Human Reproduction vol.13 no.5 pp.1139–1143, 1998
The effect of recombinant follicle stimulating hormone
(Gonal-F) on endogenous luteinizing hormone secretion
in women
M.L.Hull1, J.H.Livesey, J.J.Evans and P.S.Benny
Department of Obstetrics and Gynaecology, Christchurch School of
Medicine, Christchurch, New Zealand
1To
whom correspondence should be addressed
Parenteral administration of follicle stimulating hormone
(FSH) has been shown to lower luteinizing hormone (LH)
concentrations in women undergoing ovulation induction.
This study was designed to explore the physiological
mechanism of this effect. Seven healthy women were
recruited into a double-blind placebo-controlled study. LH
secretion, after the administration of variable i.v. boluses
(37.5, 75 and 150 IU) of recombinant FSH (Gonal-F), was
evaluated. LH was measured at 10 min intervals for 2 h
before and 4 h after the FSH/placebo infusion. LH pulse
frequency and amplitude were evaluated and there was no
significant difference between control and trial cycles for
each subject. A linear regression analysis revealed that in
the group receiving 150 IU FSH, the mean plasma LH
concentration decreased significantly due to a reduction
tonic LH secretion. This could be a result of the suppression
of secretion or an alteration of clearance. This decrease
was not seen in the other dosage groups, revealing that
above a dosage threshold, FSH reduced non-pulsatile LH
secretion. Therefore the effect of FSH in this study exposed
the likely presence of two components of LH concentration:
an FSH-sensitive, non-pulsatile tonic secretion and a gonadotrophin-releasing hormone-stimulated, pulsatile release
that is unaffected by FSH. Although an indirect effect
involving ovarian regulation is not excluded, the rapidity
of the effect suggests that FSH acts directly on the pituitary gland.
Key words: anterior pituitary/follicle stimulating hormone/
gonadotrophin-releasing hormone/gonadotrophin surge attenuating factor/luteinizing hormone
Introduction
Luteinizing hormone (LH) is secreted by the pituitary gland
primarily in response to hypothalamic gonadotrophin-releasing
hormone (GnRH). However, the administration of supraphysiological doses of follicle stimulating hormone (FSH) has been
shown to attenuate the LH surge in women undergoing ovarian
stimulation (Ferraretti et al., 1983; Messinis and Templeton,
1986; Messinis et al., 1986). LH plasma concentrations are
also lower after FSH administration in the early follicular
phase of the human menstrual cycle (Jones et al., 1984;
Anderson et al., 1989). This effect is seen even after pituitary
© European Society for Human Reproduction and Embryology
desensitization with a GnRH agonist (P.S.Benny, unpublished
data).
The physiological mechanism of FSH-induced LH suppression is unknown but several theories have been postulated.
First, it is possible that FSH administration alters GnRH
secretion at the level of the hypothalamus, suppressing pituitary
LH secretion. Alternatively, FSH may act directly on the
pituitary gland to decrease LH output or change the half-life
of LH. Finally, FSH may stimulate the ovaries to produce
substances such as inhibin, activin, ovarian steroids or gonadotrophin surge-attenuating factor (GnSAF), indirectly reducing
pituitary secretion of LH.
Several groups have attempted to elucidate the mechanism
of FSH-induced suppression of LH. All previous studies have
used purified FSH derived from the urine of post-menopausal
women, which does contain small quantities of LH (BenRafael et al., 1995). Other workers have used the attenuation
of a natural LH surge as a marker of LH suppression by FSH
(Ferraretti et al., 1983; Messinis and Templeton, 1986; Messinis
et al., 1986). Others have used the reduction of GnRH-induced
LH secretion as an endpoint (Messinis and Templeton, 1989;
Messinis et al., 1991, 1993). Lastly, several groups have
measured plasma LH concentrations at a minimum of hourly
intervals after the administration of a supraphysiological dose
of FSH (Jones et al., 1984; Anderson et al., 1989).
This study was designed to determine (i) the effect of FSH
administration on the GnRH-mediated pulsatile release of LH,
and (ii) the influence of FSH on mean baseline LH secretion.
