Hyperinsulinemia is common in family members of women with polycystic ovary syndrome*

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1 FERTILITY AND STERILITY Vol. 66, No.6, December 1996 Copyright 1996 American Society for Reproductive Medicine Printed on acid~free paper in U. S. A. Hyperinsulinemia is common in family members of women with polycystic ovary syndrome* Robert J. Norman, M.D.t Stacey Masters, R.N. William Hague, M.D. Reproductive Medicine Unit, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia Objective: To determine whether disorders of insulin secretion are common in male and female family members of subjects with polycystic ovary syndrome (PCOS). Design: Family study of siblings and parents of PCOS subjects (five families). All proband cases met the criteria of polycystic ovaries (PCO) by ultrasound (US) and hyperandrogenism. Setting: University Reproductive Medicine Unit. Patient(s): Family members of PCOS subjects. Intervention(s): Oral tolerance testing (OGTT), insulin, and lipids were measured. Clinical examination including assessment of premature baldness in men and US of ovaries in female members. Main Outcome Measure(s): Insulin, lipids, and clinical parameters. Result(s): Hyperinsulinemia (69%) and hypertriglyceridemia (56%) was common in family members as were PCO in 79% of 24 females and premature baldness in men in 88% of eight subjects. Conclusion(s): Hyperinsulinemia is a potential metabolic and genetic marker for subjects who may be carriers of a familial tendency for PCO. Fertil Steril 1996;66:942-7 Key Words: Polycystic ovary syndrome, insulin, familial incidence The etiology of polycystic ovary syndrome (PC OS) remains unclear, although there is strong evidence for genetic causes for part of its presentation (1, 2). Various familial studies have indicated autosomal dominance (3, 4), X-linked dominance (5), or segregation ratios exceeding autosomal dominance (6). The major problems in trying to determine the familial contribution have been the heterogeneity of the syndrome (7), disagreement about the diagnostic criteria (8), and absence of a clear male phenotype. In recent years, the association of hyperinsulinemia and peripheral insulin resistance with some presentations of polycystic ovaries (PCO) has become evident (9, 10). Increased fasting insulin con- Received December ; revised and accepted July 27,1996. * Supported by the National Health and Medical Research Council, Canberra, Australian Capital Territory, Australia. t Reprint requests: Robert J. Norman, M.D., Reproductive Medicine Unit, The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia (FAX: ; rnorman@medicine.adelaide.edu.au). 942 Norman et at pcas and hyperinsulinemia in families centrations and reduced insulin sensitivity are more prevalent in nonobese and obese women with PCO, particularly if they are anovulatory (11-13). We have studied family members of women with this condition and show that hyperinsulinemia after tolerance testing is common even in men and, may be a marker that may prove us~ful for familial studies in PCOS. Patients MATERIALS AND METHODS As part of a larger study into the heterogeneity of PCO and PCOS (7), we identified five women with families who agreed to be studied as part of an investigation into familial factors. All proband cases met the criteria ofpco by ultrasound (US) and hyperandrogenemia (7). All male and female subjects older than 12 years of age were approached and gave their informed written consent as approved by the Institutional Ethics Committees of The Queen Elizabeth Hospital and the University of Adelaide. Female Fertility and Sterility

2 members underwent ovarian scanning to detect the presence ofpco (14); vaginal scanning was used in the majority of subjects but, where the subject was young or refused the procedure, transabdominal scanning was offered. Male members were assessed for premature baldness (4), and all subjects had fasting blood obtained for androgens, sex hormone-binding globulin (SHBG), lipids, and insulin. A 75-gram oral tolerance test (OGTT) was performed and and insulin concentrations measured every 30 minutes for 2 hours. All methods have been described previously (7, 15). Subjects who had been on the oral contraceptive pill stopped treatment for 2=:6 weeks before testing and all were nonsmokers, thus avoiding the confounding effect of smoking on insulin resistance (16). Definition of PC OS For the purposes of this study, patients were included as PC OS if they showed an increased concentration of serum T (> 1 ng/ml; conversion factor to S1 units, 3.5) or androstenedione (A) (>2 ng/ml; conversion factor to S1 units, 3.5) together with a low concentration of sex