Synthesis Of Sex Hormone-binding Globulin Research Articles

Transcriptional regulation of the alternative sex hormone-binding globulin promoter by KLF4

In most mammals the major site of sex hormone-binding globulin (SHBG) synthesis is the liver wherefrom it is secreted into the bloodstream and is the primary determinant of sex steroid access to target tissues. The minor site of SHBG synthesis is the testis and in lower mammals testicular SHBG has long been known to be synthesized and secreted by Sertoli cells. However, human testicular SHBG is expressed in developing germ cells from an upstream alternative promoter (altP-SHBG). Transcripts arising from this region comprise an alternative first exon (1A) with the resultant protein confined to the acrosomal compartment of the mature spermatozoa. I have dissected the regulatory components of the alternative SHBG promoter and identified motifs that are required for optimal transcriptional activity from this region. Transcriptional activity is driven by two CACCC elements that appear to be functionally redundant. The transcription factor KLF4 interacts with promoter the region spanning these elements in vivo. Knockdown of Klf4 results in decreased altP-SHBG activity, while Klf4 overexpression relieves the effects of knockdown. Based on their shared patterns of expression in vivo, I conclude that KLF4 is a transcriptional regulator of SHBG in male germ cells.

Genetic regulation of testosterone level in overweight males from the Kazakh population and its association with hypogonadism.

Male hypogonadism and erectile dysfunction in different populations are associated with excess body weight. A key aspect in most studies is the metabolism of sexual hormones, primarily testosterone. At the same time, the binding protein sex hormone binding globulin (SHBG) can play a large role, as it determines the ratio of total and bioavailable testosterone in blood, i.e. both the hormone content and level of its production. Recent research has identified common mutations that affect SHBG levels, such as the rs727428 polymorphic locus, which is associated with alterations in histone protein function, affecting the regulation of ribonucleic acid (RNA) protein SHBG synthesis. Similar relationships have been observed for prevalent mutations, including rs5934505 and rs10822184, in diverse populations. This study involved 300 individuals of Kazakh nationality from the Eastern Kazakhstan region, examining three polymorphic variants of the SHBG gene (rs727428, rs5934505, and rs10822184). The participants were categorized into three groups: individuals with hypogonadism and obesity (group 1, n=85), those with excess body weight but no hypogonadism (group 2, n=70), and individuals with neither excess body weight nor hypogonadism (group 3, n=145). The frequency of mutant gene alleles impacting GPS (SHBG) synthesis in the Kazakh population was notably high, comparable to European and South-East Asian populations. However, the association between excess body weight and these mutations exhibited varying patterns. Hypogonadism was linked to decreased GPS levels, strongly correlating with total testosterone but not bioavailable testosterone. The retention of sexual functions in overweight men was not always directly related to BMI levels and GPS concentrations.

Prediction of Insulin Resistance and Impaired Fasting Glucose Based on Sex Hormone-Binding Globulin (SHBG) Levels in Polycystic Ovary Syndrome.

Objective Decreased synthesis of sex hormone-binding globulin (SHBG) related to hyperinsulinemia is one of the disturbances characteristic of polycystic ovary syndrome (PCOS). Hyperinsulinemia is a compensatory mechanism for liver insulin resistance (IR); thus, SHBG may be considered as a surrogate marker of liver IR. Therefore, this study aimed to assess the prediction of IR and impaired fasting glucose (IFG) based on SHBG levels in women with PCOS. Methods This analysis included data retrieved from medical records of 854 patients with PCOS hospitalized in the Gynecological Endocrinology Clinic from 2012 to 2019. Data including anthropometric parameters, fasting plasma glucose, insulin, and SHBG levels were analyzed. BMI and HOMA-IR were calculated with standard formulas. Results IFG and IR assessed based on HOMA-IR values > 2.0 were found in 19.5% and 47.8% of the study group, respectively. Empirical optimal cutoff values for SHBG levels were ≤41.5 nmol/L typical for IR (AUC 0.711, sensitivity 61.1%, specificity 71.6%, positive predictive value (PPV) 70.7%, and negative predictive value (NPV) 62.1%). The probability of insulin resistance occurrence for SHBG concentration 26.1 nmol/L (the lower normal range) was 61.6% (95% CI: 57.4%–65.8%). The SHBG concentration of 36.4 nmol/L and 8.1 nmol/L was related to a 10% and 20% probability of IFG, respectively. Conclusion In conclusion, this is the first study estimating the probability of liver IR and IFG occurrence based on SHBG levels in women with PCOS. Despite the low sensitivity, SHBG level below 42 nmol/L should cause closer monitoring for the fatty liver and prediabetes.

