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0021-972X/99/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1999 by The Endocrine Society Vol. 84, No. 1 Printed in U.S.A. Polycystic Ovaries Are Inherited as an Autosomal Dominant Trait: Analysis of 29 Polycystic Ovary Syndrome and 10 Control Families A. GOVIND, M. S. OBHRAI, AND R. N. CLAYTON Department of Obstetrics and Gynaecology (A.G., M.S.O.), North Staffordshire Hospital, Stoke On Trent; and Department of Medicine (R.N.C.), School of Postgraduate Medicine, Keele University, Stoke On Trent ST4 7QB, United Kingdom ABSTRACT The aim of this study was to obtain evidence for the genetic basis of polycystic ovaries (PCO) and premature male pattern baldness (PMPB) by screening first-degree relatives of women affected by polycystic ovary syndrome (PCOS). Because of the high prevalence of PCO in the general population, we also studied first-degree relatives of ten asymptomatic control volunteers of reproductive age. The probands were recruited prospectively from infertility and endocrine clinics, where they presented with various clinical symptoms of PCOS. Each had PCO, on transvaginal ultrasound scan. The families of 29 probands and 10 volunteers agreed to take part in the study. Clinical, ultrasound, and biochemical parameters were used to define PCO/PCOS. All female relatives had an ovarian ultrasound scan and hormone profile performed. History was used to assign status in postmenopausal women. All male relatives were assessed for early onset (,30 yr old) male pattern baldness, by photographs. All relatives were assigned affected (PCO/PMPB) or nonaffected status, and segregation analysis was performed. Of the relatives of 29 PCOS probands, 15 of 29 mothers (52%), 6 of 28 fathers (21%), 35 of 53 sisters (66%), and 4 of 18 brothers (22%) were assigned affected status. First-degree female relatives of affected individuals had a 61% chance of being affected. Of the firstdegree male relatives, 22% were affected. Of a total of 71 siblings of PCOS probands, 39 were affected, giving a segregation ratio of 39/32 (55%), which is consistent with autosomal dominant inheritance for PCO/PMPB. In the control families, 1 of 10 probands (10%), 1 of 10 mothers (10%), no fathers, 2 of 13 sisters (15%), and 1 of 11 brothers (9%) were affected. Of a total of 24 siblings, 3 were affected (13%), giving a segregation ratio (observed/expected) of 3/12, which was significantly different from autosomal dominant inheritance. The inheritance of PCO and PMPB is consistent with an autosomal dominant inheritance pattern in PCOS families, perhaps caused by the same gene. There was no such genetic influence in families of women without PCOS. Sisters of PCOS probands with polycystic ovarian morphology were more likely to have menstrual irregularity and had larger ovaries and higher serum androstenedione and dehydroepiandrosterone-sulfate levels than sisters without PCO. This suggests a spectrum of clinical phenotype in PCOS families. Men with PMPB had higher serum testosterone than those without. Collectively, these data are consistent with a role for genetic differences in androgen synthesis, metabolism, or action in the pathogenesis of PCOS. (J Clin Endocrinol Metab 84: 38 – 43, 1999) P tance in Caucasian first-degree relatives, using culdoscopy or wedge resection to diagnose PCO and a questionnaire revealing that male relatives had increased pilosity. Givens et al. (13) analyzed 18 families with affected members in several generations and also suggested a probable autosomal dominant mode of inheritance. Wilroy (14) suggested the possibility of X-linked dominant inheritance in analysis of other families. Ferriman and Purdie (5) described a modified dominant inheritance based on family histories obtained from 700 hirsute women with oligomenorrhea, and premature balding among male relatives. Lunde et al. (15), using a symptom questionnaire of firstand second-degree relatives of PCOS and normal volunteer probands, found significantly more mothers, sisters, and brothers with a positive history in the PCOS families, compared with control families. The proportion of symptomatic brothers (35%) and sisters (58%) of PCOS probands