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Ovarian Morphology Is a Marker of Heritable Biochemical Traits in Sisters with Polycystic Ovaries

Institute of Reproductive and Developmental Biology (S.F., L.J.W.), Imperial College London, London W12 ONN, United Kingdom; Reproductive Medicine Unit (L.J.W., M.G., A.V., D.M.W.), St. Mary’s Hospital, London W2 1PG, United Kingdom; Department of Endocrinology (G.S.C.), University College Hospital, London NW1 2BU, United Kingdom; and Oxford Centre for Diabetes, Endocrinology, and Metabolism (S.W., M.I.M.), University of Oxford, Oxford OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: Professor Stephen Franks, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom. E-mail: s.franks{at}imperial.ac.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Polycystic ovary syndrome (PCOS) is a common endocrinopathy of uncertain etiology but with strong evidence for a genetic contribution.

Objective: The objective of the study was to test the hypothesis that the typical polycystic ovarian morphology is a marker of inherited biochemical features in families of women with PCOS.

Design: A study of probands with PCOS and their sisters.

Patients: Patients included 125 probands and 214 sisters. All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected sisters were defined by polycystic ovaries, regardless of symptoms, and unaffected sisters defined by normal ovarian morphology.

Setting: This was a clinic-based study.

Main Outcome Measures: Clinical, endocrine, and metabolic features in the various groups were compared, and estimates of broad-sense heritability were obtained using the quantitative transmission disequilibrium test.

Results: Although affected sisters had fewer symptoms than probands (30% had no symptoms of PCOS), serum testosterone, androstenedione, LH, and fasting insulin and insulin sensitivity were similar in the two groups with polycystic ovaries but significantly different from those in unaffected sisters or controls. We observed moderate to high heritabilities for all traits studied in affected sister pairs, whereas heritabilities calculated from discordant siblings were substantially lower.

Conclusions: These data provide further evidence for a genetic basis of PCOS. The high heritability of biochemical features in probands and affected sisters, despite wide variation in symptoms, shows that not only are these biochemical traits strongly influenced by genetic factors but also, importantly, that polycystic ovarian morphology is an index of inherited traits in families with PCOS.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Polycystic ovary syndrome (PCOS) is a highly prevalent, heterogeneous endocrine disorder whose etiology remains unknown. There is, however, increasing evidence for the role of genetic factors in the genesis of PCOS. There is familial clustering of cases and transmission within families of both clinical and biochemical manifestations of the syndrome (1, 2, 3, 4, 5, 6, 7, 8). A recent twin study showed that concordance of symptoms of PCOS was twice as high in identical than nonidentical twins (9). Studies to determine the mode of inheritance of PCOS and the search for candidate genes have proved difficult for various reasons. These include clinical and biochemical heterogeneity of presenting features, lack of agreement about definition and diagnostic criteria, the difficulty in defining affected status other than in women of reproductive age, and uncertainty about the male phenotype (6, 10). Nevertheless, results of studies to date support the view that PCOS is a complex endocrine trait involving the contribution of several genes and that these genes act jointly with environmental, particularly nutritional, factors (10, 11).

Previous work has shown evidence for heritability of both hyperandrogenism (7, 12) and metabolic abnormalities (8, 12, 13) within families with PCOS. The definition of PCOS that has been used in these studies is based on the classic definition of the syndrome as set out in the National Institute of Child Health and Human Development (NICHD) conference of 1990 (14). By these criteria, the proband (or index case) is considered affected if she has oligomenorrhea and hyperandrogenemia (serum testosterone or free testosterone index more than 2 SD above the control mean). In the extensive studies of sister pairs by Legro and colleagues (7, 8), affected sisters were defined according to hyperandrogenemia, irrespective of menstrual history. By definition, sisters with normal androgen levels were unaffected. Pelvic ultrasonography to define the typical polycystic ovarian morphology was not undertaken routinely and was not included in the ascertainment criteria.

