Human Reproduction Update 2000, Vol. 6, No. 5 pp.

519529 European Society of Human Reproduction and Embrology

The regulation of the human corpus luteum

steroidogenesis: a hypothesis?

V.J.H.Oon and M.R.Johnson*

Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK

The corpus luteum (CL) is an important endocrine organ in the menstrual cycle and in pregnancy. The regulation of
its hormonal production has been extensively studied. The steroidogenic abilities of the CL can be rescued by human
chorionic gonadotrophin (HCG) but its role in the maintenance of CL function is not clear. We will discuss the
hypothesis that there are fetoplacental factors, other than HCG, that modulate CL steroidogenesis.

Key words: corpus luteum/fetoplacental factors/human chorionic gonadotrophins/pregnancy/steroidogenesis

TABLE OF CONTENTS
Introduction
Corpus luteum steroid production
Hormone changes of the luteal phase
LH/HCG CL receptors
Clinical studies
Ovulation stimulation studies
Conclusion
References
Introduction
The corpus luteum (CL) is the nal form of a developing follicle
and is the major endocrine component of the ovary. Of the 67 3
106 primordial follicles formed in utero, only ~350 will develop
into a CL, the remainder atrophy. CL produces a variety of
hormones such as oestradiol, progesterone, relaxin, inhibin A and
B. Other luteal products formed include cytokines and prosta-
glandins.
The CL is important in the preparation of the endometrium for
implantation and in the maintenance of pregnancy if conception
and implantation does occur. Its removal in early pregnancy
results in miscarriage. In a non-conceptive cycle, the maternal
hormonal signals, which support the continuing function of the
CL, cease, or the CL becomes insensitive to the signals, while
those required from the embryo fail to materialize, and luteolysis
and menstruation occur.
In successful pregnancies, the implanting embryo produces
human chorionic gonadotrophin (HCG) which has long been held
to ensure that the CL continues to produce progesterone in the late
luteal phase and early pregnancy. In turn, progesterone is
responsible for the maintenance of the decidua until the placental
steroid synthesis supersedes that of the CL. However there is now
evidence which suggests that HCG does not maintain the CL
function in early pregnancy. In this review, we will explore this
evidence and attempt to provide an alternative explanation for the
events of early pregnancy.
Corpus luteum steroid production
In natural pregnancy, progesterone concentrations rise initially
until 7 weeks gestation; they then remain at a plateau until 10
weeks gestation, from when the concentrations gradually increase
to term. Clearly, in early pregnancy, the circulating concentra-
tions of progesterone represent an integration of the CL and
placental production. However, 17-hydroxy progesterone is
produced predominantly by the CL and its circulating concentra-
tions peak at 6 weeks gestation and thereafter decline. From this,
we can infer that CL synthesis of progesterone peaks at 56 weeks
gestation and then declines. Csapo's seminal work showed that
luteectomy results in miscarriage if performed prior to 7 weeks
gestation (Csapo and Pulkkinen, 1978). This implies that after 7
weeks gestation, the placenta is capable of producing sufcient
progesterone to maintain decidual function and structural integrity
as well as myometrial quiescence. Thus, the presence of a
functioning CL is critical between 2 and 67 weeks gestation, the
exact upper limit varying from pregnancy to pregnancy,
depending upon placental steroidogenesis.
Hormone changes of the luteal phase
During the luteal phase of a non-conception cycle, the CL
function is maintained by LH. This has been conrmed by a series
of studies in primates and humans.
Primate data
The studies in primates used the administration of exogenous LH
or HCG, antibodies to LH, gonadotrophin-releasing hormone