Hormonal contraception in women with polycystic ovary syndrome: choices, challenges, and noncontraceptive benefits.

Polycystic ovary syndrome (PCOS) is an endocrine disorder among women of reproductive age characterized by chronic anovulation and polycystic ovary morphology and/or hyperandrogenism. Management of clinical manifestations of PCOS, such as menstrual irregularities and hyperandrogenism symptoms, includes lifestyle changes and combined hormonal contraceptives (CHCs). CHCs contain estrogen that exerts antiandrogenic properties by triggering the hepatic synthesis of sex hormone-binding globulin that reduces the free testosterone levels. Moreover, the progestogen present in CHCs and in progestogen-only contraceptives suppresses luteinizing hormone secretion. In addition, some types of progestogens directly antagonize the effects of androgens on their receptor and also reduce the activity of the 5α reductase enzyme. However, PCOS is related to clinical and metabolic comorbidities that may limit the prescription of CHCs. Clinicians should be aware of risk factors, such as age, smoking, obesity, diabetes, systemic arterial hypertension, dyslipidemia, and a personal or family history, of a venous thromboembolic event or thrombophilia. This article reports a narrative review of the available evidence of the safety of hormonal contraceptives in women with PCOS. Considerations are made for the possible impact of hormonal contraceptives on endocrine, metabolic, and cardiovascular health.

Chapter 22 - Sexual dysfunction in patients with epilepsy

Sexuality is an important and private aspect of life and sexuality and epilepsy have been intimately linked since ancient time. Disturbances of reproductive and sexual health are common in men and women with epilepsy. Multiple causes may lead to sexual dysfunction. The basis for hyposexuality has been attributed to both epilepsy and antiepileptic drug use, making it difficult to distinguish between the illness-specific and pharmacologic impacts on sexual functioning. Low levels of androgens are associated with sexual arousal insufficiency and sexual dysfunction. Data from animal studies support the hypothesis that hyposexuality occurs as a result of epileptiform activity in the temporal lobe, but not in the motor cortex. Enzyme-inducing antiepileptic drugs are metabolized in the hepatic P 450 system (e.g., 3A4, 2C9, 2C19), induce hepatic enzymes, increase the hepatic synthesis of sex hormone-binding globulin (SHBG), and increase the metabolism of sex hormones that might have an additional influence on sexuality in patients with epilepsy. When examining sexual dysfunction in men and women with epilepsy, the Arizona Sexual Experience Scale may be helpful in evaluating sexual function. Laboratory tests for estrogen, free and total testosterone, and serum SHBG may also be useful in evaluating sexual health.

MANAGEMENT OF ARTAVAKSHAYA (HYPOMENORRHOEA) WITH OBESITY BY A HERBAL COMPOUND

Obesity per se represents a condition of sex hormone imbalance in women. O besity is associated with thre e biochemical alterations that a ffect normal ovulation e.g. 1. H yperi nsulinaemia 2. Increased peripheral conversion of androgen to estrogen and 3. Decrease level of sex hormone binding globulin (SHBG) resulting in increased level of free oestradiol and tes tosterone. Level of sex hormone binding protein (SHBG) tends to linearly decrease with increasing body fat and this may lead to an increased fraction of free androgens and thus estrogen level decreases. SHBG leve ls are regulated by a complex of factor incl uding estrogen, iodothyronies and growth hormone as stimulating agents and androgens and insulin as inhibiting factor. The net balance of this regulation with the dominant role of insulin which inhibits SHBG synthesis in the liver may be responsibl e for t he decrease of SHBG concentration observed in obesity. Fat represent a site of intensive sex hormone metabolism and interconversion due to t he presence of several steroidaogenetic enzymes such as 3 beta dehydrogenese, 17 beta hydroxydehydrogenase and the a romatase systems. Obesity may thus add further specific mechanism in the development of androgen excess in women and decreases oestrogen. The present clinical study wa s planned to assess the efficacy of an indigenous compound in sthoulya janya artavakshay a, which contains Sunthi, Pippali, Maricha, Vidanga, Tvak, Guggullu, Gomutra in equal quantity and was made vati and given in the doses of 1 gm three times a day with luke warm water. The effect of indigenous compound as

Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms

Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men

Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis.