In the study described in this paper, probands have been defined by criteria agreed at the 2003 PCOS consensus meeting jointly sponsored by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine (15), although, as described in the Patients section below, 80% of probands also met the 1990 NICHD criteria for diagnosis (14). For the purpose of the present study, affected sisters were identified by the finding of polycystic ovaries on ultrasound, irrespective of symptoms or biochemical features, and unaffected sisters were those with normal ovaries.

The aim of this study was to examine the relationships between ovarian, endocrine, and metabolic phenotypes in the sisters of women with established PCOS and thereby to gain a clearer understanding of the cosegregation patterns within such families. In particular, we set out to establish whether ovarian morphology is an informative index of affection status within families with PCOS.

Our findings suggest that there is very close association of between androgen concentrations and ovarian morphology, regardless of the clinical features of affected sisters.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

The subjects studied included 125 probands with PCOS and 214 sisters. The study population included 23 families in which, in addition to the proband, more than one sister (affected or unaffected) was available for investigation. The reference group comprised 75 control subjects. Probands were defined as women with polycystic ovaries who had presented to the reproductive endocrine, general endocrine, or infertility clinics at one of two centers: St. Mary’s Hospital (Imperial College London) and the Middlesex Hospital (University College London) with menstrual disturbances (amenorrhea, oligomenorrhea) or symptoms of hyperandrogenism (hirsutism, acne) or both and were found to have polycystic ovaries on pelvic ultrasonography (15, 16, 17). Women with estrogen-deficient amenorrhea were excluded as were those with hyperprolactinemia, Cushing’s syndrome, and late-onset 21-hydroxylase deficiency (14, 15). Patients with PCOS were approached consecutively, invited to participate in the study, and information about family members sought. Specifically, permission was requested from the patients to contact any sisters, irrespective of whether the proband thought her sister had symptoms of PCOS. Sisters who agreed to take part in the study were interviewed, symptoms and signs recorded, blood drawn, and a pelvic ultrasound scan performed. Another 34 sisters were unavailable (a few refusals, distant locations, etc.) so that we were able to include 86% of known sisters in this study. Probands and sisters were all assessed by the same staff at the two centers, ultrasound scans in both probands and sisters were performed only at these centers, and biochemical analyses were all performed in the same laboratory.

In this study, sisters were considered to be affected simply on the basis of ultrasonographic findings of polycystic ovaries, i.e. irrespective of symptoms or biochemical criteria. By the same token, sisters were defined as unaffected if they had normal ovarian morphology. The control population comprised women with normal ovaries and regular cycles with no family history suggestive of PCOS. In all groups women who were postmenopausal or who had elevated serum levels of FSH were excluded from further analysis. Medical history was recorded, body mass index (BMI) and waist to hip ratio (WHR) were measured, and the presence of hirsutism (defined as a Ferriman-Gallwey score of eight or more) or acne was noted. Thirty-seven of the probands and 38 of the affected sisters were taking an oral contraceptive, but, as we have previously demonstrated (18), this did not affect the ability to identify polycystic ovarian morphology.

All probands met the Rotterdam criteria for diagnosis of PCOS, i.e. they had two of the three following features: 1) oligomenorrhea or estrogen-replete amenorrhea, 2) clinical and/or biochemical evidence of androgen excess, and 3) polycystic ovaries. Seventy-nine of 125 probands had a combination of irregular menses (or amenorrhea) with symptoms of androgen excess (69 with hirsutism ± acne, 10 with acne); of the remaining 46 probands, 23 had irregular cycles with neither hirsutism nor acne: androgen levels were available in 17 of these and were elevated in five. There were therefore 18 women (14%) of probands who had irregular cycles but neither clinical nor endocrine evidence of androgen excess (plus another six in whom androgen levels were not available). In other words, 101 of 125 probands (80%) had PCOS according to the NICHD 1990 criteria (14).