*To whom correspondence should be addressed at: Department of Maternal Fetal Medicine, Division of Paediatrics, Obstetrics and Gynaecology,
Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Phone: +44 020 8846 7887; Fax:
+44 020 8846 7796; E-mail: mark.johnson@ic.ac.uk
520 V.J.H.Oon and M.R.Johnson
(GnRH) antagonists, and chronic pulsatile administration of
GnRH to anovulatory monkeys. Hisaw rst demonstrated that
HCG was able to extend the luteal function in the Macaca mulatta
in 1944 (Hisaw, 1944). MacDonald and Greep in 1972 described
the effect of a single injection of LH, FSH and prolactin in the
rhesus monkey on day 6 and day 21 of the menstrual cycle
(MacDonald and Greep, 1972). They found that there was no
response to LH and FSH administration on day 6 of the cycle, but
that serum progesterone concentrations were elevated by their
administration on day 21. In addition, they concluded that the
effect of FSH was dependent upon endogenous LH, as the effect
of FSH was negated by the co-administration of LH antiserum.
Wilks and Noble used a 5-day regimen of increasing doses of
exogenous HCG injections to simulate the events in pregnant
rhesus monkeys after the rescue of the CL. They started the
regimen at different times after the LH surge (days 2, 6, 10 and 14)
(Wilks and Noble, 1983). They found no difference in progesterone
concentrations in the day 2 group compared with controls, but
progesterone concentrations were increased in the day 6 and 10
groups. In the day 14 group, they found an elevation in the serum
progesterone, but the concentration was not as high as the mid-
luteal groups. To determine whether the CL was responsible for the
steroid changes, they administered HCG to lutectomized monkeys
and found no response to the exogenous HCG. Interestingly, they
also found that the production of progesterone in response to
exogenous HCG increased to a plateau despite further increases in
HCG dosage, and that the concentrations of progesterone were
similar to those seen in early pregnancy (Wilks and Noble, 1983).
These data suggest that, although HCG is important in the rescue of
the CL, the maintenance of the CL function may be regulated
independently of HCG.
Groff conrmed the pivotal role of LH in the maintenance of
the CL function in the primate menstrual cycle (Groff et al.,
1984). They used a specic antiserum that neutralized the effect
of LH and administered it to naturally cycling monkeys. Serum
progesterone fell precipitously 24 h after the administration of the
antiserum and all treated monkeys experienced premature
menstruation. These data were supported by studies performed
in anovulatory rhesus monkeys, during which the monkeys
received a pulsatile infusion of GnRH to restore their menstrual
activity (Hutchison and Zeleznik, 1984, 1985; Hutchison et al.,
1986; Zeleznik and Little-Ihrig, 1990). When the infusion of
GnRH was stopped in the early and mid-luteal phases, premature
menstruation occurred after 5 days. This demonstrates that the
normal functional lifespan of the CL requires the presence of
circulating LH during the early (developmental) and mid-luteal
(fully functional) stages of the luteal phase. When the GnRH
infusion was withdrawn for 3 days in the early and mid- luteal
phases, re-establishment of the infusion results in resumption of
the progesterone secretion. This supports the hypothesis that
progesterone secretion is dependent on pituitary gonadotrophin.
When the frequency of the GnRH infusion was reduced from 1
pulse/h to 1 pulse/8 h in the early luteal phase, the luteal length
was unaffected, suggesting that such a reduction in the pulse
frequency was not sufcient to promote luteal regression
(Hutchison et al., 1986). In primates, these data indicate that
LH is important for the CL function. However, following the
transient withdrawal of LH, the steroidogenic ability can be
rescued by re-exposure to LH.
Human data
Similarly, it has been demonstrated that LH and HCG are
responsible for the maintenance of the human CL. Hanson
administered either HCG or human pituitary LH to normal
cycling women in the luteal phase. He found that serum
progesterone concentrations were signicantly elevated and that
the luteal phase could be lengthened by 39 days (Hanson et al.,
1970).
The human and primate data together conrm that the CL
function (in terms of progesterone and oestradiol production) is
dependent on LH and that it can recover following a transient
withdrawal of LH. In the normal luteal phase, as LH concentra-
tions are largely unaltered, this implies that the ability of the CL
to respond to LH is reduced or even lost and that this is the
mechanism through which CL failure and menstruation occur in
the natural cycle. This may be through a reduction in receptor
expression or a down-regulation of the post-receptor response.
Given that HCG acts through the same receptor as LH, it is
possible that the CL rescue involves an entirely LH/HCG-
independent mechanism, such as the inhibition of the secretion of
luteolytic factors. Alternatively, the higher concentrations of
HCG compared with LH, the difference in structure (and therefore
possible difference in receptor stimulation) or its longer receptor
occupancy, may mean that HCG, but not LH, is able to rescue the
CL.
Early pregnancy
Although LH probably plays an essential role in the rescue of the
CL in the late luteal phase, during pregnancy, there is no direct
relationship between the circulating concentrations of progester-
one and those of HCG in the circulation. (Tulchinsky and Hobel,
1973; Norman et al., 1988; Johnson et al., 1993b). Simple dose
response curves do not exist for HCG and progesterone as shown
by the relatively constant progesterone concentrations in early
normal intrauterine pregnancies at the time that HCG concentra-
tions are increasing markedly.
Several explanations have been advanced for this discrepancy,
which include receptor down-regulation, prolonged receptor
occupancy, changes in CL regulation such that the increments
in HCG determine CL function and not the absolute concentra-
tions or changes in the post-receptor mechanisms or the initiation
of a cascade of signals by HCG. However, an alternative
hypothesis is that although HCG is essential for the rescue of
the CL, it does not regulate the CL function in early pregnancy;
this is our favoured explanation and one which we will explore
below, having discussed the other possibilities.
LH/HCG CL receptors
LH/HCG receptors have been identied in luteal tissue. The total
number of receptors increased progressively from the early luteal
phase and then fell in the late luteal phase (Yeko et al., 1989). The
temporal pattern of total LH/HCG receptor concentrations is
similar to the known pattern of progesterone production by the CL
(Yeko et al., 1989). Early pregnancy studies have been largely
conned to tissues obtained from ectopic pregnancies. These data
suggest that the number of available LH/HCG binding sites
declines in early pregnancy (Dawood and Khan-Dawood, 1994).
 Regulation of CL function 521