Expression changes of sex hormone binding globulin in GDM placental tissues

To compare the expression of sex hormone binding globulin (SHBG) in normal placental tissues with placental tissues from patients with gestational diabetes mellitus (GDM) and to deduce the mechanism affecting placental SHBG in GDM. We detected SHBG localization and measured SHBG mRNA and protein using immunohistochemistry, reverse-transcription polymerase chain reaction, and Western blotting, respectively, in normal and GDM placental tissues. The distribution of SHBG in placental cells was examined using immune electron microscopy. Compared to controls, placental tissues from patients in the GDM group displayed disordered cell surface microvilli that were decreased in quantity, swollen, and had narrowed and broken gap junctions. Intracellular abnormalities included expanded rough endoplasmic reticula, swollen mitochondria, and irregular nuclear morphologies with non-uniform chromatin. SHBG localized primarily to trophoblast cell membranes and cytoplasm. SHBG was strongly expressed on the microvilli side and weakly expressed on the basement membrane with uneven staining. SHBG also was expressed in villous stromal cells and vascular endothelial cells. Compared to the controls, placental tissues from the GDM group displayed significantly decreased immunostaining rates for SHBG, as well as significantly lower levels of SHBG mRNA and protein expression (P<0.05). SHBG was detected in placental trophoblast cells from patients with GDM, and the synthesis and secretion of SHBG were reduced when trophoblast cells were irregular. A decrease in SHBG could affect placental function or aggravate GDM. Our results suggest that placental SHBG plays an important role in the pathogenesis of GDM.

Testosterone, the metabolic syndrome and diabetes mellitus

Abstract Both cross-sectional and longitudinal epidemiological studies have convincingly established that low plasma levels of testosterone and sex hormone binding globulin (SHBG) are correlated with / predict the metabolic syndrome and diabetes mellitus. Visceral obesity with its associated hyperinsulinism suppresses SHBG synthesis and, concomitantly, circulating testosterone levels. It also may impair the strength of LH signaling to the testis. Further, insulin and leptin have a suppressive effect on testicular steroidogenesis. Thus, there are reasons to consider adiposity a significant factor capable of lowering circulating levels of testosterone. Conversely, low levels of testosterone predict the development of the metabolic syndrome and diabetes mellitus type2. This notion is supported by the appearance of a metabolic syndrome-like condition in men with prostate cancer whose plasma testosterone levels are rendered low. Furthermore, the observation that differentiation of pluripotent stem cells is and...

Low Sex Hormone-Binding Globulin and Testosterone Levels in Association with Erectile Dysfunction among Human Immunodeficiency Virus-Infected Men Receiving Testosterone and Oxandrolone

Men with acquired immunodeficiency syndrome (AIDS) wasting and hypogonadism are frequently treated with testosterone and oxandrolone, an orally administered anabolic-androgenic steroid hormone. We observed reductions in testosterone and sex hormone-binding globulin (SHBG) levels, in association with complaints of erectile dysfunction, after prolonged exposure to this therapeutic regimen. First description of an association between long-term receipt of oxandrolone with erectile dysfunction, low SHBG and testosterone. Case report of three human immunodeficiency virus-infected hypogonadal male patients receiving treatment for wasting syndrome and hypogonadism, and highly active antiretroviral therapy. All three patients received long-term oxandrolone in addition to testosterone replacement therapy. Testosterone and SHBG levels for patients 1, 2, and 3, respectively: total testosterone 183, 71, and 151 ng/dL (260-1,000 ng/dL); free testosterone (not done for patient 3) 58.3 and 26.9 pg/mL (50-210 pg/mL); SHBG 6, 9, and 6 nmol/L (7-50 nmol/L). No other hormonal abnormalities were detected. Following discontinuation of oxandrolone, levels of total testosterone rose, consistent with increase in SHBG. One patient received repeat SHBG assay documenting rise in SHBG level. Patient 2 reported return of libido and early morning erections several weeks after discontinuation of oxandrolone. Patients had erectile dysfunction in association with low testosterone and SHBG, in spite of exogenous testosterone replacement. Discontinuation of oxandrolone led to the normalization or improvement of testosterone levels in all three patients with symptomatic improvement in one patient. First pass metabolism of orally administered oxandrolone may decrease hepatic synthesis of SHBG, allowing exogenously supplied testosterone to be excreted. Further work is necessary to elucidate the relationship.

