Human Reproduction Vol.17, No.3 pp.

771–776, 2002

Polycystic ovaries in childhood: a common finding in

daughters of PCOS patients. A pilot study

Cesare Battaglia1,5, Giorgia Regnani3, Fulvia Mancini1, Lorenzo Iughetti3, Carlo Flamigni2
and Stefano Venturoli1
1ReproductiveMedicine Unit, 2Department of Obstetrics and Gynecology, University of Bologna and 3Departments of Obstetrics and
Gynecology and 3Pediatrics, University of Modena, Italy
5To whom correspondence should be addressed at: Reproductive Medicine Unit, University of Bologna, Via Massarenti, 13 40138
Bologna, Italy. E-mail: battaglia@med.unibo.it

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a controversial endocrine pathology and, recently, it has
been suggested that the condition is hereditary. The aim of this study was to prospectively determine in daughters
of patients with PCOS, by ultrasonographic (US) and colour Doppler analyses, the incidence of polycystic ovaries
and search any correlation with specific hormonal parameters. METHODS: Fifteen prepubertal offspring (Group I)
of patients with PCOS and 10 normal control prepubertal girls (Group II) were submitted to clinical, auxological,
and basal hormonal assay. In addition all patients were submitted to US and colour Doppler ovarian and uterine
evaluation. RESULTS: Among Group I girls the prevalence of polycystic ovaries was 93%, whereas no subjects
among Group II had polycystic ovaries. The ovarian volume (2.76 ⍨ 1.21 ml versus 0.87 ⍨ 0.46 ml; P < 0.001)
and the number of small sized follicles (5.36 ⍨ 2.2 versus 0.75 ⍨ 0.92; P < 0.001) were significantly higher in
Group I than Group II patients. In addition, a normal stromal score and an absent stromal vascularization was
observed in the control group. The hormone levels did not differ between the two groups. CONCLUSION: In
conclusion we speculate that polycystic ovaries in childhood may be considered a sign of genetic predisposition to
PCOS and that environmental factors may express the adult clinical and hormonal presentation of the syndrome.

