doi:10.1093/humrep/den299
Human Reproduction Vol.23, No.12 pp. 2775–2781, 2008
Advance Access publication on August 10, 2008
Effect of rising hCG levels on the human corpus luteum
during early pregnancy
Ilkka Y. Järvelä1,3, Aimo Ruokonen2 and Aydin Tekay1
1
2
3
Department of Obstetrics and Gynecology, Oulu University Hospital, PO Box 5000, FIN-90014 Oulu, Finland;
Department of Clinical Chemistry, Oulu University Hospital, FIN-90014 Oulu, Finland
Correspondence address. E-mail: [email protected]
BACKGROUND: During early pregnancy, the most important task of the corpus luteum (CL) is to produce sufficient
progesterone until the luteoplacental shift occurs. Progesterone production is closely related to the extensive vasculature surrounding and supplying the CL. The synthesis of both progesterone and factors controlling the vasculature in
the CL is regulated by hCG, which is released initially at rising levels from the placenta. The primary aim of this
research was to evaluate changes in the CL vasculature during early pregnancy. METHODS: Twenty naturally conceived pregnancies were examined weekly from weeks 5 to 11. At each visit, blood samples were obtained to determine
the concentrations of hCG, progesterone and 17-OH progesterone (17-OHP). The vasculature in the ovaries was
assessed using three-dimensional power Doppler ultrasonography. RESULTS: The vascular supply in the ovary containing the CL was greatest at week 5, and thereafter, declined continuously until week 11. The decrease in the vasculature correlated with the decrease in 17-OHP. Mean hCG levels reached a maximum at week 8, progesterone levels
reached the nadir at week 7 and increased after that. CONCLUSIONS: Vasculature in the CL appears to be created
already by the fifth week of pregnancy and it does not enlarge despite rising hCG levels. The activity of the CL during
pregnancy may be measured non-invasively by assessing its vasculature with three-dimensional ultrasonography.
Keywords: estradiol; gestational sac; luteoplacental shift; pregnancy-associated plasma protein-A; placenta
Introduction
Continuing rescue of the corpus luteum (CL) by hCG is essential, otherwise declining progesterone secretion is detrimental
to maintaining pregnancy (Csapo et al., 1973). The CL is the
primary organ producing progesterone up to the seventh to
eighth week of pregnancy, after which the placenta is
capable of producing enough progesterone (Csapo et al.,
1973; Csapo and Pulkkinen, 1978). This period during which
the placenta is assuming the main responsibility of progesterone production from the CL is called the luteoplacental shift.
The capacity of the CL to produce progesterone is closely
related to the extent of its vascular network (Niswender
et al., 1976; Miyazaki et al., 1998; Niswender et al., 2000;
Järvelä et al., 2007). The amount of vasculature accounts for
more than 20% of the total volume of the CL, exceeding that
of any other tissue (Dharmarajan et al., 1985; Niswender
et al., 2000). The dense capillary network enables hormoneproducing cells to obtain oxygen, nutrients and hormone
precursors necessary to synthesize and release large amounts
of progesterone.
CL angiogenesis appears to be controlled by local secretion
of growth factors (Hazzard and Stouffer, 2000) such as the vascular endothelial growth factor (VEGF) (Sugino et al., 2000;
Wulff et al., 2001a,b). The expression and synthesis of these
factors is regulated by hCG (Fraser et al., 2005). Because
hCG concentrations increase up to 8 – 9 weeks of pregnancy
(Tulchinsky et al., 1972; Tulchinsky and Hobel, 1973), it
could be expected that the volume of the CL vasculature
increases as well, leading to rising systemic levels of progesterone. However, Tulchinsky et al. (1972) and Tulchinsky and
Hobel (1973) observed that progesterone levels remained
quite steady until the placental progesterone production
increased (Tulchinsky et al., 1972; Tulchinsky and Hobel,
1973).