Sex hormone-binding globulin expression in sea bass ( Dicentrarchus labrax L.) throughout development and the reproductive season

Sex hormone-binding globulin (SHBG) transports androgens and estrogens in the blood of vertebrate species, including fish, and regulates the bioavailability and metabolic clearance of these steroids. Liver is the major site of plasma SHBG synthesis, while an SHBG homologue, known as the androgen-binding protein, is produced in testes. When shbg gene expression was examined throughout European sea bass ( Dicentrarchus labrax L.) development, SHBG mRNA was clearly detectable at 7 days post-fertilization and persisted throughout embryonic development. In male and female sea bass, the liver is the principal site of shbg gene expression, as determined by SHBG mRNA analyses. Immunoreactive SHBG is present in the liver and villous stroma of the intestine in both sexes. It is also present in the interstitial space between testicular lobules, and the connective tissue surrounding the ovary in the non-reproductive season and around post-vitellogenic oocytes. Plasma SHBG levels were measured over a 10-month period as male sea bass undergo sexual maturation. Immature females of the same age were also studied over the same time interval. The mean ± S.E.M. plasma SHBG levels in 2-year-old males and females are lower (80 ± 15 nM and 82 ± 16 nM, respectively) during the winter reproductive season (December–March) than the spring (April–June) months (144 ± 32 nM and 193 ± 18 nM, respectively). In both sexes, plasma SHBG levels start to decline 1–2 months before the reproductive season, coincident with a period of rapid weight gain, while increases after the reproductive season are not accompanied by significant changes in body weight. In addition, plasma SHBG in triploid (sterile) and diploid (fertile) male sea bass do not differ during the first spawning season. These data suggest that the decrease in plasma SHBG levels during sexual maturation in sea bass is related to nutritional or metabolic effects in relation to water temperatures and food intake, rather than changes in gonadal sex steroid production.

Immunolocalization of sex hormone-binding globulin (SHBG) in human ovarian follicles and corpus luteum

Sex hormone-binding globulin (SHBG), a hepatic carrier protein for sex steroids is expressed in different steroid-sensitive tissues, including Sertoli cells of the testis. It has been suggested that this protein may be one of the local regulators of spermatogenesis. The expression of SHBG in the ovary is currently unknown. We have previously demonstrated the synthesis of SHBG in granulosa-lutein cells from patients undergoing in vitro fertilization. In this study, the presence of SHBG in human ovarian follicles and corpora lutea is investigated, using immunohistochemistry on adult and fetal ovarian tissue sections. SHBG is localized in the whole granulosa layer at all stages of folliculogenesis, whereas, only isolated theca cells are immunostained. In primordial and primary follicles, the oocyte cytoplasm shows an intense immunostaining, which disappears after the secondary stage. In the microenvironment of the mature oocytes, SHBG is present in the surrounding cumulus cells, the perivitelline space, and nearby the oolemma. In the corpus luteum, SHBG is localized in large luteal cells, whereas, small luteal cells do not show any significant staining. By analogy with the testis, these results raise the question of an involvement of SHBG in the regulation of follicular maturation as well as in luteal function.

Expression of sex hormone-binding globulin (SHBG) in human granulosa-lutein cells

Sex hormone-binding globulin (SHBG) was classically thought to be a plasma steroid-carrying protein of hepatic origin, but recently, locally produced, membrane-bound SHBG has been shown to influence cell functions in several steroid-responsive tissues. In the ovary, SHBG is known to be present in the follicular fluid, but information about a possible intracellular presence of SHBG in this organ is still very scarce. In this study the presence of SHBG was assessed by immunohistochemistry in human granulosa-lutein cells (GLC) collected by follicle puncture for in vitro fertilization. SHBG was detected in the cytoplasm of GLC before and after in vitro culture for up to 96 h. The presence of full-length SHBG messenger RNA was demonstrated in GLC by reverse transcription-polymerase chain reaction (RT-PCR) in both cultured and uncultured cells. These results demonstrate a local synthesis of SHBG in GLC and raise the question of the physiological significance of these findings in follicular physiology.

