation was also noted between the increase in TNF-α and DHEA-SO4, FSH, glucose level and total cholesterol. The increase in IGF-I was not related to anth-ropometric measurements: however, its concentration was observed to be related to the level of SHBG and HDL. After dietary intervention, the correlation between TNF-α and muscle mass percentage was confirmed, as was the correlation between WHR and fasting blood glucose levels. A significant negative correlation was observed between extracellular water, provided in litres, and SHBG level. Conclusions: One important role of IGF-I in PCOS pathogenesis is the stimulation of increased synthesis of SHBG and HDL. The increased level of IGF-I after the reduction diet had a cardioprotective effect. TNF-α inhibits FSH synthesis, preventing the growth of numerous follicles. Its synthesis is also related to DHEA-SO₄. After three-month reduction diet does not significantly reduce TNF-α.
... An increased placental weight, an altered placental structure, or expression of vascular endothelial growth factor or other angiogenic factors might interfere with placental function and risk of macrosomia. 68 Much of the concern was about insulin glargine stemmed from in vitro experiments exposing human osteosarcoma cells (Saos/B10), not confirmed on other cell lines (Table 2). Moreover, in vivo studies have shown that insulin glargine is converted into 2 metabolites, which are metabolically active, and may account for most of the action of insulin glargine but which have an affinity for the IFG1 receptor that is comparable with that of human insulin. ...
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Background: A good metabolic control before conception and throughout pregnancy with diabetes decreases the risk of short- and long-term adverse outcomes of the mothers and their offsprings. Insulin treatment remains the gold standard treatment recommended for any type of diabetes. New technologies including new insulins and insulin analogues, continuous subcutaneous insulin infusion without and with sensors, the low-glucose predictive suspension function, and closed-loop systems that persistently and automatically self-adjust according to patients' continuous glucose monitoring readings have expanded the offer to clinicians for achieving tight glucose control. Areas of uncertainty: Unsafe effects of insulin and insulin analogues in pregnancy with diabetes could be linked with changes in insulin immunogenicity, teratogenicity, and mitogenicity. Second-generation insulin analogues need to be tested and proven. Effectiveness and safety of new insulin delivery systems in real life of diabetic women in pregnancy need further confirmations. Sources: MEDLINE, EMBASE, Web of Science, Cochrane Library, randomized controlled trials, systematic review and meta-analysis, observational prospective and retrospective studies, case series reports for the most recent insulin analogues, published in English impacted journals, and consensus statements from scientific societies I excluded 60 from 221 papers as not suitable for the purpose of the subject. Results: Subcutaneous insulin infusion can be safely used during pregnancy and delivery of well-trained women. Sensors are increasingly accurate tools that improve the efficacy and safety of integrated systems' functioning. Continuous glucose monitoring provides metrics ("time in range" time in "hypoglycemia" and in "hyperglycemia," glucose variability, average glucose levels in different time intervals) used as a guide to diabetes management; these new metrics are object of discussion in special populations. Randomized controlled trials have shown that sensor-augmented pump therapy improves pregnancy outcomes in women with type 1 diabetes. Closed-loop insulin delivery provides better glycemic control than sensor-augmented pump therapy during pregnancy, before, and after delivery. Conclusion: Second-generation insulin analogues and newer insulin infusion systems that automatically self-adjust according to patients continuous glucose monitor readings are important tools improving the treatment and quality of life of these women. Multi-institutional and disciplinary teams are working to develop and evaluate a pregnancy-specific artificial pancreas.
... В экспериментах на животных введение рекомбинантного гормона роста или его антагониста не приводило к закономерной модуляции секреции овариального ИФР-1. Не отмечалось и изменения экспрессии гена ИРФ-1 или рецептора ИФР-1 в доминантном фолликуле, в отличие от других органов СТГзависимого синтеза ИФР-1 -печени, матки [58]. ...
... Its elevated concentration in follicle fluid contributes, together with insulin, to increased androgenesis, as well as to premature ovarian follicle atresia. The reciprocal effect of insulin-like IGF-1 strengthens the above mentioned symptoms [8]. The studies also showed that the elevated concentration of testosterone in blood of women with PCOS is also affected by the decreased level of SHBG (sex hormone binding globulin), which is also modulated by insulin [16]. ...
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Background: Polycystic ovary syndrome (PCOS) manifests itself with various symptoms, therefore it interests representatives of many medical specializations: general practitioners, gynecologists, endocrinologists, dermatologists, cardiologists and those who deal with metabolic disorders, such as dieticians. Objective: The aim of this study was perform the qualitative assessment of components of diets of women with PCOS as one of the major factor contributing to the disease. Material and methods: The study was performed on 54 women of childbearing age with PCOS diagnosed according to on the Rotterdam criteria. Qualitative assessment of the diets on the basis of 216 menus was performed based on the analysis of 3-day food diaries and food records taken from the last 24-hour dietary interview. Diets quality assessment was made using three types of point tests: Szewczyński’s Diets’ classification (SDC), Bielińska’s Test with Kulesza’s modification (BTK), Healthy Diet Indicator (HDI). Results: Average waist-hip ratio (WHR) and body mass index (BMI) was above the standard 0.91± 0.08 and 29.16 ± 5.8 kg/m2. Qualitative analysis performed with point tests SDC, BT-K and HDI revealed that the majority of the diets were composed inappropriately, containing many mistakes. Statistically significant correlations (Pearson’s) were determined between HDI test and the body weight and BMI. When analyzing the type of the meals also the correlations (Spearman’s) between BMI and BMI category in BT-K test. Conclusions: Mistakes in diets of women with PCOS are the cause of metabolic disorders related to improper function of ovaries. Native test BT-K seems to be a better method then test SDC and probably HDI of assessing diet in women with PCOS from Poland.
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Introduction The major functions of the human ovary are the development, nurture, and release of a mature oocyte ready for fertilization and successful propagation of the species. In support of these processes, the ovary secretes steroid hormones which stimulate growth and development of organs of reproduction; are critically involved in the elaborate endocrine interchange which directs orderly, repetitive cyclic ovulations; and finally supports successful uterine implantation, placentation, and the corpus luteum-dependent phase of pregnancy. A description of how the ovary and its secretions achieve these reproductive functions is the focus of the first two chapters of this volume. In addition, it is now clear from observations in prolonged physiologic (menopause) and non-physiologic (gonadal failure) hypogonadal states that ovarian steroid secretions have important influences on a variety of non-reproductive organ systems which determine the quality of life and the life expectancy of women. A more complete treatment of these issues is dealt with in Chapter 2, How Steroid Hormones Work, and Chapter 20, Menopause. General principles The physiologic responsibilities of the ovary are the periodic release of gametes (oocytes) and the timely sequential secretion of the hormones estradiol (E2), progesterone (P), and the inhibins A and B. These endocrine signals integrate the hypothalamus, anterior pituitary, and ovaries in a continuous repetitive process of follicle recruitment, rescue, maturation, selection, ovulation, corpus luteum formation, function, and regression. But the ovary cannot be viewed as a static, purely endocrine organ whose size and function waxes and wanes, depending on the stimulatory input of tropic hormones. Rather, the female gonad is a heterogeneous, constantly changing organ with cyclicity measured in days and weeks, with each phase governed by a specific anatomic subunit.
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Background: Growing evidence suggests that cytokines not only are associated with ovarian cancer development, drug resistance and metastasis, but also may provide valuable markers for ovarian cancer diagnosis and prognosis. Here, we determined the expression profiles of 43 plasma cytokines in ovarian cancer patients using this high throughput protein array technology developed in our laboratory. Materials and methods: The expression of 43 cytokines from 13 ovarian cancer patients and 12 normal women was determined simultaneously using human cytokine antibody microarray technology. The differential expression of cytokines was analyzed using the Student's t-test and two-way hierarchical cluster analysis approach. Results: Our data showed that 22 cytokines were significantly increased in the plasma of ovarian cancer patients compared to normal women (t-test, two-tailed, p<0.05). The results from cytokine antibody array assays were in agreement with the published data, but also revealed a new group of cytokines whose expression levels were altered in ovarian cancer. Cluster analysis suggested an interesting link between cytokine profile and ovarian cancer. Conclusion: Human cytokine antibody arrays are a valuable tool to profile cytokine expression from patients' specimen. The cytokine profile may prove to be of diagnostic and prognostic significance in ovarian cancer.
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Ovarian folliculogenesis is regulated by a fine balance between endocrine and intraovarian factors. In this review, we focus on the role of growth factors in physiological folliculogenesis and in polycystic ovaries. Recent evidence shows that the main systems implicated in polycystic ovary folliculogenesis are the growth hormone and insulin-like growth factor system, vascular endothelial growth factor, and the transforming growth factor-β family. Growth hormone and the insulin-like growth factor system could affect follicular development and oocyte maturation if their balance was altered, while vascular endothelial growth factor is implied in follicular dominance by providing an increasing vascular supply. The transforming growth factor-β family is composed of various molecules, which have different roles in cellular proliferation. Finally, a series of different factors seem to be involved in altered polycystic ovary follicular growth.
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About 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. These results are alarming, as the world knows a pandemy of obesity and, in consequence, insulin resistance. Obesity may increase risk for various cancers by several mechanisms, including increasing sex and metabolic hormones, and inflammation. Here, we present a review of epi- demiological and molecular evidences linking obesity and cancer - particularly colorectal, post- menopausal breast, endometrial, pancreatic, high grade prostate, hepatocellular, gallbladder, kidney and esophageal adenocarcinoma. The expected striking increase in the incidence of cancer in the near future related to obesity turns the knowledge of this field of great impact as it is needed to the development of strategies to prevent and treat this disease. Arq Bras Endocrinol Metab. 2009;53(2):213-226.
