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Hyperandrogenic anovulation (PCOS): A unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus

  • Andrea Dunaif
    Correspondence
    Requests for reprints should be addressed to Andrea Dunaif, M.D., Penn State University College of Medicine, PO Box 850, Hershey, Pennsylvania 17033.
    Affiliations
    From the Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Penn State University College of Medicine, Hershey, Pennsylvania, USA
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      Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. Recent prevalence estimates suggest that 5–10% of premenopausal women have the full-blown syndrome of hyperandrogenism, chronic anovulation, and polycystic ovaries. Evidence suggests that women with polycystic ovary syndrome have a unique disorder of insulin action and are at increased risk to develop non-insulin-dependent diabetes mellitus. Further, non-insulin-dependent diabetes mellitus in women with polycystic ovary syndrome has a substantially earlier age of onset (third to fourth decades) than it does in the general population (sixth to seventh decades). Studies assessing whether abnormalities in insulin action are intrinsic or secondary to the hormonal milieu have found that insulin-induced receptor autophosphorylation is markedly diminished in approximately 50% of polycystic ovary syndrome women. This defect is unique to women with polycystic ovary syndrome and is not seen in other common insulin-resistant states of obesity and non-insulin-dependent diabetes mellitus. In polycystic ovary syndrome women who have normal receptor autophosphorylation, it remains likely that signaling mechanisms downstream of the receptor are abnormal, since these women are also insulin resistant. This distinctive post-insulin-binding defect appears to be genetic, since it is present in cells removed from the in vivo environment for generations.
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      References

      1. Dunaif A Givens JR Haseltine F Merriam GR The Polycystic Ovary Syndrome. Blackwell Scientific, Cambridge1992
        • Dunaif A
        • Graf M
        • Mandeli J
        • Laumas V
        • Dobrjansky A
        Characterization of groups of hyperandrogenic women with acanthosis nigricans impaired glucose tolerance and/or hyperinsulinemia.
        J Clin Endocrinol Metab. 1987; 65: 499-507
        • Dunaif A
        • Futterweit W
        • Segal KR
        • Dobrjansky A
        Profound peripheral insulin resistance independent of obesity in the polycystic ovary syndrome.
        Diabetes. 1989; 38: 1165-1174
        • Dunaif A
        • Segal KR
        • Shelley DR
        • Green G
        • Dobrjansky A
        • Licholai T
        Evidence for distinctive and instrinsic defects in insulin action in the polycystic ovary syndrome.
        Diabetes. 1992; 41: 1257-1266
        • Harris MI
        • Hadden WC
        • Knowler WC
        • Bennett PH
        Prevalence of diabetes impaired glucose tolerance and plasma glucose levels in U.S. population aged 20–74 yr.
        Diabetes. 1987; 36: 523-534
        • Dahlgren E
        • Johansson S
        • Lindstedt G
        • et al.
        Women with polycystic ovary syndrome wedge resected in 1956 to 1965 a long-term follow-up focusing on natural history and circulating hormones.
        Fertil Steril. 1992; 57: 505-513
        • Barnett AH
        • Eff C
        • Leslie RDG
        • Pyke DA
        Diabetes in identical twins. A study of 200 pairs.
        Diabetologia. 1981; 20: 87-93
        • Haring HU
        • Mehnert H
        Pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: candidates for a signal transmitter defect causing insulin resistance of the skeletal muscle.
        Diabetologia. 1993; 36: 176-182
        • Garvey WT
        Insulin resistance and noninsulin-dependent diabetes mellitus: which horse is pulling the cart?.
        Diabetes/Metabolism Reviews. 1989; 5: 727-742
        • Taylor SI
        • Cama A
        • Accili D
        • et al.
        Mutations in the insulin receptor gene.
        Endocr Rev. 1992; 13: 566-595
        • Bell GI
        • Xiang KS
        • Newman MV
        • et al.
        Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q.
        in: Proc Natl Acad Sci USA. 88. 1991: 1484-1488
        • Stoffel M
        • Froguel P
        • Takeda J
        • et al.
        Human glucokinase gene: isolation characterization and identification of two missense mutations linked to early-onset non-insulin dependent (type 2) diabetes mellitus.
        in: Proc Natl Acad Sci USA. 89. 1992: 7698-7702
        • Dunaif A
        Insulin resistance and ovarian hyperandrogenism.
        Endocrinologist. 1992; 2: 248-260
        • Cox NJ
        • Xiang K-S
        • Fajans SS
        • Bell GL
        Mapping diabetes-susceptibility genes. Lessons learned from search for DNA marker for maturity-onset diabetes of the young.
        Diabetes. 1992; 41: 401-407
        • Robinson S
        • Kiddy D
        • Gelding SV
        • et al.
        The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries.
        Clin Endocrinol. 1993; 39: 351-355
        • Dunaif A
        • Green G
        • Lebwohl M
        • Phelps R
        • Futterweit W
        • Lewy L
        Acanthosis nigricans insulin action hyperandrogenism: clinical histological and biochemical findings.
        J Clin Endocrinol Metab. 1991; 73: 590-595
        • Lobo RA
        • Goebelsmann U
        • Horton R
        Evidence for the importance of peripheral tissue events in the development of hirsutism in the polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1983; 57: 393-397
        • Flier JS
        • Eastman RC
        • Minaker KL
        • Matteson D
        • Rowe JW
        Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and C syndromes.
        Diabetes. 1985; 34: 101-107
        • Dunaif A
        • Huffman AR
        • Scully RE
        • et al.
        The clinical biochemical and ovarian morphologic features in women with acanthosis nigricans and masculinization.
        Obstet Gynecol. 1985; 66: 545-552
        • Stuart CA
        • Peters EJ
        • Prince MJ
        • Richards G
        • Cavallo A
        • Meyer III, WJ
        Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess.
        Metabolism. 1986; 35: 197-205
        • Jailal I
        • Naiker P
        • Reddi K
        • Moodley J
        • Joubert SM
        Evidence for insulin resistance in nonobese patients with polycystic ovarian disease.
        J Clin Endocrinol Metab. 1987; 64: 1066-1069
        • Buffington CK
        • Givens JR
        • Kitabchi AE
        Opposing actions of dehydroepiandrosterone testosterone on insulin sensitivity In vivo and in vitro studies of hyperandrogenic females.
        Diabetes. 1991; 40: 693-700
        • Pederson O
        • Hjollund E
        • Lindskov HO
        Insulin binding and action on fat cells from young healthy females and males.
        Am J Physiol. 1982; 243: E158-E167
        • Ciaraldi TP
        • EI-Roeiy A
        • Madar Z
        • Reichart D
        • Olefsky JM
        • Yen SSC
        Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.
        J Clin Endocrinol Metab. 1992; 75: 577-583
        • Rosenbaum D
        • Haber R
        • Dunaif A
        Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT4 glucose transporters in adipocytes.
        Am J Physiol. 1993; 264: E197-E202
        • Dunaif A
        • Xia J
        • Tang Z
        Insulin receptor (IR) serine phosphorylation may cause insulin resistance in polycystic ovary syndrome (PCOS) [Abstr. 757.].
        in: 54th Annual Meeting of the American Diabetes Assocation, New OrleansJune 1994
        • Kahn CR
        • White MF
        • Shoelson SE
        • et al.
        The insulin receptor and its substrate: molecular determinants of early events in insulin action.
        Rec Prog Horm Res. 1993; 48: 291-339
        • Sun XJ
        • Rothenberg P
        • Kahn CR
        • et al.
        Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.
        Nature. 1991; 352: 73-77
        • Myers Jr, MG
        • White MF
        The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with SH2 domains.
        Diabetes. 1993; 42: 643-649
        • Skolnik EY
        • Batzer A
        • Li N
        • et al.
        The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
        Science. 1993; 260: 1953-1955
        • Baltensperger K
        • Kozma LM
        • Cherniack AD
        • et al.
        Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes.
        Science. 1993; 260: 1950-1952
        • Endemann G
        • Yonezawa K
        • Roth RA
        Phosphatidylinositol kinase or an associated protein is a substrate for the insulin receptor tyrosine kinase.
        J Biol Chem. 1990; 265: 396-400
        • Ruderman NB
        • Kapeller R
        • White MA
        • Cantley LC
        Activation of phosphatidylinositol 3-kinase by insulin.
        in: Proc Natl Acad Sci USA. 87. 1990: 1411-1415
        • Backer JM
        • Schroeder GG
        • Kahn CR
        • et al.
        Insulin stimulation of phosphatldylinositol-3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation.
        J Biol Chem. 1992; 267: 1367-1374
      2. Sorbara LR, Tang Z, Cama A, et al. Absence of insulin receptor gene mutations in three women with the polycystic ovary syndrome. Metabolism. In press.

