ANNUAL REVIEWS
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
Annu. Rev. Med. 1991. 42:199�204 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
POLYCYSTIC OVARIAN DISEASE Robert L. Barbieri, M.D.
Department of Obstetrics and Gynecology, Health Sciences Center, State University of New York, Stony Brook, New York 11794-8091 KEY WORDS:
insulin resistance, insulin receptor gene, HAIR-AN syndrome, acanthosis nigricans, androgens
ABSTRACT
Polycystic ovarian disease (PCOD) is a common endocrinopathy in women of reproductive age. Its molecular causes remain to be fully defined. Hyper insulinemia and hyperandrogenism are positively correlated, which sug gests that insulin resistance may be involved in the pathogenesis of PCOD. Point mutations in the insulin receptor gene that cause insulin resistance appear to be associated with the PCOD phenotype. . INTRODUCTION
Polycystic ovarian disease (PCOD) is a common endocrinopathy, affecting approximately 5% of women of reproductive age. The hallmarks of PCOD are clinical evidence of hyperandrogenism (facial hirsutism), laboratory evidence ofhyperandrogenism (elevated testosterone), and anovulation or oligo-ovulation (1, 2). In women with clinical and laboratory evidence of hyperandrogenism, other specific endocrinopathies (e.g. adrenal hyper plasia, Cushing's disease, ovarian and adrenal tumors) must be ruled out before a diagnosis of PCOD can be made. In most cases of PCOD, androgen overproduction by the ovary, the adrenal, and the skin simultaneously contribute to the disease process (1, 2). The multifactorial multiorgan nature of the disease process makes it difficult to identify a single inciting cause of PCOD. A major goal for 199 0066-4219/91/0401-0199$02.00
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
200
BARBIERI
endocrinologists is to divide peOD into distinct subgroups, each with a specific cific molecular cause of peOD is provided by the observation that there is a strong correlation between hyperinsulinemia and hyperandrogenism in women of reproductive age (3). The "insulin hypothesis" states that marked hyperinsulinemia synergizes with luteinizing hormone to stimulate ovarian androgen production.
HYPERINSULINEMIA AND PCOD
Burghen and colleagues (4) were the first statistical relationship between hyperinsulinemia and hypcrandrogcnism. Fasting, circulating levels of insulin, testosterone, and androstenedione were measured by radioimmunoassay in eight obese women with peOD and six obese women without peOD. Positive correlations between insulin and testosterone (r 0.72, p < 0.01) and between insulin and andro stenedione (r = 0.65, p < 0.0 1 ) were observed. In addition, a strong cor relation between glucose-stimulated plasma insulin and testosterone was reported (r 0.85, P < 0.001). The positive correlation between hyper insulinemia and hyperandrogenism has been reported by many other inves tigators in both obese and nonobese women. Most investigators have used fasting hormone levels or oral-glucose-stimulated hormone levels to document the correlation between hyperinsulinemia and hyper androgenism. However, in a few reports, more sophisticated techniques such as the intravenous glucose tolerance test with minimal modeling, the intravenous insulin tolerance test, and the euglycemic insulin clamp technique have been utilized to document the relationship between insulin resistance, hyperinsulinemia, and hyperandrogenism. Three hypotheses could account for the strong association between hyperinsulinemia and hyperandrogenism: (a) hyperandrogenism causes hyperinsulinemia, (b) hyperinsulinemia causes hyperandrogenism, and (c) an unidentified androgenism (5). Each of these hypotheses is discussed below. The available experimental evidence indicates that hyperandrogenism does not cause severe insulin resistance and hyperinsulinemia in women. In men, circulating testosterone concentration is in the range of 5 ng/m!. This concentration of testosterone is not associated with significant insulin resistance or hyperinsulinemia. In hyperandrogenic women with peOD, circulating concentrations of testosterone are in the range of 1 ng/m!. If this concentration of testosterone causes severe insulin resistance and hyperinsulinemia, a major difference in the insulin response to testosterone =
=
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
POLYCYSTIC OVARIAN DISEASE
20 I
