Accepted Manuscript Sex hormones, sex hormone binding globulin and liver fat: which came first, the chicken or the egg? Samer Gawrieh, MD
PII: DOI: Reference:
S1542-3565(15)00642-4 10.1016/j.cgh.2015.04.182 YJCGH 54280
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 April 2015 Please cite this article as: Gawrieh S, Sex hormones, sex hormone binding globulin and liver fat: which came first, the chicken or the egg?, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/ j.cgh.2015.04.182. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT
Correspondence Author: Samer Gawrieh, MD Division of Gastroenterology and Hepatology
M AN U
Indiana University School of Medicine
SC
RI PT
Sex hormones, sex hormone binding globulin and liver fat: which came first, the chicken or the egg?
702 Rotary Circle Indianapolis, IN 46202 Email: [email protected] Phone (317) 278 9326
TE D
Fax: (317) 278 6870
AC C
EP
The author has no conflict of interest to declare.
ACCEPTED MANUSCRIPT
Clinical conditions characterized by male hypogonadism or female hyperandrogenism highlight the role of sex hormones in regulating glucose, lipid and energy homeostasis. In males with Klinefelter’s syndrome, hypogonadism is associated with decreased muscle mass, increased total and truncal fat,
RI PT
and high prevalence of insulin resistance and metabolic syndrome (1). In women with polycystic ovarian syndrome (PCOS) and hyperandrogenism, higher testosterone (T) and lower sex hormone binding globulin (SHBG) are associated with higher prevalence of fatty liver (2). Adverse metabolic
SC
consequences are also seen following therapies that block the effects of T in men or estrogen in women. Insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic syndrome are more
M AN U
common in men with prostate cancer undergoing prolonged androgen deprivation therapy (3). Steatosis and steatohepatitis develop frequently in women with breast cancer who receive the estrogen antagonist tamoxifen (4). These observations suggest that beyond their effects on reproduction and sexual development, sex hormones have a role in modulating insulin signaling
TE D
and lipid metabolism.
How do sex hormone affect glucose and lipid metabolism? Estrogens exhibit a protective effect on development of insulin resistance and T2DM. Estrogen
EP
deficiency impairs insulin secretion from pancreatic β cells , increases adipose tissue lipolysis and inflammation, impairs glucose uptake from muscle, and increases hepatic lipogenesis and
AC C
gluconeogenesis (5). In mice, estradiol administration improved insulin sensitivity and steatosis by increasing the expression of signal transducer and activator of transcription (Stat) 3 and down regulating the expression of sterol regulatory element-binding protein (SREBP)-1 (6, 7). Testosterone is a major source estrogen in both men and postmenopausal women. It is converted to the main estrogen, 17β estradiol (E2) by aromatization in the peripheral adipose tissue. Testosterone level decreases with aging and obesity (8). In males, T decreases food intake, hepatic
ACCEPTED MANUSCRIPT
lipogenesis, visceral distribution of fat, and adipogenesis while it increases peripheral insulin sensitivity and lipid oxidation in muscle (9) . Both T and E2 are transported in the circulation by SHBG, which is the primary binding protein that
RI PT
regulates their bioavailability to target tissues. A portion of each hormone is weakly bound to albumin. SHGB is primarily produced by the liver and has bidirectional relation with both hormones: both hormones influence SHBG levels while SHGB influences the level of free T and E2
SC
(10). Higher levels of SHBG lead to lower level of free and bioavailable (free plus albumin bound) sex hormones. SHBG levels are also influenced by diet as monosaccharides (glucose and fructose)
M AN U
induced lipogenesis has been shown to reduce human SHBG production by hepatocytes (11).
Effects of sex hormones on risk of hepatic steatosis
A few studies have explored the association of sex hormones and SHBG with hepatic steatosis in humans. In a Chinese study of middle-aged diabetic patients (12), there was an inverse association
TE D
between SHBG with risk of non-alcoholic fatty liver disease (NAFLD) in both genders. This effect was independent of age, BMI or alcohol use. The initial association of NAFLD with T in men and free T in women was abolished after adjustment for SHBG. In middle-aged Korean men (13), T level
EP
was independently and inversely correlated with risk of NAFLD. This association weakened but remained significant after adjustment for visceral fat. The effect of SHBG on this association was not
AC C
assessed as SHBG was not measured in this study. Similar association between low SHBG and risk of NAFLD was noted in women with PCOS (14). In another Chinese study of 1882 healthy men, lower E2 but not T or SHBG was associated with NAFLD (15). However, hormones and SHBG levels were only adjusted for age but not for BMI or insulin sensitivity in this study.
In this issue of the Journal, Lazo et al report on the association of sex hormones and SHBG in adults with CT measured hepatic attenuation and steatosis (16). The study included 2835 postmenopausal women and
ACCEPTED MANUSCRIPT
2899 men of different ethnicities, who were recruited at 6 US centers as part of the Multiethnic Study of Atherosclerosis (MESA) project. Subjects age ranged between 45-84 years and heavy alcohol use was reported in 673 (23.7%) of participating women and 892 (30.7%) of men. Hormonal replacement therapy
RI PT
was used in 887 (31.2%) of women. The prevalence of significant hepatic steatosis (defined by hepatic attenuation < 40 Hounsfield units) was 5.8% (5.2% in women versus 5.6% in men, p 0.54) but using the more relaxed criteria of liver to spleen attenuation ratio
PII: DOI: Reference:
S1542-3565(15)00642-4 10.1016/j.cgh.2015.04.182 YJCGH 54280
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 April 2015 Please cite this article as: Gawrieh S, Sex hormones, sex hormone binding globulin and liver fat: which came first, the chicken or the egg?, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/ j.cgh.2015.04.182. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT
Correspondence Author: Samer Gawrieh, MD Division of Gastroenterology and Hepatology
M AN U
Indiana University School of Medicine
SC
RI PT
Sex hormones, sex hormone binding globulin and liver fat: which came first, the chicken or the egg?