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Endometriosis (MIM 131200) is a prevalent and complex gynecological disease polygenically inherited with multifactorial pathogenesis. It is increasingly recognized as a major women's health issue. Endometriosis is characterized by the presence of endometrial-like tissue in sites outside the uterus, mainly the pelvic peritoneum, ovaries and rectovaginal septum causing severe dysmenorrhoea, dyspareunia, chronic pelvic pain and subfertility. Recent advances in molecular technologies have provided many evidences about the underlying biological events that are likely to be involved in the development of endometriosis. Different chromosomal regions, genes and other molecules, such as microRNAs, have been identified as potentially involved in endometriosis pathogenesis. Moreover, genome-wide analyses of endometriosis have showed novel molecular signatures or individual genes that had not been previously associated with the disease. The goal of these studies is to provide information that might, in turn, lead to new therapies. In this review, some previous studies were updated supporting the polygenic/multifactorial inheritance and the association with malignant neoplasias. We have also emphasized the importance of identifying the causative genes and determining novel diagnostic and predictive biomarkers.
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Hyperglycemia in pregnancy may lead to adverse maternal, fetal and neonatal outcomes. Tight glycemic control is prudent in order to reduce pregnancy complications. For many years, the gold standard pharmacological therapy during pregnancy was human insulin. Recently, insulin analogues were also introduced to clinical use in pregnancy. This brief review aims to summarize the information on the efficacy and safety of insulin analogue therapy during gestation. The strengths and pitfalls of insulin analogue administration during gestation, compared with human insulin, are presented. According to studies in pregnant women with type 1 diabetes, insulins lispro, aspart and detemir are efficacious and safe. Accordingly, the FDA has reclassified them for the treatment of pregnant women with diabetes from category C to category B. Although large and prospective data on insulin glargine in gestation are still lacking, no major safety concerns were documented. No controlled trials with insulins glulisine and degludec were conducted in pregnancy. In sum, insulin analogues are practical therapeutic options for hyperglycemia in pregnancy, mainly due to their hypoglycemia risk reduction. More research for their use in pregnant women with gestational diabetes or type 2 diabetes should be conducted. Overall, their efficacy and safety is possibly comparable to human insulin.
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Introduction: Gestational diabetes mellitus (GDM), defined as glucose intolerance with first recognition or onset during pregnancy, is steadily rising in prevalence. GDM affects ∼ 3 - 5% of pregnancies in the US and is associated with significant adverse perinatal and maternal outcomes. Diagnosing and treating GDM early in pregnancy is of utmost importance as it can prevent poor outcomes such as macrosomia, shoulder dystocia and obstetric complications. Areas covered: This review describes the importance of treating GDM and the various available interventions for glycemic control in women with GDM, including the latest evidence regarding pharmacological treatments and specifically anti-hyperglycemic agents. It deals with timing of pharmacological treatments, recommended doses and what pharmacological agent should be used. Expert opinion: Unless diagnosed late during pregnancy, a stepwise approach is the best way to treat GDM, beginning with diet and exercise and proceeding to pharmacological interventions if failure occurred. Although insulin is the dominant treatment, the use of anti-hyperglycemic agents such as glyburide and metformin in treating GDM has gained popularity and consideration should be made using these agents as first-line pharmacological treatment. Anti-hyperglycemic agents do not require frequent monitoring or injections and may therefore appeal more to patients. Further studies are needed regarding long-acting insulin and other anti-hyperglycemic agents such as thiazolidinediones, as well as identifying treatment options more specific to an individual based on risk factors and other variables predicting treatment outcomes in GDM.
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Pregnant women with diabetes are at greater risk for adverse outcomes, such as miscarriage, macrosomia, and preterm birth. Advances in the care of diabetes have reduced maternal and perinatal mortality rates to the levels expected in nondiabetic pregnancies. Lifestyle modification such as medical nutritional therapy and exercise is a first step in therapy for gestational diabetes. Rapid-acting insulin analogs (lispro, aspart) are comparable in safety and superior in glucose control to regular human insulin. Because the safety of long-acting insulin analogs (glargine, detemir) in pregnancy has not firmly established, the use of human insulin is preferred over basal insulin. Among the oral hypoglycemic agents, metformin and glyburide might be considered as alternative therapies.
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Introduction Surgical assessment and histologic evaluation are the only means by which a neoplasm can be classified as benign or malignant, primary, or metastatic. When an early primary ovarian cancer is diagnosed, the next goal is determining the extent of disease or stage. Surgical staging is required to define those patients in whom surgery alone may be curative and those who will require adjuvant therapy, and to determine the modality, intensity, and duration of such treatment. Accurate surgical staging also permits assignment of prognosis, allows comparison of cure rates, and defines subsequent surveillance. In the 70 to 75% of patients who present with advanced ovarian cancer, the goal of laparotomy is also to remove as much tumor as possible through a process of surgical "cytoreduction" to maximize response to chemotherapy, and improve survival. We offer epithelial ovarian cancer as a model; the principles of treatment also apply to ovarian germ-cell tumors, stromal tumors, and other primary ovarian cancers.
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Introduction Germ cell tumors (GCT) are a fascinating group of tumors exhibiting a large variety of pathological patterns and occurring in clinical settings that often include developmental, genetic, and hormonal disorders. These tumors are unique because they involve gonads of both sexes, ovaries and testes, and are seen mostly in young patients. Actually, they represent about 60% of all ovarian tumors diagnosed in patients under the age of 30. With the exception of dermoid cysts (benign, mature cystic teratomas), they are uncommon neoplasms; fortunately, the most common are benign and conversely, the malignant tumors are the least common. Their clinical outlook has changed dramatically for the better, over the past decades, due to their responsiveness to chemotherapy. The pathologic characteristics of ovarian germ cell tumors are also unique: they are composed of multiple tissues, occurring in various degrees of maturation from their cells of origin (the germ cells) as well as in various histologic tissue combinations. Some germ cell tumors are associated with sex-cord tissue derivatives. Germ cell tumors represent one-third of all malignant tumors seen in young females and about 20% of all ovarian tumors in Europe and North America. In Asia and Africa, they represent a much larger proportion of ovarian tumors because the prevalence of epithelial-stromal-derived tumors is much lower.
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Introduction Menopause is the "landmark" in a woman’s life when she experiences permanent cessation of menstruation. The collective follicle capacity of the ovaries to secrete adequate estradiol diminishes to a level at which proliferation of an endometrium adequate to produce menstruation is no longer achievable. But menopause is justifiably more than simply loss of menses or even reproductive competence. Although some ovarian steroid secretion continues transiently beyond this critical point and limited extra-gonadal production of estrogen may persist, at menopause the ability of the ovaries to function as endocrine organs capable of providing sufficient hormone to sustain the estrogen-dependent biologic aspects of a wide variety of tissues has also ceased. Reviewed in Chapter 2, estrogen modulates a broad array of non-reproductive functions including bone and mineral metabolism, cardiovascular function, fuel and metabolic homeostasis, neuropsychiatric balance, and the risk of progression of age-related neurodegenerative diseases. The consequences of age combined with a prolonged hypoestrogenic state and the various reactive strategies available to meet these challenges will be reviewed in this chapter. It will deal with the definitions of the various phases surrounding menopause and the sometimes paradoxical endocrinology of each stage. In addition, the increased metabolic, endocrine, cardiovascular, and cancer risks accompanying aging and how these might be affected by a prolonged state of hypoestrogenism will be analyzed. The benefits-risks of hormonal replenishment and an individual-appropriate clinical management algorithm is provided. The effort will be inclusive but not exhaustive; it should encourage the reader to pursue more encyclopedic resources [1-6], which are emphasized in the text.
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Introduction Aside from primary ovarian malignancies, ovaries are a frequent site of metastases from other primary tumors, mostly from the gastrointestinal tract, breast, and other gynecological organs. Metastatic tumors to the ovaries are an important group of ovarian neoplasms, and their correct pathological interpretation is paramount for the right treatment of the patient. It can be very difficult for a pathologist to diagnose metastatic disease of the ovary because it often mimics a primary ovarian malignancy. Evaluating the metastatic nature of an ovarian tumor depends on the clinician’s and pathologist’s knowledge about the frequency of metastases of different primary tumors, a complete clinical history, a careful evaluation and re-evaluation of the gross pathology of the specimen and also, use of special stains and immuno-histochemistry. The diagnosis of metastatic ovarian tumor should be considered when the anatomical distribution of the disease is atypical for primary ovarian cancer, when the patient has another tumor outside the ovaries and when both ovaries are involved by the tumor, although unilaterality of the tumor is not a definite argument against one’s metastatic nature (different studies show bilaterality of ovarian metastatic tumors in approximately 70% of cases) [1,2]. Other tumoral findings suggestive of metastasis are: size less than 10 cm, tumor grossly visible on the surface of the ovary, presence of multiple tumor nodules often growing in a desmoplastic stroma, and lymphatic and/or blood vessels invasion (more pronounced in the ovarian hilum).
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Introduction Endometriosis is a common gynecological disease that affects 6% to 44% of all women of reproductive age [1]. It is defined as the presence of endometrial tissue, consisting of both glandular epithelium and stroma outside the uterus. The most frequent sites of implantation are the pelvic viscera and the peritoneum. Three different clinical entities of endometriosis can be distinguished: peritoneal endometriosis, ovarian endometriosis, and deep invasive (or infiltrating) endometriosis. They vary in appearance from a few minimal lesions on otherwise intact pelvic organs to large ovarian endometriotic cysts that affect tubo-ovarian anatomy and extensive adhesions often involving the bowel, bladder, and ureters. It is associated with pelvic pain and subfertility, and has a detrimental impact on quality of life [2,3]. Etiology Although signs and symptoms of endometriosis have been described since 1896 by von Recklinghausen, its widespread occurrence was acknowledged during the 20th century. Even 120 years after its first description, the pathogenesis of this condition remains poorly understood. Endometriosis is an estrogen-dependent disease. Three main theories have been proposed to explain the histogenesis. Ectopic transplantation of endometrial tissue Coelomic metaplasia Induction.