Key words: childhood/Doppler/echography/heredity/PCOS

Introduction segregation analyses have found an incidence of affected

Polycystic ovarian syndrome (PCOS) is one of the most
widely studied and controversial areas in gynaecological
endocrinology. Minimal signs of hyperandrogenism in lean,
normally menstruating women, and obesity, severe hirsutism
and oligo- or amenorrhoea (as originally described by Stein
and Leventhal) (Stein and Leventhal, 1935) represent opposite
poles of the clinical spectrum in this condition. The hetero-
geneity of clinical and endocrine features remains a confound-
ing factor in the investigation of PCOS patients (Franks, 1989;
Insler et al., 1993; Homburg, 1996). Despite the vast amount
of clinical, laboratory and experimental data that have been
accumulated, the aetio-pathogenesis of PCOS remains a subject
of speculation.
Recently, it has been suggested that the condition is
hereditary and that women with PCOS have additional meta-
bolic disturbances, such as hyperinsulinaemia, increased
insulin resistance, hypertriglyceridaemia and decreased high
density lipoprotein cholesterolaemia (O’Meara et al., 1993;
Morales et al., 1996; Robinson et al., 1996; Rosenfield, 1996;
Dunaif, 1997). Although some familial studies on PCOS have
indicated both X-linked and autosomal dominance, other
© European Society of Human Reproduction and Embryology
relatives exceeding autosomal dominance (Hague et al., 1990;
Legro, 1995; Govind et al., 1999). The registered differences
in trying to determine the familial contribution are, probably,
correlated with the heterogeneity of the syndrome and with
the diagnostic criteria used to identify probands with PCOS,
as well as to characterize other affected family members.
The most widely accepted definition of PCOS results from
the National Institutes of Health–National Institutes of Child
Health and Human development (NIH–NICHD) conference
on PCOS: hyperandrogenism, menstrual disturbances (oligo-
amenorrhoea) and exclusion of other known disorders such
as congenital adrenal hyperplasia, hyperprolactinaemia, or
Cushing’s syndrome (Dunaif et al., 1992). However, the
ultrasonographic (US) identification of polycystic ovaries
(PCO), has called into question the validity of the above
definition.
Assessment of ovarian morphology by means of ultrasound
is currently employed as a substitute for histological examina-
tion in the diagnosis of polycystic ovaries. The US criteria for
diagnosis of PCO has been established: enlarged ovary with
multiple small follicles scattered around an echogenic stroma.
However, the number of small follicles necessary to establish
771
C.Battaglia et al.
the diagnosis of PCO has been reported to vary between
‘above five’ (Yeh et al., 1987), ‘more than 10’ (Adams et al.,
1985) and ‘at least 15’ (Fox et al., 1991). Yoshino and co-
workers (1992) showed that the number of microcysts in PCO
is correlated with androstenedione, which in turn is correlated
with LH and LH/FSH ratio. In addition, we recently demon-
strated that as the number of ovarian microcysts increases and
ovarian volume enlarges, endocrine and clinical abnormalities
become more remarkable (Battaglia et al., 1999).
Colour Doppler facilitates the detection of small vessels in
the utero-ovarian circulation and the measurement of
impedance to flow in this vascular tree. A few years ago we
showed (Battaglia et al., 1995), and it was successively
confirmed (Zaidi, 1995a; Aleem and Predanic, 1996) that, in
patients with PCOS, significant and typical vascular changes
occur within the intraovarian vessels and that colour Doppler
analysis has a high diagnostic value for PCOS.
We serendipitously and retrospectively observed (un-
published data) that girls with premature pubarche have, in
about 60% of the cases, mothers with PCOS and/or fathers
with premature baldness (significant fronto-parietal hair loss
before the age of 30 years). The aim of the present study was
to prospectively determine in daughters of PCOS patients, by
US and colour Doppler analyses, the incidence of polycystic
ovaries and search for any correlation with specific hormonal
parameters.
Materials and methods
Study population
Nineteen Caucasian women with PCOS who previously attended the
Gynaecological Endocrinology or Infertility Clinic and that delivered
at term females of normal weight were asked to authorize us to study
their daughters. The study protocol was in accordance with the
Helsinki II declaration and was approved by the Hospital Research
Review Committee. Girls participated in the study after informed
consent from parents and assent from minors was obtained.
Fifteen women and their daughters agreed to participate in the
study. In the adult patients PCOS had been previously diagnosed on
the basis of the following criteria: hirsutism, menstrual disturbances
(oligo- or amenorrhoea), infertility, increased plasma circulating
androgens, LH/FSH ratio of ⬎2.5 and typical US ovarian findings
