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Polycystic Ovaries Are Inherited as an Autosomal Dominant Trait: Analysis of 29 Polycystic Ovary Syndrome and 10 Control Families

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

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.

	Abstract

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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 first-degree 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.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC 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, 9, 10, 11).

Cooper et al. (12) suggested a dominant mode of inheritance 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 first- and 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 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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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 members 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 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.

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.

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 = 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 = testosterone x 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 µmol/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 -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 -square test was used to test the null hypothesis.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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 -square analysis shows no significant departure from that expected, assuming an autosomal dominant mode of inheritance.

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.

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.

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 = 0.57 for right and P = 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 = 0.002); FSH being no different.

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 (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).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

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 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 his help with the biochemical analysis; and Dr. D. Lowe, Wolverhampton University, for his help with statistical analysis. We are grateful to all those family members who participated, without whom this study would not have been possible; and to the North Staffordshire Hospital Trust for providing facilities for the study.

Received May 19, 1998.

Revised August 6, 1998.

Accepted September 30, 1998.

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