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Introduction Only a minority of ovarian cancers of epithelial origin are diagnosed in early stages, when confined to the ovaries. This is the main reason for the high mortality due to this elusive neoplasm, the most lethal of all gynecologic cancers. The 5-year survival of patients diagnosed with stage I ovarian cancer, confined to the ovaries is 80-90%, as compared to the 5-year survival rate of 19-32% for late stages of the disease, when extended to other pelvic and/or abdominal sites. The majority of patients (80-85%) are diagnosed in stage III-IV [1]. Early detection of ovarian carcinoma represents a major challenge for the women healthcare community. Absence or paucity of specific symptoms and of reliable tumor markers are considered the main obstacles to unmask this "silent killer" at its inception. Histopathology and classification The vast majority of ovarian carcinomas (OC), tumors originating in the ovarian epithelium which represents an extension of the peritoneal mesothelium, are serous papillary carcinomas. According to recent histopathologic studies based on molecular biology, the serous carcinomas involving most ovarian cancers, more often than previously thought, involve the fallopian tube and the pelvic peritoneum. Actually, for many late stage ovarian cancers, it is difficult if not impossible to establish the anatomic origin of the neoplasms; therefore, it was suggested to include ovarian, fallopian tube, and peritoneal tumors in the term"pelvic serous carcinoma" [2]. They represent about 68-87% of all ovarian cancers. They are associated with BRCA1 and 2 mutations more often than the non-serous carcinomas. Also included in this group are malignant mixed Mullerian tumors (MMMT), many of which were proven by immuno-histochemistry to be poorly differentiated carcinomas, occasionally admixed with malignant stromal elements. OC histologically diagnosed as "non-serous" include endometrioid, mucinous, and clear cell carcinomas, and are by far less numerous.
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Hecht [1] was the first who studied the role of heredity in acne. Neonatal, nodulocystic, and conglobate acne have proven genetic influences [2]. Postadolescent acne is related with a first-degree relative with the condition in 50 % of the cases. Chromosomal abnormalities, HLA phenotypes, and polymorphisms of various genes have been associated with acne. Data from family studies confirmed familial clustering [3-5]. High heritability estimates for acne in twins were reported [6, 7]. Higher correlations of sebum excretion and the proportion of branched fatty acids in the fraction of sebaceous wax esters were found in monozygotic vs. dizygotic twins [8, 9]. A large twin study demonstrated that 81 % of the variance of the disease was attributed to additive genetic effects, whereas the remaining 19 % was attributed to unique, unshared environmental factors [10]. Apolipoprotein A1 serum levels were significantly lower in acne twins [10]. A family history of acne is associated with earlier occurrence of the disease, increased number of retentional lesions, and therapeutic difficulties, especially a higher risk for a relapse after oral isotretinoin treatment [11]. Another twin study revealed that heritability of acne on the back was very high [12]. Remarkably, at age 14 years, facial acne in girls was less influenced by genetic factors than in boys and was significantly influenced by common environmental factors [12].
Article
Among all cancers, increasing body mass index is most strongly associated with endometrial cancer incidence and mortality. The molecular mechanisms underlying the role of obesity, and in particular the role of visceral fat, to the pathogenesis of endometrial cancer are becoming better understood. The current body of knowledge suggests several rational strategies, including behavioral, pharmaceutical, and surgical interventions, can be used to circumvent or derail the aberrant signaling pathways and hormonal abnormalities associated with obesity. Given the growing worldwide obesity epidemic, the development and availability of therapeutics, which can reduce the impact of obesity on endometrial cancer risk is imperative. © 2013 Springer Science+Business Media New York. All rights are reserved.
Article
Unlabelled: Insulin-like growth factor 1 (IGF-1), produced and secreted locally may affect the mechanisms of folliculogenesis and cause ovarian dysfunction, characteristic of PCOS. The expression of the IGF-1 gene gives rise to three different isoforms of the original molecule. Until now, the role of IGF-1 isoforms has been documented in the repair processes of damaged muscle fibers, cardomyocytes, hepatocytes, and neurons. The literature offers no reports on the presence and role of IGF-1 isoforms in the ovary Objectives: The aim of the study was to assess the IGF-1A, B and C isoforms at the level of IGF-1 gene transcription in the ovaries of PCOS women and healthy controls. Material and methods: Serum samples and ovarian tissues from PCOS women, treated and non-treated with metformin (PCOS M(+); n = 12 and PCOS M(-), n = 37, respectively), and controls (n = 21) were obtained. The expression of mRNA species of IGF-1 in the ovaries was determined by quantitative RT-PCR. Results: The presence of transcripts of three types of IGF-1 isoforms was observed in healthy controls and PCOS patients, regardless of metformin treatment. Total expression of all isoforms was higher in the M(-)(Me-26640) group as compared to the M(+)(Me- 13470) group, as well as controls (Me-17030)-(not significant, p = 0.061). Similar results for IGF-1A were obtained in all groups. The relative expression of IGF-1A was lower in the M(-)(86.02%) group and differed statistically from controls (91.38%) (p = 0.011). Conclusions: We detected the presence of mRNA for three IGF-1 isoforms in human ovary. To the best of our knowledge, this has been the first report on the presence of mRNA for three IGF-1 isoforms in human ovary. We found differences in the relative expression of IGF-1A isoforms between the investigated groups.
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Introduction In recent studies of the origin(s) of pelvic serous carcinoma, two concepts have emerged: the fallopian tube as a major source for these tumors and a carcinogenic sequence in the distal fallopian tube. The first has immediate implications for both the early detection and classification of this disease. The second impacts on the pathogenesis of tubal malignancies and has important implications for the histologic diagnosis. In particular, the discovery of benign-appearing secretory cell outgrowths (SCOUTs) in the fallopian tube that contain functional gene perturbations shared with cancer requires a reassessment of the concept of intra-epithelial neoplasia. This exercise requires the separation of innocuous clonal expansions or outgrowths of no clinical significance from those with the potential, albeit low, to metastasize. In this chapter, we introduce the term "intra-epithelial neoplasia" to denote the latter, preferring to relegate epithelial processes of lesser degree to a descriptive category that although linked to cancer, do not belong in the diagnostic lexicon. In this spectrum may lie the genetic changes that mark the acquisition of the metastatic phenotype. We emphasize that, while this progression is most closely linked to serous carcinomas, it can occur with other phenotypes, including endometrioid and, rarely, mucinous neoplasia. Finally it is important to superimpose this new information on the existing concept of ovarian and peritoneal carcinoma. In both instances, it is useful to look at both low- and high-grade serous neoplasms and the potential contribution of the fallopian tube in their pathogenesis.
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Introduction The subject of ovarian cysts and tumors in the young patient has often been overlooked. Our house staff-resident teaching programs in gynecology teach the traditional gynecologic problems of the mature woman. Training of pediatricians also has overlooked gynecologic problems. The young patient in all aspects is completely different from the mature woman. The young patient has frequent functional physiologic benign cysts (simple follicle cysts; complex corpus luteum cysts), most of which are asymptomatic and self-limited. They are often discovered by coincidence when a pelvic or abdominal ultrasound examination is done on a child for other purpose, usually pain. It takes clinical judgment and experience to decide whether the pain is due to the cyst or perhaps due to another cause, such as a gastrointestinal problem. Ovarian cysts are often a normal developmental occurrence in neonates, children, and adolescents. They are common, frequently regress, and are seldom associated with malignancy [1]. Benign mature teratoma (dermoid cyst) is the most common cystic ovarian neoplasm in the adolescent. They are solid masses which are often palpable and with symptoms of pressure, increased abdominal girth, and with or without pain. About one-third of solid neoplasms may be malignant. The goal of surgical treatment of the young patient aside from preserving her health is to preserve fertility if at all possible. The latter is often possible because the malignant ovarian tumors including germ cell cancer (MOGC) usually do not involve the opposite ovary.
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Introduction In the United States, bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease is commonly done to prevent the subsequent development of ovarian cancer. Almost all BSOs (87%) are done at the time of hysterectomy [1]. Oophorectomy rates appear to have peaked recently, with 55% of hysterectomies accompanied by the procedure in 1999 compared with 39-45% in more recent years [2-4]. Recent data show age remains the strongest predictor of elective BSO, with 40% of women 40-44 years old, 78% of women 50-54 years old, and 68% of women 55 years or older having had BSO at hysterectomy [5]. Despite the common practice of "risk-reducing" or prophylactic oophorectomy at the time of hysterectomy for benign disease, an increasing body of evidence suggests removal of normal ovaries has minimal overall benefit for those women who are not at an increased risk of breast or ovarian cancer. Several large cohort studies suggest that, while removing normal ovaries reduces the risk of ovarian cancer to almost zero, prophylactic oophorectomy does not appear to increase overall survival. This chapter will address the history of risk-reducing oophorectomy, assess the evidence for the practice, and consider its appropriateness in light of recent studies.
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Introduction The ovaries are paired almond-shaped organs located along each pelvic sidewall. Normal ovarian volumes range up to 20 mL and 8-10 mL in pre-menopausal and post-menopausal women, respectively [1]. Each ovary is covered by surface epithelium and encloses numerous follicles, containing germ cells (eggs), within the ovarian stromal tissue [2]. With each menstrual cycle, a follicle matures and releases its ovum into the fallopian tube and then becomes a corpus luteum, which in the absence of pregnancy involutes to form a corpus albicans. Ovarian cancer is the ninth most common cancer among women worldwide. It is the fifth most common cause of female cancer-related death. Ovarian cancer causes more deaths than any other cancer of the female reproductive tract. In 2013, in the United States there will be an estimated 22,240 new cases of ovarian cancer diagnosed and 14,030 deaths from the disease [3]. Risk factors for the development of ovarian cancer include advanced age, nulliparity, early menarche, late menopause, and long-term hormone replacement therapy [4]. Furthermore, approximately 10% of ovarian cancers are related to genetic mutations with the breast and ovarian cancer genes, BRCA1 and BRCA2, and Lynch II syndrome accounting for the majority of these cases [3-5].