Recombinant FSH (Gonal-F) was used to eliminate any
influence of exogenous LH on endogenous plasma LH measurements. Samples were taken every 10 min for 4 h after FSH
administration. This ensured that LH pulses were recordable
and there was a high chance that LH suppression would be
detected. Any change in LH pulse frequency, pulse amplitude
or baseline LH secretion after the administration of an i.v.
bolus of recombinant FSH would be detected by our protocol.
Materials and methods
This study had ethical approval from the Southern Regional Health
Ethics Committee (Canterbury, New Zealand).
Seven healthy volunteers, aged between 20 and 35 years, with
regular ovulatory menstrual cycles were recruited to participate in
this study. Informed consent was obtained from all participants.
Each subject was required to have normal medical histories and
examinations, pelvic ultrasound scans and reproductive hormonal
profiles. Women taking medications that could influence reproductive
hormone concentrations (in particular the oral contraceptive pill) were
excluded from the study, as were women with signs or symptoms of
polycystic ovarian syndrome.
1139
M.L.Hull et al.
Table I. Characteristics of subjects
Age (years)
Body mass index (kg/m2)
Menstrual cycle length (days)
Day 21 progesterone concentration (nmol/l)
Day 3 follicle stimulating hormone concentration (IU/l)
Day 3 luteinizing hormone concentration (IU/l)
Mean
SD
28
21.1
28.4
23.1
6.3
4.5
5.1
2.9
2.1
7.2
1.2
1.9
The recruits acted as their own controls in this double-blind,
randomized, placebo-controlled trial. On day 3, 4 or 5 of two or three
different menstrual cycles, each subject undertook the trial protocol.
Wherever possible, each subject participated on the same day in each
cycle. To analyse intercycle variability, an initial blood test was
taken to estimate baseline oestrogen using a radioimmunoassay
(oestradiol-2; Sorin Biomedica, Saluggia, Italy) and progesterone
using an enzyme-linked immunosorbent assay (Elder et al., 1987).
Another oestrogen estimation was performed at 360 min. The average
of three FSH samples taken at 0, 10 and 20 min was compared with
the average of post-infusion FSH samples taken at 130, 140 and
150 min.
Plasma LH sampling started at time 0 and was performed every
10 min for 2 h. At this point, a 1 ml i.v. bolus of a variable dose
(37.5, 75 or 150 IU) of recombinant FSH (Gonal-F; Serono, Geneva,
Switzerland) or placebo was administered over 60 s. This infusion
was given in the arm not used for blood sampling. Plasma LH
samples were then collected at 10 min intervals for another 4 h.
Plasma from all samples was stored at –20°C for later batched
analysis. Plasma FSH and LH concentrations were measured by a
microparticle enzyme immunoassay (Abbott Laboratories, Abbott
Park, IL, USA). The intra-assay coefficient of variation (CV) for the
LH assay was 1.9% at 8 IU/l, the inter-assay CV was 5.5% at 14 IU/l
and the detection limit was 0.2 IU/l. LH pulses were identified and
analysed using the Cluster program (Veldhuis and Johnson, 1986).
Control cycles were compared with trial cycles for each individual.
Pulse frequency for each cycle was determined by the number of
peaks per hour. By subtracting the mean height of nadirs from the
mean height of peaks, the mean pulse amplitude was calculated in
each cycle. The numbers of peaks and valleys were tallied. The
numerical values of pulse frequency and pulse amplitude were
compared. A visual comparison of the shapes of the graphs was also
performed.
A linear regression analysis was performed to determine the mean
slope of LH secretion with respect to time in all cycles. The mean
slope from cycles where the same dose of recombinant FSH had
been given were grouped together and a one-way analysis of variance
(ANOVA) performed. Dunnett’s method (Steel and Torrie, 1980) was
used to compare the mean slope of the control group with that of
each of the FSH dosage groups.
Results
The characteristics of the volunteers that could potentially
influence reproductive physiology were recorded (Table I).
The recruits were aged between 21 and 34 years. Regular
menstrual cycle length and an elevated day 21 progesterone
concentration provided evidence of ovulation in the seven
recruits. The subjects all had concentrations of free T4, prolactin
and testosterone in the normal range. Day 3 FSH and LH
concentrations were those expected for ovulatory women.