Knowledge of the status of the CL vasculature in humans
during the first trimester of pregnancy is limited. Tissue
samples from women with ectopic pregnancies and from
women following treatment in vivo with increasing doses of
hCG to simulate early pregnancy has been collected and analysed (Rodger et al., 1997; Gaytan et al., 1999; Wulff et al.,
2001a,b). These methods excluded the possibility of following
up, longitudinally, a single CL and its vasculature in vivo,
especially during normal pregnancy. In addition, they did not
enable quantification of the volume of the vascular network.
Three-dimensional power Doppler ultrasonography enables
detection of the total vasculature in a whole and strictly
# The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
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Järvelä et al.
restricted volume such as the ovary (Jokubkiene et al., 2006;
Järvelä et al., 2007; Jayaprakasan et al., 2007) by mapping
and quantifying the power Doppler signal in the entire region
of interest. The power Doppler signal detected represents
moving blood cells and the three-dimensional image created
resembles microangiography in an organ. The primary advantages of using three-dimensional power Doppler ultrasonography are that the method is non-invasive and safe, the
information obtained can be restricted to the organ of interest
and the development of ovarian volume and vasculature can
be tracked longitudinally. To date, three-dimensional power
Doppler ultrasonography has not been used in clinical studies
involving evaluation of CL function during pregnancy.
The aim of the study was to evaluate changes in the CL vasculature, and placental and CL hormone output during early
pregnancy.
Materials and Methods
Patients
Pregnant patients were recruited who had contacted the local health
care centre in the city of Oulu to organize their follow-up during the
pregnancy. Only patients with no known gynecological pathology
(e.g. endometriosis, fibroids, any operation to gynecological organs)
were included in the study. All the women had conceived naturally.
The aim was to recruit the patients as early as possible at the start of
the pregnancy. In addition, the patients were examined following each
completed week of pregnancy, from the 5th to the 11th week of pregnancy. At each visit, blood samples were collected for hormonal
assays and an ultrasound examination was performed.
The estimated delivery date (EDD) was assessed according to the
last menstrual bleeding and was ascertained at the last visit by measuring the crown-rump length (CRL). If the EDD, as assessed by the
CRL, differed more than +7 days from that calculated from the last
menstrual bleeding, the date was changed.
Informed written consent was obtained from each subject, and
the study was approved by the Ethics Committee of Oulu University
Hospital, Oulu, Finland.
Assays
Serum concentrations of testosterone, progesterone and hCG were
analysed using an automated chemiluminescence system (Advia
Centaur; Bayer Healthcare LCC, Diagnostic Division, Tarrytown,
NY, USA). Serum placental pregnancy-associated plasma protein-A
(PAPP-A) concentrations were determined by fluoroimmunoassay
(PerkinElmer, Turku, Finland). Radioimmuno assays were used for
17-OH progesterone (17-OHP), androstenedione (Diagnostic Products
Corp., Los Angeles, CA, USA) and estradiol (E2) (Orion Diagnostica, Oulunsalo, Finland), following instructions provided by the
manufacturers.
The intra-assay and inter-assay coefficients of variation were 5.0
and 5.4% for 17-OHP, 5.0 and 8.6% for androstenedione, 4.0 and
5.6% for testosterone, 5.7 and 6.4% for E2, 3.7 and 5.4% for progesterone, 2.0 and 3.5% for hCG and 3.5 and 4.9% for PAPP-A, respectively. External quality control of the hormone assays was organized
by national (Labquality Ltd, Helsinki, Finland) and international
(Bio-Rad Laboratories EQAS, Irvine, CA, USA) companies.
Ultrasonography
The patients were examined at each visit using three-dimensional
ultrasonography (Voluson Expert 730; Kretz, Zipf, Austria) equipped
2776
with a transvaginal probe. This technique enabled determination of the
state of the pregnancy. In addition, the ultrasound data of the uterus
and the ovaries were stored in three-dimensional volumes for
subsequent analysis.
The power Doppler ultrasound was used to locate the blood vessels
in the ovaries and to identify the ovary containing the CL. The power
Doppler mode was not applied at any time during the visit to investigate the pregnancy itself (the fetus or the trophoblastic tissue). Therefore, data concerning the fetus, gestational sac or the placenta does not
include any power Doppler information.