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Introduction The surface ovarian epithelium is considered to be the most common origin of ovarian neoplasms, both benign and malignant. Composed of a single layer of cuboidal cells, as an extension of the peritoneal mesothelium, the ovarian surface epithelium is closely related to the adjacent ovarian cortical stroma and some tumors arising in the area include both epithelial and stromal elements. Recent studies suggest that the fallopian tube epithelium, benign or malignant, that implants on the ovary is the source of low-grade and high-grade serous carcinoma [1]. Benign ovarian tumors of epithelial origin are fortunately far more common than malignant ovarian tumors. Borderline ovarian malignancy will be discussed in a separate chapter (Chapter 5) due to their complex and often controversial clinical-pathologic correlations. The histogenesis of ovarian epithelial tumors, their classification, grading, and inter-relationship has recently been the object of extensive research and of fundamental changes, based on new molecular and genetic discoveries. This process is still unfolding, although several established facts have contributed to a revision of previously accepted histopathologic categories.
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Introduction In early 2006, a third "positive" phase 3 randomized trial examining intra-peritoneal cisplatin-based chemotherapy as primary treatment of small-volume residual advanced ovarian cancer was reported [1]. This outcome led the United States National Cancer Institute to issue a "Clinical Announcement" describing the impact of this management strategy on outcome in this malignancy [2]. Since that time, several favorable and unfavorable critiques regarding this strategy have been published [3-7], revealing the controversy surrounding this novel management strategy. This chapter will review the basic biological foundation supporting intra-peritoneal chemotherapy in the management of ovarian cancer, clinical trial data supporting its routine use, and possible strategies to improve both the efficacy and toxicity associated with regional drug delivery in this setting. Rationale for intra-peritoneal chemotherapy and early phase clinical trials The theoretical rationale for delivering regional chemotherapy as treatment of ovarian cancer has previously been described in detail [8-12]. In brief, the arguments include the following considerations: (a) anatomic localization and natural history of the malignancy [9,10]; (b) pharmacokinetic advantage associated with the intra-peritoneal delivery of anti-neoplastic agents with known activity in ovarian cancer [11], and pre-clinical evidence for the impact of a clinically relevant "dose-response" effect for specific cytotoxic drugs against ovarian cancer at concentrations that are potentially achievable with regional delivery, but not after systemic administration [12].
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Turner syndrome (TS) affects approximately one in 2500 live-born females [1]. This disorder presents the clinician with a challenging array of genetic, developmental, endocrine, cardiovascular, psychosocial, and reproductive issues. For the purpose of this chapter, Turner syndrome will be used to describe the patient with an abnormality of the chromosomal karyotype involving loss of part or all of the X chromosome associated with phenotypic abnormalities that include short stature and the potential for or the presence of ovarian failure. Definition The diagnosis of TS requires the presence of characteristic physical features in phenotypic females coupled with complete or partial absence of the second sex chromosome, with or without cell line mosaicism [2-4]. Individuals with a 45, X cell population but without clinical features are not considered to have TS. Phenotypic males are also excluded from the diagnosis of TS, regardless of karyotype. Whether to diagnose individuals with sex chromosome structural abnormalities as having TS requires clinical judgment. Abnormalities such as ring X and Xq isochromosomes are common in patients with classic TS features, and many of these patients have phenotypes indistinguishable from that of patients with apparently non-mosaic monosomy X (45, X) [4]. Patients with small distal short arm deletions (Xp-) including the SHOX gene frequently have short stature and other TS-associated skeletal anomalies, but most are at low risk of ovarian failure and should generally not be diagnosed with TS if band Xp22.3 is not deleted [5]. Individuals with deletions of the long arm distal to Xq24 frequently have primary or secondary amenorrhea without short stature or other TS features [6]; the diagnosis of premature ovarian failure is more appropriate for them. Table 3.1 summarizes the cytogenetic findings in TS patients.
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Introduction Estrogen (E) and progesterone (P) play central roles in both the endocrine and intracrine regulation of all aspects of female reproduction [1-3]. In the reproductive system they act at the level of the hypothalamus, anterior pituitary, ovary, and uterus to coordinate neuroendocrine-directed pulsatile secretion of gonadotropin releasing hormone, cyclic release of gonadotropins FSH and LH, ovulation, and endometrial development in preparation for implantation and maintenance of the fertilized embryo. In addition, both hormones are essential for pubescent and pregnancy mammary gland development (a complex set of multiple instructions condensed in simplest terms as ductal morphogenesis in the case of E and further ductal branching with lobulo-alveolar differentiation in the case of P). However, the physiologic activities of these steroids are not limited to reproductive system functions; their roles, particularly those of estradiol (E2), the primary estrogen, also include regulation of lipid and carbohydrate metabolism, the integrity of the cardiovascular system, the central nervous system, and skeletal homeostasis. It is in this broad spectrum of effects that the general understanding of the biology of these hormones has been expanded, distilled, and crystallized in cell- and tissue-specific receptor and post-receptor functional contexts. It is in the unraveling of the complexities of how these steroids work that the most revealing biologic and pharmacologic information has emerged. Among these new insights are: (1) ligand availability, variability, and tissue specificity; (2) new signaling pathways responsive to variable ligand/receptor aggregates localized in various cellular sites; (3) new modes of genomic and non-genomic action; (4) fuller understanding of the formation of receptor complexes with assemblies of either activators or repressors (transcriptomes and signalsomes); and (5) the translational and post-translational epigenetic accommodations which achieve signal-specific functional impact.
Article
Background Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. The present study aimed to evaluate the effects of Rosa damascena (RD) extract in estradiol valerate (EV) induced polycystic ovary syndrome rats. Material and Methods Adult female Wistar rats were divided into control (n = 12) and PCOS groups (n = 36). The PCOS model was induced using EV (4 mg/kg/day), which was confirmed in 6 rats in each control and PCOS group by observation of irregular estrous cycles in vaginal smears and ovarian multiple cystic. Then, the rest of the control group (n = 6) and PCOS rats (n = 30 in 5 divided groups) were treated orally for 28 days with metformin (MET) as a positive control (200 mg/kg/day) and RD extract (400, 800, and 1200 mg/kg/day, respectively). Body and ovary weights, biochemical and histological parameters, and expression of the IGF-1 gene were measured. Results Compared to the PCOS group, metformin and higher doses of RD extract (800 and 1200 mg/kg/day) significantly reduced BW, HOMA-IR, FBS, FINS, TG, LDL, TT, E2, LH, TC, and liver enzymes, and increased HDL and FSH levels. In addition, ovarian weight and CFs decreased, and the findings showed an increment in PFs, CLs, PAFs, AFs, and GFs. IGF-1 gene expression levels were significantly decreased (P < 0.001). Conclusions RD extract seems to have the potential therapeutic effect of alleviating PCOS complications, and IGF-1 signaling may be involved in the beneficial effects of RD on PCOS.
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Estrogen sensitizes the MCF-7 estrogen-responsive breast cancer cell line to the mitogenic effect of insulin and the insulin-like growth factors (IGFs). This sensitization is specific for estrogen and occurs at physiological concentrations of estradiol. Dose-response experiments with insulin, IGF-I, and IGF-II suggested that the sensitization is mediated through the type I IGF receptor. Binding experiments with 125I-IGF-I and hybridization of a type I IGF receptor probe to RNA showed that the levels of the type I IGF receptor and its mRNA are increased 7- and 6.5-fold, respectively, by estradiol. IGF-I and estradiol had similar synergistic effects on other estrogen-responsive breast cancer cell lines, but IGF-I alone increased the proliferation of the MDA MB-231 cell line which is not responsive to estrogens. These experiments suggest that an important mechanism by which estrogens stimulate the proliferation of hormone-dependent breast cancer cells involves sensitization to the proliferative effects of IGFs and that this may involve regulation of the type I IGF receptor.
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The GH/IGF-I axis has a clearly established role in somatic growth regulation and there is much evidence suggesting that it can play a contributing role in neoplastic tissue growth; a number of recent epidemiological reports indicate that it may also be an important determinant of cancer incidence. Whilst there have been previous reports of changes to the axis in patients with established cancers, these new studies are distinct in being prospective and the inferences that can be made from this are outlined in this review. The recent studies are considered within the context of other indirect epidemiological evidence, and together indicate that the GH/IGF-I axis may establish the level of predisposition to a number of common cancers and indeed that such risk may be programmed from early life. There is considerable evidence for a number of possible mechanisms, both direct and indirect, which could account for the associations between GH/IGF-I levels and cancer incidence; these mechanisms are briefly sum-marised. The implications of the new findings are then discussed in relation to the increasing clinical usage of chronic GH administration and the need for further studies to establish any consequent increase in cancer risk. Finally the opportunities for further work to optimise cancer risk assessment and risk reduction strategies are highlighted.
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The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.
Article
While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin‐like growth factor‐I (IGF‐I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor‐β1 (TGF‐β1), an antagonist of IGF‐I, in endometrial carcinoma, we investigated the expression of IGF‐I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF‐I receptor in 30 formalin‐fixed, paraffin‐embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF‐I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF‐I mRNA in endometrial carcinomas compared with non‐neoplastic tissues, despite equivalent immunohistochemical expression of IGF‐I and IGF‐I receptor. Our data suggest that IGF‐I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF‐I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression. Int. J. Cancer 80:188–193, 1999. © 1999 Wiley‐Liss, Inc.
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Understanding whether granulosa cells are normal or abnormal in women with polycystic ovary syndrome (PCO) could have clinical importance. For this purpose, we compared the ability of normal and PCO granulosa cells to synthesize oestrogen and progesterone in vitro in response to follicle stimulating hormone (FSH) and/or insulin-like growth factor-I (IGF-1). The normal granulosa cells were from a 7 mm dominant follicle from a women with regular menstrual cycles. The PCO granulosa cells were from 5–7 mm follicles of three patients who had classical PCO. Several interesting points emerge from the comparison: in each PCO patient there was a high level of bioactive FSH in the follicular microenvironment (≥5 mIU/ml; ≥250 ng/ml). This is paradoxical because the concentration of steroids in follicular fluid suggests that PCO follicles are highly atretic and therefore should not contain detectable FSH activity. The capacity to secrete progesterone when challenged with a maximally effective dose of FSH and/or IGF-I, was markedly reduced (8- to 10-fold) in PCO compared to normal granulosa cells. This is in sharp contrast to the oestradiol responses which were much the same for PCO and normal granulosa cells. Also, the time course and dose-response effects of FSH showed some major differences between normal and PCO cells, that is, PCO cells lost their capacity to produce oestradiol when treated continuously with a maximally effective dose of FSH. They were also significantly more sensitive to FSH and failed to become more sensitive to IGF-1 when treated with FSH. Thus, it seems that PCO granulosa cells may have abnormal responses to FSH. The importance of understanding the mechanism is apparent since it may in part explain the blockade of follicle selection in PCO.