(⬎10 small sized 2–10 mm subcapsular follicles, ovarian volume
⬎8 ml, and increased ovarian stroma echogenicity) (Battaglia et al.,
1998). Girls (Group I; n ⫽ 15) were referred to the Paediatric
Endocrine Clinic for history, physical, auxological and hormonal
evaluation.
The pubertal development was staged by a single examiner (L.I.)
according to the classification of Tanner (Tanner, 1962; Marshall
and Tanner, 1969). Staging of the breast was as follows: stage I,
preadolescent; stage II, elevation of breast and papilla as a small
mound, enlargement of areola diameter; stage III, further enlargement
of breast and areola, with no separations of contours; stage IV,
projection of areola and papilla to form a secondary mound above
the level of the breast; stage V, projection of mature papilla, areola
part of general breast contour. Staging for pubic hair was as follows:
stage I, preadolescent; stage II, sparse, slightly pigmented, straight;
stage III, darker, coarser, beginning to curl, increased amount; stage
772
IV, adult in type, but less area covered; stage V, adult in quantity and
type, distributed as an inverse triangle, spread to medial surface of
thighs. In the presence of pubic hair, a breast stage II development
was taken as a definitive sign of gonadal puberty.
Standing height was measured using a Harpeden stadiometer
(Holtain Ltd., Crymych, UK) to the nearest 0.1 cm; weight was
measured on a digital scale with a precision of 0.1 kg (SECA 707;
HH, Modena, Italy). The mean body mass index (BMI; weight in
kg/height in m2) was calculated. Skeletal maturation and hirsutism
were staged according to established criteria (Greulich and Pyle,
1959; Ferriman-Gallwey, 1971) respectively.
Girls were further submitted to basal hormonal assay, US and
colour Doppler ovarian and uterine evaluation.
Ten healthy girls (Group II), referred to the Paediatric Endocrine
Clinic for Auxological evaluation and found to be normal on clinical
examination and anthropometric assessment, served as control. The
control group was selected among prepubertal girls whose parents
presented with no PCOS or premature male baldness. Similarly to
Group I, healthy girls were submitted to basal hormonal assay, US
and colour Doppler ovarian and uterine evaluation.
None of the patients had received hormonal therapy before the study.
Ultrasound and Doppler examination
Uterine and ovarian US examinations were performed with the use
of a 3.5 MHz. convex transducer (AU4 Idea; ESAOTE, Milan, Italy).
The ultrasound scans were performed transabdominally when the
participants had a full bladder, obtained by voluntary urine retention
and oral administration of fluids. Uterine and ovarian volume,
endometrial thickness, number, diameter and distribution of the
follicles were recorded. Volumes were calculated by measuring length,
width and depth assuming the forms to be ellipsoid, using the formula
based on a prolate ellipsoid: V ⫽ π/6⫻D1⫻D2⫻D3, where D1, D2,
and D3 are the maximal longitudinal, antero-posterior and transverse
diameters. The maximum diameter of each follicle was reported.
Echogenicity of ovarian stroma (stromal score ⫽ SS) was subjectively
scored as 0 (normal), 1 (moderately increased), or 2 (markedly
increased) (Pache et al., 1992, 1993). No significant differences
between left and right ovaries were observed, and therefore, the
average value of both ovaries was used for statistical analysis.
Midline endometrial echo was checked and endometrial thickness
was measured as the distance between the two internal sides of the
myometrium.
Doppler flow measurements of the uterine and intraovarian vessels
were performed transabdominally with a 3.5 MHz colour Doppler
system (AU4 Idea colour Doppler). All the patients were in recumbent
position and were evaluated between 08.00 and 11.00 h to exclude
the effects of circadian rhythmicity on utero-ovarian blood flow (Zaidi
et al., 1995b). Furthermore, they rested in a waiting room for at least
15 min before being scanned in order to minimize external effects
on pelvic blood flow (Battaglia et al., 1994). A 50 Hz filter was used
to eliminate low-frequency signals originating from vessel wall
movements. Colour signals were sought in the ovarian stroma at the
maximum distance from the surface of the ovary. The ovarian stroma
was considered to be ‘avascular’ if no blood vessels were demonstrated
by colour Doppler imaging. When several blood vessels were detected
inside the ovarian stroma, only the one with the lowest downstream
impedance was selected for Doppler measurements. Colour flow
images of the ascending branches of the uterine arteries were sampled
laterally to the cervix in a longitudinal plane. The angle of insonation
was always adjusted to obtain maximum colour intensity. When good
signals were obtained, blood flow velocity waveforms were recorded
by placing the sample volume across the vessel and activating the
pulsed Doppler mode. The Pulsatility Index (PI), defined as the
 PCO in childhood