is consistent with autosomal dominant inheritance with incomplete penetrance in brothers. More recently, Carey et al. (16) determined the mode of inheritance for 10 large families; and if premature male pattern baldness (PMPB) was taken as the male phenotype, segregation analysis was consistent with autosomal dominant inheritance, consistent with a single OLYCYSTIC ovaries (PCO) are common in the general population. On ovarian ultrasound scan, they seem to occur in 23% of the population (1, 2), but only 3–10% of women with these ovaries have the polycystic ovary syndrome (PCOS). PCOS is the commonest cause of oligomenorrhea, hirsutism (3), and anovulatory infertility (4). The possibility that PCOS may be genetically determined has been suggested for over 40 yr. Presence of PCO on ultrasound is accepted as the female phenotype, and premature balding has been suggested as the male counterpart (5). Hyperandrogenism is the most consistent biochemical finding in all groups of women with PCOS and PCO (6, 7). The initial suggestions of a heritable component were case reports on sisters, including monozygotic twins and mothers and daughters in whom the condition might have been present (8 –11). Cooper et al. (12) suggested a dominant mode of inheriReceived May 19, 1998. Revision received August 6, 1998. Accepted September 30, 1998. Address all correspondence and requests for reprints to: Professor R. N. Clayton, School of Postgraduate Medicine, Keele University, Thornburrow Drive, Hartshill, Stoke on Trent, ST4 7QB United Kingdom. 38 PCO, INHERITED AUTOSOMAL DOMINANT TRAIT gene defect in PCO/PCOS. However, a twin study (17) did not confirm PCO to be an autosomal genetic disorder. In this study, we sought to obtain further evidence for a genetic component for PCO by examining the families of 29 probands with PCOS. Subjects and Methods Subjects The individuals identified with the PCOS are designated as probands, and each had PCO by pelvic ultrasound scan and was known to have at least one sister. These postmenarchal and premenopausal women were recruited prospectively from the infertility and endocrine clinics at the North Staffordshire Hospital Centre. They presented with a variety of symptoms of PCOS, oligomenorrhea, and/or hirsutism, together with raised serum testosterone, androstenedione, or both. They and their families agreed to take part after informed consent was obtained. This study was approved by the North Staffordshire District ethical committee. All interviews, examinations, and tests were performed at one visit, after fasting from midnight. All blood samples on the female relatives were taken on the day of ultrasound, which was performed within 1–7 days of menstruation in those with less marked menstrual irregularity (intermenstrual interval ,3 months) and randomly in women with severe oligomenorrhea/amenorrhea. The degree of hirsutism was assessed by Ferriman and Gallwey score (18) and deemed present at a score greater than 7. The presence or absence of acne was noted. Past and present history of alopecia was obtained. Body mass index (BMI) was calculated for each subject as weight (kg)/height (m2). Twenty-nine families from PCOS probands and 10 from the control volunteers completed the study by screening of all first-degree relatives. Twenty-seven PCOS probands were of Caucasian, and two of Asian, origin. One hundred thirty-four first-degree relatives were identified from the 29 PCOS probands (Table 1a). It was possible to perform biochemical analysis on 100 of these relatives, given that 5 were deceased (1 father, 3 mothers, and 1 sister), 1 sister lived abroad, 22 mothers and 1 sister were postmenopausal, 1 sister was categorized unassignable because she was premenarchal, 3 brothers were below the age of 15 yr and therefore unsuitable for status assignment; 1 brother, aged 24, was not bald but could not be assigned because he may become bald before the age of 30. Medical histories were obtained on the 5 deceased mem- 39 bers and 1 relative who was living abroad. One deceased father was excluded from analysis because he had died at the age of 23 yr, from an accident. Before entering the study, the female subjects (probands and