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Insulin-like growth factor I (IGF-I) levels were measured in both serum and fluid of preovulatory follicles (n = 156) in 43 women undergoing in vitro fertilization (IVF). The mean IGF-I level in follicular fluid (FF) was significantly lower than in serum (0.52 ± 0.02 IU/L versus 0.66 ± 0.23 IU/L), and FF levels were significantly correlated with individual serum IGF-I levels as well as with follicular size and FF volume but not with oocyte maturity, granulosa cell appearance, or IVF. This suggests that FF IGF-I levels cannot serve as a clinical indicator for the degree of oocyte/granulosa cell differentiation or a predictor for IVF. Serum IGF-I levels were inversely correlated with the number of human menopausal gonadotropin ampules administered during treatment, suggesting that IGF-I might enhance ovarian gonadotropic stimulation.
Article
Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. Objective To investigate the effect of oral contraceptive (OC) pills, given for 3months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. Patients Seven women with PCOD and five healthy control subjects. Interventions An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. Results After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326±70 μ g/L to 199±28 μ g/L, after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235±11 μ g/L to 226±11 μ g/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24±7 μ g/L to 73±14 μ g/L, in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44±11 μ g/L to 61±9 μ g/L). Conclusion The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.
Article
Transferrin and somatomedin C receptors (TFr and SMCr) were studied in human ovaries by immunostaining using monoclonal antisera. The oocyte of evoluting follicles was intensely positive for both types of receptors, but this positivity decreases in large follicles. An evident positivity for both TFr and SMCr was shown in granulosa cells of evoluting follicles. However, not all of these cells were equally immunoreactive. An intense positivity was present in the developing thecal cells of early cavitary follicles as well as in thecal cells of follicles of medium and large size (>6 mm) and in some cells of involuting follicles in initial atresia. These results seem to demonstrate that TFr and SMCr are present in different cellular components of the human developing and early involuting follicles.
Article
Two prepubertal girls with Laron Syndrome (GH resistance) aged 11.6 and 13.8 years were treated by daily injections of insulin-like growth factor-I (IGF-I) (150 υg/kg) to improve their short stature. The treatment induced puberty and a progressive increase in serum androgens with clinical virilization resembling polycystic ovary syndrome. These effects were shown to be due to a progressive increase in serum IGF-I levels by generation of IGFBP (binding protein)-3 by IGF-I. Temporary interruption of the treatment and its resumption in smaller doses (50 μg/kg) abolished the virilization and permitted normal feminine pubertal development. It is concluded that long-term IGF-I treatment requires constant monitoring of serum IGF-I to avoid progressive overdosage and the appearance of undesirable effects.
Article
Intraovarian regulation and the potentiating effect of growth hormone, growth factors and their binding globulins on theca and granulosa cell response to gonadotropins has been demonstrated. This may have a significant impact in ovulation inducing therapy, in the understanding of some ovulatory disorders such as the polycystic ovarian syndrome, and in the pathogenesis of the hyperstimulation syndrome. Recently 3 observations claimed that GH administration increased ovarian sensitivity to gonadotropin stimulation, while one author, investigating ovulatory patients in an IVF program, could not demonstrate such an effect. This contradictory finding could be explained by our demonstration that anovulatory patients with 'poor response' and a low GH reserve either need excessive amounts of gonadotropins to obtain an acceptable response, or despite higher doses of hMG respond inadequately. The combined administration of GH and hMG to such patients resulted in good ovarian response despite a significantly lower dose of hMG. In patients with a good GH reserve the addition of GH had no significant effect on hMG dosage or response. Such tests may serve as preliminary differentiating indicators of ovarian sensitivity to hMG in poor responders and may help to select patients who may benefit from the combined GH-hMG therapy. However the role of growth factors in ovarian modulation must not be overestimated, since we also demonstrated, that follicular stimulation, ovulation and conception can occur in a 'Laron Dwarf', a condition characterized by elevated GH, absence of GH receptors, and lack of IGF-1. It can thus be concluded that IGF-1 is not obligatory for normal follicular development, but may play a permissive modulating role in ovarian function. This hypothesis endorses the possibility that pathologies leading to an imbalance of growth factors and their binding globulins may augment ovarian response to both FSH and LH resulting in enhanced follicular development, excessive androgen production and finally in the formation of a typical polycystic ovary with all the clinical consequences. These new insights may permit a cause related therapy for PCOD.
Article
Bovine oviductal monolayer and vesicle primary cultures express insulin-like growth factor (IGF)-I and -II mRNAs and polypeptides. Early bovine embryos also express IGF-I, IGF-II, IGF-I receptor, IGF-II receptor, and insulin receptor mRNAs. This study reports the expression of IGF binding protein (IGFBP) mRNAs and polypeptides in bovine oviduct primary cultures and IGFBP mRNAs in preattachment embryos. Release of immunoreactive IGF-I and IGF-II by oviduct cultures and bovine blastocysts was also determined. IGFBP-2, -3, -4, and -5 transcripts were observed in oviduct primary cultures throughout an 8-day interval. IGFBP-1 and -6 mRNAs were consistently not detected in the oviduct. Messenger RNAs encoding IGFBPs -2, -3, and -4 were detected throughout bovine preattachment development, while transcripts encoding IGFBP-5 were detected only in blastocysts. IGFBP-1 and -6 transcripts were not detected in early embryos. Ligand blot analysis with 125I-labeled IGF-II revealed the presence of four prominent polypeptide bands of approximate molecular masses 24, 31, and 36 kDa, and a broad band extending from 46 to 53 kDa, in conditioned media samples prepared from oviduct primary cultures. Western immunoblot analysis confirmed the identity of the 24-kDa, 31-kDa, and 36-kDa species as IGFBP-4, -5, and -2, respectively. Levels of the release of IGF-II from oviductal vesicle cultures were significantly greater than levels observed for monolayer cultures (p < 0.005). No significant difference in the levels of IGF-I release between monolayer and vesicle cultures was observed. Pools of 10 blastocysts released on average 36.2 +/- 3.9 pg of IGF-II per embryo, while the release of embryonic IGF-I was below the levels of detection for our assay. The results suggest that maternally derived IGF may be regulated by IGFBPs to support bovine preattachment development.
Article
Although it has been accepted that osteoporosis is common in women, only recently have we become aware that it is also widespread in men; one in twelve men in the UK have osteoporosis. In many cases, there are recognisable causes for their osteoporosis, but a significant proportion (approximately one third) of these men have idiopathic disease. A major problem is that these cases are difficult to treat. An important therapeutic strategy would be to identify men at risk from osteoporosis sufficiently early, so that they can begin preventative measures. Moreover, development of novel means of treating these men would be an important clinical advance. With the emphasis on osteoporosis in women, however, the cellular and molecular basis for male idiopathic osteoporosis (MIO) is still poorly understood. Nevertheless, there are some aspects of skeletal regulation which may be specific for men and which could form the basis for addressing these problems. Thus, the importance of oestrogen in maintaining the adult skeleton in men as well as women implies that bone cells in men can respond to low levels of the hormone. Both oestrogen receptor (ER) alpha and beta are expressed in bone in vivo, which may be important for oestrogen action on bone in men. Furthermore, in osteoporosis generally, there is increasing evidence for defective osteoblast differentiation such that there is a surfeit of adipocytes over osteoblasts. A low peak bone mass is a powerful risk factor for osteoporosis in later life; bone formation and, by implication, osteoblast differentiation, is key to the mechanism by which it is accrued. GH and IGFs are important for regulating osteoblast differentiation. Evidence now suggests that they are associated with bone mineral density, particularly in men. The genes for ERs, GH and IGF-I might be useful candidates with which we can begin to detect men at risk from osteoporosis. Furthermore, the mechanisms by which oestrogen, GH and IGF-I regulate the male skeleton could provide the basis for developing novel means of treating MIO.
Article
This study was designed to investigate the expression of insulin-like growth factor-1 (IGF-1) during cystogenesis in the dehydroepiandrosterone (DHEA)-induced rat polycystic ovarian syndrome (PCO) model. IGF-1 expression patterns in DHEA-treated rat ovaries were compared with those in control ovaries. In situ hybridization revealed a similar distribution of IGF-1 mRNA in DHEA-treated and control ovaries: in both, IGF-1 mRNA expression was confined to the granulosa cells of preantral and small antral follicles. Some hybridization signals for IGF-1 mRNA were also found in theca and infrequently in the interstitial cells. No signal was observed in larger antral follicles, atretic follicles, or cysts. This similarity indicates that there might be a shared mechanism in the early follicular development of normal folliculogenesis and DHEA-induced cystogenesis. The effects of DHEA on granulosa cells were analyzed in vitro in their quiescent, proliferative, differentiative, and preovulatory stages. Northern analysis revealed three transcripts for IGF-1 (7.5 kilobases [kb], 1.6 kb, and a group of signals between 0.4 and 0.9 kb) in cells at all stages except the preovulatory. The strongest signal was observed in cells of the proliferative stage of control cultures, while expression of IGF-1 increased only in the DHEA-treated cells cultured in the differentiative stage (when they secrete estrogen). Increase in IGF-1 expression may contribute to the hypersteroidogenism observed in the DHEA-treated rat PCO model.
