Endocrine Reviews 20 (3): 249-252
Copyright © 1999 by The Endocrine Society
Assisted Reproduction-In Vitro Fertilization Success Is Improved by Ovarian Stimulation with Exogenous Gonadotropins and Pituitary Suppression with Gonadotropin-Releasing Hormone Analogues1
Robert L. Barbieri and
Mark D. Hornstein
Department of Obstetrics, Gynecology and Reproductive Biology,
Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts 02115-6110
 |
Abstract
|
|---|
- I. Introduction
- II. Ovarian Stimulation with Exogenous Gonadotropin Improves In
Vitro Fertilization and Embryo Transfer (IVF-ET) Success
- III. Pituitary Suppression Improves IVF-ET Success: GnRH Agonist Analogues
- IV. Pituitary Suppression Improves IVF-ET Success: GnRH Antagonist
Analogues
|
I. Introduction
|
|---|
THE ESSENCE of mammalian reproduction is the fusion of a
sperm and oocyte to form a conceptus. In this miraculous process, the
single-cell conceptus contains all the biological information necessary
to produce a new life. In nature, the important processes in mammalian
reproduction occur within the bodies of the female and male partners.
The essence of assisted reproduction is that a third party, the
reproductive endocrinologist-biologist, directly manipulates the sperm
and/or oocyte to enhance the probability of achieving a pregnancy.
Although assisted reproduction appears to be a new field, it was being
practiced before the discovery of insulin. In 1890, Heape (1) reported
the successful transfer of embryos from a donor rabbit to a recipient,
resulting in the first birth by a surrogate gestational carrier. In
1944, Rock and Menkin (2) reported the successful fertilization of
human oocytes in vitro and their development to the two- and
three-cell stage. In 1959, Chang (3) successfully fertilized a rabbit
oocyte in vitro. In humans, the successful capacitation of
sperm in vitro and the successful fertilization of human
oocytes matured in vitro (4) were followed by the discovery
that preovulatory oocytes were relatively easy to fertilize in
vitro (5). These discoveries culminated in 1978 with the birth of
a baby girl resulting from the in vitro fertilization of a
single preovulatory oocyte obtained from a natural menstrual cycle (6).
Assisted reproduction has evolved rapidly over the past two decades
with significant progress in our understanding and techniques in three
major areas: 1) the endocrinology of the assisted reproduction process;
2) the biology of gamete function and the technology of gamete
micromanipulation; and 3) the genetics of reproduction. This minireview
will focus on advances in the endocrinology of the assisted
reproductive process with an emphasis on data from well designed
(randomized) clinical trials. The specific focus will be on data that
demonstrate that in humans, given our current technology, successful
in vitro fertilization and embryo transfer (IVF-ET) requires
both stimulation of the ovary and suppression of the pituitary.
|
II. Ovarian Stimulation with Exogenous Gonadotropins Improves
In Vitro Fertilization and Embryo Transfer (IVF-ET)
Success
|
|---|
A characteristic feature of IVF-ET is that a very clear and easily
measurable endpoint (birth of a normal newborn) is the goal of the
treatment. There are few endocrine treatments with such a clearly
relevant and precisely measured endpoint. Many factors influence the
success of IVF-ET including the age of the female partner (7), early
follicular phase FSH concentration (8), evidence of good ovarian
reserve (9), and the number of oocytes retrieved. An important
determinant of IVF-ET success is the ovarian stimulation regimen
employed.
Although the first birth from IVF-ET used a single oocyte obtained from
a natural cycle, most studies demonstrate that the pregnancy rate is
very low when natural cycles are used for IVF. In one randomized study,
IVF success was compared using a natural cycle vs. a
clomiphene citrate-stimulated cycle. In the group of women randomized
to treatment in a natural cycle, 0.3 oocytes were retrieved per cycle
and no pregnancies occurred. In the group randomized to the
clomiphene-stimulated cycles, 1.8 oocytes were retrieved per cycle and
there was a 6% pregnancy rate (10). Even with refinements in natural
cycle IVF-ET, the average pregnancy rate per cycle initiated tends to
be in the 3–10% range (11, 12, 13). This low success rate makes natural
cycle IVF-ET unsuitable for clinical use, except in unusual clinical
circumstances such as reluctance of the female partner of the infertile
couple to use agents that stimulate ovarian follicular growth.