It is possible to simulate early pregnancy changes in the rhesus
monkey by giving increasing dosages of HCG. Examination of
the LH/HCG binding sites showed that after an initial increase,
prolonged exposure to HCG was associated with a marked decline
in receptor expression which preceded the fall in circulating
progesterone concentrations (Ottobre et al., 1984). Such data
support the idea that in early pregnancy in the human LH/HCG
receptor availability is reduced.
Cloning of the human LH receptor has allowed LH receptor
mRNA expression in luteal tissue to be assessed. Expression of
LH/HCG receptor mRNA in human CL parallels the presence of
the receptors during the menstrual cycle. Expression seen in the
early luteal phase increases in the mid-luteal phase and is absent
by the time of menstruation (Nishimori et al., 1995). During early
pregnancy, despite high concentrations of mRNA, actual
concentrations of the receptor were low (Nishimori et al.,
1995). In contrast to these data, Duncan et al., using a model of
early human pregnancy, found that both LH/HCG receptor
mRNA expression and binding activity were maintained,
suggesting that in humans, there is no alteration in the LH/HCG
receptor function (Duncan et al., 1996). However, this model was
of very early pregnancy, as HCG administration was started on
LH surge plus 7 and the longest that an individual received HCG
before her operation was 8 days, i.e. expected date of
menstruation plus one day (Duncan et al., 1996). These data,
although of interest, do not provide strong evidence against the
idea of reduced LH/HCG receptor availability in early human
pregnancy.
The possibility that the LH/HCG receptor is masked may
explain the ndings from molecular data (which suggest that LH/
HCG receptor mRNA expression is maintained) and the receptor
studies (which suggest that the binding activity is reduced).
Yamoto et al. showed that the pre-treatment of the CL extracts
with neuraminidase signicantly enhanced the binding of human
LH to the CL at different stages of the luteal phase (Yamoto et al.,
1988). Using Scatchard plots, they showed that neuraminidase
increased the number of LH binding sites without altering the
afnity for LH. Such data suggest that the LH/HCG receptors may
be masked during the luteal phase and early pregnancy accounting
for the method-dependent results.
Given that the number of available receptors is reduced in early
pregnancy, then it is possible that factors such as receptor
occupancy or rate of rise of HCG are important. In the case of the
former, should prolonged receptor occupancy be responsible,
then, unless this varies from individual to individual, there should
still be a relationship between the circulating concentrations of

Table I. Preoperative HCG data in vivo and the stimulatory effects of HCG and PGE2 in vitro on cAMP and P formation in CL specimens obtained from
patients with ectopic pregnancies (EP) and normal intrauterine pregnancies (IUP) (Hagstrom et al., 1996 with permission)

cAMP production in vitro Progesterone production in vitro

Serum Daily HCG PGE2 Control HCG PGE2

Pregnancy HCG Change Control HCG 10 IU/l) (10 IU/l) (1 mg/ml) (1 mg/ml)
Patient no. type IU/l % pmol/mg protein % of control % of control ng/mg protein % of control % of control

1 EP 693 40 4.8 181 215 341 170 151

2 EP 423 21 3.3 273 224 218 169 143

3 EP 2479 19 4.7 187 406 614 151 149
4 EP 1189 9 6.1 234 339 306 167 191
5 EP 11808 5 71.5 134 181 334 118 139
6 EP 1822 4 12.6 183 301 219 94 132
7 EP 2400 6 16.2 140 181 430 120 161

8 EP 4561 7 3.9 126 270 331 140 141

P* 0.0078 0.0078 0.016 0.016
9 IUP 5494 24 13.4 104 140 200 98 146
10 IUP 896 34 8.1 105 165 399 119 141
11 IUP 2498 47 6.9 86 210 565 104 148
12 IUP 720 63 4.7 123 334 285 116 164