Article
Pubertal mammary development in the rat is largely dependent upon GH and estrogen. We recently showed that insulin-like growth factor-I (IGF-I) can substitute for GH in inducing mammary development in male rats, suggesting that IGF-I mediates GH action. The present study investigated whether IGF-I, like GH, required estradiol (E2) to act or whether IGF-I could substitute for both GH and E2. The effects of IGF-I were tested in the presence and absence of E2. Elvax pellets containing IGF-I or des(1-3) IGF-I were implanted into right lumbar mammary glands of sexually immature, hypophysectomized, oophorectomized female rats, with control BSA-containing pellets in the contralateral glands. After 5 days, both lumbar mammary glands were removed and examined in whole mounts for mammary development by counting terminal end buds and alveolar structures. E2, administered in SILASTIC brand capsules, had no independent effect on mammary development. In the absence of E2, des(1-3) IGF-I had a small, but significant, independent effect on mammary development; native IGF-I was ineffective. The addition of E2 significantly enhanced the effects of IGF-I and des(1-3) IGF-I on mammary development, similar to that noted when E2 was given along with GH. We also studied the effects of E2 and/or hGH on mammary gland IGF-I messenger RNA (mRNA) in hypophysectomized castrated male animals. E2 alone did not increase mammary gland IGF-I mRNA concentrations, but E2 enhanced the effect of hGH on IGF-I mRNA by 4- to 6-fold. These studies indicate that IGF-I can have a small independent effect on mammary development, but like GH, E2 is required for a full effect. They also indicate that E2 is capable of synergizing with GH in the production or expression of IGF-I mRNA, and that the action of E2 on mammary development may take place at multiple sites. If locally produced IGF-I does indeed mediate the action of GH in mammary development, then although E2 is capable of enhancing the effect of GH on IGF-I mRNA, its major effect in mammary development occurs after IGF-I is produced.
Article
In the ovary, insulin and insulin-like growth factor-I (IGF-I) act synergistically with FSH to augment estrogen production by granulosa cells and with LH to augment androgen production by thecal stromal cells. It is also evident that insulin resistance is common in patients with polycystic ovary syndrome (PCO). Thus, in the present study we investigated the expression of insulin and IGF-I receptors in PCO ovaries and compared them with those in normal ovaries. Ovarian tissues were obtained from four PCO patients undergoing wedge resection, and from six patients who underwent radical hysterectomy. Immunohistochemical staining for insulin and IGF-I receptors was performed by avidin/biotin immunoperoxidase techniques. In normal ovaries, the expression of insulin and IGF-I receptors in follicular compartment became apparent in the preantral follicle stage and augmented with the follicular growth, while the stromal cells, regardless of the follicle stage, possessed insulin and IGF-I receptors. In PCO ovaries associated with hyperinsulinemia, no expression of insulin receptors was detected in granulosa or thecal stromal cells, while IGF-I receptor expression increased in thecal stromal cells but decreased in granulosa cells compared to those in normal ovaries. However, in PCO ovaries from patients without hyperinsulinemia, insulin receptor expression was apparent in both granulosa and thecal stromal cells, with a similar intensity to that observed in normal ovaries, while IGF-I receptor expression was negligible in granulosa cells but sustained in thecal stromal cells. These findings suggest that decreased expression of insulin receptors in PCO ovaries associated with hyperinsulinemia may be secondary to receptor down regulation, whereas defective expression in granulosa cells along with elevated or persisted expression in thecal stromal cells of IGF-I receptors may be common in PCO ovaries and contribute to the endocrine profiles of PCO in which varying degrees of hyperandrogenism is a predominant feature.
Article
La souris, eprouvette vivante, permet d'approcher la fonction du produit des genes par les effets observes apres leur invalidation ou leur surexpression. A chaque etape, de l'organogenese ovarienne a la fecondation de l'ovule, l'activation de certains genes est indispensable. Certains sont d'expression ubiquiste, d'autres sont, a l'inverse, tres specifiques, controlant la constitution du stock de cellules germinales, la croissance et la differenciation du follicule puis l'ovulation... Si le fait que les gonadotrophines hypothalamo-hypophysaires soient indispensables a la croissance du follicule n'a surpris personne, la mise en evidence des roles de la leptine et du facteur hypothalamique Nlh12, entre autres, a permis de preciser les liens entre metabolisme et fertilite.
Article
While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin-like growth factor-I (IGF-I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor-β1 (TGF-β1), an antagonist of IGF-I, in endometrial carcinoma, we investigated the expression of IGF-I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF-I receptor in 30 formalin-fixed, paraffin-embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF-I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF-I mRNA in endometrial carcinomas compared with non-neoplastic tissues, despite equivalent immunohistochemical expression of IGF-I and IGF-I receptor. Our data suggest that IGF-I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF-I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression. Int. J. Cancer 80:188–193, 1999. © 1999 Wiley-Liss, Inc.
Article
Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91–2.81]. The OR decreased to 1.49 (95% CI 0.80–2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07–4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82–4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50. Int. J. Cancer 88:828–832, 2000. © 2000 Wiley-Liss, Inc.
Article
Problem: To ascertain if cervical epithelial epidermal growth factor receptor (EGF-R) and serum insulin-like growth factor II (IGF-II) levels are potential markers for cervical cancer. Method of study: We tested cervical biopsies obtained from 18 controls, 3 women with cervical intraepithelial neoplasia (CIN) I, 17 women with CIN II and III, and 12 women with cervical cancer for EGF-R using a quantitative immunofluorescent antibody assay. We measured serum IGF-II levels using an enzyme-linked immunosorbent assay in 20 controls, 26 CIN patients, 12 with cervical cancer before therapy, 5 with cervical cancer for < 1 year, and 9 others > 1 year after therapy. Results: The levels of cervical EGF-R in women with CIN and cervical cancer were significantly higher (P<0.05 for CIN I; P<0.001 for patients with CIN II and III or cervical cancer) than in controls. Women with cervical cancer (P<0.001 vs. controls) or advanced CIN (P = 0.03) had elevated levels of serum IGF-II, while the women with CIN I had levels similar to controls. Women with cervical cancer in the post-therapy period had significantly lower serum IGF-II levels than the women with cervical cancer before therapy (P<0.001). Conclusion: Cervical epithelial EGF-R and serum IGF-II levels may be used for the diagnosis and prognosis of cervical cancer.
Article
Evidence suggests that insulin resistance and hyperinsulinaemia are associated with ovarian hyperandrogenism and menstrual irregularities in polycystic ovary syndrome (PCOS). Sixteen obese women with PCOS on a weight-maintaining diet were studied before and after 6 months of therapy with the insulin-sensitizing antidiabetic agent metformin at a dose of 1700 mg per day. Compared with baseline values, glucose utilization was markedly enhanced at 6 months using the two-step euglycaemic-hyperinsulinaemic clamp to measure changes in insulin sensitivity (2.56 +/- 0.32 vs 4.68 +/- 0.49 mg/kg per min, P = 0.0001, when 40 mU insulin/m2 per min was infused, and 6.48 +/- 0.58 vs 9.84 +/- 0.72 mg/kg per min, P = 0.0002, when 400 mU insulin insulin/m2 per min was infused). The improvement in insulin action was accompanied by significant increases in the levels of sex hormone-binding globulin (24.5 +/- 7.2 vs 39.8 +/- 16.2 nmol/l, P = 0.003) and decreases in free testosterone (12.8 +/- 5.8 vs 9.0 +/- 3.0 pmol/l, P = 0.03) and androstenedione (12.9 +/- 5.6 vs 7.3 +/- 1.7 nmol/l, P = 0.003). No significant changes were recorded in body weight. Seven subjects resumed normal menstruation and two cases of spontaneous pregnancy occurred during treatment. Metformin was well tolerated except for one case of flatulence. These results confirm that metformin treatment can lead to improvements in insulin resistance and ovarian hyperandrogenism.
Article
Introduction INSULIN-like growth factor-I (IGF-I) and its structural homologue, IGF-II, are low molecular weight peptides that promote cellular mitosis and differentiation in a variety of systems and are believed to play a role in cyclic ovarian follicular development. In 1978, IGF-I and IGF-II were purified and sequenced by Rinderkneckt and Humbel (1, 2), and since that time there has been an exponential accumulation of information regarding these peptides, as well as their receptors, and their binding proteins (IGFBPs), constituents of the “IGF autocrine/paracrine system.” These constituents have been examined in various tissues in vivo under a variety of physiological conditions and in vitro in numerous cell and tissue culture systems in several species (for review see Refs. 3–9). A decade ago, research on the IGFs focused on skeletal growth in childhood, a subspecialty of pediatric endocrinology. In the intervening years, the arena of research inquiry extended to other disciplines, including nephrolog...
Article
Follicular fluid sex-steroids, insulin-like growth factor-I (IGF-I), IGF-I binding protein (IGF-I-BP) and epidermal growth factor were investigated in patients with polycystic ovaries and normally ovulating women, following ovulation induction with gonadotrophins or growth hormone plus gonadotrophins. Growth hormone supplementation enhanced the ovarian response to gonadotrophins, and significantly increased follicular fluid IGF-I in both groups, without affecting follicular fluid epidermal growth factor; growth hormone supplementation significantly decreased follicular fluid androstenedione in both groups.
Article
The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
Article
The follicular fluid (FF) of human ovaries contains insulin-like growth factor binding proteins (IGFBPs) which may regulate the bioavailability of the IGFs. Previously we showed discrete changes in IGFBP concentrations in FF which correlated with the physiological state of the follicle. The purpose of the present study was to test the hypothesis that IGFBPs in FF may be increased in polycystic ovarian disease (PCO). FF was aspirated from PCO follicles and size matched healthy and atretic follicles from normal ovaries of naturally cycling women. The IGFBPs in FF samples were studied by ligand blot analysis with 125I-IGF-II and by immunoblot analysis using specific antisera to five human IGFBPs. Of six IGFBP bands in PCO FF, three were identified as IGFBP-2, IGFBP-3, and IGFBP-4. Bands (29K and 31K) were not identified by any of the five IGFBP antisera. The total IGF binding capacity was increased in PCO FF relative to normal healthy or atretic FF. IGFBP-3 was the predominant BP present in FF from PCO follicles as well as normal healthy and atretic follicles with no significant difference in any of the groups of follicles studied. IGFBP-2, IGFBP-4, and the 29K BP were present in smaller amounts, but there were significantly higher levels of each of these BPs in PCO follicles than in normal healthy follicles. Only IGFBP-4 was elevated in PCO follicles relative to normal atretic follicles indicating that the pattern of IGFBP expression in PCO FF was very similar to the pattern observed in atretic follicles. To determine the source of the IGFBPs in FF, granulosa or theca cells were cultured (up to 6 days) in serum-free medium. Ligand blot analysis of the conditioned medium revealed basal secretion of IGFBP-3 by both theca and granulosa cells. FSH inhibited granulosa cell IGFBP-3 production but increased the 29K BP in the medium. Transforming growth factor-beta stimulated basal IGFBP-3 secretion and reversed the FSH effects. Human CG (100 ng/mL) inhibited theca cell IGFBP-3 production but did not stimulate any other IGFBP. The results of our studies indicate that IGFBP-2, IGFBP-4, and the 29K BP are significantly increased in PCO FF and that gonadotropins and TGF-beta regulate the production of IGFBPs by human theca and granulosa cells.
