- Email: [email protected]
What is new in the area of androgen excess?
EDITOR’S CORNER What is new in the area of androgen excess? Rogerio A. Lobo, M.D.a a
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Columbia University, Columbia University Medical Center, New York, New York
A summary is provided regarding some of the latest advancements in the field of androgen excess. These presentations were made at the Fourth Annual Meeting of the Androgen Excess Society in Boston, Massachusetts, June 23, 2006. (Fertil Steril 2007;87:1250–2. 2007 by American Society for Reproductive Medicine.) Key Words: Androgens, polycystic ovary syndrome, genetics, metabolism
The Androgen Excess Society held its Fourth Annual Meeting in June 2006. The mission of the Society is to promote knowledge and to foster original clinical and basic research, thus improving the understanding, diagnosis, treatment, and prevention of these disorders. What follows is a summary of the major presentations at the meeting that bring to light new developments in the field. There were plenary presentations reviewing important areas in androgen excess, and there were selected research papers covering many aspects of the field. The presentations will be grouped together highlighting new developments and concepts. CLINICAL ISSUES RELATING TO ANDROGENS: ANABOLIC STEROIDS AND DIFFICULTIES ASSESSING WHAT CONSTITUTES ANDROGEN EXCESS When pharmacologic doses of androgens are administered, it is clear that this constitutes androgen excess. This pattern of use and abuse of anabolic steroids was reviewed. On the opposite end of the spectrum, sometimes it is difficult to ascertain that there is the presence of androgen excess. A woman may have manifestations of androgen excess, for example, hirsutism, but blood androgen levels do not reflect an excess. Why is this? Two key presentations were made to highlight some issues relating to this observation. The high prevalence of use and abuse of anabolic steroids was the topic of a presentation by Robert McLachlan (Prince Henry’s Institute, Monash, Australia). Already in high school, the prevalence of anabolic steroid ever-use was reported to be as high as 6.6% in boys, although it is lower (approximately one third of the prevalence) in girls. Clearly
Received October 3, 2006; revised November 21, 2006; accepted November 27, 2006. Reprint requests: Rogerio A. Lobo, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Columbia University, Columbia University Medical Center, 622 West 168th St., New York, NY 10032 (E-mail: [email protected]).
1250
the aim of anabolic agents is to activate the androgen receptor. There is a growing list of ‘‘designer’’ anabolic agents that seek to avoid detection in screening programs. Although there was some doubt about the myotropic and ergogenic effects of testosterone, pivotal trials by Bhasin and others have proved these effects. In that only the body synthesizes epitestosterone, measurements of the urinary ratio of testosterone/epitestosterone has been used widely as a screen for exogenous testosterone abuse. Other strategies include the measurement of C13/C12 ratios, which reflect a nonhuman source of steroid. The risks of using anabolic steroids include infections and cardiovascular, hepatic, reproductive, and neuropsychological adverse effects. Research continues, however, for the legitimate use of anabolic agents in states of frailty, muscle-wasting diseases including HIV/AIDS, chronic obstructive pulmonary disease, and chronic renal failure. The issue of not being able to document androgen action by measurement of testosterone in blood was the subject of two different presentations. A new field called ‘‘intracrinology’’ was introduced by Fernand Labrie (Laval University, Quebec, Canada). This concept involves the conversion of precursors such as DHEA into sex steroids in tissues where they act locally and are not reflected in blood levels in the circulation. Thus DHEA can give rise to testosterone production in skin, for example, and skin changes may not be reflected by abnormalities in testosterone levels in the circulation. It was suggested that serum measurements that better reflect local cellular androgen action are androsterone glucuronide and androstane-3a17b-diol-glucuronide. A similar discussion, but from the vantage point of difficulties in measurements, was presented by William Rosner (Columbia University and St. Luke’s–Roosevelt Hospital, New York, New York). Rosner stated that current commercial assays for testosterone in blood are too insensitive and inaccurate to be very useful. This has been borne out in several recent publications (Wang, 2004, and Taieb, 2003), which