13 IUP 1556 74 12.3 79 360 524 92 160

14 IUP 2286 108 59.8 97 174 425 112 144

P* NS 0.031 NS 0.0078

HCG = human chorionic gonadotrophin; PGE = prostaglandin E; NS = not significant

*Compared with control.
522 V.J.H.Oon and M.R.Johnson
HCG and progesterone. In the case of the latter, relationships have
been reported between the rate of rise of the circulating
concentrations of HCG and those of progesterone (Kratzer and
Taylor, 1990). However, these are conned to ectopic pregnancies
and not all pregnancies as a group (including ectopic, mis-
carriages and normal intrauterine pregnancies). The fact that no
relationship is seen between the rate of rise of HCG and
progesterone concentrations in normal pregnancy weakens the
argument that it is the rate of rise of HCG which is important in
the regulation of the CL and progesterone production.
If post-receptor mechanisms were altered in a variable fashion
in early pregnancy, then an inconsistent relationship may be
observed between HCG and progesterone. However, we are not
aware of any comparison of HCG-induced cyclic AMP (cAMP)
generation from dispersed cells derived from CLs of the luteal
phase and early pregnancy. There is no increase in cAMP
generation in response to HCG by dispersed CL cells of normal
pregnancies (Table I; Hagstrom et al., 1996), but this may be
because the receptors are blocked as discussed above.
Clinical studies
Norman and his colleagues were the rst group to draw attention
to the differences in the progesterone concentrations between
normal and ectopic pregnancies (Norman et al., 1988). They
matched women with ectopic and normal intrauterine pregnancies
of the same gestation by HCG concentration and found
consistently lower concentrations of progesterone, 17-OH pro-
gesterone and oestradiol in the ectopic set. This group
investigated whether differences in HCG bioactivity were
responsible for the lower steroid concentrations, but found that
the HCG bioactivity was similar in each set (Figure 1, Norman et
al., 1988). They concluded that the difference in the steroid
concentrations may be a reection of a primary defect in the CL
function, the absence of another stimulator of ovarian steroid
biosynthesis or that there were more subtle variations in the
bioactivity of HCG than could be detected in their assays.
Kratzer and Taylor found that there was considerable overlap
between the progesterone concentrations in ectopic pregnancies,
intrauterine pregnancies and spontaneous abortions (Kratzer and
Figure 1. Number of doublings of human chorionic gonadotrophin (HCG)
concentration per day for the individual samples from ectopic pregnancies
(EP, d), normal intrauterine pregnancies (IUP, s), and spontaneous abortions
(SAB, n). Means for each group are indicated by the horizontal bars. Mean
rate for the ectopic pregnancies was signicantly less than that for the
intrauterine pregnancies (P < 0.05; Student's t-test) (Taken from Kratzer and
Taylor, 1990, with permission).
Taylor, 1990). However, the rate of change of HCG concentration
was signicantly correlated with progesterone concentrations in
ectopic pregnancies and all pregnancies. The rate of change of
HCG is expressed as the number of HCG doubling per day, which
is the reciprocal of the doubling time. In addition, Kratzer and
Taylor did not detect any difference in the bioactivity and the
immunoreactivity of the HCG measured in the various subgroups.
They concluded that the mechanism underlying the relationship
between the rate of change of HCG and the CL function involved
the number and percentage of occupied LH/HCG receptors. In
early pregnancy, this would imply that the percentage of occupied
LH/HCG receptors increases from very few to a concentration at
which the maximal stimulation is achieved. This suggestion is
based on the idea that the number of receptors increases as a result
of the growth and development of the CL. The increasing number
of receptors would require an increase in HCG concentration at a
sufcient rate to maintain the optimal receptor occupancy.
Therefore, using this mechanism, maximal CL stimulation can
only be achieved when the production of HCG increases in
keeping with the number of receptors. The obvious weaknesses of
this hypothesis are: (i) that while relationships were found in
ectopic pregnancies and in all pregnancies collectively, none were
found for intrauterine pregnancies or miscarriages; and (ii) it is
not clear that the number of LH/HCG receptors increases from the
luteal phase to early pregnancy (see above).
Further evidence against Kratzer's hypothesis that the rate of
rise of HCG controls the CL function was provided by Lower and
colleagues. They studied asymptomatic women in early preg-
nancy at the time when the serum concentrations of HCG were
rising normally and found that, even at this early gestation, the
concentrations of progesterone in ectopic pregnancies were
signicantly lower than those with normal intrauterine pregnan-
cies which proceeded to >20 weeks gestation. (Figure 2ae;
Lower et al., 1993). In addition, it was noted that there was no
difference between progesterone concentrations in the group
with blighted ovum and their matched controls, and in the
oestradiol concentrations between all three groups. In women
who conceived using assisted reproduction techniques and
received additional luteal phase support in terms of either
HCG or progesterone injections, there were no signicant
differences. Lower et al. concluded that their results suggested
that there was a specic and selective deciency in progesterone
synthesis in ectopic pregnancy, implying that there are other
factors, besides HCG, which inuence the CL function (Lower
et al., 1993).
It must be remembered that the study of the CL function during
early pregnancy, following spontaneous conception, with the
measurement of steroid concentrations alone is complicated by
the ever-increasing placental contribution to the circulating pool
(see above). This may account for the relationships seen in the
study of Kratzer and Taylor (1990). As the most active placentae
will be producing a relatively greater and faster increasing
concentration of HCG, such placentae will also be producing the
most progesterone. Pregnancies with the least active placentae
(ectopic and spontaneous miscarriages) will have the lowest rate
of rise of HCG and the concentrations of progesterone will be
relatively lower. This would explain the presence of a relationship
between the rate of rise of HCG and progesterone concentrations
across all pregnancies.

