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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. 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.
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