Fertility and Sterility Vol. 87, No. 6, June 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.146
pointed out the great variation between assays and the lack of correlation with gas chromatography–mass spectroscopy analyses. There are several initiatives underway to address this issue clinically (Endocrine Society Task Force) in that it should be possible for more standardized assays to be employed. The commercial assays for free testosterone are even more problematic, although it is generally agreed that the measurement of the free component of testosterone should better reflect the biologic activity of testosterone. Once an accurate measurement of testosterone can be made, then free testosterone may be calculated with use of sex hormone–binding globulin measurements. PEDIATRIC ENDOCRINOLOGY Metabolic syndrome is characterized by increased cardiovascular disease and diabetes mellitus, and this may be further compounded by the presence of polycystic ovary syndrome (PCOS) in women. That these disorders may begin in children and adolescents was discussed by Sharon Oberfield (Columbia University, New York, New York). It was stated that premature adrenarche (adrenarche before age 8 years) is one such possible antecedent to adult metabolic syndrome, as well as PCOS. Identifying those girls at risk would seem to be important. Risk factors include the findings of an increased percentage of body fat (which can be assessed by magnetic resonance imaging), insulin resistance, and elevated triglycerides. Although it is not known definitively in which girls metabolic syndrome will develop, identifying such ‘‘at risk’’ individuals might be useful in allowing for lifestyle and other adjustments. A research paper resented by Nicolas Crisosto from the University of Chile studied the daughters of women with PCOS. Antimu¨llerian hormone (AMH) or mu¨llerian-inhibiting substance (MIS) is elevated in women with PCOS, reflecting altered ovarian morphology plus folliculogenesis. Here the authors determined that as a group the prepubertal and perimenarchal daughters of women with PCOS had values of serum AMH and ovarian volumes that were higher than in controls and free androgen indices that also were higher in perimenarchal daughters. Although it is unknown in which of the daughters PCOS may develop (it is anticipated that approximately 40% may be affected), these data are interesting in suggesting a potential early marker. Another research paper by Karen Lin-Su in Maria New’s group at Mount Sinai in New York reported on a retrospective review of 72 cases of classical congenital adrenal hyperplasia. Specific mutations of CYP21A2 were correlated with the degree of genital ambiguity (Prader score) before corrective surgery in those children not receiving prenatal therapy. It was found that certain mutations (deletion/deletion and Ex8318/Int2) were associated with higher Prader scores. Also more severe ambiguity was correlated with a salt-wasting disorder rather than a simple virilizing one. These data have consequences for prenatal diagnosis and counseling. Fertility and Sterility
POLYCYSTIC OVARY SYNDROME A large number of papers were presented on PCOS, which represents the most common disorder among women presenting with androgen excess. This section will cover a debate that was conducted regarding the definition of PCOS and then various basic science and clinical presentations. The Debate According to the Rotterdam (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine) criteria for the diagnosis of PCOS, a woman needs to have only two out of three findings (irregular cycles, hyperandrogenism, and polycystic ovaries on ultrasound examination). Thus several different phenotypes are possible rather than those diagnosed with use of a more classic definition that includes only women with irregular cycles and hyperandrogenism. One of these phenotypes allows for the diagnosis of PCOS in women with only irregular cycles and polycystic ovaries, without requiring the presence of hyperandrogenism. This issue was the focus of the debate, ‘‘Is It Necessary to Have Findings of Androgen Excess for the Diagnosis of PCOS?’’ Richard Legro (Pennsylvania State University, Hershey, Pennsylvania) took the ‘‘pro’’ position, and Robert Norman (University of Adelaide, Woodville, Australia) took the ‘‘con’’ position. Although it is not possible here to do justice to the content and spirit of the debate, and there was no attempt to declare a winner, a few points made on both sides of the debate will be mentioned. Dr. Legro’s concerns were that, without clear androgen excess, women with hypothalamic amenorrhea may be diagnosed as having PCOS; that insulin resistance may be missed, which is a major component of the diagnosis; and that clinical trials would be adversely affected with an imprecise definition. Dr. Norman took the practical view that the majority of women in whom this diagnosis will be made in fact have PCOS, and it is easier for generalists to have a straightforward guideline for the diagnosis. His major point, however, dwelt on other presentations (reviewed above) that determining androgen excess is often difficult, and measuring testosterone is notoriously inaccurate and cannot be relied on to rule in or rule out the diagnosis. Basic Science Research in PCOS Multiple signaling defects in the theca cells of women with PCOS were described in a presentation by Jan McAllister (Pennsylvania State University, Hershey, Pennsylvania). It is known that there are enhancements of key steroidogenic enzyme activities in ovarian theca cells in PCOS. This has been related to decreased mitogen-activated protein kinase signaling activity, but recently it has been found that there are other signaling defects such as decreased MEK/ERK and enhanced MKK7 and JNK signaling. It is not clear what leads to this disordered signaling. It was also discussed that the ovarian effect of metformin, which decreases androgen production, may be related to decreased phosphorylation 1251
of LKB1 and adenosine monophosphate–activated protein kinase. It was stated that LKB1 signaling, which links cellular metabolic and proliferative changes, may be a possible therapeutic target of the future in PCOS. In a related research paper presentation by Jessica Wickenheisser in the McAllister group (Hershey, Pennsylvania), the author outlined the enhanced CYP11A1 activity in theca cells from women with PCOS. Mechanistically it was reported that this enhanced gene expression is the result of increased transactivation of the CYP11A1 promoter, as well as prolonged stability of messenger RNA. SGTA was presented as a novel candidate gene for PCOS by Mark Goodarzi (Cedars-Sinai, Los Angeles, California). SGTA is a gene on 19p13 that encodes a cochaperone protein that binds to the androgen receptor and keeps it in the cytoplasm. Various haplotypes of SGTA (using SNPs) were evaluated in PCOS and controls, and the most common haplotype (G-A-T) was associated with a significant odds ratio of 4.1 for development of PCOS. The second most common haplotype (A-G-C) was also associated with insulin resistance. The direct role of metformin on the ovary was investigated by Suman Rice and colleagues (St. George’s University of London, London, United Kingdom). Granulosa cells from IVF aspirations were studied. It was found that metformin inhibited both basal and insulin-stimulated aromatase expression in granulosa cells, as well as the expression of AMH/MIS (which is markedly increased in PCOS ovaries). The authors proposed that, taken together with the known effects on insulin resistance, these additional two effects of metformin on granulosa cells (inhibition of aromatase and AMH/MIS) provide metformin with a ‘‘triple benefit.’’ Clinical Research in PCOS The clinical presentations in PCOS dealt largely with the metabolic concerns of the disorder. A potential strategy for weight loss in obese women with PCOS is bariatric surgery. The results of a prospective study using bariatric surgery was presented by Hector Escobar-Morreale (Madrid, Spain). It was stated that in a cohort of 113 obese women, 28.3% were found to have PCOS, much higher than the 5.5% prevalence in lean Spanish women. It was postulated that obesity contributes to insulin resistance (directly and indirectly through adipocytokine secretion), which enhances hyperandrogenism. Androgens in turn may enhance abdominal obesity, leading to a vicious circle. Bariatric surgery in the cohort of obese women (body mass index [BMI] >40) resulted in a weight loss of 41 kg with marked improvement in metabolic parameters and resulted in symptoms and signs of PCOS tending to ‘‘disappear’’ in some women. A research paper by K. I. Cheang (Virginia Commonwealth University, Richmond, Virginia) addressed the role of inositol phosphoglycan (IPG) mediators and insulin sensi-
1252
Lobo
Androgen excess 2006