Obesity and the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype. Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

Plasma insuline, IGF-I et cancer du sein

Several recent epidemiological studies have shown an increase in breast cancer risk among women who have elevated plasma levels of testosterone, reduced levels of sex hormone-binding globulin (SHBG), and hence elevated levels of bioavailable androgens and estrogens not bound to SHBG. This endocrine profile is generally associated with obesity and chronic hyperinsulinemia, of which it is most likely a result. Lack of physical activity, obesity, and a diet rich in rapidly digestible carbohydrates and poor in fibre favour the development of insulin resistance and hyperinsulinemia. The elevated insulin levels, in turn are related to decreases in plasma and tissue levels of IGFBP-1 and IGFBP-2 (insulin-like growth factor-binding proteins), and this may increase the availability of insulin-like growth factor-I (IGF-I) to its receptors. Like insulin, IGF-I also inhibits the hepatic synthesis of SHBG, whereas both hormones stimulate the ovarian synthesis of sex steroids. Moreover, insulin and IGF-I can both enhance the development of breast tumours, through their cognate receptors within the mammary tissue. Taken together, these observations lead to the hypothesis that breast cancer risk may be increased in women with elevated plasma insulin levels, and/or with elevated levels of bioactive IGF-I. Hyperinsulinemia and an increased IGF-I bioactivity could thus be an important physiological link between a western lifestyle, overnutrition, a hyperandrogenic sex steroid profile, and increased breast cancer risk. Prospective cohort studies will be needed to test this hypothesis, and to study in greater detail the possible relationships of breast cancer risk with plasma levels of IGF-I and IGFBPs. Confirmation of a relationship of breast cancer risk with plasma insulin levels, on the one hand, or with total plasma IGF-I, on the other hand, could open up new prespectives for breast cancer prevention, either by changes in dietary intake patterns and physical activity, or by the use of certain chemopreventive drugs.

Energy balance and cancer: the role of insulin and insulin-like growth factor-I.

Recent theories propose that a Western lifestyle may increase cancer risk through alterations in the metabolism of insulin and insulin-like growth factors (IGF: McKeown-Eyssen, 1994; Giovannucci, 1995; Kaaks, 19%; Werner & LeRoith, 1996). Insulin regulates energy metabolism, and increases the bioactivity of IGF-I, by enhancing its synthesis. and by decreasing several of its binding proteins (IGFBP; IGFBP-1 and -2). Insulin and IGF-I both stimulate anabolic processes as a function of available energy and elementary substrates (e.g. amino acids). The anabolic signals by insulin or IGF-I can promote tumour development by inhibiting apoptosis, and by stimulating cell proliferation. Furthermore, both insulin and IGF-I stimulate the synthesis of sex steroids, and inhibit the synthesis of sex hormone-binding globulin (SFIBG), a binding protein that regulates the bioavailability of circulating sex steroids to tissues. The present paper reviews epidemiological findings relating the risk of cancers of the colo-rectum, pancreas, breast, endometrium and prostate to body size (obesity, height) and physical activity, and discusses the relationships between obesity and physical activity and plasma levels of insulin, IGF-I and IGFBP. Subsequent sections review epidemiological findings relating cancer risk to indices of chronic hyperinsulinaemia, and to plasma levels of IGF-I and IGFBP. Conclusions are that chronic hyperinsulinaemia may be a cause of cancers of the colon, pancreas and endometrium, and also possibly of the breast. On the other hand, elevated plasma IGF-I, as total concentrations or relative to levels of IGFBP-3, appears to be related to an increased risk of prostate cancer, breast cancer in young women, and possibly cob-rectal cancer. For cancers of the endometrium, breast and prostate, these findings are discussed in the context of relationships between insulin and IGF-I and levels of bioavailable sex steroids.