Article
Caloric restriction (CR) without malnutrition in mice and rats reduces the incidence of spontaneous tumors and delays their appearance while increasing maximum life span. These results depend largely on CR per se, and not on low intakes of fat or other nutrients. Although most studies have tested CR imposed early in life, CR started in midadulthood also retards cancer and aging. The way(s) by which CR impedes cancers remain unclear, but possibilities include less cellular oxidative damage, retarded immunologic aging, hormonal changes, less energy available for cell proliferation, reduced exposure to dietary carcinogens and promoters, enhanced DNA repair, and less carcinogen activation. Far less is known about the relationship between caloric intake and cancer incidence in humans; however, recent findings suggest a positive association for certain cancers.
Article
Raised insulin levels are now recognized as a characteristic feature of women with polycystic ovaries (PCO), and hyperinsulinism has been shown to stimulate androgen production in such women. We have, however, recently shown that hyperinsulinaemia is present only in the obese subjects with PCO in whom insulin concentrations correlate with those of luteinizing hormone. We therefore studied 24-hour blood profiles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in obese and non-obese women with PCO, for comparison with their levels of insulin, C-peptide and other hormones, such as androgens which are known to be disturbed in PCO. Mean 24-hour GH levels were higher overall in PCO than in control subjects, although the difference was not significant. When, however, a separate analysis was made in obese as compared with non-obese PCO patients, GH concentrations were significantly higher in the non-obese group than in the obese (p = 0.0005). There was a significant negative correlation between body mass index and mean 24-hour GH concentrations (r = -0.641; p = 0.0006). IGF-I concentrations were however similar in the PCO group overall and in controls, as well as in the obese and non-obese PCO patients. The 24-hour blood glucose profile pattern was significantly different in PCO women from controls (p = 0.009), with absence of post-prandial peaks in blood glucose concentrations. These changes were most marked in the non-obese PCO group, who also had significantly lower blood glucose levels than either controls or obese PCO subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
In order to evaluate the GH/insulin-like growth factor-I (IGF-I) axis in the polycystic ovary syndrome (PCO), 21 women aged 18-38 yr were studied. The GH responses to the GH-releasing hormone (GHRH), and plasma concentrations of IGF-I were measured in seven obese women with PCO, seven obese healthy controls without PCO, and in seven nonobese subjects. Total GH secretion, as expressed by the integrated GH response to GHRH, in PCO obese women (617.4 +/- 150 micrograms/L.min) and in obese women without PCO (327.1 +/- 161.4 micrograms/L.min) were lower than that in nonobese healthy controls (3181.4 +/- 644.3 micrograms/L.min, P less than 0.001 and P less than 0.001, respectively). Plasma concentrations of IGF-I in obese PCO women (199.5 +/- 39.1 micrograms/L), and in obese women without PCO (192.4 +/- 36.8 micrograms/L) were similar to the IGF-I levels in nonobese controls (224.3 +/- 33.2 micrograms/L). In obese women with and without PCO, a negative correlation was found between the body mass index and the peak GH responses to GHRH (r = -0.639, P less than 0.02) and between age and IGF-I levels (r = -0.520, P less than 0.05). These findings suggest that an abnormality of the GH/IGF-I axis in PCO women may be due to coexistent obesity.
Article
Understanding whether granulosa cells are normal or abnormal in women with polycystic ovary syndrome (PCO) could have clinical importance. For this purpose, we compared the ability of normal and PCO granulosa cells to synthesize oestrogen and progesterone in vitro in response to follicle stimulating hormone (FSH) and/or insulin-like growth factor-I (IGF-I). The normal granulosa cells were from a 7 mm dominant follicle from a women with regular menstrual cycles. The PCO granulosa cells were from 5-7 mm follicles of three patients who had classical PCO. Several interesting points emerge from the comparison: in each PCO patient there was a high level of bioactive FSH in the follicular microenvironment (greater than or equal to 5 mIU/ml; greater than or equal to 250 ng/ml). This is paradoxical because the concentration of steroids in follicular fluid suggests that PCO follicles are highly atretic and therefore should not contain detectable FSH activity. The capacity to secrete progesterone when challenged with a maximally effective dose of FSH and/or IGF-I, was markedly reduced (8- to 10-fold) in PCO compared to normal granulosa cells. This is in sharp contrast to the oestradiol responses which were much the same for PCO and normal granulosa cells. Also, the time course and dose-response effects of FSH showed some major differences between normal and PCO cells, that is, PCO cells lost their capacity to produce oestradiol when treated continuously with a maximally effective dose of FSH. They were also significantly more sensitive to FSH and failed to become more sensitive to IGF-I when treated with FSH.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Oviductal fluid (OvF) was collected from gilts by indwelling catheters during the estrous cycle and analyzed for content of insulin-like growth factors (IGF-I, IGF-II). Group 1, composed of 9 gilts in a summer environment near a boar, yielded mean daily fluid volumes of 1.18 +/- 0.16 ml during estrus and 0.69 +/- 0.03 ml post-estrus. Group 2, composed of 7 gilts in a moderate-temperature, light-regulated room, yielded 1.20 +/- 0.18 ml during estrus and then OvF flow essentially stopped. Serum samples were also collected 2 times daily during the cycle and analyzed along with the OvF for IGF-I and IGF-II. Serum was also analyzed for estradiol-17 beta (E2). For group 1, OvF content (concentration x fluid volume) of IGF-I and IGF-II was greater (p less than 0.05) at estrus than pre- and post-estrus. Daily mean content values (ng/day) for IGF-I and IGF-II during peri-estrus were 30.9 +/- 6.3 and 62.2 +/- 12.3, respectively. During nonestrus, values were 6.8 +/- 6.3 and 11.7 +/- 12.3, respectively. For group 2, OvF content of IGF-I and IGF-II during estrus was similar to that of group 1. Whereas IGF content differed between estrus and nonestrus periods, IGF concentrations were similar (p greater than 0.05), a finding that results from the difference in OvF produced. Compared with OvF concentrations of IGF for a given pig, blood plasma concentrations of IGF-I and IGF-II were 2- to 5-fold higher in the plasma sample collected the same day.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We have studied the regulation by estradiol of the mannose-6-phosphate (Man-6-P)/insulin-like growth factor-II (IGF-II) receptor concentration in different breast cancer cell lines. The mRNA level was assayed by Northern blot using the H5.1 cDNA probe. The protein level was assayed by Western ligand blot, by binding saturation with [125I]procathepsin-D on total membrane preparations, and by immunoprecipitation of 35S-labeled proteins. In three estrogen receptor-positive cell lines (MCF7, T47D, and ZR75-1), estradiol specifically decreased the steady state level of the Man-6-P/IGF-II receptor protein and mRNA. Moreover, in different cell lines and in primary culture of normal mammary cells, the secretion of procathepsin-D was inversely correlated with the level of Man-6-P/IGF-II receptor protein and mRNA. We conclude that estradiol down-regulates the Man-6-P/IGF-II receptor in breast cancer cells. Since two of its ligands, procathepsin-D and IGF-II, are induced by estrogen, we propose that the Man-6-P/IGF-II receptor becomes saturated after estrogen treatment. This model might explain the previously described estrogen-induced secretion of procathepsin-D and other lysosomal proenzymes routed by the same transport system.
Article
A human hepatoma cell line, HepG2, secretes a discrete insulin-like growth factor-binding protein (IGFBP-1) into serum-free medium, which is identical to the 25K mol wt BP in amniotic fluid and plasma. IGFBP-1 levels in vivo have been shown to be inversely correlated with circulating insulin concentrations. This study investigated the direct effects of insulin on IGFBP-1 production in vitro. Addition of insulin to HepG2 cultures induced a rapid dose-dependent decrease in IGFBP-1 synthesis and secretion independent of the glucose concentration in the medium. As assessed by ligand binding and specific RIA, levels of IGFBP-1 were 20-50% of control levels in 18-h conditioned medium from insulin-treated cells. Monoclonal antibody studies indicated that the suppressive effect of insulin on IGFBP-1 synthesis was mediated through specific interaction with the insulin receptor. Therefore, HepG2 cells respond to insulin by altering the synthesis and secretion of IGFBP-1 in a manner that mimics many of the changes in plasma IGFBP-1 levels observed in vivo and provide an in vitro model for studies of IGFBP-1 biosynthesis.