must exist between men and women. To date, there is no evidence to support this contention. Multiple, dynamic endocrine suppression studies also indicate that, in women with hyperinsulinemia and hyperandrogenism, the hyper androgenism does not cause the insulin resistance. For example, Nagamani and colleagues (6) demonstrated that, in women with ovarian hyper androgenism and hyperinsulinemia, bilateral oophorectomy eliminated the hyperandrogenism but did not reduce the severity of the hyperinsulinemia. Geffner et al (7) treated hyperandrogenic, hyperinsulinemic women with a long-acting gonadotropin-releasing hormone agonist (GnRH agonist). The GnRH agonist therapy produced complete resolution of the hyper androgenism, but it did not alter the hyperinsulinemia. The hypothesis that hyperinsulinemia causes hyperandrogenism is sup ported by multiple, separate lines of investigation. The data that support this hypothesis include (a) the acute administration of insulin to women with PCOD causes an increase in circulating androstenedione (8, 9); (b) the administration ofglucose to hyperinsulinemic hyperandrogenic women results in an increase in circulating insulin and androgens (10); (c) in women, weight loss, fasting, or a hypocaloric diet is associated with a decrease in circulating androgens (11); (d) in vitro, insulin stimulates human ovarian stromal androgen production, possibly by interacting via an ovarian IGF-I receptor (12, 13); and (e) diverse disease states that result in severe hyperinsulinemia (Kahn type A and type B diabetes, leprechaunism, and Iipoatrophic diabetes) are uniformly associated with hyperandrogenism (3, 5). The recent demonstration that point mutations in the insulin receptor gene are genetically linked to the PCOD phenotype provides strong evidence that hyperinsulinemia, a compensatory response to insulin resistance, causes hyperandrogenism (14-16). THE HAIR-AN SYNDROME
The best clinical example of the possible linkage between point mutations in the insulin receptor gene and PCOD is found in women with the syndrome of hyperandrogenism (HA), insulin resistance (IR), and acan thosis nigricans ( AN)-the HAIR-AN syndrome (3). In women with the HAIR-AN syndrome the hyperandrogenism is due to the overproduction of testosterone and androstenedione by the ovaries. The ovarian androgen overproduction results in facial hirsutism, acne, and in severe cases, vir ilization. The insulin resistance can be due to many causes, including point mutations in the insulin receptor gene (Kahn type A diabetes), anti-insulin receptor antibodies (Kahn type B diabetes), and postreceptor defects. The insulin resistance results in a compensatory hyperinsulinemia. It is our
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
202
BARBIERI
hypothesis that the hyperinsulinemia, acting via ovarian IGF-l receptors, synergizes with luteinizing hormone to stimulate ovarian testosterone and androstenedione production. The acanthosis nigricans is a hyperplastic response of the skin to stimulation by insulin and androgen. The acanthosis nigricans represents an epiphenomenon of the hyperandrogenism and insulin resistance. Four reports (14-17) detail the association of point mutations in the insulin receptor gene and the peOD phenotype (Table 1 ). Although the data are still scanty, it appears that certain point mutations in the insulin receptor gene coding for the beta subunit are dominant. In contrast, certain point mutations in the insulin receptor gene coding for the alpha subunit are apparently recessive. An important genetic principle is that if a phenotypic trait (such as the HAIR-AN syndrome) segregates in a family and is linked to a single gene marker, then that trait is caused by the gene. Accili and colleagues (15) recently reported a linkage analysis of one pedigree with the HAIR-AN syndrome (Kahn type A diabetes), which included two affected daughters, three unaffected daughters, and one unaffected son. Insulin receptor cDNA cloned from one affected sister showed a single missense mutation in both alleles of the insulin receptor gene, resulting in the substitution of a valine for phenylalanine at position 382 of the alpha subunit. Analysis of restric tion fragment length polymorphisms (RFLPs) demonstrated that the two affected sisters are homozygous for this mutation while the two parents and the unaffected sibs are heterozygous carriers. Using the homozygosity mapping method, a LOD (logarithm of the odds) score of 2.25 was cal culated for this pedigree. This LOD score supports the hypothesis that the mutation in the insulin receptor gene causes the HAIR-AN phenotype. Of Table 1