Volume acquisition and storage were described in detail elsewhere
(Järvelä et al., 2003a). Identical, pre-installed settings were used to
acquire the ultrasound and the power Doppler information. The
setting conditions for this study were as follows: frequency, mid;
dynamic set, 2; balance, G . 170; smooth, 5/5; ensemble, 16; line
density, 7; power Doppler map, 5; and the setting conditions for the
subpower Doppler mode were: gain, 25.6; quality, normal; wall
motion filter, low 1; and velocity range, 0.9 kHz.
Determination of ovarian volume and vascularization was performed using the built-in virtual organ, computer-aided analysis
Imaging Program (VOCAL, GE Healthcare, Zipf, Austria) for threedimensional power Doppler histogram analysis. The manual mode
of the VOCAL Contour Editor was used to cover the entire threedimensional volume of the ovary, with 308 rotation steps (Järvelä
et al., 2007). Hence, six contour planes were analysed for each
ovary to cover 1808. After obtaining the total ovarian volume, the
programme calculated the ratio of coloured voxels to all voxels; this
fraction of the total volume (%) was expressed as the vascularization
index (VI). Vascularized volume (ml) in the ovary was calculated by
multiplying the total ovarian volume by the VI.
Similarly, the three-dimensional ultrasound data of the uterus,
including the fetus, gestational sac and placenta, were analysed.
During the first weeks of pregnancy, the trophoblastic tissue surrounds
entirely the gestational sac, giving an almost uniform diameter. By the
end of first trimester, two-thirds of this primitive placenta disappear
(Jauniaux et al., 2006) and the trophoblastic tissue (placenta) polarizes
to a specific place inside the uterine cavity.
The volume of the gestational sac was first assessed by determining
the outlines of the gestational sac in six contour planes (308 rotation
steps) using the manual mode of the VOCAL Contour Editor. The
volume of the gestational sac constituted the entire exocoelomic
cavity including the amnionic cavity and secondary yolk sac. Similarly, the outlines of the trophoblastic tissue were determined in six
contour planes (308 rotation steps). The volume obtained included
not only the gestational sac but also all of the trophoplastic tissue
(i.e. placenta), and therefore, after subtracting the volume of the gestational sac from this latter volume, the actual volume of the placenta
was obtained.
Statistics
The Statistical Package for the Social Sciences (SPSS) for Windows
12.0.1 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
The general linear model for repeated measures was used to measure
significance within the study group. Departure from a normal distribution was assessed using the Kolmogorov–Smirnov test. To
compare serum hormone levels between different time points, the
paired samples t-test was used as a post hoc test for normally distributed variables, and the Wilcoxon test was used for variables with
skewed distribution. A value of P , 0.05 was considered statistically
significant. All values given are the mean + SE.
The reproducibility of volume and VI measurements using transvaginal three-dimensional power Doppler ultrasonography was assessed
by calculating the intraclass correlation coefficient and repeatability
Human corpus luteum and hCG during early pregnancy
coefficient (r) separately for dominant and non-dominant ovaries at
pregnancy week 9. To determine the intra-observer reproducibility,
one observer (I.Y.J) analysed the same volume twice, 2 years apart,
being unaware of the results of the first analysis when performing
the second one. The coefficients were assessed for volume, VI and
vascularity (¼volume VI/100). The statistical analysis for reproducibility has described earlier (Järvelä et al., 2003b).
Results
The results of the statistical analysis for reproducibility
(Table I) indicate good reproducibility of the technique and
are in line with those observed earlier (Jokubkiene et al.,
2006; Järvelä et al., 2007).