difference between the peak systolic and end-diastolic flow divided

by the mean maximum flow velocity, was calculated for the ovarian Table I. Auxological data in PCOS offspring (Group I; n ⫽ 15) and
stromal and uterine arteries. For each examination, the mean value of controls (Group II; n ⫽ 10)
three consecutive waveforms was obtained. No significant differences
Group I Group II Significance
between the PIs of the left and right uterine arteries were observed,
and therefore, the average value of both arteries was used. Similarly,
Chronological age (years) 7.6 ⫾ 0.6 6.9 ⫾ 0.6
the lowest PIs of the stromal arteries were not significantly different Bone age (years) 8.9 ⫾ 1.2 6.8 ⫾ 06 0.001
between the left and right ovaries and the mean value was utilised. Height (cm) 128.3 ⫾ 3.3 118.9 ⫾ 1.6 0.021
The correlation between PI and heart rate was not tested (Battaglia BMI (kg/m2) 17.7 ⫾ 2.5 17.1 ⫾ 1.6
et al., 1999). Ultrasound and colour Doppler analyses were performed
by single examiner (C.B.). The hormonal status of the scanned BMI ⫽ body mass index.
patients was unknown. An indication of within-patients precision of
the Doppler procedures was obtained by analysing the flow velocity
waveforms recorded on three occasions from uterine and intra-
ovarian arteries at 1 min intervals. An analysis of variance of the Table II. Hormonal data in PCOS offspring (Group I; n ⫽ 15) and controls
(Group II; n ⫽ 10)a
results from 10 patients gave a mean coefficient of variation of 5.8%
for uterine and 6.3% for intraovarian arteries and showed no significant
Group I Group II Normal rangeb
differences between the replicate analysis.
LH (mUI/ml) 0.15 ⫾ 0.18 0.12 ⫾ 0.08 ⬍1.5
Hormonal assay FSH (mUI/ml) 1.07 ⫾ 0.5 0.55 ⫾ 0.69 ⬍1.5
E2 (pmol/l) 43 ⫾ 7 45 ⫾ 10 ⬍50
Peripheral blood was obtained from all patients between 08.00 T (nmol/l) 39 ⫾ 19 50 ⫾ 23 0.3–1.0
and 11.00, after an overnight fast, on the same day that US and A (nmol/l) 2.0 ⫾ 0.3 1.89 ⫾ 0.5 1.2–3.0
Doppler examinations took place, and different hormonal parameters 17-OH-Pg (nmol/l) 3.0 ⫾ 0.8 2.8 ⫾ 1.3 0.75–4.5
were analysed. Plasma concentrations of LH, FSH, estradiol (E2), DHEAS (µmol/l) 1.73 ⫾ 1.3 1.41 ⫾ 0.51 0.8–3.25
and testosterone were assayed as previously described (Battaglia aNo significant differences among groups were observed.
et al., 1999). Dehydroepiandrosterone sulphate (DHEAS), and 17- bThe normal range is derived from 50 prepubertal girls with no evidence of
hydroxy progesterone (17-OH-Pg) were determined by RIA using hormonal pathologies.
the Coat-A-Count kit (DPC; Los Angeles, USA). Androstenedione
was measured by RIA with the Quantitative Measurement of
Androstenedione in Serum and Plasma kit (DSL Inc.; Webster, USA).
syndrome, hyperprolactinaemia, hypo-hyperthyroidism, and
Furthermore, to exclude other endocrinopathies, thyroid hormones,
sex steroid-secreting tumours. None of the studied girls had
prolactin, and adrenocorticotrophic hormone (ACTH) were assayed.
To exclude a pubertal activation a GnRH stimulation test developed gonadal puberty, and, according to the Tanner scale,
was performed in those patients who showed a baseline LH value all the girls presented at breast stage I.
⬎0.3 IU/l. The GnRH stimulation test was performed using a standard Among girls with PCOS affected mothers, the prevalence
dose of 100 µg GnRH administered as an i.v. bolus. Serum LH and of US PCO-like ovaries (⬎5 small 2–10 mm in maximum
FSH concentrations were measured at 0, ⫹30, ⫹60, and ⫹90 min. diameter subcortical follicles, increased ovarian volume and
As criteria for defining a pubertal GnRH test a peak LH level increased ovarian stroma echogenicity) was of 14/15 (93%).
⬎15 IU/l and a LH/FSH ratio ⬎0.66 was used. All hormone analyses In five cases (33%) a paternal premature baldness was also
were performed in duplicate. present. None of the control group presented polycystic ovaries.
Results of hormonal values were converted to SI units using The chronological age was similar in Group I (7.6 ⫾ 0.6
the following conversion factors: LH (IU/l) ⫽ mIU/ml⫻1.0; FSH years) and Group II (6.9 ⫾ 0.6 years) patients. However,
(IU/l) ⫽ mIU/ml⫻1.0; E2 (pmol/l) ⫽ pg/ml⫻3.761; testosterone the bone age (8.9 ⫾ 1.2 versus 6.8 ⫾ 0.8 years; P ⫽ 0.001),
(nmol/l) ⫽ ng/ml⫻3.467; androstenedione (nmol/l) ⫽ ng/dl⫻ and the basal height (128.3 ⫾ 3.3 versus 118.9 ⫾ 1.6 cm;
0.0349; 17-OH-Pg (nmol/l) ⫽ ng/dl⫻0.03026; DHEAS (µmol/l) ⫽ P ⫽ 0.021) was higher in Group I girls. The BMI was below
µg/ml⫻2.714.
the 75th centile of reference data for obesity (Must et al.,
1991) and no significant differences were observed among the
Statistical analysis groups in this respect (Table I).
A statistical analysis (SPSS software; SPSS Inc., Illinois, USA) was None of the subjects studied was hirsute (Ferriman–Gallwey
performed using the Mann–Witney test and one-way analysis of score ⬎8). However, in daughters of PCOS patients, 4/15 girls
variance. The relationship between the parameters analysed was (26%) presented pubic hair limited to labia majora and in two
assessed using the stepwise linear regression method. A probability
of them axillary hair was associated. In addition, in almost
of ⬍ 0.05 was considered as statistically significant. Data are presented
half (7/15) of Group I girls, a slight increased hair distribution
as mean ⫾ standard deviation, unless otherwise indicated.
on the distal part of both arms and legs was observed.
The plasma levels of FSH, LH, E2, androstenedione,
testosterone, 17-OH-Pg, DHEAS were in the normal range
Results and did not differ among the groups (Table II). None of the
On the basis of history, physical examination, basal ultrasono- girls with a baseline LH value ⬎0.3 IU/l showed a pubertal
graphy and laboratory data the following conditions were response to the GnRH test (Table III).
excluded in all the participants: chronic diseases, Cushing’s The US assessments allowed us to evaluate the uterine size
773
C.Battaglia et al.