702 Rotary Circle Indianapolis, IN 46202 Email: [email protected] Phone (317) 278 9326
TE D
Fax: (317) 278 6870
AC C
EP
The author has no conflict of interest to declare.
ACCEPTED MANUSCRIPT
Clinical conditions characterized by male hypogonadism or female hyperandrogenism highlight the role of sex hormones in regulating glucose, lipid and energy homeostasis. In males with Klinefelter’s syndrome, hypogonadism is associated with decreased muscle mass, increased total and truncal fat,
RI PT
and high prevalence of insulin resistance and metabolic syndrome (1). In women with polycystic ovarian syndrome (PCOS) and hyperandrogenism, higher testosterone (T) and lower sex hormone binding globulin (SHBG) are associated with higher prevalence of fatty liver (2). Adverse metabolic
SC
consequences are also seen following therapies that block the effects of T in men or estrogen in women. Insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic syndrome are more
M AN U
common in men with prostate cancer undergoing prolonged androgen deprivation therapy (3). Steatosis and steatohepatitis develop frequently in women with breast cancer who receive the estrogen antagonist tamoxifen (4). These observations suggest that beyond their effects on reproduction and sexual development, sex hormones have a role in modulating insulin signaling
TE D
and lipid metabolism.
How do sex hormone affect glucose and lipid metabolism? Estrogens exhibit a protective effect on development of insulin resistance and T2DM. Estrogen
EP
deficiency impairs insulin secretion from pancreatic β cells , increases adipose tissue lipolysis and inflammation, impairs glucose uptake from muscle, and increases hepatic lipogenesis and
AC C
gluconeogenesis (5). In mice, estradiol administration improved insulin sensitivity and steatosis by increasing the expression of signal transducer and activator of transcription (Stat) 3 and down regulating the expression of sterol regulatory element-binding protein (SREBP)-1 (6, 7). Testosterone is a major source estrogen in both men and postmenopausal women. It is converted to the main estrogen, 17β estradiol (E2) by aromatization in the peripheral adipose tissue. Testosterone level decreases with aging and obesity (8). In males, T decreases food intake, hepatic
ACCEPTED MANUSCRIPT
lipogenesis, visceral distribution of fat, and adipogenesis while it increases peripheral insulin sensitivity and lipid oxidation in muscle (9) . Both T and E2 are transported in the circulation by SHBG, which is the primary binding protein that
RI PT
regulates their bioavailability to target tissues. A portion of each hormone is weakly bound to albumin. SHGB is primarily produced by the liver and has bidirectional relation with both hormones: both hormones influence SHBG levels while SHGB influences the level of free T and E2
SC
(10). Higher levels of SHBG lead to lower level of free and bioavailable (free plus albumin bound) sex hormones. SHBG levels are also influenced by diet as monosaccharides (glucose and fructose)
M AN U
induced lipogenesis has been shown to reduce human SHBG production by hepatocytes (11).
Effects of sex hormones on risk of hepatic steatosis
A few studies have explored the association of sex hormones and SHBG with hepatic steatosis in humans. In a Chinese study of middle-aged diabetic patients (12), there was an inverse association
TE D
between SHBG with risk of non-alcoholic fatty liver disease (NAFLD) in both genders. This effect was independent of age, BMI or alcohol use. The initial association of NAFLD with T in men and free T in women was abolished after adjustment for SHBG. In middle-aged Korean men (13), T level
EP
was independently and inversely correlated with risk of NAFLD. This association weakened but remained significant after adjustment for visceral fat. The effect of SHBG on this association was not
AC C
assessed as SHBG was not measured in this study. Similar association between low SHBG and risk of NAFLD was noted in women with PCOS (14). In another Chinese study of 1882 healthy men, lower E2 but not T or SHBG was associated with NAFLD (15). However, hormones and SHBG levels were only adjusted for age but not for BMI or insulin sensitivity in this study.
In this issue of the Journal, Lazo et al report on the association of sex hormones and SHBG in adults with CT measured hepatic attenuation and steatosis (16). The study included 2835 postmenopausal women and
ACCEPTED MANUSCRIPT
2899 men of different ethnicities, who were recruited at 6 US centers as part of the Multiethnic Study of Atherosclerosis (MESA) project. Subjects age ranged between 45-84 years and heavy alcohol use was reported in 673 (23.7%) of participating women and 892 (30.7%) of men. Hormonal replacement therapy
RI PT
was used in 887 (31.2%) of women. The prevalence of significant hepatic steatosis (defined by hepatic attenuation < 40 Hounsfield units) was 5.8% (5.2% in women versus 5.6% in men, p 0.54) but using the more relaxed criteria of liver to spleen attenuation ratio