tivity in women with PCOS. With the hypothesis that a deficiency in D-chiro-inositol (DCI) containing IPG (DCI-IPG) can lead to the insulin resistance in PCOS, supplements of oral DCI 1500 mg or placebo twice a day were given to women with PCOS. With use of the frequently sampled intravenous glucose tolerance test, to assess insulin sensitivity, it was found that increased glucose–stimulated DCI-IPG release was correlated with improved insulin sensitivity. The authors suggest that DCI-IPG mediator (which is also enhanced by metformin) may be a specific target for therapy in women with PCOS. In another research paper by Jean-Patrice Baillargeon (University of Sherbrooke, Sherbrooke, Quebec, Canada), the authors reported their study of 17 brothers of women with PCOS to assess them for metabolic abnormalities compared with matched controls. Significant findings included elevated triglycerides, plasminogen activator-inhibitor (PAI-1), factor VIII, 2-hour glucose, and the area under the curve for glucose and insulin in response to an oral glucose challenge, even after appropriate adjustments for BMI, waist circumferences, and the percentage of body fat. Three of the 17 brothers had impaired glucose tolerance. These data parallel other findings by Legro of an increased prevalence of elevated DHEAS in brothers of women with PCOS and suggest the possible heritability of the metabolic traits typical of PCOS. The importance of visceral fat contributing to the cardiovascular risk of women with PCOS was studied by Teresa Cascella and colleagues (University of Naples, Naples, Italy). In a group of women with PCOS (n ¼ 20), visceral fat was determined by ultrasound examination, as well as a number of metabolic and cardiovascular parameters in these women and controls. The amount of visceral fat was highly correlated with markers of insulin resistance. Visceral fat was found to be an independent predictor of carotid intima-media thickness, brachial flow–mediated dilation, and C-reactive protein, all of which have been found to be abnormal in women with PCOS.
IN SUMMARY It appears that the field of androgen excess is very active, and there is exciting new research being carried out at both the basic and clinical level. There were stimulating discussions during the meeting, and the program also had poster presentations that have not been summarized here. A total of 17 posters were presented, which were excellent in quality; additional information was presented on the genetics of PCOS, as well as on issues relating to the diagnosis and management of PCOS. An opportunity exists here not only to form international collaborations for research but also to help further our knowledge in the diagnosis and treatment of this group of disorders.
Vol. 87, No. 6, June 2007
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Columbia University, Columbia University Medical Center, New York, New York
A summary is provided regarding some of the latest advancements in the field of androgen excess. These presentations were made at the Fourth Annual Meeting of the Androgen Excess Society in Boston, Massachusetts, June 23, 2006. (Fertil Steril 2007;87:1250–2. 2007 by American Society for Reproductive Medicine.) Key Words: Androgens, polycystic ovary syndrome, genetics, metabolism
The Androgen Excess Society held its Fourth Annual Meeting in June 2006. The mission of the Society is to promote knowledge and to foster original clinical and basic research, thus improving the understanding, diagnosis, treatment, and prevention of these disorders. What follows is a summary of the major presentations at the meeting that bring to light new developments in the field. There were plenary presentations reviewing important areas in androgen excess, and there were selected research papers covering many aspects of the field. The presentations will be grouped together highlighting new developments and concepts. CLINICAL ISSUES RELATING TO ANDROGENS: ANABOLIC STEROIDS AND DIFFICULTIES ASSESSING WHAT CONSTITUTES ANDROGEN EXCESS When pharmacologic doses of androgens are administered, it is clear that this constitutes androgen excess. This pattern of use and abuse of anabolic steroids was reviewed. On the opposite end of the spectrum, sometimes it is difficult to ascertain that there is the presence of androgen excess. A woman may have manifestations of androgen excess, for example, hirsutism, but blood androgen levels do not reflect an excess. Why is this? Two key presentations were made to highlight some issues relating to this observation. The high prevalence of use and abuse of anabolic steroids was the topic of a presentation by Robert McLachlan (Prince Henry’s Institute, Monash, Australia). Already in high school, the prevalence of anabolic steroid ever-use was reported to be as high as 6.6% in boys, although it is lower (approximately one third of the prevalence) in girls. Clearly
Received October 3, 2006; revised November 21, 2006; accepted November 27, 2006. Reprint requests: Rogerio A. Lobo, M.D., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Columbia University, Columbia University Medical Center, 622 West 168th St., New York, NY 10032 (E-mail: [email protected]).