relatives) continued on hormonal preparations [i.e. combined oral contraceptive pill (OCP), dianette, or depot provera]. Where necessary (e.g. for LH and testosterone measurements), the results of those on hormonal treatment were considered separately. The 10 control volunteers were all Caucasians. They were asymptomatic healthy women between the ages of 15– 45 yr, from the nursing and secretarial staff of the hospital. They had normal ovaries (on transvaginal ultrasound), had no evidence of hyperandrogenism (hirsutism or acne), had regular menstrual cycles (intermenstrual intervals between 21 and 35 days but with no more than 4 days variation from cycle-cycle), and had not sought treatment for menstrual disturbances, infertility, or hirsutism at any time. The 10 control volunteers had 44 first-degree relatives (Table 1b). Of these, 23 were women and 21 were men. Only 42 of these were available for full biochemical screening because 1 mother was deceased, 1 volunteer (although only 42 yr old) had blood results in the menopausal range, and 9 mothers were postmenopausal (as was 1 sister). In the control group of 23 of the first-degree female relatives studied, 4 were taking an OCP for contraception purposes. Assignment of status PCO. The presence of PCO on transvaginal scan of the pelvis on both sides was considered confirmatory of PCO. Women were considered affected if they had bilateral PCO on ultrasound. Those women with two ovaries and unilateral PCO were assigned a normal status. There was only one such woman in the proband sibling group (sister) and 3 women in the control group (1 volunteer and 2 sisters). Postmenopausal women, and those who were deceased but had a history of persistent menstrual irregularity, were considered affected (16); but those with a negative history were assigned normal status. PMPB has been defined as significant frontoparietal hair loss [type IV of Hamilton (19)] before the age of 30 yr. Each male family member was also assessed for the degree and time of onset of balding. All men were asked to produce photographs as near to age 30 yr as possible if they exhibited type IV balding after 30 yr of age. Five mothers (3 in the PCOS proband and 2 in the control group) and one sister in the control group had undergone a hysterectomy and bilateral salpingo oophorectomy. Status in these cases were assigned according to the history. TABLE 1a. PCOS proband families Expected to be included Attended Total women attended PCO status Normal status Total males attended Type IV PMPB status Normal hair pattern Subjects included for biochem analysis Proband Mothers Fathers Sisters Brothers Total 29 29 29 29 0 29 26 26 15 14 29 28 54 52 52 35 19 22 22 22 4b 14b 18 163 157 107 79 33 50 10 35 129 29 4 28 6a 21a 28 50 a 1 unassigned (died at age 23). b 4 unassigned 5 3 ,15 yr of age and 1 normal hair pattern aged 24 (could still become bald by aged 30). TABLE 1b. Control volunteer families Expected to be included Attended Total women attended PCO status Normal status Total men attended PMPB type IV status Normal hair status Subjects included for biochem analysis Probands Mothers Fathers Sisters Brothers Total 10 10 10 1 9 10 10 10 1 9 10 9 13 13 13 2 11 11 11 54 53 33 4 29 20 1 20 42 9 1 9 0 10 9 12 11 1 10 11 40 JCE & M • 1999 Vol 84 • No 1 GOVIND ET AL. TABLE 2. Segregation analysis of PCO and PMBP a) Proband families (n 5 29) Number (1) Siblings PCO status PMPB status (2) All first-degree relatives PCO status PMPB status 71 35 4 128 50 10 Observed (O) affected Expected (E) affected Ratio (O/E) Chi-Sq 39 35.5 39:35.5 0.68 60 64 60:64 0.5 b) Control families (n 5 10) Number (1) Siblings PCO status PMPB status a 24 2 1 Observed affected 3 Expected affected Ratio (O/E) Chi-Sq 3:12 6.7a 12 Significance departure from O/E ratio of 1:1 expected with autosomal dominant inheritance. (P , 0.05). Ultrasonography The ultrasound scan was performed transvaginally, using a 6.5-MHz transducer (Hitachi EUB 515 Echo Scan machine; Sonotron, Bedford Ltd., UK), and was used to determine ovarian morphology and volume and was performed by one observer who recorded the images in all patients. The precision of diagnosis of PCO was 97% when the hard copies were checked