Article
Recent studies have shown that human decidual explants synthesize a 25,272 dalton form of insulin-like growth factor binding protein (IGFBP-1) that is identical to the most abundant form of IGFBP detected in human amniotic fluid. To determine whether decidual cells also secrete other structurally distinct forms of IGFBP, conditioned medium obtained from human decidual cells was analyzed by ligand blotting and immunoblotting using antisera that were specific for IGFBP-1 or 2. IGFBP-2 is a form of binding protein that is structurally distinct from IGFBP-1. Ligand blotting analysis (which detects all forms of IGFBPs) showed that 3 forms of IGFBP with Mr estimates of 34,000, 30,000 and 24,000 were present in basal, unstimulated, conditioned media. Immunoblotting showed that the 30,000 Mr form reacted with an antibody that is specific for IGFBP-1, whereas the 34,000 Mr form reacted with an antibody that is specific for IGFBP-2. The 24,000 Mr band did not react with antisera to either IGFBP-1 or 2. Basal IGFBP-1 release from human decidual cultures, as measured by RIA, showed a significant decrease during the 5 day period from 34 +/- 1.6 on day 1 to 12 +/- 1.9 ng/ml on day 5. Exposure of the cells to (Bu)2cAMP (1.0 mM) for 5 days had no significant effect on IGFBP-1 release during the first day of exposure, but caused a progressive stimulation of release during the subsequent 4 days. By day 5, exposure to (Bu)2cAMP induced a 5- to 6-fold increase in IGFBP-1 release that was completely inhibited by exposure to cycloheximide. Exposure of the cells to cholera toxin (0.1 micrograms/ml) for 4 days caused a 3.7-fold increase in IGFBP-1 release. The stimulation of IGFBP-1 release by (Bu)2cAMP was completely inhibited by simultaneous exposure to insulin (100 ng/ml) and/or IGF-I (100 ng/ml) (day 5 control = 35 ng/ml, (Bu)2cAMP alone = 248 ng/ml, insulin + (Bu)2cAMP = 36 ng/ml, or IGF-I + (Bu)2cAMP = 10.1 ng/ml). Hydrocortisone and the phorbol ester (phorbol myristate acetate) caused no significant changes in basal IGFBP-1 release but prevented the decrease in the basal rate of release that occurred between day 1 and 5. Ligand blotting studies showed that the 24,000 Mr form of binding protein was also stimulated by (Bu)2cAMP (3.3-fold increase); however, cholera toxin and phorbol myristate acetate were without effect. In contrast, the release of the 34,000 Mr form was unaffected by exposure to any of these agents, suggesting that regulation of this form of IGFBP is distinct from the other 2 forms.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Breast tumor cell lines have been shown to secrete several distinct polypeptide growth factors, although conflicting results exist for the insulin-like growth factors (IGFs). In contrast a limited number of breast tumor cell lines have definitely been shown to secrete the high affinity IGF binding proteins (IGFBPs) that modify IGF actions. To characterize the types of IGFBPs that are secreted by breast tumor cell lines, conditioned medium was collected from seven separate tumor cell lines, three of which were estrogen receptor (ER) negative, and four of which were ER positive. All three of the ER negative cell lines, MDA-231, MDA-330, and HS578T, secreted binding proteins of 49,000 and 43,000 Mr (IGFBP-3) as well as 29,000 (IGFBP-1) and 24,000 Mr. In contrast, all four ER positive cell lines secreted 34,000 (IGFBP-2) or 24,000 Mr forms, and none secreted the 49,000 and 43,000 or 29,000 Mr forms. BT-20, a cell line that is positive for ER messenger RNA (mRNA) but negative for ER protein, secreted predominantly a 34,000 Mr protein. The amount of total IGFBP activity released in 24 h ranged between 0.4 and 5.6 nM equivalents of IGFBP-1, and there was no significant difference between the ER positive and negative cell lines. The MCF-7 cells that produced predominantly 34,000 and 24,000 Mr forms showed a 1.8-fold increase in IGFBP secretion after estrogen stimulation. Immunoblotting and a specific RIA for IGFBP-1 showed that only the ER negative lines MDA-330, MDA-231, and HS578T secreted this form. Northern blotting analysis for the mRNA encoding this protein showed that both MDA-330 and MDA-231 contained a single 1.6 kilobase mRNA species that hybridized with an IGFBP-1 complementary DNA (cDNA) probe. Immunoblotting analysis of the other cell lines showed that only the 34,000 Mr form secreted by the ER positive cell lines reacted with IGFBP-2 antisera. Exposure of the conditioned media from the three ER negative cell lines to N-glycanase revealed that the 49,000 and 43,000 Mr forms of IGFBP were glycosylated and therefore probably represent IGFBP-3. We conclude that ER negative cell lines secrete three forms of IGFBPs, IGFBP-1, IGFBP-3, and a 24,000 Mr form. In contrast, the ER positive cell lines secrete predominantly IGFBP-2 and the 24,000 Mr form but do not secrete IGFBP-3 or 1.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
This chapter provides an overview of insulin-like growth factor-binding proteins (IGF-BP). The insulin-like growth factors (IGFs)—or somatomedins—constitute a family of growth hormone (GH)-dependent peptides with both anabolic and mitogenic activities for a wide variety of tissues and cell lines. IGF-I and -II are characterized by a striking structural homology with human proinsulin. The human gene for IGF-II is located on the short arm of chromosome 11 in close proximity to the gene for insulin and spans over 30 kb of DNA. This gene is composed of at least eight exons. The preprohormone consists of a 24-amino-acid signal peptide, a 67-amino-acid mature peptide, and a carboxy-terminal peptide of 89 amino acids. Significant diversity exists in the 5'-untranslated regions, where different mRNA species arise as a result of distinct promoters and alternative RNA splicing. Both IGF-I and -II are synthesized in a wide variety of tissues. The close relationship between insulin and IGF-I receptors is not surprising, given the binding affinities and structural similarities of the two receptors. Unlike the insulin and IGF-I receptors, the type 2 IGF receptor is characterized by a long extracellular domain, containing 15 repeat sequences of approximately 150 residues, a 23-residue transmembrane domain, and a small 164-residue cytoplasmic domain. No homology exists between the type 2 IGF receptor and the insulin or type 1 receptor. The initial characterization of IGF-BPs was done by gel filtration chromatography. The chapter discusses radioreceptor assays, affinity labeling, western ligand blotting, and immune-precipitation among other methods of detection.
Article
Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. To investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. Seven women with PCOD and five healthy control subjects. An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L). The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.
Article
The insulin-like growth factors (IGF-I and -II) are believed to be important in endometrial differentiation and blastocyst nidation, and proteins that regulate IGF action (IGF-binding proteins, IGFBPs) are hormonally regulated in endometrium during the menstrual cycle. To characterize further steroid-dependence of the IGFBPs, we established endometrial stromal cells in culture in the absence and presence of oestradiol (E2) and progesterone (P) and examined the conditioned medium for IGFBPs by Western ligand blot analysis. Stromal cells constitutively synthesized IGFBP-3, IGFBP-2, a 27 kd, and a 24 kd IGFBP. In the presence of E2 and P, a 10- to 15-fold increase in IGFBP-2 was detected in the conditioned medium beginning after about 7 days in culture, when cells decidualized and steroid-mediated prolactin secretion began. Withdrawal of steroids resulted in a marked decrease in IGFBP-2, comparable to control levels, and cells increased their IGFBP-2 production when rechallenged with E2 and P. Total RNA was isolated from stromal cells, and Northern blot analysis using a cDNA probe specific for IGFBP-2 revealed differential expression of a 1.4 kb mRNA transcript in steroid-treated compared to control cells. The effects of progestational agents alone on IGFBP synthesis was also examined. Progesterone, medroxyprogesterone acetate and norethindrone all stimulated IGFBP-2 synthesis 12- to 15-fold compared to controls, and a progesterone receptor antagonist, RU 486, blocked the stimulatory effect of progesterone. IGFBP-2 synthesis was increased two-fold above controls by 17-alpha-hydroxyprogesterone, and RU 486 alone and hydrocortisone were without effect. Identification of IGFBP-2 in conditioned medium was made using IGFBP-specific antiserum. These data show that (a) endometrial stromal cells synthesize and secrete IGFBP-2, (b) IGFBP-2 protein synthesis is controlled by steroid hormones, (c) P, by interacting with its receptor, modulates IGFBP-2 synthesis and (d) expression of IGFBP-2 mRNA is controlled by sex steroids.
Article
To explore the effect of cotreatment with growth hormone (GH) for ovarian stimulation after pituitary suppression. A randomized, double-blind, placebo-controlled study. Specialist Reproductive Endocrine and In Vitro Fertilization (IVF) Unit. Twenty-five IVF patients who had responded suboptimally in a previous treatment cycle. A subgroup of 18 patients were found to have ultrasound (US) findings of polycystic ovaries (PCO). The amount of gonadotropin used, development of follicles greater than or equal to 14 mm, number of oocytes collected, fertilized, cleaved and replaced, serum and follicular fluid (FF) insulin-like growth factor I (IGF-I) concentrations. Cotreatment with GH was associated with a significant reduction in gonadotropins requirement (P less than 0.05). In patients with US-diagnosed PCO more follicles developed (P less than 0.05), more oocytes were collected (P less than 0.03), fertilized (P less than 0.004), and cleaved (P less than 0.02). A significantly higher FF IGF-I concentrations were found in patients receiving cotreatment with GH compared with those who received placebo (P less than 0.04). We believe that there may be a place for GH treatment in selected IVF cycles after pituitary suppression but what the role of IGF-I should further be investigated.
Article
The objective of this study was to investigate the possible effect of recombinant bovine somatotropin (BST) on ovarian folliculogenesis and ovulation rate. Twelve Hereford x Friesian heifers received daily injections of either 25 mg BST (6 heifers) or vehicle (6 heifers) for a period of two estrous cycles until slaughter. Blood samples were collected three times a week for measurements of peripheral growth hormone (GH), insulin-like growth factor I (IGF-I), FSH, LH, estradiol, and progesterone. Serial blood samples were also taken every 10 min for 8 h on Days 12 and 19 of the second estrous cycle to monitor GH, IGF-I, FSH, and LH profiles. At the end of treatment (Day 7 of the third estrous cycle), the heifers were killed and their ovaries were collected. Ovulation rate was determined by counting the number of fresh corpora lutea (CL). All antral follicles greater than or equal to 2 mm in diameter were dissected to assess antral follicle populations. Granulosa and thecal cells from the three largest follicles and CL from each heifer were collected for FSH and LH binding measurements. All heifers had a single ovulation. The treated heifers had significantly more antral follicles (60.2 +/- 6.7) than did the animals in the control group (33.2 +/- 3.2) (p less than 0.001). When follicles were grouped according to diameter, the mean numbers of follicles greater than 10 mm, 5-10 mm, and 2-5 mm in diameter were 0.8 +/- 0.2, 6.8 +/- 1.4, and 52.5 +/- 6.5 for the treated group, and 0.8 +/- 0.2, 6.5 +/- 1.0, and 25.8 +/- 2.7 for controls.(ABSTRACT TRUNCATED AT 250 WORDS)