1140
All women were in the early follicular phase of the menstrual
cycle as indicated by a low basal progesterone concentration.
Similarity of baseline oestrogen concentrations in each cycle
suggested that most subjects undertook the protocol on the
same day of the cycle. Post-infusion oestradiol concentrations
fluctuated from those taken pre-infusion, even in placebo
cycles. The non-significant differences between oestradiol
concentrations at time 5 0 min and time 5 360 min were
similar between dosage groups, and thus were unlikely to have
influenced the LH attenuation seen only in the 150 IU dosage
group. Predictably, a dose-dependent post-infusion increase in
plasma FSH concentrations was seen (Table II).
LH pulses were assessed visually as well as numerically
using the Cluster program. LH pulses were detected in all
cycles. Graphs representing the control and trial cycles for
subjects receiving 150 IU FSH are presented (Figure 1).
Although subtle differences in pulse frequency and amplitude
were seen in each cycle, there were no dose-related trends in
pulsatility or pulse amplitude noted when an analysis of the
numerical data was performed (Table III). Because of the
number of subjects, this study might not have detected small
differences in the LH pulses.
The rate of change of LH concentration with time was
determined using a linear regression analysis for each dose
for each subject. The means of the slopes (Table IV) for each
of the four FSH doses (0, 37.5, 75 and 150 IU) differed
significantly (P , 0.001) by a one-way ANOVA. Using
Dunnett’s method, the mean slope of the 150 IU dose group
differed significantly (P , 0.05) from that of the control
group, but the slopes of the other FSH dose groups did not.
Discussion
It is well recognized that there are different mechanisms
controlling LH and FSH secretion from pituitary gonadotrophs
(De Paolo, 1985; Culler and Negro-Villar, 1986). Because
there were no pure FSH or LH preparations, interactions
between FSH and LH have been unable to be defined. By
using recombinant FSH (Gonal-F) in this study, it was shown
that FSH can influence basal plasma LH concentrations above
a dosage threshold.
LH is predominantly phasically secreted from the pituitary
gland in response to GnRH. However, in this study the
peripheral plasma LH pulse amplitude and pulse frequency,
which reflect GnRH-mediated LH release from the pituitary,
were unaltered. Because high-dose FSH administration selectively reduced non-pulsatile LH concentrations, the existence
of at least two distinct components of LH secretion or
elimination is suggested: a GnRH-dependent phasic secretion
and a GnRH-independent tonic basal secretion.
Phasically regulated secretion of both FSH and LH is well
characterized (Pohl et al., 1983; Conn et al., 1987; Kiesel,
1993). Tonically regulated FSH secretion by the pituitary
gonadotrophs is also well described (Hall et al., 1988; De
Paolo et al., 1992; Farnworth, 1995), but there is less evidence
to support tonically regulated LH secretion. Tonically regulated
LH secretion may account for the finding that when women
were administered pulsatile GnRH, those who were con-
Effect of rFSH on endogenous LH secretion
Table II. Analysis of intercycle variability
Dose of
FSH (IU)
Subject 1
Subject 2
Subject 3
Subject 4
Subject 5
Subject 6
Subject 7
0.0
37.5
150
0.0
37.5
150
0.0
37.5
150
0.0
37.5
0.0
75
0.0
75
0.0
150
Day of
cycle
4
4
4
4
4
5
3
4
3
4
4
5
5
4
4
4
4
Oestradiol concentration (pmol/l)
Time 5 0 min
Time 5 360 min
70
50
66
200
230
906
91
180
121
150
110
300
280
110
106
44
62
86
136
246
85
166
578
79
245
201
138
178
94
185
156
202
74
117
Pre-infusion Post-infusion
FSH (mIU/l) FSH (mIU/l)
6.7
7.4
7.4
5.5
4.9
2.9
4.4
5.5
5.5
8.0
6.5
4.4
4.5
5.5
4.6
4.5
5.1
6.7
15.4
24.5
5.6
11.0
20.7
4.4
9.7
15.2
8.7
11.5
4.0
12.2
6.6
13.0
5.0
17.0
FSH 5 follicle stimulating hormone.
currently given FSH had attenuation of LH secretion in
response to GnRH when compared with the control group
(Messinis and Templeton, 1990). It has also been demonstrated
that women who received an FSH infusion after pituitary
desensitization with a gonadotrophin agonist had reduced
plasma LH concentrations (P.S.Benny, unpublished data).