randomly by independent observers unaware of the clinical and biochemical features. We included only those women whose scan showed unequivocal PCO, which fulfilled the strict criteria of Adams et al. (3) and Eden (20). Ovarian volume was calculated according to the formula for a prolate ellipsoid. No individual in the PCOS proband group had multicystic ovaries, which can be distinguished from PCO as being of normal size and without any increase in stroma (21). Biochemical measurements LH, FSH, estradiol, progesterone, dehydroepiandrosterone-sulfate (DHEAS), sex hormone binding globulin and testosterone were measured using Immulite, a solid-phase, chemilumiscent enzyme immunometric assay. These have a broad working range, with an intraassay coefficient of variation (CV) of 3– 4% and interassay CV of 4 –10% within the working range. Coat-A-Count, a solid-phase RIA, was used to measure 17alpha OH progesterone, and androstenedione (interassay CV, 4 –10%). Reference ranges were established from a group (n 5 218) of regularly menstruating women sampled within 7 days of menses. We defined an abnormal value as being more than 95th centile of the normal women, viz: LH more than 8.9 U/L; testosterone more than 3.0 nmol/L; androstenedione more than 12.0 nmol/L, and free testosterone index (FTI) more than 7.2. Free androgen index was calculated using the formula: free androgen index 5 testosterone 3 100/SHBG. In the amenorrheic women, recent ovulation was excluded by progesterone measurement (,5 nmol/L). No woman had late onset 21-hydroxylase deficiency based on early follicular phase level of 17 alpha OH progesterone less than 6 nmol/L and DHEAS less than 12 mmol/L. Calculations and statistical analysis Statistical analysis was performed using the SPSS/PC package (SPSS, Inc., Chicago, IL). Student’s t test was used for calculating differences between anthropometric measurements. The hormone data and ovarian volumes were not normally distributed; and hence, results were expressed as the median and range and compared with the Mann Whitney test. Statistical significance is taken as P , 0.05. Analysis of frequency difference between groups was evaluated using a x-square test. Segregation analysis was used to study the mode of inheritance by comparing the observed proportion of affected siblings and first-degree relatives with the proportion expected, according to a dominant pattern of inheritance; and the x-square test was used to test the null hypothesis. Results Segregation analysis The segregation ratio was calculated for the proband and control families, excluding the probands to avoid ascertainment bias. Considering a total of 71 postpubertal siblings of PCOS probands, 39 were assigned affected status (PCO or PMPB), which is not significantly different from the 50% (35.5) expected, on the assumption of autosomal dominant inheritance (Table 2). The computed x-square analysis shows no significant departure from that expected, assuming an autosomal dominant mode of inheritance. Of the 29 PCOS proband families, 15 of 29 mothers (52%), 6 of 28 fathers (21%), 35 of 53 sisters (66%), and 4 of 18 brothers (22%) were assigned affected status. First-degree female relatives of affected individuals had 61% chance of being affected. Of the first-degree male relatives, 22% were found to be affected. When all the first-degree female relatives were considered, 50 relatives (35 sisters and 15 mothers) were assigned affected status, as were 10 first-degree male relatives (6 fathers and 4 brothers) (Table 1a), giving a segregation ratio of 60/64, which is still consistent with the autosomal dominant pattern of inheritance (x-square, 0.5). Of the 29 proband families, there were 20 families with at least 1 parent assigned affected status. However, in 9 families, no parent was affected with either PCO or PMPB. In the control families, 1 of 10 probands (10%), 1 of 10 mothers (10%), 0 of 10 fathers, 2 of 13 sisters (15%), and 1 of 11 brothers (10%) were affected. Out of a total of 24 siblings, 3 (13%) were affected, this being a significant departure from autosomal dominant inheritance (Table 2). In the PCOS proband families, 6 of the 28 fathers were affected, as were 4 of the 