Altogether, 20 women with normal ongoing pregnancies
were recruited. Ten of the patients were examined at the fifth
week of pregnancy. At week 6, 15 women were examined; at
weeks 7 and 8, 19 women were examined; at weeks 9 and
10, 20 women were examined; and, at week 11, 19 women
were examined. The mean age of the patients was 25.4 + 1.0
years (range 19.0 –35.9). The mean number of pregnancies
was 1.8 + 0.3 (range 1 – 6) and the mean number of deliveries
was 0.6 + 0.2 (range 0 – 3). The mean BMI was 22.8 + 0.8
(range 18.4– 30.1).
Hormone levels
Mean hCG levels (Fig. 1) increased from 8825.6 + 2338.2 IU/ml
at week 5 to 118 254.8 + 9491.6 IU/ml at week 8 (P , 0.001);
thereafter, a non-significant decrease in the mean hCG levels
was observed. At the final check-up (11 weeks of pregnancy),
the mean hCG level (SE) was 96 786.2 (7933.2) IU/ml.
The increase in hCG levels before 8 weeks of pregnancy did not
correlate with the increase in placental volume during the same
period.
Mean PAPP-A levels (Fig. 1) exhibited a continuous
increase throughout the follow-up period. The lowest value
(5.2 + 1.0 mIU/l) was observed at week 5 and the greatest
value (1607.7 + 249.4 mIU/l) at week 11. The increases in
PAPP-A, and the placental volume between weeks 6 and 11
of pregnancy, correlated significantly (R ¼ 0.644, P , 0.05).
Concentrations of progesterone (Fig. 1) exhibited a slight,
but non-significant, decrease from weeks 5 to 7 of pregnancy.
The lowest level (65.6 + 6.0 nmol/l) during the follow-up
period was observed at week 7. Subsequently, progesterone
levels began to increase, reaching the maximum level
(112.6 + 7.4 nmol/l) at the end of the follow-up period at
week 11 (week 7 versus week 11, P , 0.001).
Concentrations of 17-OHP (Fig. 1) were at the greatest level
(21.3 + 2.4 nmol/l) initially at week 5 of pregnancy. A steady
decrease occurred in the concentrations during the follow-up
period and the nadir (10.1 + 0.5 nmol/l) was observed at
week 10 (week 5 versus week 10, P , 0.001). The decrease
in 17-OHP concentrations and dominant ovarian vascularization between weeks 6 and 11 of pregnancy correlated significantly (R ¼ 0.606, P , 0.05). No differences were observed
in androstenedione or testosterone levels during the study
period (data not presented).
Similar to PAPP-A, levels of E2 increased throughout the
follow-up period (data not shown). At 5 weeks of pregnancy,
the mean level was 1.1 + 0.1 and was significantly higher at
11 weeks, at 8.2 + 0.7 nmol/l (P , 0.001). The increase in
E2 levels between the 6th and 11th weeks of pregnancy did
not correlate with the corresponding increase in placental
volume.
Gestational sac and placental volume
The volume of the gestational sac increased steadily
from 0.4 + 0.1 ml at week 5 to 69.3 + 4.6 ml at week
11 (P , 0.001) (Fig. 2). Similarly, the placental volume
increased from 1.0 + 0.3 ml at week 5 to 59.6 + 6.3 ml at
week 11 (P , 0.001) (Fig. 2).
Ovarian volume and vascularization
Analysis of repeated measurements showed changes in the
dominant ovarian volume (Fig. 2) during the follow-up
period. At week 5, the volume was 13.5 + 2.3 ml and increased
to 15.5 + 1.7 ml at week 7 (P , 0.05). Thereafter, the volume
decreased, continuously, to 9.0 + 0.5 ml at week 11 (P , 0.01,
Table I. The descriptive statistics and intraobserver repeatability for ovarian volume, vascularization index (VI) and vascularity measurements at pregnancy
week 9.