These reports concur with the conclusion from our results,
that a GnRH-independent mechanism is involved in FSHmediated attenuation of basal LH. It may be that the regulation
of tonically secreted LH occurs and, if so, it can be influenced
by FSH.
Alternatively, increased clearance of LH could account for
the decline in LH seen after FSH administration. LH exists in
a sialylated and desialylated form (Levy and Ben-Rafael,
1996). FSH may promote desialylation of LH which is then
cleared more rapidly from the blood system and is likely to
be seen as a decline in non-pulsatile basal LH.
FSH could act at the level of the pituitary by an ultrashort
loop feedback mechanism to attenuate LH secretion. It has
been shown in rabbits that an ultrashort loop feedback mechanism exists whereby self-regulation of FSH and LH at the
pituitary occurs (Patritti-Laborde et al., 1981, 1982). The
rapidity of LH suppression seen in this study and in other
research (Messinis et al., 1993) supports the hypothesis that
LH attenuation by FSH is a pituitary control mechanism.
FSH may also act indirectly via the ovary to control LH
secretion. It has been suggested that FSH induction of the
ovarian production of oestrogen, progesterone or inhibin may
lead to LH suppression at the pituitary. Several studies have
shown that ovarian steroids do not have a role in midcycle
FSH induced suppression of LH secretion (Messinis et al.,
1986; Messinis and Templeton, 1987, 1990). Culler (1992)
suggested that in rats, inhibin may have a role in FSH mediated
LH suppression. Messinis et al. (1996) refuted this role for
inhibin in humans.
Several researchers have suggested that there is a putative
ovarian factor, called GnSAF, which is recognized by its in-
Figure 1. Control and trial cycles for subjects receiving 150 IU
follicle stimulating hormone.
vivo bioactivity — the attenuation of LH secretion in response
to GnRH administration (Fowler et al., 1990; Messinis and
Templeton, 1991). It has been asserted that FSH induction of
ovarian GnSAF may lead to indirect pituitary suppression of
LH. However it seems unlikely that GnSAF can explain the
observations reported in this study. The rapid time frame of
1141
M.L.Hull et al.
Table III. Luteinizing hormone pulse frequency and amplitude for all cycles
n
Placebo
Placebo
150 IU
75 IU
37.5 IU
7
4a
4
2
4
Frequency (cycles/h)
Amplitude (IU/l/min)
Mean
SD
Mean
SD
0.642
0.582
0.666
0.666
0.707
0.139
0.149
0.264
0.000
0.072
1.74
1.87
1.8
2.00
1.58
0.29
0.28
0.47
0.60
0.17
aThe
control cycles of subjects receiving 150 IU follicle stimulating
hormone were analysed separately to allow direct comparison with trial
cycles.
Table IV. Regression of luteinizing hormone concentrations on time
FSH dose (I/U)
0
37.5
75
150
No. of subjects
7
4
2
4
Slope (IU/l/h)
Mean
SEM
–0.032
0.012
–0.021
–0.276a
0.029
0.039
0.014
0.050
FSH 5 follicle stimulating hormone.
aP , 0.05 compared with 0 dose.
LH suppression by FSH seen in this study suggests a direct
pituitary effect rather than indirect ovarian involvement. The
relationship between the results obtained during the investigation of GnSAF and those of our study is difficult to discern
because no study exploring GnSAF has provided controls for
the known presence of FSH in follicular fluid (Erickson et al.,
1992; Mason et al., 1994; Suchanek et al., 1994).
High-dose FSH attenuation of LH in the early follicular
phase of the menstrual cycle has clinical implications for
reproductive medicine. These results may have particular
application to women with a low or high baseline LH concentration.