        • Takayama S
        • White MF
        • Kahn CR
        Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity.
        J Biol Chem. 1988; 263: 3440-3447
        • Grunberger G
        Interplay between insulin signaling and protein kinase C.
        Cellular Signaling. 1991; 3: 171-177
        • Chin JE
        • Dickens M
        • Tavare JM
        • Roth RA
        Overexpression of protein kinase C isoenzymes α βl λ ε in cells overexpressing the insulin receptor. Effects on receptor phosphorylation and signaling.
        J Biol Chem. 1993; 268: 6338-6347
        • Carey AH
        • Chan KL
        • Short F
        • White DM
        • Wllliamson R
        • Franks S
        Evidence for a single gene effect in polycystic ovaries and male pattern baldness.
        Clin Endocrinol. 1993; 38: 653-658
      3. Weiss DJ, Charles MA, Dunaif A, et al. Hyperinsulinemia is associated with menstrual irregularity and altered serum androgens in Pima Indian women. Metabolism. In press.

        • Ullrich A
        • Schlessinger J
        Signal transduction by receptors with tyrosine kinase activity.
        Cell. 1990; 61: 203-212
        • Théroux SJ
        • Latour DA
        • Stanley K
        • Raden DL
        • Davis RJ
        Signal transduction by the epidermal growth factor receptor is attenuated by a COOH-terminal domaine serine phosphorylation site.
        J Biol Chem. 1992; 267: 16620-16626
        • Cochet C
        • Gill GN
        • Meisenhelder J
        • Cooper JA
        • Hunter T
        C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity.
        J Biol Chem. 1984; 259: 2553-2558
        • Firth R
        • Bell P
        • Rizza R
        Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extra-hepatic insulin resistance and obesity.
        Metabolism. 1987; 36: 1091-1095
        • Foley JE
        Mechanisms of impaired insulin action in isolated adipocytes from obese and diabetic subjects.
        Diabetes/Metabolism Reviews. 1988; 4: 487-505
        • Caro JF
        • Dohm LG
        • Pories WJ
        • Sinha MK
        Cellular alterations in liver skeletal muscle and adipose tissue responsible for insulin resistance in obesity and type II diabetes.
        Diabetes/Metabolism Reviews. 1989; 5: 665-689
        • Warram JH
        • Martin BC
        • Krolewski AS
        • Soeldner JS
        • Kahn CR
        Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic patients.
        Ann Intern Med. 1990; 113: 909-915