Dominant ovary
Volume (ml)
VI
Vascularity (ml)
Non-dominant ovary
Volume (ml)
VI
Vascularity (ml)
Measurement
Minimum
Maximum
Mean
SD
Intraclass correlation
coefficient (95% CI)
Repeatability
coefficient (95% CI)
1
2
1
2
1
2
1
2
1
2
1
2
4.38
4.10
12.01
10.49
0.74
0.87
2.02
2.06
0
0.15
0
0.00
25.23
24.13
31.62
37.30
5.52
5.31
6.91
6.54
6.50
5.51
0.41
0.36
11.84
11.50
21.50
21.12
2.45
2.39
4.37
4.09
2.63
2.64
0.13
0.12
4.56
4.49
5.01
6.32
1.04
1.04
1.47
1.39
2.19
1.75
0.14
0.11
0.99 (0.97– 1.00)
1.40 (0.97– 1.83)
0.85 (0.67– 0.94)
6.16 (4.26– 8.05)
0.94 (0.86– 0.98)
0.72 (0.50– 0.94)
0.94 (0.85– 0.98)
0.98 (0.45– 1.30)
0.89 (0.73– 0.96)
1.87 (1.25– 2.49)
0.88 (0.70– 0.95)
0.13 (0.0.8– 0.17)
95% CI, 95% confidence interval; vascularity ¼ volume VI/100.
After obtaining the total ovarian volume, the ratio of coloured voxels to all voxels was calculated; this fraction of the total volume (%) was expressed as the
vascularization index (VI). Vascularity in the ovary was calculated by multiplying the total ovarian volume by the VI.
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Järvelä et al.
Figure 1: The behaviour of hCG, PAPP-A, progesterone and 17-OHP between pregnancy weeks 5 and 11. For details, see the Results section.
compared with week 7). At week 11, the volume was significantly lower than at week 5 (P , 0.01).
The data for VI and vascularized volume for both dominant
and non-dominant ovaries during the follow-up period are
presented in Table II. Vascularization in the dominant ovary
containing the CL (Fig. 2) showed significant changes. The
volume at week 11 was significantly lower than at week 6 or
7 (P , 0.05). The volume was at its highest, initially, at
week 5 (3.4 + 0.8 ml) and reached the nadir at week 11
(1.7 + 0.2 ml).
In the non-dominant ovary (Fig. 2, Table II), no changes either
in the total volume or in the vascularized volume were observed
during the follow-up period. The dominant ovary was larger and
more completely vascularized than the non-dominant ovary at
each measurement.
Discussion
In this study, CL function in women who conceived naturally
was followed, longitudinally, from weeks 5 to 11 of pregnancy.
According to these results, despite rising hCG levels, CL
activity declined after week 5 of pregnancy, confirming that
the hCG-induced CL rescue is only temporary. Although CL
activity decreased continuously during the follow-up period,
at 11 weeks of pregnancy the CL was clearly still functioning,
although its activity had diminished considerably.
The most important task of the CL is to produce sufficient
progesterone up to the luteoplacental shift (Csapo et al., 1973).
The vasculature in the CL is extensive and closely related to
2778
progesterone secretion (Niswender et al., 1976; Miyazaki
et al., 1998; Niswender et al., 2000; Järvelä et al., 2007). CL
activity was assessed in this research using two different
methods. First, systemic hormone levels were assessed, which
represented hormone secretion, not only from the CL but also
from other endocrine organs, the most important of which
is the placenta. Second, CL vascularity was assessed using
three-dimensional power Doppler ultrasonographic equipment,
which enabled quantification of the total volume and the
vascularized volume of the dominant ovary containing the CL
and to follow the pregnancies, longitudinally, throughout the
study period. Because the patients were not recruited until
their pregnancy test was positive, the period from ovulation to
testing (i.e. pregnancy weeks 2–4) was excluded from the
follow-up period.
A decline in progesterone levels was observed from pregnancy week 5 onwards and the nadir was achieved at pregnancy
week 7, after which the levels increased. Secretion of 17-OHP,
which is believed to be produced only in the CL during
early pregnancy (Tulchinsky and Simmer, 1972), declined
continuously from the fifth week of pregnancy onwards.