hormone-binding globulin (SHBG < 20 mmolll), in addition to characteristic ovarian morphology on US (defined as the presence of eight or more peripheral cysts < 10 mm in diameter with increased stromal-echo in one or both ovaries). Clinical features, such as menstrual abnormalities, hirsutism, and infertility were present in the majority of subjects. All scans were performed in the follicular phase of the cycle in which this could be determined or at any time in anovulatory women. The same definition of PCO morphology for vaginal and abdominal scanning was used, as there is no clear agreement in the literature about the criteria for PCO on vaginal scanning. It should be recognized that use of these definitions may have excluded subjects who have PCO or PCOS by other criteria and may have included subjects with asymptomatic PCO. Definition of Premature Baldness in Men and Hirsutism This was determined on examination, photographic evidence, or clear history from the individual or his family of the onset of baldness in male family members before the age of 40 years. Hirsutism in females was established by the presence of increased body hair on the face, chest, back, abdomen, and upper legs; a quantitative score was not used. Reference Values These were derived from control subjects with regular menstrual periods and no evidence of PCO or hyperandrogenemia. Reference values were adjusted on the basis of the body mass index (BMI) into normal and overweight groups (7). Reference values for men were obtained from 20 men of equivalent BM1 (10 normal and 10 overweight) without premature baldness in men if >40 years and with no features of hair loss if <40 years. Mter standard practice, hyperinsulinemia and high levels of lipids were defined on values greater than the 75th centile for normal men and women adjusted for BM1 (Table 1). Values of T > 1 ng/ml, A > 2 ng/ml, and SHBG < 20 nmolll generally were used for females. Index Cases All the subjects who initially presented to the clinic had clear evidence of PCOS with the presence of anovulation. Families were identified for study on their geographic availability, size, and willingness to participate. Body Mass Index and Obesity The BM1 was calculated as weight (kg) divided by height (m 2 ). Subjects were defined as being overweight if the BM1 was >25 kg/m 2 RESULTS Five families agreed to the study. Thirty-three of 38 members underwent the requisite testing (Table 2, Fig. 1). Table 1 The 75th Centile Values for the Study* Female Male BMI < 25 BMI > 25 BMI < 25 BMI > 25 Fasting insulin (pg/mll Integrated insulin (pg/mll Triglycerides (mg/100 mll Low-density lipoprotein cholesterol (mg/100 mll High-density lipoprotein cholesterol (mg/100 mll , , ,583 18, * Conversion factors to SI units are as follows: insulin, 0.024; triglycerides, ; low-density lipoprotein cholesterol, ; and high-density lipoprotein cholesterol, Vol. 66, No.6, December 1996 Norman et al. pegs and hyperinsulinemia in families 943

3 Table 2 Detail of Families Menstrual irregularity/ PCO premature Hyper- Hyper- Increased BMI Age Sex scan baldness in men insulinemia triglyceridemia androgens SHBG* kg/m2 Family 1 Ia Female?t History~ b Male NAIl 11 a Female b Female c Female d Female e Male + + (Impaired + NA 14 f Female g Female h Male + NA ND~ Female I Not tested Family 2 Ia Female (Impaired 44 b Not tested Male a Female + 72 b Female c Female d Female I alb 5/2 MalelFemale Family 3 Ia Female? History b Male + Diabetic 11 a Female b Female c Female d Male + NA 12 e Female NA 6 Ib Female Family 4 Ia Female? History b Deceased a Male + + NA 12 b Not tested Male c Female 6 d Female e Female ND I Not tested Family 5 Ia Female (Impaired + 73 b Male + (Impaired + NA 9 a Miscarriage b Not tested c Not tested d Female e Female I Not tested * Normal range for women 20 to 100 and for men 10 to 50 ~ Diagnosis made on basis of past clinical history in the case mmolll. of postmenopausal subjects. t History strongly suggestive of PCOS but not scanned because +, present; -, absent. postmenopausal status. NA not applicable. ~ ND, not performed. mmol/l 944 Norman et a1. peas and hyperinsulinemia in families Fertility and Sterility