Case reports linking point mutations in the insulin receptor gene and the PCOD phenotype Codon and
Number of Investigator
alleles
Subunit
amino acid
affected
affected
replacement
Moller & Flier
beta 2
(16) Kadawaki et al
Phenotype
dominant
PCOD
735, serine for arginine
recessive
PCOD
460, glutamic acid for
recessive
leprechaunism
recessive
PCOD
1200, serine for tyrosine
(14)
Y oshimasa et al
Inheritance
processing site
2
(17)
alpha and beta
lysine 671, STOP codon
Accili et al (15)
2
alpha
382, valine for phenylalanine
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
POLYCYSTIC OVARIAN DISEASE
203
interest, transfection of mutant insulin receptor cDNA into NIH-3T3 cells demonstrated that the substitution of valine for phenylalanine at position 382 impairs posttranslational processing and retards the transport of the insulin receptor to the plasma membrane. The mutation causes insulin resistance (and the HAIR-AN syndrome) by decreasing the number of insulin receptors on the cell surface (15). The importance of the observation that point mutations in the insulin receptor gene can result in the HAIR-AN syndrome cannot be over estimated. It is the first example of a specific hyperandrogenism ("polycystic ovary syndrome"), and should allow detailed genetic analysis of large pedigrees with familial polycystic ovary syndrome. In addition, it suggests that any cause of severe hyper insulinemia, such as obesity, may result in ovarian hyperandrogenism. This hypothesis is strengthened by the observation that acquired causes of insulin receptor dysfunction are also associated with ovarian hyper androgenism. IMPLICATIONS FOR DIAGNOSIS AND THERAPY
The insulin hypothesis states that hyperinsulinemia, acting via an ovarian IGF-I receptor, synergizes with luteinizing hormone to cause ovarian androgen overproduction and the peOD phenotype. The association between hyperinsulinemia and hyperandrogenism has a number of impli cations for the diagnosis and therapy of peOD. Approximately 50% of women with peOD are insulin resistant, and approximately 10% of these are severely insulin resistant (18). The women with severe insulin resistance are at high risk for developing non-insulin dependent diabetes mellitus (19). Given this association, it may be reason able to screen women with peOD for diabetes. In addition, women with peOD appear to have multiple lipid abnormalities, including elevated cholesterol, decreased HDL-cholesterol, and increased triglycerides (20). This finding and the relationship between lipid abnormalities and the risk for coronary artery disease both argue in favor of performing a lipid screen on women with peOD. Recent evidence suggests that obese women with hyperinsulinemia and peOD respond very favorably to weight loss (21). In obese women with peOD, weight loss decreases their insulin resistance and their hyper insulinemia (40%), as well as decreasing their levels of circulating lutein izing hormone (45%) and testosterone (3 5%). In addition, weight loss resulted in resumption of ovulation and fertility in many of the women. It may be that weight loss reduces cumulative insulin secretion, which thereby reduces ovarian androgen production and resolves the peOD phenotype.
204
BARBIERI
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
In the past ten years tremendous progress has been made in under standing the relationship between hyperinsulinemia and hyper androgenism. Future studies undoubtedly will further characterize the molecular mechanisms by which hyperinsulinemia stimulates ovarian androgen production.
Literature Cited 1. Yen, S. S. C. 1980. C/in. Endocrinol. 12: 77-108 2. Goldzieher, J. W. 1981. Fertil. Steril. 35: 371-79 3. Barbieri, R. L., Ryan, K. J. 1983. Am. J. Obstet. Gynecol. 147: 90-101 4. Burghen, G. A., Givens, J. R., Kitabchi, A. E. 1980. J. C/in. Endocrinol. Metab. 50: 113-16 5. Barbieri, R. L., Smith, S., Ryan, K. J. 1988. Fertil. Steril. 50: 197-212 6. Nagamani, M., Dinh, T. V., Kelver, M. E. 1986. Am. J. Obstet. Gynecol. 154: 384-89 7. Geffner, M. E., Kaplan, S. E., Bersch, N., Golde, D. W., Landaw, E. M., Chang, R.I. 1986. Fertil. Steril. 45: 32733 8. Stuart, C. A., Prince, M. J., Peters, E. J., Meyer, W. J. 1987. Obstet. Gynecol. 69: 921-25 9. Dunaif, A. M., Graf, M. 1989. J. c/in. Invest. 83: 23-29 10. Smith, S., Ravnikar, V. A., Barbieri, R. L. 1987. Ferti!. Steri!. 48: 72-77 11. Bates, G. W., Whitworth, N. S. 1982. Fertil. Steril. 38: 406-10 12. Barbieri, R. L., Makris, A., Randall, R. W., Daniels, G., Kistner, R. W., Ryan,
13. 14. 15.