Discussion
Table III. GnRH test in those PCOS offspring (Group I; n ⫽ 3) and
controls (Group II; n ⫽ 4) who presented a basal LH value ⬎0.3 IU/l A small number of clinical studies on the PCOS familial
clustering have been performed over the last two decades.
Group I Group II Significance These segregation analyses of PCOS, focused on probands
and their relatives, showed a high incidence of affected relatives
LH peak (mUI/ml) 2.5 ⫾ 1.7 2.3 ⫾ 2.2 NS suggesting a genetic component to its aetiology (Cooper et al.,
FSH peak (mUI/ml) 7.7 ⫾ 2.3 8.2 ⫾ 6.5 NS
LH/FSH 0.37 ⫾ 0.15 0.31 ⫾ 0.26 NS 1968; Legro et al., 1995).
In the present study a strong association between maternal
NS⫽ not significant. PCOS and US polycystic ovaries in prepubertal offspring
has been evidenced supporting the hypothesis of a genetic
transmission of the syndrome.
Assessment of ovarian morphology by means of ultrasound is
Table IV. Main US and colour Doppler data in PCOS offspring (Group I; currently employed as a substitute for histological examination
n ⫽ 15) and controls (Group II; n ⫽ 10) in the diagnosis of PCO. It has been shown that anatomical
structure of the pelvic organs could not be adequately assessed
Group I Group II Significance
with a transabdominal approach in as many as 42% of cases
Uterine volume (ml) 3.65 ⫾ 1.81 1.73 ⫾ 1.1 0.016
(i.e. obesity, limited resolution of low-frequency transducers,
Ovarian volume (ml) 2.76 ⫾ 1.21 0.87 ⫾ 0.46 ⬍0.001 troublesome full bladder technique and dilated bowel loops)
Subcapsular follicles (n) 6.36 ⫾ 2.2 0.75 ⫾ 0.92 ⬍0.001 (Hull, 1989; Pache et al., 1992) and that transvaginal US
Stromal score (%)
0 6 100
appears to provide a more accurate ovarian picture (Takahashi
1 20 – NC et al., 1993). Although we did not perform the transvaginal
2 73 – procedure in our girls, owing to their ages and virginal status,
Uterine artery (PI) 3.16 ⫾ 0.74 4.23 ⫾ 1.01 0.031
Ovarian stromal artery (PI) 1.62 ⫾ 0.33 – NC we visualised the uterine structure in 100%, both ovaries in
Visualization (%) 93 – NC 92% and at least one ovary in 100% of the cases. From this
we derived that, by using the transabdominal approach, the
NC⫽ not calculated. percentage of visualization of prepubertal pelvic organs is
basically dependent on the operator’s skill and the quality of
the US machine.
and shape in 100% of the cases. The uterine volume was In daughters of PCOS probands, the US polycystic ovary
significantly higher in PCO-like than control patients (Table prevalence was of 93% and evidently exceeded either the 6%
IV). The endometrial echo was never present. (Bridges et al., 1993) in 6 year old children found in 6 years
In 23 (92%) out of 25 participants, both ovaries were and the 22–25% found in healthy adult women (Polson et al.,
visualized. The two cases in whom only one ovary was 1988). In the present study we observed that patients of the
visualized were in the control group. In group II, the ovarian control group presented a homogeneous echo-structure of the
volume (0.87 ⫾ 0.46 ml) was in the reference range of ovaries, an ovarian volume in the normal range of the prepuber-
prepubertal stage (Bridges et al., 1993; Buzi et al., 1998), tal stage (Bridges et al., 1993; Buzi et al., 1998) and no
whereas in patients with PCO-like ovaries the volume was stromal vascularization. On the other hand, girls with polycystic
significantly higher (2.76 ⫾ 1.21 ml; P ⬍ 0.001) and was appearance of the ovaries were characterized by increased
similar to those of patients at Tanner stage B2. The number ovarian volumes (similar to those of patients at Tanner stage
of small sized follicles was statistically different among Group I B2) (Bridges et al., 1993; Buzi et al., 1998), increased
(6.36 ⫾ 2.2) and controls (0.75 ⫾ 0.92; P ⬍ 0.001). The echogenic stroma, and a high number of small sized subcortical
ovarian stroma was scored as normal (SS ⫽ 0) in 100% of follicles. Furthermore, specific colour Doppler changes in
controls. In the PCO-like patients, the stromal score was ovarian vascularization (high percentage of intraovarian vessel
normal in 1/15 (6%), moderately increased in 3/15 (20%) and visualization and low PIs values) occurred at the level of the
markedly increased in 11/15 (73%) of the cases (Table III). intraovarian arteries.
On Doppler analysis, elevated resistances within the uterine The above data were associated with circulating hormone
arteries were observed in all patients and the values were levels in the normal range of prepubertal girls, an advanced
higher in Group II (PI ⫽ 4.23 ⫾ 1.01) than in Group I bone age and a slightly increased hair distribution.
(3.16 ⫾ 0.74; P ⫽ 0.031). In the control group we failed, by We previously reported that the typical vascular modification
colour flow mapping, to identify any ovarian stromal artery, occurs in adult PCOS, that colour Doppler analysis has a high
whereas in Group I, the intraovarian arteries were identified, diagnostic value and that elevated plasma levels may be
at least in one ovary, in 93% of the cases and a low responsible for increased stromal vascularization (Battaglia
downstream impedance to flow (PI⫽ 1.62 ⫾ 0.33) was shown et al., 1995). Our data, with the gonadotrophins in the
(Table III). prepubertal range, seem to not confirm, in childhood, the direct
In the whole studied population, bone age correlated with and prominent role of high LH plasma levels in the determinism
ovarian (r ⫽ 0.447; P ⫽ 0.048), and uterine volume (r ⫽ of those structural, vascular and hormonal modifications
0.543; P ⫽ 0.013). expressed in adult PCOS. In prepubertal girls alternative
774