Ovulation stimulation studies
The study of pregnancies achieved by assisted reproductive
techniques involving ovulation stimulation, e.g. IVF/embryo
transfer and gamete intra-Fallopian transfer (GIFT) has the
advantage of a longer duration of CL dominance in terms of
circulating concentrations of progesterone, and so a greater
opportunity to study the regulation of the CL function.
Initially, in ovulation stimulated pregnancies, the concentra-
tions of progesterone decline and those of oestradiol remain static
(Figure 3a,b; Johnson et al., 1993b). Given an ever-increasing
contribution from the placenta, this represents a decline in ovarian
production of both progesterone and oestradiol. The oestradiol
concentrations remain static because placental production of
oestradiol increases more rapidly than it does for progesterone,
which declines until placental dominance is achieved (Figure
3a,b). Using the point at which the circulating concentrations of
progesterone and oestradiol increase signicantly, it is possible to
estimate the time of the luteoplacental shift. Thus, for singleton
Regulation of CL function 523
Figure 2. (a) Serum progesterone concentrations after spontaneous ovulation
in 14 asymptomatic women with ectopic pregnancies at 45 weeks gestation
(n) compared with 14 women with normal intrauterine pregnancies matched
for human chorionic gonadotrophin (HCG) concentration and gestation age
(h). (b) Serum progesterone concentrations after spontaneous ovulation in
nine women with blighted ova at 4 weeks gestation (s) compared with nine
women with normal intrauterine pregnancies, i.e. matched normal controls at
the same pregnancies (h). (c) Serum progesterone concentrations after
spontaneous ovulation in six women with ectopic pregnancies at 4 weeks
gestation (n) compared with six women with blighted ova (s) matched for
serum HCG concentration and gestational age. (d) Serum progesterone
concentrations after ovulation induction in 20 asymptomatic women with
ectopic pregnancies at 45 weeks gestation (n) compared with 20 matched
women with normal intrauterine pregnancies after similar stimulation (h). (e)
Serum progesterone concentrations after ovulation stimulation in 20 women
with blighted ova at 4 weeks gestation (s) compared with matched normal
controls at the same gestation (h) (Taken from Lower et al., 1993, with
permission).
ovulation stimulated pregnancies, the placenta becomes the
dominant source of oestradiol after 12 weeks gestation, but for
progesterone, this seems to be later than 14 weeks (Figure 3a). For
twin ovulation stimulated pregnancies the dates are 8 and 11
weeks respectively (Figure 3b). These data suggest that in terms
of steroid synthesis and secretion, the corpora lutea of IVF
pregnancies appear to be maximally active at ~45 weeks and
thereafter to decline as the placenta gradually takes over as the
main source of hormones. Yoshimi and colleagues measured
steroid concentrations following ovulation induction and found
that the concentrations of progesterone declined from a peak
achieved at 34 weeks to a nadir at 68 weeks and thereafter rose
(Yoshimi et al., 1969). The concentrations of 17-OH progesterone
peaked at a similar time and continued to decline until luteal
phase concentrations were reached at ~10 weeks gestation. The
authors concluded that after ovulation induction the CL has a life
span of ~10 weeks (Yoshimi et al., 1969). They noted that despite
increasing concentrations of HCG, CL production of progesterone
declined. They therefore concluded that `either HCG does not
524 V.J.H.Oon and M.R.Johnson
Figure 3. (a) Geometric means of serum oestradiol concentration at weeks 4
14 of ovulation stimulated IVF patients with singleton (d) and twin (...s...)
pregnancies. In this longitudinal study, there were a total of 86 women who
became pregnant following IVF. (b) Geometric means of serum progesterone
concentration at weeks 414 of ovulation stimulated IVF patients with
singleton and twin pregnancies. In this longitudinal study, there were a total of
86 women who became pregnant following IVF.
control the CL of early pregnancy or that the period of high
steroid production by the early CL has a predetermined life span'.
They also felt that `other control mechanisms could not be
dismissed' (Yoshimi et al., 1969).
In our studies, we found no association between the HCG and
either progesterone or oestradiol in early pregnancy until 12
weeks gestation (Johnson et al., 1993b). This coincided with
associations between other placental hormones (HCG,
Schwargerschaft protein 1 (SP-1) and pregnancy-associated
plasma protein-A), and both oestradiol and progesterone. We
concluded that these data reect the common origin of the
hormones at this stage (the placenta) (Figure 4a,b).
Comparing the concentrations of HCG and progesterone in
ectopic and anembryonic pregnancies, it appears that although the
circulating concentrations of HCG are lower in the anembryonic
group, the progesterone concentrations are consistently higher in
this group (Figure 5a,b; Johnson et al., 1993a,c). Given that only
Figure 4. (a) The correlation between serum progesterone and placental
protein concentrations in ovulation stimulated IVF patients with singleton
pregnancies in a longitudinal study of 86 women who underwent IVF.
HCG = human chorionic gonadotrophin; SP-1 = ; PAPP-A = pregnancy-asso-
ciated plasma protein-A. (b) The correlation between serum oestradiol and
placental proteins levels in ovulation stimulated IVF patients with singleton
pregnancies in a longitudinal study of a total of 86 women who became
pregnant following IVF.
the placenta and CL produce progesterone during pregnancy, the
difference must lie in the function of one or the other. HCG
concentrations were consistently lower in anembryonic pregnancy
suggesting a lower concentration of placental activity, progester-
one concentrations in contrast were higher and therefore must
reect a greater contribution from the CL.
HCG relates to both progesterone and oestradiol in anem-
bryonic pregnancies, suggesting that HCG is stimulating CL
production of progesterone and oestradiol and that the CL is the
dominant source of both progesterone and oestradiol (Figure 6a,b;
Johnson et al., 1993a). Had all three (HCG, oestradiol,
progesterone) been derived from the placenta (as described in
normal intrauterine pregnancies at the end of the rst trimester
above), then a relationship would have been expected between
SP-1 and both oestradiol and progesterone. However, such a
relationship was not found. The suggestion that the CL is the
dominant source of progesterone in anembryonic pregnancy
would also explain the relatively higher concentrations of
progesterone in the face of the relatively lower concentrations
of HCG (Figure 5a,b). The fact that a consistent relationship
between HCG and both progesterone and oestradiol was apparent
only after fetal demise (after 6 weeks) suggests that the presence
of a viable embryo in the uterine cavity overrides the stimulatory

