Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight
Katherine Michelmore,
Ken Ong, Sam Mason, Simon Bennett, Leslie Perry,
Martin Vessey,
Adam Balen,
David Dunger,
Katherine Michelmore
Division of Public Health and Primary Health Care, University of Oxford,
Search for more papers by this authorLeslie Perry
Department of Clinical Biochemistry, St. Bartholomew's Hospital, London,
Search for more papers by this authorMartin Vessey
Division of Public Health and Primary Health Care, University of Oxford,
Search for more papers by this authorAdam Balen
Reproductive Medicine Unit, The General Infirmary, Leeds, UK
Search for more papers by this authorDavid Dunger
Department of Paediatrics, University of Cambridge,
Search for more papers by this authorKatherine Michelmore,
Ken Ong, Sam Mason, Simon Bennett, Leslie Perry,
Martin Vessey,
Adam Balen,
David Dunger,
Katherine Michelmore
Division of Public Health and Primary Health Care, University of Oxford,
Search for more papers by this authorLeslie Perry
Department of Clinical Biochemistry, St. Bartholomew's Hospital, London,
Search for more papers by this authorMartin Vessey
Division of Public Health and Primary Health Care, University of Oxford,
Search for more papers by this authorAdam Balen
Reproductive Medicine Unit, The General Infirmary, Leeds, UK
Search for more papers by this authorDavid Dunger
Department of Paediatrics, University of Cambridge,
Search for more papers by this author should be addressed to: Professor David B. Dunger, Department of Paediatrics, University of Cambridge, Cambridge, UK. E-mail: [email protected]
Abstract
OBJECTIVE Polycystic ovaries are a common ultrasound finding, yet few of these women have many clinical features of polycystic ovary syndrome. Clinical presentation may relate to degree of insulin resistance, common polymorphism at the insulin gene VNTR, and birth weight. We therefore examined the relationship between insulin sensitivity, insulin gene VNTR genotype, birth weight and presence of polycystic ovaries/features of polycystic ovary syndrome in a normal population study.
DESIGN AND PATIENTS In 224 young women recruited as normal volunteers, ovarian morphology was determined by transabdominal ultrasound and features of polycystic ovary syndrome were identified on clinical and biochemical examination. Insulin sensitivity was estimated from fasting glucose and insulin levels using the homeostasis model. Insulin gene VNTR genotypes were determined in women and their parents.
MEASUREMENTS AND RESULTS Thirty-three per cent (74/224) had polycystic ovaries on ultrasound. These women had higher birth weights (P = 0·004), higher insulin sensitivity (P = 0·02) and higher leptin levels for body mass index (P = 0·04) than women with normal ovaries. However among women with polycystic ovaries, increasing severity of clinical phenotype (based on number of features of: menstrual irregularity, acne, hirsuitism, serum testosterone > 3 mmol/l and LH > 10 IU/l) was associated with decreasing insulin sensitivity (P < 0·0001) and related to paternally transmitted insulin gene VNTR class III alleles (P = 0·03).
CONCLUSION Women with polycystic ovaries on ultrasound have increased insulin sensitivity and possible leptin resistance, which could predispose to future weight gain. However, in these women the appearance of clinical features of polycystic ovary syndrome is related to insulin resistance and insulin gene VNTR class III alleles.
References
- Adams, J., Polson, D.W., Franks, S. (1986) Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. British Medical Journal, 293 355–359.
- Adcock, C.J., Perry, L.A., Lindsell, D.R., Taylor, A.M., Holly, J.M., Jones, J., Dunger, D.B. (1994) Menstrual irregularities are more common in adolescents with type 1 diabetes: association with poor glycaemic control and weight gain. Diabetic Medicine, 11 465–470.
- Balen, A.H., Conway, G.S., Kaltsas, G., Techatrasak, K., Manning, P.J., West, C., Jacobs, H.S. (1995) Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Human Reproduction, 10 2107–2111.
- Balen, A.H., (1999) Pathogenesis of polycystic ovary syndrome – the enigma unravels?[Editorial]. Lancet, 354 966–967.
- Bennett, S.T. & Todd, J.A. (1996) Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annual Reviews in Genetics, 30 343–370.
- Bennett, S.T., Todd, J.A., Waterworth, D.M., Franks, S., McCarthy, M.I. (1997) Association of insulin gene VNTR polymorphism with polycystic ovary syndrome [letter]. Lancet, 349 1771–1772.