Clomiphene citrate as a single agent has been evaluated for ovarian
stimulation in IVF-ET in very few clinical trials. As noted above, use
of clomiphene citrate as a single agent for ovarian stimulation
resulted in a pregnancy rate per cycle of 6% (10). In other small
clinical trials the use of clomiphene for ovarian stimulation in IVF-ET
typically results in pregnancy rates per cycle in the range of 6%
(14). These pregnancy rates are far lower than rates achieved by
stimulation protocols that use exogenous gonadotropins for ovarian
stimulation. One explanation for these observations is that in IVF-ET,
clomiphene stimulation does not produce enough mature oocytes to
maximize the chance of pregnancy. Clomiphene has also been used in
conjunction with pulsatile administration of the native decapeptide
GnRH at doses of 14 µg every 90 min. The use of clomiphene followed
by pulsatile GnRH resulted in the stimulation of five to seven large
follicles and can be associated with pregnancy (15). Use of pulsatile
GnRH requires a programmable infusion pump and chronic parenteral
access. These factors have limited its use in IVF-ET.
Most IVF programs now utilize exogenous gonadotropins for ovarian
stimulation. Gonadotropin preparations that are commonly used include
human menopausal gonadotropins (Pergonal, Serono, Randolph, MA;
Humegon, Organon, West Orange, NJ;
Repronex, Ferring, Tarrytown, NY), highly purified
urinary FSH (Fertinex, Serono) and recombinant FSH
(Gonal-F-Serono,
Follistim-Organon). There are few randomized
clinical trials that evaluate the efficacy of exogenous gonadotropins
against clomiphene alone or natural cycles alone in IVF-ET. However, in
IVF-ET, ovarian stimulation regimens that include human gonadotropins
are routinely associated with pregnancy rates per cycle in the range of
20% to 50%. These pregnancy rates are far greater than those observed
when clomiphene is used alone or natural cycles are used for IVF-ET.
|
III. Pituitary Suppression Improves IVF-ET Success: GnRH Agonist
Analogues
|
|---|
Many randomized clinical trials demonstrate that in IVF-ET, the
combination of exogenous gonadotropin plus a GnRH agonist for
suppression of pituitary LH and FSH secretion is associated with higher
pregnancy rates than the use of gonadotropins without a GnRH agonist.
Most GnRH agonist analogues differ from the native decapeptide GnRH in
amino acid positions 6 and 10 and are resistant to degradation by
endopeptidases, thus giving them long half-lives. In addition, the GnRH
agonist analogues have high affinity for the receptor and long receptor
occupancy (16). The initial administration of GnRH agonist analogues is
associated with an increase in LH and FSH secretion (agonist phase).
Prolonged administration causes down-regulation and partial
desensitization of the pituitary GnRH receptor, resulting in the
suppression of LH and FSH secretion. The addition of GnRH agonist
analogues to regimens of gonadotropin stimulation for IVF-ET appears to
be associated with an increase in the number of oocytes retrieved, the
number of embryos transferred, and the clinical pregnancy rate.