Figure 5. (a) Serum concentrations (on a log scale) of human chorionic
gonadotrophin (HCG) in normal (n = 52), anembryonic (n = 22) and ectopic
pregnancies (n = 10). **Signicant difference (P < 0.01) between the
circulating concentration in normal or anembryonic pregnancies and that in
ectopic pregnancies. (b) Serum progesterone concentrations in normal
(n = 52), anembryonic (n = 22) and ectopic pregnancies (n = 10). Asterisks
indicate signicant differences between the circulating concentration in
normal or anembryonic pregnancies and that in ectopic pregnancies (*P <
0.05; **P < 0.01) (Reproduced with permission from Johnson et al., 1993c).
effect of HCG on the CL. Moreover, that the concentrations of
progesterone declined following embryo demise, despite the
maintenance of HCG concentrations, emphasizes that another
factor, other than HCG, must have been responsible for the
maintenance of the CL function and that this mechanism must
involve the embryo.
The concentrations of HCG are higher in ectopic than in
anembryonic pregnancies, but the concentrations of progesterone
are lower (Figure 5a,b; Johnson et al., 1993c). The relationships
between the circulating concentrations of placental products and
those of progesterone and oestradiol suggest that the placenta is
the dominant source of both steroids and of HCG and SP-1
(Figures 7a,b). The lower concentrations of progesterone suggest
that the CL in ectopic pregnancies has failed or makes relatively
little contribution to circulating progesterone concentrations.
Regulation of CL function 525
Figure 6. (a) The correlation between serum progesterone and placental
protein concentrations in anembryonic pregnancy at 59 weeks. In this
longitudinal study, there were a total of 22 women who conceived in an IVF
programme. Signicant correlation (*P < 0.05;** P < 0.01) between progester-
one and human chorionic gonadotrophin (HCG). (b) The correlation between
serum oestradiol and placental proteins concentrations in anembryonic
pregnancy. In this longitudinal study, there were a total of 22 women who
conceived in an IVF programme. **Signicant correlation (P < 0.01) between
oestradiol and HCG.
Why should the CL fail in ectopic pregnancy but be the
dominant source of circulating progesterone in anembryonic
pregnancy, where the concentrations of HCG are lower? The
differences are predominantly two-fold; (i) the embryo in an
ectopic pregnancy is probably viable, and (ii) the site of
implantation is in the tube as opposed to the endometrium.
Thus, the presence of a viable embryo (in the tube or uterus)
seems to block the effects of HCG on the CL. Indeed, there is
some evidence which suggests that LH/HCG receptors are present
in the CL of early pregnancy, but they are in some manner
covered (see above, Yamato et al., 1988). However, when the
viable embryo is present in the uterine cavity, it is associated
with the CL stimulation, as seen prior to embryo demise in
anembryonic pregnancy (compare the concentrations at 5 and 6
weeks, pre- and post-embryo demise, Figure 5a,b). Clearly
a viable embryo in the tube does not exert the same
stimulatory effect, but nevertheless it is still able to block the
effect of HCG.
Thus, these data suggest that a viable intrauterine pregnancy
both blocks the effect of HCG on the CL, while exerting a
526 V.J.H.Oon and M.R.Johnson
Figure 7. (a) The correlation between serum progesterone and placental
protein levels in ectopic pregnancy. There were 10 cases of ectopic
pregnancies in a series of 93 pregnancies conceived in an IVF programme.
Asterisks indicate a signicant association between the placental proteins and
progesterone (*P< 0.05; **P < 0.01). There is no correlation between HCG
and progesterone at week 5 but signicant correlation thereafter. (b) The
correlation between serum oestradiol and placental protein concentrations in
ectopic pregnancy. There were 10 cases of ectopic pregnancies in a series of
93 pregnancies conceived in an IVF programme. Asterisks indicate a
signicant association between oestradiol and placental proteins (*P< 0.05;
**P < 0.01). A signicant association between SP1 and oestradiol (E2) was
noted at week 5 and week 7 and between HCG and SP-1 at week 7.
stimulatory effect itself. If the embryo then dies, as in an
anembryonic pregnancy, the stimulatory effect is lost and
progesterone concentrations fall (Figure 5a,b). However, because
the embryo has died, the block on HCG stimulation of the CL is
also removed and CL production of progesterone can again be
stimulated by HCG. In contrast, in an ectopic pregnancy, because
the embryo is viable, the effect of HCG on CL production of
progesterone is blocked. However, possibly because the embryo is
implanted in the tube, the stimulatory effect of the viable embryo
is lost, the CL fails, the concentrations of progesterone are low
and derived from the placenta. (Figure 5a,b)
The data of Hagstrom et al. (1996) shed some light on these
hypotheses. They took CLs from women with viable intrauterine
pregnancies and from women with ectopic pregnancies, dispersed
the cells and observed the effects of HCG on cAMP and
progesterone production. As expected from our hypothesis, the
luteal cells from women with viable intrauterine pregnancies
showed no response to HCG (Table I). At rst sight, the data for
the luteal cells derived from women with ectopic pregnancies are
Figure 8. (a) Serum concentrations of human chorionic gonadotrophin (HCG)
in singleton (n = 52), twin (n = 24) and singleton/anembryonic pregnancies
(n = 22). Asterisks denote a signicant difference (*P < 0.05; **P < 0.01)
between the serum concentrations of each analyte in singleton/anembryonic
pregnancies and either singleton or twin pregnancies. (b) Serum progesterone
concentrations in singleton (n = 52), twin (n = 24) and singleton/anembryonic
pregnancies (n = 22). The respective numbers in each group are 52, 24 and 22.
Asterisks denote a signicant difference (*P < 0.05; **P < 0.01) between the
serum concentrations of progesterone in singleton, twin and singleton/
anembryonic pregnancies (reproduced with permission from Johnson et al.,
1993d).
conicting, as it appears that HCG evokes a response of both
cAMP and progesterone (Table II). However, the fact that the four
ectopic pregnancies showing the highest concentrations of
progesterone production were also those showing the greatest
falling HCG concentrations suggest that the progesterone
response (and possibly also the cAMP response) may occur in
non-viable pregnancies. Most of the cases showing relatively
lower responses had increasing HCG concentrations suggesting
the pregnancy was still viable. Thus, these data support the notion
that the effect of HCG is blocked in a viable pregnancy, whether
the pregnancy is intrauterine or ectopic, but that with embryo
demise, the block is removed.
We tested these ideas in two other groups of pregnancies,
singleton/anembryonic (viable intrauterine with an anembryonic
pregnancy) and heterotopic (viable intrauterine and ectopic
pregnancy). We made comparisons between the circulating
concentrations of HCG and progesterone in these pregnancies
and in singleton and twin pregnancies. (Johnson et al., 1993d).
HCG concentrations were similar in the singleton/anembryonic
group to those in twins until 6 weeks gestation; they then declined
 Regulation of CL function 527