- Bowsher, R.R., Lee, W.H., Apathy, J.M., O'Brien, P.J., Ferguson, A.L., Henry, D.P. (1991) Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids. Endocrinology, 128 805–814.
- Bowtell, D.D. (1987) Rapid isolation of eukaryotic DNA. Analytical Biochemistry., 162 463–465.
- Brzechffa, P.R., Jakimiuk, A.J., Agarwal, S.K., Weitsman, S.R., Buyalos, R.P., Magoffin, D.A. (1996) Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 81 4166–4169.
- Cameron, N. (1984) The Measurement of Human Growth. Croom-Helm Ltd, Kent.
- Chapman, I.M., Wittert, G.A., Norman, R.J. (1997) Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters. Clinical Endocrinology, 46 175–181.
- Chessler, S.D., Fujimoto, W.Y., Shofer, J.B., Boyko, E.J., Weigle, D.S. (1998) Increased plasma leptin levels are associated with fat accumulation in Japanese Americans. Diabetes, 47 239–243.
- Christensen, J.T., Boldsen, J., Westergaard, J.G. (1997) Ovarian Volume in gynecologically healthy women using no contraception, or using IUD or oral contraception. Acta Obstetricia et Gynecologica Scandinavica, 76 784–789.
- Clayton, R.N., Ogden, V., Hodgkinson, J., Worswick, L., Rodin, D.A., Dyer, S., Meade, T.W. (1992) How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clinical Endocrinology, 37 127–134.
- Considine, R.V., Sinha, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., Ohannesian, J.P., Marco, C.C., McKee, L.J., Bauer, T.L.& et al. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine, 334 292–295.
- Cresswell, J.L., Barker, D.J., Osmond, C., Egger, P., Phillips, D.I., Fraser, R.B. (1997) Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet, 350 1131–1135.
- Dahlgren, E., Johansson, S., Lindstedt, G., Knutsson, F., Oden, A., Janson, P.O., Mattson, L.A., Crona, N., Lundberg, P.A. (1992) Women with polycystic ovary syndrome wedge resected in 1956–65: a long-term follow-up focusing on natural history and circulating hormones. Fertility and Sterility, 57 505–513.
- Dunaif, A. (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocrine Reviews, 18 774–800.
- Dunger, D.B., Ong, K.K., Huxtable, S.J., Sherriff, A., Woods, K.A., Ahmed, M.L., Golding, J., Pembrey, M.E., Ring, S., Bennett, S.T., Todd, J.A. (1998) Association of the INS VNTR with size at birth. Nature Genetics, 19 98–100.
- Durnin, J.V. & Womersley, J. (1974) Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. British Journal of Nutrition, 32 77–97.
- Eaves, I.A., Bennett, S.T., Forster, P., Ferber, K.M., Ehrmann, D., Wilson, A.J., Bhattacharyya, S., Ziegler, A.G., Brinkmann, B., Todd, J.A. (1999) Transmission ratio distortion at the INS-IGF2 VNTR. Nature Genetics, 22 324–325.
- Emoto, M., Nishizawa, Y., Maekawa, K., Hiura, Y., Kanda, H., Kawagishi, T., Shoji, T., Okuno, Y., Morii, H. (1999) Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas. Diabetes Care, 22 818–822.
- Ferriman, D.M. & Gallwey, J.D. (1961) Clinical assessment of body hair growth in women. Endocrinology and Metabolism, 21 1440–1447.
- Franks, S. (1995) Polycystic ovary syndrome. New England Journal of Medicine, 333 853–861.
- Franks, S., Gharani, N., Waterworth, D., Batty, S., White, D., Williamson, R., McCarthy, M. (1997) The genetic basis of polycystic ovary syndrome. Human Reproduction, 12 2641–2648.
- Gennarelli, G., Holte, J., Wide, L., Berne, C., Lithell, H. (1998) Is there a role for leptin in the endocrine and metabolic aberrations of polycystic ovary syndrome? Human Reproduction, 13 535–541.
- Gondos, B. (1976) Histologic changes associated with oral contraceptive usage. Annals of Clinical and Laboratory Science, 6 291–299.
- Haffner, S.M., Miettinen, H., Stern, M.P. (1997) The homeostasis model in the San Antonio Heart Study. Diabetes Care, 20 1087–1092.
- Helle, S.I., Anker, G.B., Meadows, K.A., Holly, J.M., Lonning, P.E. (1998) Alterations in the insulin-like growth factor system during the menstrual cycle in normal women. Maturitas, 28 259–265.
- Holte, J. (1996) Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. Baillières Clinical Endocrinology and Metabolism, 10 221–247.