16.
17.
18. 19.
20.
21.
K. J. 1986. J. c/in. Endocrinol. Metab. 62: 904 10 Barbieri, R. L., Makris, A., Ryan, K. J. 1984. Obstet. Gynecol. 64: 73S-80S Moller, D. E., Flier, J. S. 1988. N. Engl. J. Med. 319: 1526-29 Accili, D., Frapier, c., Mosthaf, L., McKeon, C., Elbein, S. C., et al. 1989. EMBO J. 8: 2509-17 Yoshimasa, Y., Seino, S., Whitaker, J., Kakehi, T., Kosaki, A., et a!. 19RR. Sci ence 240: 784-87 Kadawaki, T., Bevins, C. L., Cama, A., Oj amaa, K., Marcus-Samuels, B., et al. 1988. Science 240: 787-90 Dunaif, A., Graf, M., Mandeli, J. 1987. J. Clin. Endocrinol. Metab. 65: 499-505 Kissebah, A. R., Vydelingum, N., Murray, R. 1982. J. C/in. Endocrinol. Metab. 54: 254-61 Wild, R. A., Painter, P. c., Coulson, P. B., Carruth, K. B., Ranney, G. B. 1985. J. elin. Endocrinol. Metab. 61: 946-51 Pasquali, R., Antenucci, D., Casimirri, F., Venturoli, S., Paradisi, R., et a!. 1989. Clinical and hormonal characteristics of obese amennorrheic hyperandrogenic women before and after weight loss. J. c/in. Endocrinol. Metab. 68: 173-79
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
Annu. Rev. Med. 1991. 42:199�204 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
POLYCYSTIC OVARIAN DISEASE Robert L. Barbieri, M.D.
Department of Obstetrics and Gynecology, Health Sciences Center, State University of New York, Stony Brook, New York 11794-8091 KEY WORDS:
insulin resistance, insulin receptor gene, HAIR-AN syndrome, acanthosis nigricans, androgens
ABSTRACT
Polycystic ovarian disease (PCOD) is a common endocrinopathy in women of reproductive age. Its molecular causes remain to be fully defined. Hyper insulinemia and hyperandrogenism are positively correlated, which sug gests that insulin resistance may be involved in the pathogenesis of PCOD. Point mutations in the insulin receptor gene that cause insulin resistance appear to be associated with the PCOD phenotype. . INTRODUCTION
Polycystic ovarian disease (PCOD) is a common endocrinopathy, affecting approximately 5% of women of reproductive age. The hallmarks of PCOD are clinical evidence of hyperandrogenism (facial hirsutism), laboratory evidence ofhyperandrogenism (elevated testosterone), and anovulation or oligo-ovulation (1, 2). In women with clinical and laboratory evidence of hyperandrogenism, other specific endocrinopathies (e.g. adrenal hyper plasia, Cushing's disease, ovarian and adrenal tumors) must be ruled out before a diagnosis of PCOD can be made. In most cases of PCOD, androgen overproduction by the ovary, the adrenal, and the skin simultaneously contribute to the disease process (1, 2). The multifactorial multiorgan nature of the disease process makes it difficult to identify a single inciting cause of PCOD. A major goal for 199 0066-4219/91/0401-0199$02.00
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
200
BARBIERI
endocrinologists is to divide peOD into distinct subgroups, each with a specific cific molecular cause of peOD is provided by the observation that there is a strong correlation between hyperinsulinemia and hyperandrogenism in women of reproductive age (3). The "insulin hypothesis" states that marked hyperinsulinemia synergizes with luteinizing hormone to stimulate ovarian androgen production.