Table II. The effects of various combinations of interleukin-1 (IL-1), tumour necrosis factor (TNF) a, and
interferon (IFN) g on HCG-stimulated progesterone production and FSH-stimulated oestradiol production by
human luteinized granulosa cells (adapted from Fukuoka et al., 1992 with permission)

Effect on HCG Effect on FSH-stimulated

stimulated progesterone oestradiol production
Cytokines production (% inhibition) (% inhibition)

IL-1 (1 ng/ml) NS 23

TNFa (1 ng/ml) NS 61
IFNg (1 ng/ml) 26 28
IFNg (10 ng/ml) 37 66
IFNg (1ng/ml) + IL-1 (1 ng/ml) 28 38
IFNg (10 ng/ml) + IL-1 (1 ng/ml) 47 74
IFNg (1 ng/ml) + TNFa (1 ng/ml) 34 76

IFNg (10 ng/ml) + TNFa (1 ng/ml) 81 97

IL-1 (1 ng/ml) + TNFa (1 ng/ml) 30 70

HCG = human chorionic gonadotrophin; NS = not significant.

to become equivalent, but slightly higher than in the singleton

group by week 8 (Figure 8a). The concentrations of progesterone
were equivalent to those of the twin group at 4 weeks gestation
but then declined rapidly to be slightly less than the singleton
group by 6 weeks and to remain at this relative concentration
thereafter (Figure 8b). These data emphasize the effect of
embryonic demise (occurring at 45 weeks) on the CL function,
despite the maintenance of the HCG concentrations.
In a heterotopic pregnancy (weeks 48), the concentrations
of HCG was signicantly lower than in twin pregnancies and
occasionally singleton pregnancies (Figure 9a). In contrast,
there were no signicant differences in progesterone concen-
trations which were usually intermediate between singleton
and twin concentrations, but at times equivalent to twin
pregnancies (Figure 9b). Therefore, despite the concentrations
of HCG being below those of singletons, the concentrations of
progesterone were at times equivalent to those of twin
pregnancies. (Figure 9a,b). These results suggest that the
presence of an additional embryo in a heterotopic pregnancy
appears to increase the activity of the CL to that resembling a
twin pregnancy. This contrasts to the effects of an isolated
ectopic, where the concentrations of progesterone are markedly
suppressed and suggests that the presence of the intrauterine
pregnancy in heterotopic pregnancies may induce the synthesis
of another factor, which can be further induced by the ectopic
component of the heterotopic pregnancy. It is likely that this
factor is endometrial in origin and that its synthesis requires
the direct interaction between trophoblast and decidua, and yet Figure 9. (a) Serum concentrations of human chorionic gonadotrophin (HCG)
can be enhanced by a blood-borne embryonic signal. The in singleton (n = 52), twin (n = 24) and heterotopic pregnancies (n = 4).
lower concentrations of HCG and relatively higher concentra- Asterisks denote signicant differences (*P < 0.05; **P < 0.01) between the
tions of progesterone in heterotopic pregnancies further serum concentrations in heterotopic pregnancies and either singleton or twin
pregnancies. (b) Serum progesterone concentrations in singleton (n = 52), twin
emphasize the lack of importance of HCG in CL regulation. (n = 24) and heterotopic pregnancies (n = 4). Asterisks denote signicant
Thus, we suggest that, in anembryonic pregnancies, implanta- differences (*P < 0.05; **P < 0.01) between the serum concentrations of each
tion in the uterus triggers the synthesis of the endometrial factor, analyte in heterotopic pregnancies and either singleton or twin pregnancies.
528 V.J.H.Oon and M.R.Johnson
which is enhanced by the embryo until its demise at 56 weeks.
Thereafter, progesterone concentrations fall followed 12 weeks
later by HCG. Embryo death also removes the blocking effect on
HCG, which regains control of the CL function. In ectopic
pregnancies, implantation does not occur in the uterus and
therefore the synthesis of this endometrial factor, and so CL
stimulation, does not occur. In addition, the presence of a viable
embryo blocks HCG stimulation, accounting for the markedly
lower concentrations of progesterone.
Potential mediators
Several potential candidates for this putative endometrial factor
exist. These include cytokines that have been shown to interact to
modulate the steroidogenic function of luteal cells in the
developing CL (Table II; Fukuoka et al., 1992).
Further work by the same group have shown that these
cytokines, e.g. interleukin (IL)-1a, tumour necrosis factor
(TNF)a and interferon g, regulate the expression of differentia-
tion-related molecules which are specically expressed on luteal
cells during the formation of the CL and its transition to the CL of