With increasing use of FSH preparations containing no LH
(such as Gonal-F), plasma concentrations of LH in some
women could be severely depressed during parenteral FSH
treatment. The 2-cell theory of oestrogen production suggests
that low circulating LH concentrations could depress ovarian
androgenesis, which could in turn reduce follicular oestrogen
production. Monkeys treated with recombinant FSH had lower
oestrogen concentrations than monkeys treated with LH containing FSH preparations, although follicular size and numbers
of follicles were unaffected (Karnitis et al., 1994). Several
studies have compared recombinant FSH with highly purified
FSH (Fisch et al., 1995; Recombinant Human FSH Study,
1995) or highly purified FSH with urinary FSH (Balasch et al.,
1996; Check and Fine, 1997) in in-vitro fertilization cycles.
These investigations suggest that women receiving FSH preparations containing lower quantities of LH tend towards lower
oestrogen concentrations. However a large multicentre trial
(Out et al., 1995) has shown a non-significant increase in
oestrogen concentrations in the group of women receiving
recombinant FSH. Although it is difficult to comment on the
influence of administered LH on oestrogen concentrations, no
1142
study has shown pharmacological doses of LH to have any
influence on fertilization rates, implantation rates or take-home
baby rates in in-vitro fertilization cycles. It would be interesting
to study the effect of administering different preparations of
FSH to a group of women identified as having low baseline
LH concentrations. It may be that for these women reproductive success can be improved by LH therapy in the early
follicular phase of the cycle, particularly if recombinant FSH
is used.
Women with polycystic ovarian syndrome have high plasma
LH concentrations and reduced LH plasma concentrations after
an infusion of high-dose FSH (Anderson et al., 1989). Ovarian
stimulation by administering FSH to these women can often
be complicated by an ‘all or nothing’ ovarian response. Below
an FSH dose threshold there is no follicular development,
whereas above this threshold multiple follicles develop. Both
scenarios can result in cancelled treatment cycles, the first
because of a reduced chance of pregnancy and the second
because of the significant risk of the development of ovarian
hyperstimulation syndrome. Our study showed a dosage threshold effect when FSH attenuated LH secretion (also seen by
Messinis et al., 1994). It is possible that it is the reduction in
circulating LH after FSH administration which permits, at
least in part, the excessive follicular development seen in the
‘all or nothing’ response of polycystic ovarian syndrome.
This study has shown that supraphysiological doses of FSH
suppressed LH secretion by the pituitary gland. Tonic secretion
of pituitary LH was attenuated, indicating that this effect is
not influenced by pulsatile GnRH release by the hypothalamus.
Thus the results provide persuasive evidence for at least two
components in the concentration profile of LH. Evidence in
the literature suggests that FSH promotes the production of
an ovarian factor called GnSAF, suppressing LH secretion
indirectly. Another separate, direct effect of FSH attenuating
LH secretion at the pituitary gland is strongly suggested by
the rapidity of effect seen in this study. These results have
clinical implications for women with low baseline LH concentrations who may require LH supplementation when undergoing
FSH therapy. This study’s findings may also relate directly to
the ‘all or nothing’ response seen in women with polycystic
ovarian syndrome who receive gonadotrophin therapy. Reproductive technology will benefit from further delineation of
gonadotrophin control processes.
Acknowledgements
This study was sponsored by Serono (Australia) Pty Ltd.
References
Anderson, R.E., Cragun, J.M., Chang, R.J. et al. (1989) A pharmacodynamic
comparison of human urinary follicle stimulating hormone and human
menopausal gonadotrophin in normal women and polycystic ovary
syndrome. Fertil. Steril., 52, 216–220.
Balasch, J., Fabregues, F., Creus, M. et al. (1996) Pure and highly purified
follicle-stimulating hormone alone or in combination with human
menopausal gonadotrophin for ovarian stimulation after pituitary suppression
in in-vitro fertilization. Hum. Reprod., 11, 2400–2404.
Ben-Rafael, Z., Levy, T. and Schoemaker, J. (1995) Pharmacokinetics of follicle
stimulating hormone: clinical significance. Fertil. Steril., 63, 689–700.
Check, J.H. and Fine, W. (1997) Similar pregnancy and spontaneous abortion
Effect of rFSH on endogenous LH secretion
rates after treatment with low-dose human menopausal gonadotrophin versus
pure follicle stimulating hormone in women with luteal phase defects. Clin.
Exp. Obstet. Gynecol., 24, 5–7.