For example, one study of IVF-ET demonstrated that treatment with a
GnRH agonist (buserelin) plus hMG resulted in more oocytes retrieved
(9.3 vs. 6.2), more embryos (4.3 vs. 2.8), and a
higher clinical pregnancy rate (20% vs. 14%) than
stimulation with hMG in the absence of buserelin (17). In another
clinical trial that used the same medications, treatment with a GnRH
agonist plus hMG resulted in a higher pregnancy rate than treatment
with hMG without a GnRH agonist (36% vs. 18%) (18). In a
meta-analysis of 15 clinical trials evaluating the impact of a GnRH
agonist on IVF-ET, Hughes and colleagues (19) reported that the
available data support the routine use of pituitary suppression in
assisted reproduction including IVF-ET and gamete intrafallopian tube
transfer (GIFT). The Hughes meta-analysis demonstrated that the use of
GnRH agonists in the ovarian stimulation protocols reduced cycle
cancellation rate by 67% and increased IVF-ET clinical pregnancy rate
by approximately 70%. Figure 1
is a
schematic representation of a common protocol combining GnRH agonist
suppression of pituitary gonadotropin secretion with exogenous
gonadotropin administration to stimulate ovarian follicular growth.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 1. Schematic representation of the long GnRH agonist
analogue protocol with step-down gonadotropin stimulation. [Reproduced
with permission from O. K. Davis and Z. Rosenwaks: In
vitro fertilization. In: Keye WR, Chang RJ, Rebar RW, Soules MR
(eds) Infertility: Evaluation and Treatment. WB Saunders, Philadelphia,
1995, p 763.]
|
|
The biological mechanisms that subserve these clinical findings are not
fully characterized. However, with gonadotropin stimulation of ovarian
multifollicular development, it is common to observe premature surges
of LH. Surges of LH that occur before full follicle maturity may cause
premature luteinization of the granulosa cells, which may be detected
in some cases by an increase in circulating progesterone before full
follicle maturation. In addition, a premature surge of LH may disrupt
oocyte maturation (20, 21). The suppression of pituitary gonadotropin
secretion with a GnRH analogue permits longer ovarian stimulation,
which results in the development of a greater number of large mature
follicles. In turn, this permits the retrieval of a greater number of
competent oocytes, which increases the number of healthy embryos
created and thereby improves the pregnancy rate in IVF.
|
IV. Pituitary Suppression Improves IVF-ET Success: GnRH Antagonist
Analogues
|
|---|
A major problem with the GnRH agonist analogues is that LH
secretion is stimulated at the initiation of treatment. In some women,
prolonged daily use of a GnRH agonist may cause a small increase in LH
secretion directly after the daily administration of the GnRH agonist.
In turn, residual pituitary LH secretion stimulates ovarian androgen
production, which may have detrimental effects on follicular
development and endometrial function (22). The GnRH antagonists offer
the possibility of acutely suppressing LH secretion without an initial
increase in LH secretion (23, 24). The GnRH antagonists have been used
either as small daily doses (cetrorelix, 0.25 mg daily sc injection)
during the early or midfollicular phases of the stimulation cycle (25)
or as a single dose (cetrorelix, 3 mg sc) on approximately cycle day 8
(26). Both regimens block the occurrence of spontaneous LH surges.
The GnRH antagonists suppress LH secretion in a dose-dependent manner.
At small doses, the suppression of LH is minimal. At large doses,
near-complete suppression of LH can be achieved. In one study the
impact of six doses of the GnRH antagonist ganirelix on LH secretion
and IVF outcomes was studied (27). Ganirelix produced a dose-dependent
suppression of LH (Table 1). Ganirelix
also produced a dose-dependent suppression of both androstenedione and
estradiol. The larger doses of ganirelix were associated with a
markedly reduced pregnancy rate. These data support the importance of
both FSH and LH in the development of the ovarian follicle. Ovarian
estradiol production requires the coordinated action of LH on the
ovarian theca to stimulate the production of androstenedione and FSH on
the granulosa cells to stimulate the aromatization of the
androstenedione to estrogen. Large doses of GnRH antagonists can nearly
ablate LH secretion, resulting in a reduction in follicular
androstenedione and estradiol production. When LH secretion is
completely blocked, pregnancy rates appear to be reduced. These
findings support the hypothesis that both high LH levels (premature LH
surge) and very low LH levels can be associated with low pregnancy
rates in IVF-ET. A major advantage of the GnRH antagonists is that they
can acutely reduce LH secretion. This effect is not possible with the
GnRH agonist analogues. The ultimate role of the GnRH antagonists in
IVF-ET will require large prospective studies to directly compare the
efficacy of the GnRH agonists vs. GnRH antagonists in
IVF-ET.