These findings are consistent with those from earlier studies
(Tulchinsky and Simmer, 1972, Tulchinsky et al., 1972,
Tulchinsky and Hobel, 1973). Changes in CL vascularity
were similar to 17-OHP in that both decreased steadily up to
the 11th week of pregnancy. The close connection between
CL hormone secretion and its vascularity was confirmed
by the determination that the decline in 17-OHP secretion
correlated with the decrease in CL vascularity.
Human corpus luteum and hCG during early pregnancy
Figure 2: The changes in the dominant and the non-dominant
ovarian, the gestational sac and the placental volumes between pregnancy weeks 5 and 11. For details, see the Results section.
Table II. VI and vascularity (ml) in the dominant and non-dominant ovary
from pregnancy week 5 to pregnancy week 11.
Pregnancy
week
5
6
7
8
9
10
11
Dominant ovary
Non-dominant ovary
VI (SE)
Vascularity
(SE)
VI
(SE)
Vascularity
(SE)
24.42 (1.88)
21.36 (1.13)
21.29 (1.54)
20.64 (1.48)
21.50 (1.12)
17.65 (1.64)
19.13 (2.26)
3.36 (0.83)
2.90 (0.30)
2.87 (0.37)
2.65 (0.31)
2.45 (0.23)
1.72 (0.16)
1.70 (0.21)
1.67 (0.57)
1.37 (0.28)
1.89 (0.41)
2.10 (0.36)
2.63 (0.53)
2.74 (0.60)
2.22 (0.40)
0.09 (0.04)
0.07 (0.01)
0.09 (0.02)
0.10 (0.02)
0.13 (0.03)
0.12 (0.03)
0.11 (0.02)
According to earlier studies, it is not clear whether the
hCG-induced rescue of the CL is accompanied by further angiogenesis and vessel stabilization (Fraser and Wulff, 2003). The
production of angiogenic factors such as VEGF in the CL
during pregnancy appears to be under the influence of hCG
(Sugino et al., 2000; Wulff et al., 2000; Wulff et al., 2001a,b;
Fraser and Wulff, 2003). Rodger et al. (1997) simulated early
pregnancy by administrating increasing hCG doses during the
luteal phase, and thereafter collecting CL samples for analysis.
Endothelial cell proliferation was assessed using quantitative
immunochemistry for CD34 and Ki-67. They observed unchanging levels of proliferation in the endothelial cells, suggesting
that vascularization of the CL was already established during
the luteal phase (Rodger et al., 1997). However, when luteal
cell hypertrophy after hCG treatment was taken into consideration, the hCG-induced rescue of the CL was found to be associated with increased angiogenic activity (Wulff et al., 2001a,b).
Previous studies were cross-sectional and the experimental
design used did not enable a longitudinal follow-up of patients.
According to the results of our study, serum hCG levels
rose from weeks 5 to 8 during pregnancy as observed earlier
(Tulchinsky et al., 1972, Tulchinsky and Hobel, 1973). The vascular network supplying the CL was formed already at week 5 of
the pregnancy, and thereafter gradually decreased, reaching the
nadir at the last follow-up visit, at pregnancy week 11. VEGF
response to hCG was not measured in this study because systemic
VEGF does not represent accurately local changes occurring in a
single CL (Järvelä et al., 2007). Despite not measuring angiogenic factors, the results of our research suggest that rising
hCG stimulation during early pregnancy is not accompanied by
further neoangiogenesis or increase in the vasculature in the
human CL.
The critical step in CL synthesis of progesterone is the
delivery of cholesterol to cytochrome P450scc, which is governed by the steroidogenic acute regulatory protein, StAR
(Devoto et al., 2002). According to Devoto et al. (2001),
StAR protein levels in the CL are highly correlated with
plasma progesterone levels (Devoto et al., 2001). During the
luteal phase, expression of the StAR protein is under the
control of LH and is greatest during the early and mid luteal
phases and declines significantly in the late luteal phase
(Devoto et al., 2002). Luteal rescue with hCG has been
found to be associated with continued expression of the
StAR protein (Duncan et al., 1999). The secretion pattern of
progesterone in the present study was in agreement with
earlier studies concerning early pregnancy (Tulchinsky et al.,
1972; Tulchinsky and Hobel, 1973). Despite the rising hCG
stimulus, progesterone levels decreased rather than increased
from the fifth week of pregnancy onwards, and the nadir was
achieved at the seventh week of pregnancy. Thereafter, the
luteoplacental shift probably occurred and progesterone
levels started to rise. This study did not allow assessment of
corpus luteal StAR expression in response to rising hCG stimulation, and therefore, it is not possible to conclude whether
changes in StAR protein levels were of any significance.