Conn, P.M., Huckle, W.R., Andrews, W.V. et al. (1987) The molecular
mechanism of action of gonadotrophin releasing hormone (GnRH) in the
pituitary. Rec. Prog. Horm. Res., 43, 29–61.
Culler, M.D. (1992) In vivo evidence that inhibin is a gonadotrophin surgeinhibiting/attenuating factor. Endocrinology, 131, 1556–1558.
Culler, M.D. and Negro-Villar, A. (1986) Evidence that pulsatile folliclestimulating hormone secretion is independent of endogenous luteinizing
hormone-releasing hormone. Endocrinology, 118, 609–612.
De Paolo, L.V. (1985) Differential regulation of pulsatile luteinizing hormone
(LH) and follicle stimulating hormone secretion in ovariectomized rats
disclosed by treatment with a LH releasing hormone antagonist and
phenobarbital. Endocrinology, 117, 1826–1833.
De Paolo, L.V., Bald, L.N. and Fendly, B.M. (1992) Passive
immunoneutralization with a monoclonal antibody reveals a role for
endogenous activin-B in mediating FSH hypersecretion during estrus
and following ovariectomy of hypophysectomized pituitary grafted rats.
Endocrinology, 130, 1741–1743.
Elder, P.A., Yeo, K.H.J., Lewis, J.G. et al. (1987) An enzyme-linked
immunosorbent assay (ELISA) for plasma progesterone: immobilized
antigen approach. Clin. Chim. Acta, 162, 199–206.
Erickson, G.F., Magoffin, D.A., Garzo, G.V. et al. (1992) Granulosa cells of
polycystic ovaries: are they normal or abnormal? Hum. Reprod., 7, 293–299.
Farnworth, P.G. (1995) Gonadotrophin secretion revisited. How many ways
can FSH leave a gonadotroph? J. Endocrinol., 145, 387–395.
Ferraretti, A.P., Garcia, J.E., Acosta, A.A. et al. (1983) Serum luteinizing
hormone during ovulation induction with human menopausal gonadotrophin
for in vitro fertilisation in normally menstruating women. Fertil. Steril., 40,
742–747.
Fisch, B., Avrech, O.M., Pinkas, H. et al. (1995) Superovulation before IVF
by recombinant versus urinary human FSH (combined with a long GnRH
analog protocol): a comparative study. J. Assist. Reprod. Genet., 12, 26–31.
Fowler, P.A., Messinis, I.E. and Templeton, A.A. (1990) Inhibition of LHRHinduced LH and FSH release by gonadotropin surge-attenuating factor
(GnSAF) from human follicular fluid. J. Reprod. Fertil., 90, 587–594.
Hall, J.E., Brodie, T.D., Badger, T.M. et al. (1988) Evidence of differential
control of FSH and LH secretion by gonadotrophin-releasing hormone
(GnRH) from the use of a GnRH antagonist. J. Clin. Endocrinol. Metab.,
67, 524–534.
Jones, G.S., Garcia, J.E. and Rosenwaks, Z. (1984) The role of pituitary
gonadotrophs in follicular stimulation and oocyte maturation in the human.
J. Clin. Endocrinol. Metab., 59, 178–180.
Karnitis, V.J., Townson, D.H., Friedman, C.I. et al. (1994) Recombinant
human follicle-stimulating hormone stimulates multiple follicular growth,
but minimal estrogen production in gonadotropin-releasing hormone agonisttreated monkeys: examining the role of luteinizing hormone in follicular
development and steroidogenesis. J. Clin. Endocrinol. Metab., 79, 91–97.
Kiesel, L. (1993) Molecular mechanisms of gonadotrophin releasing hormonestimulated gonadotrophin secretion. Hum. Reprod., 8 (Suppl. 2), 23–28.
Levy, T. and Ben-Rafael, Z. (1996) Pharmacokinetics of gonadotrophin
therapy. Reprod. Med. Rev., 5, 18–35.
Mason, H.D., Willis, D.S., Beard, R.W. et al. (1994) Estradiol production by
granulosa cells of normal and polycystic ovaries: relationship to menstrual
cycle history and concentrations of gonadotrophins and sex steroids in
follicular fluid. J. Clin. Endocrinol. Metab., 79, 1355–1360.