A major goal of reproductive endocrinologists is to assist infertile
couples to build their families. As the cost of IVF-ET decreases and
the success of this procedure increases, the importance of IVF-ET in
the treatment of infertility will continue to increase. The data
reviewed in this article suggest that exogenous gonadotropins and GnRH
analogues are the key hormones required to maximize IVF-ET success.
|
Footnotes
|
|---|
Address reprint requests to: Robert Barbieri, M.D., Department of Obstetrics and Gynecology, ASB1–3, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 USA. e-mail: RLBarbieri@BICS.BWH.Harvard.edu
1 Supported in part by NIH Grant U54HD-29164. 
|
References
|
|---|
-
Heape W 1890 Preliminary note on the
transplantation and growth of mammalian ova within a uterine foster
mother. Proc R Soc Lond 48:457–458
-
Rock J, Menkin MF 1944 In vitro
fertilization and cleavage of human ovarian eggs. Science 100:105–107[Free Full Text]
-
Chang MC 1959 Fertilization of rabbit ova in
vitro. Nature 184:466–467
-
Edwards RG, Bavister BD, Steptoe PC 1969 Early
stages of fertilization in vitro of human oocytes matured
in vitro. Nature 221:632–635[CrossRef][Medline]
-
Edwards RG, Steptoe PC, Purdy JM 1970 Fertilization and cleavage in vitro of preovulatory human
oocytes. Nature 227:1307–1309[CrossRef][Medline]
-
Steptoe PC, Edwards RG, Purdy JM 1980 Clinical
aspects of pregnancies established with cleaving embryos grown in
vitro. Br J Obstet Gynecol 87:757–768[Medline]
-
Dor J, Seidman DS, Ben-Shlomo I, Levran D, Ben-Rafael
Z, Mashiach S 1996 Cumulative pregnancy rate following in
vitro fertilization: the significance of age and infertility
etiology. Hum Reprod 11:425–428
-
Toner JP, Philput CB, Jones GS, Muasher SJ 1991 Basal follicle stimulating hormone level is a better predictor of
in vitro fertilization performance than age. Fertil Steril 55:784–791[Medline]
-
Scott Jr RT, Hofmann GE 1995 Prognostic assessment
of ovarian reserve. Fertil Steril 63:1–11[Medline]
-
MacDougall MJ, Tan SL, Hall V, Balen A, Mason BA, Jacobs
HS 1994 Comparison of natural with clomiphene citrate stimulated
cycles in in vitro fertilization: a prospective randomized
trial. Fertil Steril 61:1052–1057[Medline]
-
Seibel MM, Kearnan M, Kiessling A 1995 Parameters
that predict success for natural cycle in vitro
fertilization-embryo transfer. Fertil Steril 63:1251–1254[Medline]
-
Claman P, Domingo M, Garner P, leader A, Spence JE 1993 Natural cycle in vitro fertilization-embryo transfer at
the University of Ottowa: an inefficient therapy for tubal infertility.