4 I Family 1 Family 2 Family 1 All except two members exhibited PCO or premature balding in men. Both parents and six of nine children had significant hyperinsulinemia, including both male children. Generally, hyperinsulinemia and hyperlipidemia were found together. Surprisingly, the presence ofpco and hyperinsulinemia did not predispose to menstrual abnormalities and, in the only sister with menstrual abnormalities, hyperinsulinemia was not present. All the female members had significant hyperandrogenemia. Apart from the mother, who had a BMI of 35 kg/m2, none of the other members were overweight. Family 2 I I Family 3 Family 4 The mother and three daughters exhibited PCO and the father exhibited premature balding in men. The mother and two children were hyperinsulinemic whereas the fourth daughter had insulin concentrations between the 50th and 75th centile and also had hypertriglyceridemia. All female members had oligomenorrhea or had been on the oral contraceptive pill for heavy bleeding. Members with PCO had hyperandrogenemia but there were normal responses to oral tolerance, except for the mother who had impaired tolerance. The BMI of the mother was 38 kg/m2, that of the second daughter was 33 kg/m2, whereas all the other daughters had a BMI < 22 kg/m2. I I Potycys1ic ovaries or p~emature balding present ~ Menstrual abnormajilies p<esent Family 5 ~ Hyperinsulinaemia ~ presen1 Hypef1riglyceridaemia I present Figure 1 Families 1 to 5 showing patterns of pea, premature balding, hyperinsulinemia and hyperlipidemia, and menstrual abnormalities. In families 4 and 5, some of the males declined investigation. Vol. 66, No.6, December 1996 Family 3 The father and son exhibited premature balding in men and two daughters had PCO. Hyperinsulinemia was present in the mother and all daughters. The father was a diagnosed noninsulin-dependent diabetic (NIDDM) and the second daughter had had gestational diabetes. All female memqers had hyper- ~ triglyceridemia, but only the mother and last daughter were oligomenorrheic. All women were hirsute and obese. There was a high prevalence of miscarriage in the family. Family 4 Two daughters had PCO and one brother had premature balding in men. One brother declined all investigation. The mother was diagnosed with NIDDM and one brother was hyperinsulinemic. None of the daughters had hyperinsulinemia, but one had hypertriglyceridemia. The second daughter had menstrual abnormalities not shared by the others. All subjects were overweight and the daughters with PCO both had hyperandrogenemia. Norman et al. peas and hyperinsulinemia in families 945

5 i. I_.!2!!!±±! 2Z Family 5 This family was not studied completely in that both male siblings were unwilling to be contacted. Both daughters had PCO, although the father did not have premature balding in men. The mother had impaired tolerance, with one daughter exhibiting hyperinsulinemia. The mother and one daughter had hypertriglyceridemia and both daughters (but not the mother) had hyperandrogenemia. The daughters also had oligomenorrhea and the first was diagnosed with hypothyroidism. All had BMIs in the normal range. DISCUSSION Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age, with a prevalence of symptomatic disorders of 5% to 10%, whereas asymptomatic PCO is reported to be as high as 20% to 25% in women of reproductive age (17, 18). Laws et al. (19) have suggested that nondiabetic relatives of patients with NIDDM are more likely to have insulin resistance. Noninsulindependent diabetes is substantially more common in women with PCOS (20) and occurs earlier in such women than in women in the general population (9). Hyperinsulinemia in fasting and -stimulated subjects is reflected by the impaired uptake found on euglycemic clamp testing or in rapidly sampled IV infusion tests (21). The current study shows that -stimulated hyperinsulinemia in the absence of intolerance is common in sisters and brothers of women with PCOS regardless of obesity. Although our study has not confirmed insulin resistance as opposed to hyperinsulinemia, all previous studies in females with PCOS confirm that hyperinsulinemia is a reflection of tissue insulin resistance. The measured insulin concentrations are likely to reflect biologic activity, as Conway et al. (22) have shown that the immunoactive insulin in serum of women with PCOS is true insulin rather than proinsulin or split peptides. In the presence of relatively normal values, a high insulin suggests the presence of insulin resistance and there is evidence for the problem to be a postreceptor phenomenon (9). Dunaif (9) has shown increased insulin receptor serine phosphorylation, which appears to decrease protein tyrosine kinase activity in PCOS; this appears to be a genetic phenomenon, as the abnormality is perpetuated in tissue culture (23). In this situation, it would be expected that a proportion of the males in an affected family would also manifest insulin resistance. This study also confirms other work that premature balding in men and polycystic ovaries in women 946 Norman et al. peds and hyperinsulinemia in families are common in the families of subjects with PCOS (4). There were insufficient subjects and families to establish the form of