Messinis, I.E. and Templeton, A.A. (1986) The effect of pulsatile follicle
stimulating hormone on the endogenous luteinizing surge in women. Clin.
Endocrinol., 25, 633–640.
Messinis, I.E. and Templeton, A.A. (1987) Effect of high dose exogenous
oestrogen on midcycle luteinizing hormone surge in human spontaneous
cycles. Clin. Endocrinol., 27, 453–459.
Messinis, I.E. and Templeton, A.A. (1989) Pituitary response to exogenous
LHRH in superovulated women. J. Reprod. Fertil., 87, 633–639.
Messinis, I.E. and Templeton, A.A. (1990) Superovulation induction in women
suppresses luteinizing hormone secretion at the pituitary level. Clin.
Endocrinol., 32, 107–114.
Messinis, I.E. and Templeton, A.A. (1991) Attenuation of gonadotrophin
release and reserve in superovulated women by gonadotrophin surge
attenuating factor (GnSAF). Clin. Endocrinol., 34, 259–263.
Messinis, I.E., Templeton, A.A. and Baird, D.T. (1986) Endogenous luteinizing
hormone surge in women during induction of multiple follicular development
with pulsatile follicle stimulating hormone. Clin. Endocrinol., 24, 193–201.
Messinis, I.E., Hirch, P. and Templeton, A.A. (1991) Follicle stimulating
hormone stimulates the production of gonadotrophin surge-attenuating factor
(GnSAF) in vivo. Clin. Endocrinol., 35, 403–407.
Messinis, I.E., Lolis, D., Papadopoulos, L. et al. (1993) Effect of varying
concentrations of follicle stimulating hormone on the production of
gonadotrophin surge attenuating factor (GnSAF) in women. Clin.
Endocrinol., 39, 45–50.
Messinis, I.E., Lolis, D., Papasterigiopaulou, L. et al. (1994) Effect of follicle
stimulating hormone treatment on the pituitary response to luteinizing
hormone-releasing hormone in post-menopausal women. Hum. Reprod., 9,
141–144.
Messinis, I.E., Lolis, D., Zikopoulous, K. et al. (1996) Effect of follicle
stimulating hormone or human chorionic gonadotrophin treatment on the
production of gonadotrophin surge attenuating factor (GnSAF) during the
luteal phase of the menstrual cycle. Clin. Endocrinol., 44, 169–175.
Out, H.J., Mannaerts, B.M.J.L., Driessen, S.G.A.J. et al. (1995) A prospective,
randomized, assessor-blind, multicentre study comparing recombinant and
urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro
fertilization. Hum. Reprod., 10, 2534–2540.
Patritti-Laborde, N., Wolfsen, A.R. and Odell, W.D. (1981) Short loop
feedback system for the control of follicle stimulating hormone in the
rabbit. Endocrinology, 108, 72–75.
Patritti-Laborde, N., Asch, R.H., Paverstein, C.J. et al. (1982) Prevention of
the post coital luteinizing hormone surge by ultrashort feedback control.
Fertil. Steril., 38, 349–353.
Pohl, C.R., Richardson, D.W., Hutchison, J.S. et al. (1983) Hypophysiotrophic
signal frequency and the functioning of the pituitary–ovarian system in the
rhesus monkey. Endocrinology, 112, 2076–2080.
Recombinant Human FSH Study Group (1995) Clinical assessment of
recombinant human follicle-stimulating hormone in stimulating ovarian
follicular development before in-vitro fertilisation. Fertil. Steril., 63, 77–86.
Steel, R.G.D. and Torrie, J.H. (1980) Principles and Procedures of Statistics.
McGraw-Hill International, London, UK.
Suchanek, E., Simonic, V., Juretic, D. et al. (1994) Follicular fluid contents
of hyaluronic acid, follicle-stimulating hormone and steroids relative to the
success of in vitro fertilisation of human oocytes. Fertil. Steril., 62, 347–352.
Veldhuis, J.D. and Johnson, M.L. (1986) Cluster analysis: a simple versatile
and robust algorithm for endocrine pulse detection. Am. J. Physiol., 250,
E486–493.
Received on August 26, 1997; accepted on January 20, 1998
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