Ninety-one of 125 probands and their families were of white British/Irish origin, 14 were of other white European origin, seven were south Asian, seven were Afro-Caribbean, and the remaining six were of various racial backgrounds.

The study was approved by the Research Ethics Committees of the St. Mary’s National Health Service Trust and the University College Hospitals National Health Service Trust (Middlesex Hospital).

Biochemical measurements

Biochemical analyses were performed only on women not taking hormonal contraceptives or other medication known to affect the measured parameters. Serum testosterone, androstenedione, SHBG, LH, and FSH were measured in the follicular phase of the cycle in women (subjects and controls) who had regular cycles, within 7 d of onset of menses in those with oligomenorrhea (with an intermenstrual interval of <8 wk) and at random in those with less frequent menses or amenorrhea. Serum LH and FSH were measured by the sandwich immunoassay by immuno 1 analyzer (Bayer Corp., Tarrytown, NY). Interassay coefficients of variation for FSH and LH were less than 2.5% (19). Testosterone was measured by RIA as previously described (20). Androstenedione was assayed using in-house RIAs using ether extraction and dextran-coated charcoal separation. ³H-androstenedione were obtained from Amersham PLC (Aylesbury, UK). The antibody to androstenedione was purchased from Guildhay Ltd. (Surrey, UK). The coefficient of interassay variation for a midrange value was less than 10% for androstenedione. SHBG was measured using the Immulite method (Diagnostic Products Corp., Llanberis, Gwynedd, UK) (21).

Fasting samples were taken for analysis of serum glucose and insulin. The in-house insulin ELISA specifically measures insulin, and there is no significant cross-reactivity with proinsulin and split proinsulin (22). Insulin sensitivity was measured by means of the homeostatic model assessment algorithm (23) using either (in most cases) the average value of two fasting samples obtained with a 30-min collection interval or the value in a single sample when only one was available.

Statistical analysis

Data are presented as mean and SD for most indices or as median with interquartile range for nonnormally distributed data [LH, fasting insulin, and homeostatic model assessment for insulin sensitivity (HOMA-S)]. Free androgen index (FAI) was calculated as the ratio of serum testosterone to SHBG x 100. Statistical analyses were performed using InStat 3.0a for Macintosh Graph Pad, San Diego, CA. Comparisons between groups were made with Student’s t test or (for LH, fasting insulin, and HOMA-S) the Mann-Whitney U test. Correlations of serum testosterone and fasting insulin within affected sister pairs were performed using Pearson regression.

Estimates of broad-sense heritability (i.e. the proportion of the total variance of the trait attributable to genetic factors) were obtained using the QTDT program (24, 25). Specifically, we compared a model in which both polygenic and nonshared environmental variance components were estimated, with a model in which only the environmental component was estimated to obtain the magnitude and significance of the polygenic component of the trait variance, from which we calculated the heritability. The analyses reported in this manuscript include age (at diagnosis for probands, at study for sisters) as covariate. Analyses were performed using three sample sets: 1) all, including all individuals (affected and unaffected for PCOS); 2) affecteds only, in which analysis was effectively restricted to those sibships with two or more affected individuals; and 3) those sibships discordant for affection status (i.e. containing one affected and one unaffected individual).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Clinical features of probands and affected sisters

Clinical and biochemical data of the subjects who were studied are summarized in Table 1. Of the 214 sisters, 151 were designated affected and 63 were unaffected. Both probands and affected sisters were significantly younger than the controls (Table 1). Probands had a significantly higher BMI and WHR than affected sisters, whereas BMI and WHR were similar in affected sisters to controls. There were significant differences between probands and their affected sisters in the prevalence of symptoms of PCOS (Fig. 1). Eighty-six percent of probands complained of oligo- or amenorrhea, compared with 47% of affected sisters. Significant hirsutism (Ferriman-Gallwey score 8) was found in 73% of probands and 45% of affected sisters; acne was present in 37% of probands and 24% of affected sisters and androgenic alopecia was a major complaint in 13% of probands and 6% of affected sisters. Of 41 nonhirsute probands, eight had acne alone, two had acne with alopecia, but none had alopecia alone. Of the 63 unaffected sisters, 58 (82%) had regular menstrual cycles and five had irregular menses. Eighteen (29%) complained of hirsutism, but no sister with normal ovarian morphology (and therefore designated unaffected) had both irregular menses and hirsutism.