- Holte, J., Gennarelli, G., Wide, L., Lithell, H., Berne, C. (1998) High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus. Journal of Clinical Endocrinology and Metabolism, 83 1143–1150.
- Huxtable, S.J., Saker, P.J., Haddad, L., Walker, M., Frayling, T.M., Levy, J.C., Hitman, G.A., O'Rahilly, S., Hattersley, A.T., McCarthy, M.I. (2000) Analysis of parent-offspring trials provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes, 49 126–130.
- Ibanez, L., Potau, N., Francois, I., De Zegher, F. (1998) Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. Journal of Clinical Endocrinology and Metabolism, 83 3558–3562.
- Ibanez, L., Potau, N., Marcos, M.V., De Zegher, F. (1999) Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age. Journal of Clinical Endocrinology and Metabolism, 84 4739–4741.
- Lee, P.J., Patel, A., Hindmarsh, P.C., Mowat, A.P., Leonard, J.V. (1995) The prevalence of polycystic ovaries in the hepatic glycogen storage diseases: its association with hyperinsulinism. Clinical Endocrinology, 42 601–606.
- Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28 412–419.
- McKeigue, P.M., Lithell, H.O., Leon, D.A. (1998) Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia., 41 1133–1138.
- Michelmore, K.F., Balen, A.H., Dunger, D.B., Vessey, M.P. (1999) Polycystic ovaries and associated clinical and biochemical features in young women. Clinical Endocrinology, 51 779–786.
- Moller, D.E., Cohen, O., Yamaguchi, Y., Assiz, R., Grigorescu, F., Eberle, A., Morrow, L.A., Moses, A.C., Flier, J.S. (1994) Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance. Diabetes, 43 247–255.
- Mueller, W.H., Wear, M.L., Hanis, C.L., Emerson, J.B., Barton, S.A., Hewett Emmett, D., Schull, W.J. (1991) Which measure of body fat distribution is best for epidemiologic research? American Journal of Epidemiology, 133 858–869.
- Oberfield, S.E. (2000) Metabolic lessons from the study of young adolescents with polycystic ovary syndrome. Is insulin the culprit? Journal of Clinical Endocrinology and Metabolism, 85 3520–3525.
- Ong, K.K., Phillips, D.I., Fall, C., Poulton, J., Bennett, S.T., Golding, J., Todd, J.A., Dunger, D.B. (1999) The insulin gene VNTR, type 2 diabetes and birth weight. Nature Genetics, 21 262–263.
- Phillips, D.I., Barker, D.J., Hales, C.N., Hirst, S., Osmond, C. (1994) Thinness at birth and insulin resistance in adult life. Diabetologia., 37 150–154.
- Polson, D.W., Adams, J., Wadsworth, J., Franks, S. (1988) Polycystic ovaries—a common finding in normal women. Lancet, 1 870–872.
- Schwartz, M.W., Boyko, E.J., Kahn, S.E., Ravussin, E., Bogardus, C. (1995) Reduced insulin secretion: an independent predictor of body weight gain. Journal of Clinical Endocrinology and Metabolism, 80 1571–1576.
- Simmons, R.A., Flozak, A.S., Ogata, E.S. (1993) The effect of insulin and insulin-like growth factor-I on glucose transport in normal and small for gestational age fetal rats. Endocrinology, 133 1361–1368.
- Tayob, Y., Robinson, G., Adams, J.& et al. (1990) Ultrasound appearance of the ovaries during the pill-free interval. British Journal of Family Planning, 16 94–96.
- Waterworth, D.M., Bennett, S.T., Gharani, N., McCarthy, M.I., Hague, S., Batty, S., Conway, G.S., White, D., Todd, J.A., Franks, S., Williamson, R. (1997) Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet, 349 986–990.
- Wathen, N.C., Perry, L.A., Rubenstein, E., Chard, T. (1987) A relationship between sex hormone binding globulin and dehydroepiandrosterone sulfate in normally menstruating females. Gynecological Endocrinology, 1 47–50.
- Zavaroni, I., Zuccarelli, A., Gasparini, P., Massironi, P., Barilli, A., Reaven, G.M. (1998) Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration? Journal of Clinical Endocrinology and Metabolism, 83 3498–3500.
- Zhang, L., Cui, X., Schmitt, K., Hubert, R., Navidi, W., Arnheim, N. (1992) Whole genome amplification from a single cell: implications for genetic analysis. Proceedings of the National Academy of Sciences USA, 89 5847–5851.
Citing Literature