HYPERINSULINEMIA AND PCOD
Burghen and colleagues (4) were the first statistical relationship between hyperinsulinemia and hypcrandrogcnism. Fasting, circulating levels of insulin, testosterone, and androstenedione were measured by radioimmunoassay in eight obese women with peOD and six obese women without peOD. Positive correlations between insulin and testosterone (r 0.72, p < 0.01) and between insulin and andro stenedione (r = 0.65, p < 0.0 1 ) were observed. In addition, a strong cor relation between glucose-stimulated plasma insulin and testosterone was reported (r 0.85, P < 0.001). The positive correlation between hyper insulinemia and hyperandrogenism has been reported by many other inves tigators in both obese and nonobese women. Most investigators have used fasting hormone levels or oral-glucose-stimulated hormone levels to document the correlation between hyperinsulinemia and hyper androgenism. However, in a few reports, more sophisticated techniques such as the intravenous glucose tolerance test with minimal modeling, the intravenous insulin tolerance test, and the euglycemic insulin clamp technique have been utilized to document the relationship between insulin resistance, hyperinsulinemia, and hyperandrogenism. Three hypotheses could account for the strong association between hyperinsulinemia and hyperandrogenism: (a) hyperandrogenism causes hyperinsulinemia, (b) hyperinsulinemia causes hyperandrogenism, and (c) an unidentified androgenism (5). Each of these hypotheses is discussed below. The available experimental evidence indicates that hyperandrogenism does not cause severe insulin resistance and hyperinsulinemia in women. In men, circulating testosterone concentration is in the range of 5 ng/m!. This concentration of testosterone is not associated with significant insulin resistance or hyperinsulinemia. In hyperandrogenic women with peOD, circulating concentrations of testosterone are in the range of 1 ng/m!. If this concentration of testosterone causes severe insulin resistance and hyperinsulinemia, a major difference in the insulin response to testosterone =
=
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
POLYCYSTIC OVARIAN DISEASE
20 I
must exist between men and women. To date, there is no evidence to support this contention. Multiple, dynamic endocrine suppression studies also indicate that, in women with hyperinsulinemia and hyperandrogenism, the hyper androgenism does not cause the insulin resistance. For example, Nagamani and colleagues (6) demonstrated that, in women with ovarian hyper androgenism and hyperinsulinemia, bilateral oophorectomy eliminated the hyperandrogenism but did not reduce the severity of the hyperinsulinemia. Geffner et al (7) treated hyperandrogenic, hyperinsulinemic women with a long-acting gonadotropin-releasing hormone agonist (GnRH agonist). The GnRH agonist therapy produced complete resolution of the hyper androgenism, but it did not alter the hyperinsulinemia. The hypothesis that hyperinsulinemia causes hyperandrogenism is sup ported by multiple, separate lines of investigation. The data that support this hypothesis include (a) the acute administration of insulin to women with PCOD causes an increase in circulating androstenedione (8, 9); (b) the administration ofglucose to hyperinsulinemic hyperandrogenic women results in an increase in circulating insulin and androgens (10); (c) in women, weight loss, fasting, or a hypocaloric diet is associated with a decrease in circulating androgens (11); (d) in vitro, insulin stimulates human ovarian stromal androgen production, possibly by interacting via an ovarian IGF-I receptor (12, 13); and (e) diverse disease states that result in severe hyperinsulinemia (Kahn type A and type B diabetes, leprechaunism, and Iipoatrophic diabetes) are uniformly associated with hyperandrogenism (3, 5). The recent demonstration that point mutations in the insulin receptor gene are genetically linked to the PCOD phenotype provides strong evidence that hyperinsulinemia, a compensatory response to insulin resistance, causes hyperandrogenism (14-16). THE HAIR-AN SYNDROME
The best clinical example of the possible linkage between point mutations in the insulin receptor gene and PCOD is found in women with the syndrome of hyperandrogenism (HA), insulin resistance (IR), and acan thosis nigricans ( AN)-the HAIR-AN syndrome (3). In women with the HAIR-AN syndrome the hyperandrogenism is due to the overproduction of testosterone and androstenedione by the ovaries. The ovarian androgen overproduction results in facial hirsutism, acne, and in severe cases, vir ilization. The insulin resistance can be due to many causes, including point mutations in the insulin receptor gene (Kahn type A diabetes), anti-insulin receptor antibodies (Kahn type B diabetes), and postreceptor defects. The insulin resistance results in a compensatory hyperinsulinemia. It is our
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
202
BARBIERI