18 sons. In the control families, all 10 fathers were unaffected, but there was 1 son who showed PMPB. He belonged to a family where the control volunteer had PCO and the mother was assigned affected status. His father had Hamilton type III baldness (borderline) by the age of 30 yr but not quite stage IV, which has been taken as significant for the purpose of the study. PCO, INHERITED AUTOSOMAL DOMINANT TRAIT Clinical findings Table 3a compares the clinical findings between the 29 PCOS probands and 10 control volunteers. Twenty-eight of the 29 PCOS women (97%) presented with oligomenorrhea, 20 of the 29 had hirsutism (69%), 16 of the 29 had acne (55%), and 14 of the 21 had subfertility (67%). When the same features were compared in the control volunteers, just 1 of the 10 (10%) suffered oligomenorrhea, 2 (20%) had hirsutism, 1 (10%) had acne, and none had subfertility as the presenting complaint. All these differences are statistically significant. Table 3b compares the same variables for the PCO-scanpositive and PCO-scan-negative sisters from the PCOS proband families. The proportion of PCO-positive sisters with oligomenorrhea was significantly higher (P , 0.02) than PCO negative sisters, although the proportion with hirsutism or acne was not different. Six women in the PCOS proband group had past or present history of alopecia (7%). This was the presenting complaint in one proband. Acanthosis was present in two PCOS proband patients. None of the control volunteers or their first degree relatives had hirsutism, but one had acne. A history was taken to be positive for PCOS if it included 1 or more features of menstrual irregularity, unwanted hair, or acne. Of all the women with PCO morphology, 64 of 71 (90%) had at least 1 clinical feature of PCOS, whereas 46 of 71 (65%) had at least 2 symptoms, making PCO on scan highly predictive of symptoms. Of the 32 women with irregular menses and hirsutism, 30 had PCO (94% sensitivity) on scan. Ovarian volume As expected, the median (range) ovarian volume was greater in the PCOS probands than in the women in the control volunteer group (Table 3a). This significance was maintained when ovarian volumes of PCO v normal ovaries were compared in affected and unaffected sisters in the PCOS proband families (Table 3b) and when all first-degree female relatives were included from both proband and control families (P , 0.0001 for right and left ovaries). Ovarian volume in those PCO sisters who were on the OCP was not significantly different (P 5 0.57 for right and P 5 0.77 for left ovary) from those PCO-positive sisters who were not on the OCP. Hormone levels for women PCOS probands and control volunteers (Table 4a). The LH values for the PCOS proband women were significantly higher than those for the control volunteers (P 5 0.002); FSH being no different. Serum testosterone concentrations were significantly higher (P 5 0.005) in women with PCOS than in control women, as was the FTI (P 5 0.05). Similarly, androstenedione and DHEAS concentrations were significantly higher in PCOS probands than in control women. There was no difference in the other hormones measured. First-degree relatives of PCOS probands. Only 1 of the 15 (7%) affected mothers and 1 of the 35 (2.8%) affected sisters in the PCOS proband group had LH levels more than 8.9 41 TABLE 3a. Clinical findings in PCOS probands and control volunteers Age (yr) BMI Menstrual cycle Regular Oligomenorrhoea Number with (%) F 1 G . 7 Acne present Ovarian volume (mm3) Right (median:min-max) Left (median:min-max) Ovarian structure 1. Normal 2. PCO PCOS probands (n 5 29) Control volunteers (n 5 10) 28 (19 –39) 25.6 (17.1– 46.0) 33 (21– 44) 25.4 (19.0 –30.8) 1 (3%) 28 (97%) 21 (72.4%)b 16 (55%)a 8.9 (3.5–17.6)c 9.9 (3.9 –19.7)c 0 29 9 (90%)a 1 (10%)a 0 (0%) 1 (10%) 5 (2.4 –9.0) 4.0 (1.2–17) 9 1 Values are median (range). Intermenstrual interval: regular ,35 days; oliogmenorrhoea .35 days. F & G, Ferriman & Gallwey score. a P , 0.05 PCOS probands vs. controls. b P , 0.001 PCOS probands vs. controls. c P , 0.01 PCOS proband ovarian vol vs. control ovarian vol. TABLE 3b. Clinical findings in PCO-affected and PCO-unaffected sisters from proband families PCO affected (n 5 35) Age BMI Menstrual cycle Regular Oligomeorrhoea Number (%) with F 1 G score . 