1250
the aim of anabolic agents is to activate the androgen receptor. There is a growing list of ‘‘designer’’ anabolic agents that seek to avoid detection in screening programs. Although there was some doubt about the myotropic and ergogenic effects of testosterone, pivotal trials by Bhasin and others have proved these effects. In that only the body synthesizes epitestosterone, measurements of the urinary ratio of testosterone/epitestosterone has been used widely as a screen for exogenous testosterone abuse. Other strategies include the measurement of C13/C12 ratios, which reflect a nonhuman source of steroid. The risks of using anabolic steroids include infections and cardiovascular, hepatic, reproductive, and neuropsychological adverse effects. Research continues, however, for the legitimate use of anabolic agents in states of frailty, muscle-wasting diseases including HIV/AIDS, chronic obstructive pulmonary disease, and chronic renal failure. The issue of not being able to document androgen action by measurement of testosterone in blood was the subject of two different presentations. A new field called ‘‘intracrinology’’ was introduced by Fernand Labrie (Laval University, Quebec, Canada). This concept involves the conversion of precursors such as DHEA into sex steroids in tissues where they act locally and are not reflected in blood levels in the circulation. Thus DHEA can give rise to testosterone production in skin, for example, and skin changes may not be reflected by abnormalities in testosterone levels in the circulation. It was suggested that serum measurements that better reflect local cellular androgen action are androsterone glucuronide and androstane-3a17b-diol-glucuronide. A similar discussion, but from the vantage point of difficulties in measurements, was presented by William Rosner (Columbia University and St. Luke’s–Roosevelt Hospital, New York, New York). Rosner stated that current commercial assays for testosterone in blood are too insensitive and inaccurate to be very useful. This has been borne out in several recent publications (Wang, 2004, and Taieb, 2003), which
Fertility and Sterility Vol. 87, No. 6, June 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.11.146
pointed out the great variation between assays and the lack of correlation with gas chromatography–mass spectroscopy analyses. There are several initiatives underway to address this issue clinically (Endocrine Society Task Force) in that it should be possible for more standardized assays to be employed. The commercial assays for free testosterone are even more problematic, although it is generally agreed that the measurement of the free component of testosterone should better reflect the biologic activity of testosterone. Once an accurate measurement of testosterone can be made, then free testosterone may be calculated with use of sex hormone–binding globulin measurements. PEDIATRIC ENDOCRINOLOGY Metabolic syndrome is characterized by increased cardiovascular disease and diabetes mellitus, and this may be further compounded by the presence of polycystic ovary syndrome (PCOS) in women. That these disorders may begin in children and adolescents was discussed by Sharon Oberfield (Columbia University, New York, New York). It was stated that premature adrenarche (adrenarche before age 8 years) is one such possible antecedent to adult metabolic syndrome, as well as PCOS. Identifying those girls at risk would seem to be important. Risk factors include the findings of an increased percentage of body fat (which can be assessed by magnetic resonance imaging), insulin resistance, and elevated triglycerides. Although it is not known definitively in which girls metabolic syndrome will develop, identifying such ‘‘at risk’’ individuals might be useful in allowing for lifestyle and other adjustments. A research paper resented by Nicolas Crisosto from the University of Chile studied the daughters of women with PCOS. Antimu¨llerian hormone (AMH) or mu¨llerian-inhibiting substance (MIS) is elevated in women with PCOS, reflecting altered ovarian morphology plus folliculogenesis. Here the authors determined that as a group the prepubertal and perimenarchal daughters of women with PCOS had values of serum AMH and ovarian volumes that were higher than in controls and free androgen indices that also were higher in perimenarchal daughters. Although it is unknown in which of the daughters PCOS may develop (it is anticipated that approximately 40% may be affected), these data are interesting in suggesting a potential early marker. Another research paper by Karen Lin-Su in Maria New’s group at Mount Sinai in New York reported on a retrospective review of 72 cases of classical congenital adrenal hyperplasia. Specific mutations of CYP21A2 were correlated with the degree of genital ambiguity (Prader score) before corrective surgery in those children not receiving prenatal therapy. It was found that certain mutations (deletion/deletion and Ex8318/Int2) were associated with higher Prader scores. Also more severe ambiguity was correlated with a salt-wasting disorder rather than a simple virilizing one. These data have consequences for prenatal diagnosis and counseling. Fertility and Sterility