View larger version (18K): [in this window] [in a new window]   FIG. 1. Distribution of symptoms in probands with PCOS and affected sisters (defined by ultrasound ovarian morphology).

Serum concentrations of androstenedione and testosterone were very similar in probands and affected sisters (Tables 1 and 2, and Fig. 2); in both these groups, levels of A and T were significantly greater than in either unaffected sisters or controls (Tables 1 and 2, and Fig. 2). There was a positive correlation of testosterone concentrations between probands and affected sisters (r² = 0.20, P = 0.0002) but not between probands and unaffected sisters (r² = 0.03, P = 0.17). In contrast, serum concentrations of SHBG in affected sisters were higher than in probands but similar to those in unaffected sisters. Consequently, the FAI was higher in probands than in affected sisters and was, in turn, greater in affected than unaffected sisters. Serum LH concentrations were similar in probands and affected sisters and higher, in both groups, than in unaffected sisters and controls. FSH concentrations, however, were no different between the groups.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Serum testosterone concentrations in individual probands, affected sisters, and unaffected sisters.

Biochemical indices in affected sisters according to symptoms

The biochemical data for the affected sisters have been presented (Table 1), irrespective of the presenting symptoms within this group. Given the clear difference in the profile of clinical presentation between probands and affected sisters but the concordance in biochemical values, it was considered important to subdivide the affected sisters according to symptoms and reevaluate the biochemical data. The results are presented in Table 3. Affected sisters with oligo- or amenorrhea had higher levels of LH than those with regular cycles, but there were no differences in other endocrine or metabolic indices according to menstrual history. Hirsute sisters had similar serum testosterone and androstenedione concentrations to those in non-hirsute affected siblings, but SHBG concentrations were significantly lower in hirsute women. Accordingly, FAI was higher in hirsute than nonhirsute sisters. Fasting insulin and HOMA-S values were unaffected by symptoms in affected sisters. A striking feature of this analysis was that, for A, T, SHBG, FAI, and LH, values were significantly greater in affected sisters with no symptoms of PCOS than control subjects (Table 3). Testosterone and androstenedione concentrations were significantly higher in asymptomatic affected sisters than in unaffected sisters (Table 3).

We observed moderate to high heritabilities for all the traits studied in our affecteds-only analyses; the measures for the all-individuals analyses (in which affected and unaffected patients were included) were slightly lower in all cases (Table 4). In contrast, heritabilities calculated from discordant siblings (i.e. one affected and one unaffected for PCOS) were substantially lower (zero for LH, androstenedione, and HOMA-S), with the exception of SHBG, which was similar to that seen in the analyses of affected-only sisters and all sisters, but all were nonsignificant due to substantially smaller sample sizes.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

In more than 80% of families, we were able to include data on all sisters. Nevertheless, in the heritability analysis, we considered any possibility of bias attributable to lack of data from any missing siblings. Clearly the best (most unbiased) heritability estimates will be obtained using all the available and appropriate information (i.e. available sisters), which we have done and quoted in this paper, mindful of the fact that to perform the heritability calculations, we need at least two individuals of the appropriate PCOS status in the family (i.e. all affected or one affected and one unaffected for the discordant analyses) with quantitative trait measures. It is nonetheless impossible to know what the effect of unknown information is (i.e. additional siblings who were unavailable or whose existence is unknown), but we nevertheless examined the effects of varying the number of additional siblings per family (in those with more than two eligible) on our heritability estimates in a simplistic fashion. For the affected sisters-only analyses, we used just the first two sisters in families with three or more siblings (or the first two with phenotyped data if some had no quantitative measures) and observed that, on the whole, the effects on our heritability estimates were modest, although there were a few instances of more sizable differences. For the discordant analyses, we included all unaffected sisters (rather than a single unaffected, in the cases of families with more than one unaffected sister); again the effects were mainly modest. We are confident, therefore, that the heritability measures quoted here represent the best possible estimates given the available data in this study.