7 Acne present Ovarian volume (mm3) Right Left a b unaffected (n 5 18) 28 (15– 43) 23 (18 – 47) 29 (15– 48) 23 (19 –29) 16 (46%) 19 (54%) 15 (43%) 12 (34%) 15 (84%)a 3 (16%)a 4 (22%) 3 (16%) 6.7 (3.2–24) 6.9 (2.9 –23) 5.2 (2.4 –7.7)b 4.5 (1.2–7.1)b P , 0.02 affected vs. unaffected. P , 0.001 affected vs. unaffected. (95th centile). The androstenedione levels were elevated (.12.0) in none of the 15 mothers and in only 4 of the 35 sisters. Again, only 1 of 15 (7%) affected mothers and 8 of 35 (23%) affected sisters in the same group had abnormal testosterone levels. When LH, testosterone, androstenedione, and DHEAS values were compared in affected and unaffected sisters from proband families, only that for androstenedione was significantly different, though DHEAS was nearly so (Table 4b). There were no significant differences in any of these hormone values in affected or unaffected sisters who were on the OCP, compared with those who were not; so, the data were combined. Serum testosterone values for all first-degree female relatives (sisters and premenopausal mothers) with PCO were not different from those without PCO. However, LH, androstenedione, and DHEAS were significantly higher in those premenopausal mothers and sisters with PCO (Table 4c). Male relatives. In the PCOS proband family group, 6 of 28 fathers (21%) and 4 of 18 brothers (22%) were affected with PMPB. In the control families, no father and 1 of 11 brothers (9%) were affected. Thus, the prevalence of PMPB was 22% in PCOS proband families and 5% in control families (P 5 42 JCE & M • 1999 Vol 84 • No 1 GOVIND ET AL. TABLE 4a. Serum hormone values in PCOS probands and control volunteers (median 1 range) FSH (IU/L) LH (IU/L) Testosterone (nmol/L) Androstenedione (nmol/L) DHEAS (mmol/L) SHBG (nmol/L) FTI Estradiol pmol/L PRL (U/L) Progesterone (nmol/L) 17 alpha OH progesterone (nmol/L) PCOS probands (n 5 29) Control volunteers (n 5 9) Significance (P value) 5 (1– 8) 11 (2–28) 3 (0.8 –5.2) 9 (4 –26) 6.8 (1.6 –17) 42 (10 –220) 7.4 (1.05–32.6) 180 (48 –350) 353 (134 –770) 2.6 (1–9.6) 2.5 (1–24) 6 (4 – 8) 3 (2–5.8) 1.9 (0.5–3.9) 7 (4.0 – 8.0) 4.9 (1.1–7.2) 50 (19 –110) 4.1 (1.4 –10) 190 (33–280) 377 (167– 895) 2.8 (0.6 – 4.5) 1.9 (0.9 –2.8) NS 0.002 0.005 0.001 0.02 NS 0.05 NS NS NS NS NS, Not significant. TABLE 4b. Serum hormone values in PCO affected vs. PCO unaffected sisters from PCOS proband families (median 1 range) FSH (IU/L) LH (IU/L) Testosterone (nmol/L) Androstenedione (nmol/L) DHEAS (mmol/L) SHBG (nmol/L) FTI PCO (n 5 35) Normal ovaries (n 5 15) Significance (P value) 5.2 (1–9.3) 5.1 (2–19) 2.2 (1.1– 6.0) 9.3 (3.7–17.0) 7.0 (2.2–11.0) 48 (3.3–220) 4.7 (1– 83) 6 (2.3–12) 4 (2.8 –7.6) 2.2 (1.5–3.6) 6.1 (4.7–10.0) 5.9 (2.0 –7.8) 55 (2.2–200) 4.3 (0.8 –10.8) NS NS NS 0.004 0.06 NS NS NS, Not significant. TABLE 4c. Serum hormone values in all sisters and mothers from PCOS and control families with or without PCO on ultrasound (median 1 range) FSH (IU/L) LH (IU/L) Testosterone (nmol/L) Androstenedione (nmol/L) DHEAS (mmol/L) SHBG (nmol/L) FTI PCO (n 5 41) Normal ovaries (n 5 29) Significance (P value) 5.9 (1–29) 5.2 (2–19) 2.2 (1.1– 6.0) 8.9 (3.7–17.0) 6.7 (1.4 –11.0) 49 (3–220) 4.5 (1– 83) 6.0 (2.3–14) 4.0 (2–7.6) 1.9 (0.9 –5.4) 6.1 (3.4 –12.0) 4.9 (2.0 –9.3) 50 (5–200) 3.8 (0.8 –11) NS 0.04 NS 0.002 0.009 NS NS NS, Not significant. 0.006). Of the 50 first-degree male relatives in the PCOS proband family group, 5 were excluded from hormone analysis because 1 father had died at the age of 23 yr, 3 brothers were too young (,15) to be evaluated, and 1 brother could not be assigned. The mean serum testosterone level was significantly greater in men with PMPB, compared with unaffected men (P 5 0.02) (Table 5). Discussion The relative importance of genetic and environmental factors in the etiology of PCOS is unclear. Recent attention has focussed on defining the former, because molecular genetic approaches can now be employed to assess the contributions of individual genes in complex genetic disorders. Both autosomal (12, 13, 15, 16) and X-linked dominant (14) modes of inheritance have been suggested to explain