pregnancy (Fujiwara et al., 1994; Hattori et al., 1995; Fujiwara et
al., 1996). It has been shown that these cytokines are produced by
leukocytes such as macrophages, neutrophils and lymphocytes
that inltrate the CL (Wang et al., 1992). More recent work using
cultures of puried human granulosa cells have shown that the
effect of IL-1 a and b on oestradiol and progesterone production
is changed in the presence of white blood cells (Best and Hill,
1998).
Insulin-like growth factors (IGF-1 and IGF-II) have been
shown to stimulate the production of progesterone directly and
amplify the steroidogenic HCG effect in luteal cell culture (Apa et
al., 1996). More recently, the steroidogenic acute regulatory
protein (StAR) has been suggested to have a role in luteolysis and
the control of CL steroidogenesis. StAR has been demonstrated to
be an indispensible component in the acute regulation of steroid
hormone synthesis (Stocco, 1999). IGFs stimulate StAR mRNA
and protein expression in human granulosalutein cells (Devoto et
al., 1999). The IGF system can also affect the steroidogenic
ability by inuencing the CL synthesis of prostaglandin (PG) F2a
(Apa et al., 1999). PGE2 and PGF2a have been shown to have
luteolytic effect (Bennegard et al., 1991).
The immune system has been implicated in CL regulation.
Indeed, luteolysis is associated with a marked increase in immune
cells in the CL (Wang et al., 1992; Best et al., 1996) which has
been linked with the production of luteolytic cytokines (Wang et
al., 1992). During simulated maternal recognition of pregnancy
with daily doubling doses of HCG, it can be shown that there is a
marked reduction in CL macrophages compared with the
unstimulated luteal phase, suggesting that one of the effects of
HCG is to prevent the normal inux of macrophages into the CL
(Duncan et al., 1998). However, peripheral blood mononuclear
cells from pregnant women have a luteotrophic effect and result in
an increased production of progesterone from luteal cells in
culture. The production of IL-4 and IL-10 was also enhanced in
the luteal cell culture derived from pregnant women (Hashii et al.,
1998). This would suggest the involvement of the immune
system, namely mononuclear cells in the CL function and the
differentiation via the T-helper (Th)-2 type, which secrete IL-4
and IL-10. Using leukocyte depleted cell culture, the progesterone
production has been shown to increase two-fold in basal
conditions. However, in HCG-stimulated conditions, the leuko-
cyte-depleted cell culture had a reduced production of progester-
one (Castro et al., 1998). Thus, it is no longer doubted that the
immune system plays a role in the regulation of the CL function,
but the precise mechanisms involved are still unclear (Bukulmez
and Arici, 2000).
The increased blood ow to the CL-bearing ovary may be due
to the presence of the immune mediators (Miyazaki et al., 1998).
Blood ow to the CL in early pregnancy, measured in terms of the
maximum peak velocity (PSV) and the resistance index
(RI = systole diastole/systole), does not vary with gestational
age. The maximum peak velocity values to the CL correlate with
the concentrations of progesterone and oestradiol, while the
resistance index values are correlated with progesterone and intact
HCG values, but not with free b-HCG subunits (Jauniaux et al.,
1992). Thus, blood ow to the CL appears to be modulated
hormonally and not simply by gestational age.
The molecular mechanisms of luteolysis and the loss of the
structural and functional integrity of the CL are still unclear.
Recently, it has been shown that the loss of structural integrity of
the CL during luteolysis are mediated by apoptosis (Juengel et al.,
1993; Fraser et al., 1995; Young et al., 1997) and remodelling of
the extracellular matrix by matrix metallo-proteinase enzymes
(Endo et al., 1993). This would also be supported by the inux of
macrophages as they can clear cellular debris and activate the
matrix metalloproteinase enzymes.
Conclusion
In conclusion, the function of the CL and its regulation is
complex. HCG certainly rescues the CL, but its role thereafter is
probably short lived. We suggest that a viable pregnancy blocks
the effect of HCG on the CL. If this viable pregnancy is implanted
in the uterine cavity, it then produces a factor, which supersedes
the luteotrophic effect of HCG, to maintain the CL function in
early pregnancy. The mechanisms involved, which remain to be
claried, could include immune mechanisms, cytokine production
and apoptosis.
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Received on December 13, 1999; accepted on May 16, 2000