The similarity of endocrine and metabolic indices between probands and affected sisters with fewer or no symptoms is in contrast to the observations in subjects with asymptomatic polycystic ovaries in the general population. The prevalence of polycystic ovaries (i.e. presence of the typical ovarian morphology on ultrasound) in the general population is around 20% [as reported by ourselves and others (18, 27, 28)], and as a group, these women have some of the biochemical markers of PCOS. However, there is an important difference between the finding of polycystic ovaries (regardless of symptoms) in the general population (which will very likely include spurious cases) and the occurrence of polycystic ovaries within families who have been identified because of a patient presenting to our clinics with symptomatic PCOS. Thus, in women with PCOS in the general population, androgen and LH levels are minimally raised but largely within the normal range (18), whereas the striking feature of this paper is that affected sisters, i.e. those identified by ovarian morphology, have endocrine and metabolic abnormalities that are very similar to those of the proband, irrespective of symptoms. It is axiomatic that using polycystic ovarian morphology as a marker of heritable biochemical traits is appropriate only within families that have been defined by the proband with clinical and biochemical features of polycystic ovary syndrome.

Although the finding of elevated concentrations of androgens and metabolic abnormalities in sister pairs is in agreement with previous studies of familial PCOS, our study differs from those of Legro et al. (7) in that definition of probands and ascertainment of affected status were based primarily on polycystic ovarian morphology, as identified by pelvic ultrasonography, rather than on serum androgen concentrations. Nevertheless, that study, like ours, showed that there was no significant difference in serum androgen concentrations between affected sisters who had oligo- or amenorrhea and those with hyperandrogenism and regular cycles. This emphasizes the similarity in endocrine indices between affected sister pairs despite differences in clinical presentation. The key finding in this study was that the presence of polycystic ovaries is a marker of the characteristic endocrine and metabolic abnormalities of PCOS, even though the spectrum of clinical symptoms and signs in affected sisters differed significantly from that observed in probands. This finding supports the view that an ovarian abnormality is central to the etiology of this disorder (11). The basis of the ovarian abnormality remains unclear, and it remains possible that exposure to excess androgen plays a part in the characteristic morphological features. The finding of substantial heritabilities between probands and affected sisters but low heritabilities when estimated from discordant (affected and unaffected) sister pairs for most of these traits supports the hypothesis that these traits are influenced strongly by genetic, physiological, and environmental factors that are shared between sisters affected with PCOS but not shared between affected and unaffected sisters.

	Acknowledgments

 
We are very grateful to Carole Robertson and Karen Rush for their invaluable help in recruitment of patients and their sisters for this study.

	Footnotes

 
This work was supported by a Program Grant (S.F. & M.I.M.) from the Medical Research Council, UK (G9700020).

Disclosure statement: None of the authors has any potential conflicts of interests to declare.

First Published Online June 17, 2008

Abbreviations: BMI, Body mass index; FAI, free androgen index; HOMA-S, homeostatic model assessment for insulin sensitivity; PCOS, polycystic ovary syndrome; WHR, waist to hip ratio.

Received February 15, 2008.

Accepted June 6, 2008.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Franks, S. Articles by McCarthy, M. I. Search for Related Content PubMed PubMed Citation Articles by Franks, S. Articles by McCarthy, M. I. Related Collections Female Endocrinology