Taking into account, however, the close relationship between
the CL vasculature and the 17-OHP secretion observed here,
it is likely that the primary reason for the decline in CL
hormone secretion during the first weeks of pregnancy was
the vanishing blood supply to the CL.
The dominant ovary enlarged slightly from the fifth to the
seventh week of pregnancy whereas no change was observed in
the non-dominant ovary, suggesting that the variation in the
volume of the dominant ovary was due to changes in the CL.
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Järvelä et al.
Determination of the exact position in the CL at which the
increase in volume occurred was not possible. Because the CL
vasculature started to decrease after the fifth week of pregnancy,
the increase in volume of the endothelial cells and pericytes is
excluded. One option is that the increase in volume was due to
extravasation of blood and plasma into the cavity of the CL,
which earlier was the dominant follicle. Another option is the
enlargement of the hormonally active luteal cell volume.
However, because progesterone or 17-OHP secretion decreased
before the eighth week of pregnancy, the latter option is unlikely.
The blood supply of the non-dominant ovary remained
unchanged during the first weeks of pregnancy. The vasculature in the non-dominant ovary was minimal in comparison
with the dominant ovary, suggesting that the vascular
network in the dominant ovary was predominantly supplying
the CL, and therefore, closely related to CL activity. At 11
weeks of pregnancy, the dominant ovary was still larger than
the non-dominant ovary, indicating that functional activity
continued at some level.
We measured the volume of the gestational sac and trophoblastic tissue (i.e. placenta) and related this to hormone
secretion. As far as is known, the volume of the placenta has
not been measured as early during pregnancy as in this
research. The volume of the gestational sac and placenta
increased exponentially, the gestational sac becoming larger
than the placenta at 9 weeks of pregnancy, just after the luteoplacental shift. The volume measurements concerning the
gestational sac are in agreement with earlier studies using the
same methodology (Lee et al., 2006).
The increase in the placental volume was correlated with the
systemic levels of PAPP-A. PAPP-A primarily originates from
placental syncytiotrophoblasts (Bischof et al., 1981; Sinosich
et al., 1982) and has gained favour as a clinically useful firsttrimester screening marker of trisomy 21 (Niemimaa et al.,
2001). The PAPP-A levels in the current study were similar to
those in previous reports (Bischof et al., 1981; Sinosich et al.,
1982). Changes in mean hCG or E2 concentrations were not
associated with enlargement of the placenta. According to
current knowledge (Hay, 1988), hCG secretion is related directly
to the mass of hCG-producing trophoblastic tissue. The decline
in hCG levels after 8 weeks of pregnancy is explained by
the reduction in the mass of syncytiocytotrophoblast and trophoblast tissue and mirrors the morphologic change of the placenta
from an organ of invasion to an organ of transfer (Hay, 1988).
The vascular network of the CL appears to be formed by the
fifth week of pregnancy. As observed by the decrease in both vascular supply and 17-OHP secretion, CL activity declines despite
increasing stimulation by hCG. The reason for the inadequacy of
the CL to respond to increasing stimulation during early pregnancy remains to be assessed. Because vascularity in the dominant ovary appears to reflect CL activity, three-dimensional
power Doppler ultrasonography could be used as a non-invasive
tool for evaluating CL function during early pregnancy.
Funding
I.Y.J. was supported by a grant from The Finnish Medical
Foundation.
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Submitted on March 10, 2008; resubmitted on July 1, 2008; accepted on
July 10, 2008
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