hypothesis that the hyperinsulinemia, acting via ovarian IGF-l receptors, synergizes with luteinizing hormone to stimulate ovarian testosterone and androstenedione production. The acanthosis nigricans is a hyperplastic response of the skin to stimulation by insulin and androgen. The acanthosis nigricans represents an epiphenomenon of the hyperandrogenism and insulin resistance. Four reports (14-17) detail the association of point mutations in the insulin receptor gene and the peOD phenotype (Table 1 ). Although the data are still scanty, it appears that certain point mutations in the insulin receptor gene coding for the beta subunit are dominant. In contrast, certain point mutations in the insulin receptor gene coding for the alpha subunit are apparently recessive. An important genetic principle is that if a phenotypic trait (such as the HAIR-AN syndrome) segregates in a family and is linked to a single gene marker, then that trait is caused by the gene. Accili and colleagues (15) recently reported a linkage analysis of one pedigree with the HAIR-AN syndrome (Kahn type A diabetes), which included two affected daughters, three unaffected daughters, and one unaffected son. Insulin receptor cDNA cloned from one affected sister showed a single missense mutation in both alleles of the insulin receptor gene, resulting in the substitution of a valine for phenylalanine at position 382 of the alpha subunit. Analysis of restric tion fragment length polymorphisms (RFLPs) demonstrated that the two affected sisters are homozygous for this mutation while the two parents and the unaffected sibs are heterozygous carriers. Using the homozygosity mapping method, a LOD (logarithm of the odds) score of 2.25 was cal culated for this pedigree. This LOD score supports the hypothesis that the mutation in the insulin receptor gene causes the HAIR-AN phenotype. Of Table 1
Case reports linking point mutations in the insulin receptor gene and the PCOD phenotype Codon and
Number of Investigator
alleles
Subunit
amino acid
affected
affected
replacement
Moller & Flier
beta 2
(16) Kadawaki et al
Phenotype
dominant
PCOD
735, serine for arginine
recessive
PCOD
460, glutamic acid for
recessive
leprechaunism
recessive
PCOD
1200, serine for tyrosine
(14)
Y oshimasa et al
Inheritance
processing site
2
(17)
alpha and beta
lysine 671, STOP codon
Accili et al (15)
2
alpha
382, valine for phenylalanine
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
POLYCYSTIC OVARIAN DISEASE
203
interest, transfection of mutant insulin receptor cDNA into NIH-3T3 cells demonstrated that the substitution of valine for phenylalanine at position 382 impairs posttranslational processing and retards the transport of the insulin receptor to the plasma membrane. The mutation causes insulin resistance (and the HAIR-AN syndrome) by decreasing the number of insulin receptors on the cell surface (15). The importance of the observation that point mutations in the insulin receptor gene can result in the HAIR-AN syndrome cannot be over estimated. It is the first example of a specific hyperandrogenism ("polycystic ovary syndrome"), and should allow detailed genetic analysis of large pedigrees with familial polycystic ovary syndrome. In addition, it suggests that any cause of severe hyper insulinemia, such as obesity, may result in ovarian hyperandrogenism. This hypothesis is strengthened by the observation that acquired causes of insulin receptor dysfunction are also associated with ovarian hyper androgenism. IMPLICATIONS FOR DIAGNOSIS AND THERAPY
The insulin hypothesis states that hyperinsulinemia, acting via an ovarian IGF-I receptor, synergizes with luteinizing hormone to cause ovarian androgen overproduction and the peOD phenotype. The association between hyperinsulinemia and hyperandrogenism has a number of impli cations for the diagnosis and therapy of peOD. Approximately 50% of women with peOD are insulin resistant, and approximately 10% of these are severely insulin resistant (18). The women with severe insulin resistance are at high risk for developing non-insulin dependent diabetes mellitus (19). Given this association, it may be reason able to screen women with peOD for diabetes. In addition, women with peOD appear to have multiple lipid abnormalities, including elevated cholesterol, decreased HDL-cholesterol, and increased triglycerides (20). This finding and the relationship between lipid abnormalities and the risk for coronary artery disease both argue in favor of performing a lipid screen on women with peOD. Recent evidence suggests that obese women with hyperinsulinemia and peOD respond very favorably to weight loss (21). In obese women with peOD, weight loss decreases their insulin resistance and their hyper insulinemia (40%), as well as decreasing their levels of circulating lutein izing hormone (45%) and testosterone (3 5%). In addition, weight loss resulted in resumption of ovulation and fertility in many of the women. It may be that weight loss reduces cumulative insulin secretion, which thereby reduces ovarian androgen production and resolves the peOD phenotype.