mechanisms must be sought to explain hyperandrogenism,
morpho-structural ovarian modifications and increased ovarian
vascularization.
In the present study, although none of the studied girls
showed any evidence of hirsutism (Ferriman–Gallwey score
⬎8), the offspring of patients with PCOS demonstrated a
relatively high incidence of premature pubarche (26%) with
pubic hair limited to labia majora and, in almost half
(7/15), a slight increased hair distribution on the distal part of
both arms and legs. The different hair distribution among
PCO-like girls may be related to specific congenital sensi-
tivity of the pilosebaceous unit to circulating androgens and/or
to an enhanced peripheral conversion of testosterone to
dihydrotestosterone by 5α-reductase (Ehrmann and Rosenfield,
1990).
The supposed increased sensitivity of target tissues to low
levels of circulating androgens allows us to speculate that, in
the absence of increased circulating estrogen concentrations,
the growth spurt and skeletal maturation may be positively
influenced, as demonstrated in PCOS offspring, by an increased
height and a more advanced bone age than in matched controls
(Ibanez et al., 1992).
On the basis of the data presented, we postulated that
PCO in childhood may be considered a sign of a genetic
predisposition to PCOS and that enviromental factors (mainly
nutritional) may express the adult clinical and biochemical
presentation of the syndrome. It is our opinion that a therapeutic
intervention (i.e. calorie restriction) in childhood may avoid
or consistently limit the phenotypical expression of PCOS. In
any case, in agreement with a previously published study
(Homburg et al., 1996), we think that an ‘...early therapeutic
intervention will not only temporarily alleviate the symptoms
but will place the progress of the syndrome on hold. This
would appear to be beneficial for future fertility prospects and
possible delay or prevention of long-term sequelae...’.
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Submitted on March 21, 2001; resubmitted on August 3, 2001; accepted on
November 6, 2001