the observed familial clusterings of cases of PCOS. Conclusions drawn clearly depend heavily on the criteria used to establish the phenotype. Lack of a sensitive diagnostic marker has previously made it difficult to follow segregation of the syn- drome in families. Ovarian ultrasound enables definition of the phenotype more precisely than can be achieved by consideration of symptoms or biochemical parameters of the syndrome alone, and can thus be used to more accurately assign affected status. This study provides further evidence that PCO (not the syndrome) are inherited in an autosomal dominant manner, because when the assignment of affected status was made assuming PMPB as the male phenotype, a positive ultrasound scan for postmenarchal-premenopausal women, and a positive history for postmenopausal women, the segregation ratio was entirely consistent with this. Thus, we confirm, in a larger group of families, the study of Carey et al. (16). We included a cohort of families of normal women without any history or ultrasound appearance of PCO and, in them, found no evidence of any familial clustering. Although only a small group was involved, this result adds to the evidence that the phenotype has a genetic basis, in that they would not be expected to exhibit it, given no affected parents. Like other studies, we have shown that typical findings of PCO, INHERITED AUTOSOMAL DOMINANT TRAIT 43 TABLE 5. PMPB and serum hormone levels in PCOS and control families (median and range) a) Families Evaluable men Men with PMPB PCOS (n 5 29) Control (n 5 10) Significance (P value) 50 10 (22%) 20 1 (5%) 0.006 PMPB men (n 5 11) Men without PMPB (n 5 56) 3.8 (1.0 – 6.0) 22 (16 –35) 6.0 (3–10.9) 5.2 (1.0 –7.8) 4.0 (1–20) 19 (7–32) 6.0 (2.1–12.0) 4.1 (1.0 –13.0) b) Serum hormones LH (IU/L) Testosterone (nmol/L) Androstenedione (nmol/L) DHEAS (mmol/L) PCO on ultrasound have a high concordance with a symptomatic history. These findings are in agreement with the work of Polson et al. (1), who showed that 94% of women could be identified by symptoms alone. Our observations agree with a previous study in which menstrual history was used to assign status in postmenopausal women, and studies in which full screening was not possible (16). In the present study, sisters with PCO had significantly larger ovaries and higher serum androstenedione concentrations than sisters with normal ovaries, but serum LH and testosterone values were no different between the normal and PCO sisters, results which are consistent with previous studies (1, 6, 16). The sisters with PCO, therefore, had less hormonal abnormality, and their ovarian volumes were smaller than those of the PCOS probands, suggesting that these women have a phenotype more towards the normal end of the spectrum of PCOS. Nevertheless, such women may be at risk of becoming symptomatic, perhaps with change in environmental circumstances. The prevalence of PMPB in the PCOS families studied was higher than expected for the nonaffected families, as has been reported previously (5, 15). There was a significantly higher serum testosterone concentration in men with PMPB and those without, supporting the view that androgens may be implicated in the cause of PMPB (6, 7). The idea that an abnormality of androgen biosynthesis and/or metabolism is causative in both PCO and PMPB is compatible with the findings of this study. In conclusion, the present evidence suggests that the genetic component of polycystic ovarian morphology is autosomal dominant, with nearly complete penetrance. Undoubtedly environmental factors, particularly weight gain, possibly mediated through changes in peripheral insulin resistance, impinge on the genetic background of polycystic ovarian morphology, to determine the expression of the clinical syndrome. Acknowledgments We wish to thank Professor S. Bundey, Department of Clinical Genetics, Birmingham Womens Hospital, for valuable discussion and help with the genetic analysis; Dr. R. Neary, North Staffordshire Hospital, for NS 0.02 NS NS his help with the biochemical analysis; and Dr. D. Lowe, Wolverhampton University, for his help with statistical analysis. 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