Fertil Steril 60:298–302[Medline]
-
Zayed F, Lenton EA, Cooke ID 1997 Natural cycle
in vitro fertilization in couples with unexplained
infertility: impact of various factors on outcome. Hum Reprod 12:2402–2407[Abstract/Free Full Text]
-
Hurd WW, Randolph Jr JF, Christman GM, Ansbacher R,
Menge AC, Gell JS 1996 Luteal support with both estradiol and
progesterone after clomiphene citrate stimulation for in
vitro fertilization. Fertil Steril 66:587–592[Medline]
-
Shaw RW, Ndukwe G, Imoedemhe D, Burford G, Chan R 1986 Stimulation of multiple follicular growth for in vitro
fertilization by administration of pulsatile luteinizing
hormone-releasing hormone during the midfollicular phase. Fertil Steril 46:135–137[Medline]
-
Conn PM, Crowley Jr WF 1994 Gonadotropin-releasing
hormone and its analogs. Annu Rev Med 45:391–405[CrossRef][Medline]
-
Lejeune B, Barlow P, Puissant F, Delvigne A,
Vanrysselberge M, Leroy F 1990 Use of buserelin acetate in an
in vitro fertilization program; a comparison with classical
clomiphene citrate-human menopausal gonadotropin treatment. Fertil
Steril 54:475–481[Medline]
-
MacNamee MC, Howles CM, Edwards RG, Taylor PJ, Elder
KT 1989 Short term luteinizing hormone agonist treatment
prospective trial of a novel ovarian stimulation regimen for in
vitro fertilization. Fertil Steril 52:264–269[Medline]
-
Hughes EG, Fedorkow DM, Daya S, Sagle MA, Van de Koppel
P, Collins JA 1992 The routine use of gonadotropin releasing
hormone agonists prior to in vitro fertilization and gamete
intrafallopian transfer: a meta-analysis of randomized controlled
trials. Fertil Steril 58:888–896[Medline]
-
Yen SSC 1983 Clinical application of gonadotropin
releasing hormone and gonadotropin releasing hormone analogs. Fertil
Steril 39:257–266[Medline]
-
MacLachlan V, Besanko M, O’Shea F, Wade H, Wood C,
Trounson A, Healy DL 1989 A controlled study of luteinizing
hormone releasing hormone agonist (buserelin) for the induction of
folliculogenesis before in vitro fertilization. N Engl
J Med 320:1233–1237[Abstract]
-
Martin KA, Hornstein MD, Taylor AE, Hall JE, Barbieri
RL 1997 Exogenous gonadotropin stimulation is associated with
increases in serum androgen levels in in vitro
fertilization-embryo transfer cycles. Fertil Steril 68:1011–1016[CrossRef][Medline]
-
Frydman R, Cornel C, de Ziegler D, Taieb J, Spitz
IM, Bouchard P 1991 Prevention of premature luteinizing hormone
and progesterone rise with a gonadotropin releasing hormone antagonist,
Nal-Glu, in controlled ovarian hyperstimulation. Fertil Steril 56:923–927[Medline]
-
Diedrich K, Diedrich C, Santos E, Zoll C, Al-Hasani S,
Reissmann T, Krebs D, Klingmuller D 1994 Suppression of the
endogenous luteinizing hormone surge by the gonadotropin releasing
hormone antagonist cetrorelix during ovarian stimulation. Hum Reprod 9:788–791[Abstract/Free Full Text]
-
Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van
Steirteghem A, Devroey P 1997 Comparison of different doses of
gonadotropin releasing hormone antagonist cetrorelix during controlled
ovarian hyperstimulation. Fertil Steril 67:917–922[CrossRef][Medline]
-
Olivennes F, Alvarez S, Bouchard P, Franchin R,
Salat-Baroux J, Frydman R 1998 The use of a GnRH antagonist
(Cetrorelix-R) in a single dose protocol in IVF-embryo transfer:
a dose finding study of 3 vs. 2 mg. Hum Reprod 13:2411–2414[Abstract/Free Full Text]
-
Mannaerts B, Devroey P, Abyholm T, Diedrich K,
Hillensjo T, Hedon B, Itskoviteldor J, Kahn J, Naether O, Oivennes F,
Pavlou S, Tarlatzis B, Westergaard L, Vanderheijden B, Coelingh H 1998 A double-blind randomized dose fining study to assess the efficacy
of the gonadotropin releasing hormone antagonist ganirelix (Org 37462)
to prevent premature luteinizing hormone surges in women undergoing
ovarian stimulation with recombinant follicle stimulating hormone
(Puregon-R). Hum Reprod 13:3023–3031[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
J. Balasch, F. Fabregues, J. Penarrubia, F. Carmona, R. Casamitjana, M. Creus, D. Manau, G. Casals, and J. A. Vanrell
Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH
Hum. Reprod.,
July 1, 2006;
21(7):
1884 - 1893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser
The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization
Endocr. Rev.,
April 1, 2006;
27(2):
170 - 207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Balasch, E. Vidal, J. Penarrubia, R. Casamitjana, F. Carmona, M. Creus, F. Fabregues, and J. A. Vanrell
Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH
Hum. Reprod.,
August 1, 2001;
16(8):
1636 - 1643.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
I. Introduction