POLYCYSTIC OVARY SYNDROME A large number of papers were presented on PCOS, which represents the most common disorder among women presenting with androgen excess. This section will cover a debate that was conducted regarding the definition of PCOS and then various basic science and clinical presentations. The Debate According to the Rotterdam (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine) criteria for the diagnosis of PCOS, a woman needs to have only two out of three findings (irregular cycles, hyperandrogenism, and polycystic ovaries on ultrasound examination). Thus several different phenotypes are possible rather than those diagnosed with use of a more classic definition that includes only women with irregular cycles and hyperandrogenism. One of these phenotypes allows for the diagnosis of PCOS in women with only irregular cycles and polycystic ovaries, without requiring the presence of hyperandrogenism. This issue was the focus of the debate, ‘‘Is It Necessary to Have Findings of Androgen Excess for the Diagnosis of PCOS?’’ Richard Legro (Pennsylvania State University, Hershey, Pennsylvania) took the ‘‘pro’’ position, and Robert Norman (University of Adelaide, Woodville, Australia) took the ‘‘con’’ position. Although it is not possible here to do justice to the content and spirit of the debate, and there was no attempt to declare a winner, a few points made on both sides of the debate will be mentioned. Dr. Legro’s concerns were that, without clear androgen excess, women with hypothalamic amenorrhea may be diagnosed as having PCOS; that insulin resistance may be missed, which is a major component of the diagnosis; and that clinical trials would be adversely affected with an imprecise definition. Dr. Norman took the practical view that the majority of women in whom this diagnosis will be made in fact have PCOS, and it is easier for generalists to have a straightforward guideline for the diagnosis. His major point, however, dwelt on other presentations (reviewed above) that determining androgen excess is often difficult, and measuring testosterone is notoriously inaccurate and cannot be relied on to rule in or rule out the diagnosis. Basic Science Research in PCOS Multiple signaling defects in the theca cells of women with PCOS were described in a presentation by Jan McAllister (Pennsylvania State University, Hershey, Pennsylvania). It is known that there are enhancements of key steroidogenic enzyme activities in ovarian theca cells in PCOS. This has been related to decreased mitogen-activated protein kinase signaling activity, but recently it has been found that there are other signaling defects such as decreased MEK/ERK and enhanced MKK7 and JNK signaling. It is not clear what leads to this disordered signaling. It was also discussed that the ovarian effect of metformin, which decreases androgen production, may be related to decreased phosphorylation 1251
of LKB1 and adenosine monophosphate–activated protein kinase. It was stated that LKB1 signaling, which links cellular metabolic and proliferative changes, may be a possible therapeutic target of the future in PCOS. In a related research paper presentation by Jessica Wickenheisser in the McAllister group (Hershey, Pennsylvania), the author outlined the enhanced CYP11A1 activity in theca cells from women with PCOS. Mechanistically it was reported that this enhanced gene expression is the result of increased transactivation of the CYP11A1 promoter, as well as prolonged stability of messenger RNA. SGTA was presented as a novel candidate gene for PCOS by Mark Goodarzi (Cedars-Sinai, Los Angeles, California). SGTA is a gene on 19p13 that encodes a cochaperone protein that binds to the androgen receptor and keeps it in the cytoplasm. Various haplotypes of SGTA (using SNPs) were evaluated in PCOS and controls, and the most common haplotype (G-A-T) was associated with a significant odds ratio of 4.1 for development of PCOS. The second most common haplotype (A-G-C) was also associated with insulin resistance. The direct role of metformin on the ovary was investigated by Suman Rice and colleagues (St. George’s University of London, London, United Kingdom). Granulosa cells from IVF aspirations were studied. It was found that metformin inhibited both basal and insulin-stimulated aromatase expression in granulosa cells, as well as the expression of AMH/MIS (which is markedly increased in PCOS ovaries). The authors proposed that, taken together with the known effects on insulin resistance, these additional two effects of metformin on granulosa cells (inhibition of aromatase and AMH/MIS) provide metformin with a ‘‘triple benefit.’’ Clinical Research in PCOS The clinical presentations in PCOS dealt largely with the metabolic concerns of the disorder. A potential strategy for weight loss in obese women with PCOS is bariatric surgery. The results of a prospective study using bariatric surgery was presented by Hector Escobar-Morreale (Madrid, Spain). It was stated that in a cohort of 113 obese women, 28.3% were found to have PCOS, much higher than the 5.5% prevalence in lean Spanish women. It was postulated that obesity contributes to insulin resistance (directly and indirectly through adipocytokine secretion), which enhances hyperandrogenism. Androgens in turn may enhance abdominal obesity, leading to a vicious circle. Bariatric surgery in the cohort of obese women (body mass index [BMI] >40) resulted in a weight loss of 41 kg with marked improvement in metabolic parameters and resulted in symptoms and signs of PCOS tending to ‘‘disappear’’ in some women. A research paper by K. I. Cheang (Virginia Commonwealth University, Richmond, Virginia) addressed the role of inositol phosphoglycan (IPG) mediators and insulin sensi-
1252
Lobo
Androgen excess 2006
tivity in women with PCOS. With the hypothesis that a deficiency in D-chiro-inositol (DCI) containing IPG (DCI-IPG) can lead to the insulin resistance in PCOS, supplements of oral DCI 1500 mg or placebo twice a day were given to women with PCOS. With use of the frequently sampled intravenous glucose tolerance test, to assess insulin sensitivity, it was found that increased glucose–stimulated DCI-IPG release was correlated with improved insulin sensitivity. The authors suggest that DCI-IPG mediator (which is also enhanced by metformin) may be a specific target for therapy in women with PCOS. In another research paper by Jean-Patrice Baillargeon (University of Sherbrooke, Sherbrooke, Quebec, Canada), the authors reported their study of 17 brothers of women with PCOS to assess them for metabolic abnormalities compared with matched controls. Significant findings included elevated triglycerides, plasminogen activator-inhibitor (PAI-1), factor VIII, 2-hour glucose, and the area under the curve for glucose and insulin in response to an oral glucose challenge, even after appropriate adjustments for BMI, waist circumferences, and the percentage of body fat. Three of the 17 brothers had impaired glucose tolerance. These data parallel other findings by Legro of an increased prevalence of elevated DHEAS in brothers of women with PCOS and suggest the possible heritability of the metabolic traits typical of PCOS. The importance of visceral fat contributing to the cardiovascular risk of women with PCOS was studied by Teresa Cascella and colleagues (University of Naples, Naples, Italy). In a group of women with PCOS (n ¼ 20), visceral fat was determined by ultrasound examination, as well as a number of metabolic and cardiovascular parameters in these women and controls. The amount of visceral fat was highly correlated with markers of insulin resistance. Visceral fat was found to be an independent predictor of carotid intima-media thickness, brachial flow–mediated dilation, and C-reactive protein, all of which have been found to be abnormal in women with PCOS.
IN SUMMARY It appears that the field of androgen excess is very active, and there is exciting new research being carried out at both the basic and clinical level. There were stimulating discussions during the meeting, and the program also had poster presentations that have not been summarized here. A total of 17 posters were presented, which were excellent in quality; additional information was presented on the genetics of PCOS, as well as on issues relating to the diagnosis and management of PCOS. An opportunity exists here not only to form international collaborations for research but also to help further our knowledge in the diagnosis and treatment of this group of disorders.
Vol. 87, No. 6, June 2007