Changes in Sex Hormone-Binding Globulin, Insulin, andSerum Lipids in Postmenopausal Women on aLow-Fat, High-Fiber Diet Combined With Exercise

Dietary factors including fat and fiber have been reported to play a role in the development of breast cancer, possibly mediated by changes in estradiol. Diet and exercise have been shown to affect levels of sex hormone-binding globulin (SHBG), which in turn regulate the bioavailability of estradiol. Diet and exercise also affect insulin levels, which play a role in the synthesis of SHBG, and the hormone itself is a potent mitogen for many cancer cell lines. This study was designed to measure the effects of a low-fat, high-fiber diet, combined with regular aerobic exercise, on the levels of SHBG, insulin, and serum lipids in postmenopausal women with or without hormone replacement therapy (HRT). Two groups of postmenopausal women, 11 on HRT and 11 not on HRT, underwent a low-fat (10% fat calories), high-fiber (65-70 g/day) diet-and-exercise intervention for three weeks. Serum SHBG, insulin, and lipids were measured before and after the regimen. After the intervention, SHBG levels were significantly increased for the women on HRT (44.5 ± 3.4 vs. 62 ± 6.4 nmol/l) and the women not on HRT (32.1 ± 4.6 vs. 45.5 ± 6.1 nmol/l, both changes p < 0.01). Also after the intervention, insulin levels were significantly reduced for the women on HRT (196 ± 44.4 vs. 119.8 ± 28.7 pmol/l) and the women not on HRT (144.2 ± 17.9 vs. 115.5 ± 20.8 pmol/l, both changes p < 0.01). Body mass index and total cholesterol were significantly reduced for both groups of women (all changes p < 0.01). Although the exact mechanism for the change in SHBG is not known, the increases in SHBG and reductions in insulin as a result of this lifestyle intervention should reduce the risk for breast cancer in postmenopausal women.

Plasma androgens, IGF-1, body size, and prostate cancer risk: a synthetic review

We present a review of the epidemiological evidence for relations of prostate cancer risk to circulating total and bioavailable androgens, to alterations in the metabolism of insulin-like growth factor-1 (IGF-1), and to anthropometric indices of longitudinal growth (body stature) and overweight. In addition, we review the physiological inter-relationships between insulin, growth hormone/IGF-1 axis, and sex steroid metabolism, as well as the associations of bioavailable sex steroid levels with overweight and obesity. A first conclusion of this review is that, taken together, epidemiological studies have provided little support for the hypothesis that prostate cancer risk is increased in men with elevated total or biovailable testosterone (T). Although one prospective study showed an increased risk in men with low plasma sex hormone-binding globulin (SHBG) and with elevated plasma T for given levels of SHBG, this was not confirmed by results from other cohort studies. A second conclusion is that overweight, which is generally associated with moderate reductions in both total and bioavailable plasma T, appears to be unrelated to any significant increase or decrease in prostate cancer risk. However, significant increases in risk have been observed for men with a taller body stature, or with elevated plasma IGF-1. IGF-1 may directly enhance prostate tumorigenesis by inhibiting apoptosis and by stimulating cell proliferation. In addition, IGF-1 downregulates the synthesis of SHBG, and enhances sex steroid synthesis. Therefore, we do not entirely rule out that due to an elevation of plasma IGF-1 levels, men at increased risk of prostate cancer also have mildly elevated plasma bioavailable T, which epidemiological studies may have failed to demonstrate because of methodological problems. Prostate Cancer and Prostatic Diseases (2000) 3, 157-172

Levels of sex hormone-binding globulin and corticosteroid-binding globulin mRNAs in corpus luteum of human subjects: Correlation with serum steroid hormone levels

To understand regulation of the function of human ovarian corpus luteum by sex steroid-binding proteins, the levels of luteal intracellular sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNAs and serum steroid hormones were simultaneously determined. The expression of SHBG and CBG mRNAs was detected in all samples analyzed. SHBG mRNA level was positively correlated with serum estradiol-17β level (p < 0.05), but not with serum progesterone level. There was a positive correlation between SHBG mRNA level and serum estradiol-17β/progesterone ratio (p < 0.01). On the other hand, CBG mRNA level was positively correlated with serum estradiol-17β and progesterone level (p < 0.01 and p < 0.01, respectively). There was no correlation between CBG mRNA level and serum estradiol-1 17β/progesterone ratio. SHBG and CBG mRNA levels were not correlated with the levels of serum testosterone, free testosterone or Cortisol. These findings suggest that the synthesis of luteal SHBG and CBG is complexly regulated by estrogen and progesterone, and that SHBG and CBG interact with estrogen and progesterone, respectively, for luteal steroidal activity.