inheritance, but it would not be incompatible with an autosomal dominant pattern. Robinson et al. (11) have suggested that anovulation occurs when PCO and increased immunoactive insulin concentrations occur together, which suggests that the presence of two components are required for the full expression of PCOS, namely a "PCO" element and an "insulin resistance" element. In family 1, this concordance did not lead to anovulation, although there was significant hyperandrogenemia and there was incomplete association between oligomenorrhea and hyperinsulinemia in most families. There was, however, much better concordance with low concentrations of SHBG and (to a lesser extent) with hypertriglyceridemia. This study does not allow a full examination of the relationship of increased insulin concentrations with oligomenorrhea, but the effects of BMI and fat distribution in modulating insulin and reproductive function clearly are of importance. In conclusion, this preliminary study of five families suggests that hyperinsulinemia may be an important marker in family members in whom PCOS is present and also supports previous findings of premature baldness in male relatives as an independent marker. Hyperinsulinemia appears to be independent of obesity in PCOS and may prove a valuable marker for genetic studies and in time could be coupled with tissue studies of in vitro insulin activity or gene abnormality. REFERENCES 1. Simpson JL. Elucidating the genetics of polycystic ovary syndrome. In: Dunaif A, Givens JR, Haseltine FP, Merrian GR, editors. Polycystic ovary syndrome. Current issues in endocrinology and metabolism. Boston: Blackwell, 1992; Legro RS. The genetics of polycystic ovary syndrome. Am J Med 1995; 98(Suppl 1A): Cooper HE, Spellacy WN, Prem KA, Cohen WD. Hereditary factors in Stein-Leventhal syndrome. Am J Obstet Gynecol 1968; 100: Carey AH, Chan KL, Short F, White D, Williamson R, Franks S. Evidence for a single gene causing polycystic ovaries and male pattern baldness. Clin Endocrinol (Ox ) 1993;38: Givens JR. Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 1988;17: Hague WM, Adams J, Reeder ST, Peto TE, Jacobs HS. Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Ox ) 1988;29: Norman RJ, Masters SC, Hague WM, Beng C, Pannall P, Wang JX. Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil Steril 1995;63: Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, editors. Polycystic ovary syndrome. Current issues in endocrinology and metabolism. Boston: Blackwell, 1992: Fertility and Sterility

6 9. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med 1995;98(Supp 1A): Barbieri RL, Smith S, Ryan KJ. The role of hyper ins ulinemi a in the pathogenesis of ovarian hyperandrogenism. Fertil Steril 1988;50: Robinson S, Chan SP, Spacey S, Anyaoku V, Johnston DG, Franks S. Postprandial thermogenesis is reduced in polycystic ovary syndrome and is associated with increased insulin resistance. Clin Endocrinol (Ox ) 1992;36: Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: Meirow D, Yossepowitch 0, RosIer A, Brzezinski A, Schenker JG, Laufer N, et al. Insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinology subgroups. Hum Reprod 1995;10: Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J 1986;293: Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Norman RJ. Weight loss results in significant improvement in pregnancy and ovulation rates in infertile, obese women. Hum Reprod 1995; 10: Facchini FS, Hollenbeck CB, Jappesen J, Chen Y-DI, Reaven GM. Insulin resistance and cigarette smoking. Lancet 1992;339: Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries-a common finding in normal women. Lancet 1988; 1: Clayton RN, Ogden V, Hodgkinson J, Worswick L, Rodin DA, Dyer S, et al. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin Endocrinol (Ox ) 1992;37: Laws A, Stefanick ML, Reaven GM. Insulin resistance and hypertriglyceridemia in non diabetic relatives of patients with non insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1989;69: Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson PO, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long term follow-up focussing on natural history and circulating hormones. Fertil Steril 1992;57: Dunaif A, Segal KR, Futterweit W, Dobransky A. Profound peripheral insulin resistance independent of obesity in polycystic ovary syndrome. Diabetes 1989;38: Conway GS, Clark PM, Wong D. Hyperinsulinaemia in the polycystic ovary syndrome confirmed with a specific immunoradiometric assay for insulin. Clin Endocrinol (Ox ) 1993; 38: Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. J Clin Invest 1995;96: Vol. 66, No.6, December 1996 Norman et al. pcas and hyperinsulinemia in families 947