204
BARBIERI
Annu. Rev. Med. 1991.42:199-204. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/24/15. For personal use only.
In the past ten years tremendous progress has been made in under standing the relationship between hyperinsulinemia and hyper androgenism. Future studies undoubtedly will further characterize the molecular mechanisms by which hyperinsulinemia stimulates ovarian androgen production.
Literature Cited 1. Yen, S. S. C. 1980. C/in. Endocrinol. 12: 77-108 2. Goldzieher, J. W. 1981. Fertil. Steril. 35: 371-79 3. Barbieri, R. L., Ryan, K. J. 1983. Am. J. Obstet. Gynecol. 147: 90-101 4. Burghen, G. A., Givens, J. R., Kitabchi, A. E. 1980. J. C/in. Endocrinol. Metab. 50: 113-16 5. Barbieri, R. L., Smith, S., Ryan, K. J. 1988. Fertil. Steril. 50: 197-212 6. Nagamani, M., Dinh, T. V., Kelver, M. E. 1986. Am. J. Obstet. Gynecol. 154: 384-89 7. Geffner, M. E., Kaplan, S. E., Bersch, N., Golde, D. W., Landaw, E. M., Chang, R.I. 1986. Fertil. Steril. 45: 32733 8. Stuart, C. A., Prince, M. J., Peters, E. J., Meyer, W. J. 1987. Obstet. Gynecol. 69: 921-25 9. Dunaif, A. M., Graf, M. 1989. J. c/in. Invest. 83: 23-29 10. Smith, S., Ravnikar, V. A., Barbieri, R. L. 1987. Ferti!. Steri!. 48: 72-77 11. Bates, G. W., Whitworth, N. S. 1982. Fertil. Steril. 38: 406-10 12. Barbieri, R. L., Makris, A., Randall, R. W., Daniels, G., Kistner, R. W., Ryan,
13. 14. 15.
16.
17.
18. 19.
20.
21.
K. J. 1986. J. c/in. Endocrinol. Metab. 62: 904 10 Barbieri, R. L., Makris, A., Ryan, K. J. 1984. Obstet. Gynecol. 64: 73S-80S Moller, D. E., Flier, J. S. 1988. N. Engl. J. Med. 319: 1526-29 Accili, D., Frapier, c., Mosthaf, L., McKeon, C., Elbein, S. C., et al. 1989. EMBO J. 8: 2509-17 Yoshimasa, Y., Seino, S., Whitaker, J., Kakehi, T., Kosaki, A., et a!. 19RR. Sci ence 240: 784-87 Kadawaki, T., Bevins, C. L., Cama, A., Oj amaa, K., Marcus-Samuels, B., et al. 1988. Science 240: 787-90 Dunaif, A., Graf, M., Mandeli, J. 1987. J. Clin. Endocrinol. Metab. 65: 499-505 Kissebah, A. R., Vydelingum, N., Murray, R. 1982. J. C/in. Endocrinol. Metab. 54: 254-61 Wild, R. A., Painter, P. c., Coulson, P. B., Carruth, K. B., Ranney, G. B. 1985. J. elin. Endocrinol. Metab. 61: 946-51 Pasquali, R., Antenucci, D., Casimirri, F., Venturoli, S., Paradisi, R., et a!. 1989. Clinical and hormonal characteristics of obese amennorrheic hyperandrogenic women before and after weight loss. J. c/in. Endocrinol. Metab. 68: 173-79
