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Modulating Fertility Outcome in Assisted Reproductive
Technologies By the Use of Dydrogesterone
December 14, 2007
By Patki, Ameet Pawar, Vijay C
Abstract The aim of the present study was to evaluate dydrogesterone for luteal-phase support in
assisted reproductive technologies (ART) and to compare it with micronized vaginal progesterone. All
patients underwent long-term downregulation with gonadotropin-releasing hormone agonists. In phase
I, 498 patients were divided into three groups: long protocol and not at risk of ovarian hyperstimulation
syndrome (OHSS) (group A); long protocol and at risk of OHSS (group B); and those in a donor oocyte
program (group C). All patients received micronized progesterone 600 mg/ day, vaginally. They were
also randomized to dydrogesterone 20 mg/ day (n = 218) or placebo (n = 280). The pregnancy rate was
higher with dydrogesterone than with placebo in group A (33.0% vs. 23.6%), group B (36.8% vs. 28.1%)
and group C (42.9% vs. 15.6%; p
Keywords: Assisted reproductive technologies, dydrogesterone, fertility, progesterone, luteal-phase
support
Introduction
Aspiration of the granulosa cells during oocyte retrieval and the use of gonadotropin-releasing hormone
agonists (GnRHa) in treatments using assisted reproductive technologies (ART) interfere with the
production of progesterone, which is necessary for successful implantation of the embryo during the
luteal phase [1,2].
A Cochrane review suggests that luteal-phase support with human chorionic gonadotropin (hCG) or
progesterone after assisted reproduction results in an increased pregnancy rate [3]. However, hCG does
not provide better results than progesterone and is associated with a greater risk of ovarian
hyperstimulation syndrome (OHSS) when used with GnRHa. Apart from the need for frequent dosing at
intervals of 3-4 days, it also increases luteal estradiol (E^sub 2^) to undesirable levels, thereby upsetting
the E^sub 2^/ progesterone ratio.
Thus, progesterone would appear to be the obvious choice over hCG in the management of luteal-phase
support. Progesterone acts via its own receptor to produce a mediator protein known as
progesteroneinduced blocking factor (PIBF). PIBF favors the development of human T helper (Th) cells
producing Th2-type cytokines and promotes the production of interleukin (IL)-4, while inhibiting
embryotoxic Thl cytokine production [4].
Over the past few years, a variety of progestogens have been used to improve pregnancy outcome.
These include 17alpha- hydroxyprogesterone and micronized progesterone. As far as the route of
administration is concerned, the intravaginal route is as effective as the intramuscular route. However,
both have local sideeffects and hence are not popular among patients.
Dydrogesterone, a retroprogesterone derivative, has good oral bioavailability combined with all of the
clinical properties of endogenous progesterone, as well as being devoid of local side- effects. It has been
used effectively for endogenous progesterone deficiency, premenstrual syndrome, menstrual
abnormalities, endometriosis, infertility, and in combination with estrogen in hormone replacement
therapy. Dydrogesterone has demonstrated immunomodulatory effects that are successfully utilized in
patients with recurrent spontaneous abortion. Hence its role in modulating fertility outcomes in ART
cycles was investigated in the current trial [1,4]. The aim of the trial was to evaluate the role of
dydrogesterone for luteal-phase support in ART cycles and to compare the efficacy of dydrogesterone
with that of micronized vaginal progesterone.
Methods
The study was carried out over a period of two years, from January 2003 to December 2005, at the
ReGenesis Centre for Assisted Reproduction, Endoscopy & Foetal Medicine in Mumbai, India. The ethical
committee approved the trial and informed consent was obtained from all the patients who volunteered
to enroll in the study after extensive counseling. The study involved two phases.
Phase I
Phase I was conducted from January 2003 to December 2004. All patients underwent long-term
downregulation with a GnRHa for a minimum of 10 days. The patients were divided into three groups:
group A included all patients on a long protocol who were not at risk of OHSS; group B included all
patients who were on a long protocol but who were at risk of OHSS; and group C included all patients
enrolled in a donor oocyte program. The patients in group C were started on oral estradiol valerate
(Progynova(R) German Remedies Mumbai India) in increasing doses from the day of stimulation of die
donor with gonadotropins. Patients who were on any other protocol were excluded from the study. The
groups were matched for demographic factors including age, social status, infertility factors and years of
infertility. All patients received 600 mg micronized progesterone (Utrogestan(R) Solvay Pharmaceuticals
India) vaginally from the day of oocyte retrieval. In addition, patients were randomized to receive either
20 mg dydrogesterone or placebo daily from the day of embryo transfer until determination of serum
beta-hCG. If serum beta-hCG was > 50 mlU/ml, treatment was continued. Ultrasonography was
performed after 3 weeks to confirm a viable pregnancy; only intrauterine viable pregnancies were
considered positive.
Phase II
Phase II of the trial was initiated after confirming the results of phase I, and was carried out over a
period of one year from January 2004 to December 2005. All patients underwent long-term
downregulation with a GnRHa for a minimum of 10 days. As in phase I, the patients were then divided
into three groups: group D included those on a long protocol who were not at risk of OHSS; group E
included those who were on a long protocol but who were at risk of OHSS; and group F included
recipients in a donor oocyte program who received increasing doses of estradiol valerate (Progynova(R))
from the day of stimulation of the donor. The groups were matched for demographic factors. All
patients were randomized to receive either 600 mg micronized progesterone vaginally or 30 mg
dydrogesterone orally daily from the day of oocyte retrieval. Serum beta-hCG was measured 14 days
after embryo transfer; if the level was > 50 mlU/ ml, treatment was continued. Viable pregnancies were
confirmed by ultrasonography after 3 weeks.
Statistical analyses
Statistical analyses were performed using the chi^sup 2^ test.
Results
Phase I
A total of 498 patients were included in phase I; 315 patients were on a long protocol and had no risk of
OHSS (group A), 89 patients were on a long protocol and had a risk of OHSS (E^sub 2^ > 2000 pg/ml;
group B), and 94 were recipients in a donor oocyte program (group C) (Table I). All patients received
micronized progesterone with either dydrogesterone (n = 218) or placebo (n = 280).
The pregnancy rate was consistently higher in the dydrogesterone group. As shown in Table II, the
pregnancy rate in group A was 33.0% in the dydrogesterone group and 23.6% in the placebo group (p =
not significant). In group B, the pregnancy rate was 36.8% with dydrogesterone and 28.1 % with placebo
(p = not significant). In group C, the pregnancy rate was statistically significantly higher in the
dydrogesterone group than in the placebo group (42.9% vs. 15.6%; p
Table I. Patients included in phase I.
Phase II
A total of 675 patients were included in phase II; 450 were on a long protocol and had no risk of OHSS
(group D), 105 were on a long protocol and had a risk of OHSS (group E), and 120 were recipients in a
donor oocyte program (group F) (Table III). The patients were randomized to receive either
dydrogesterone (n = 366) or micronized progesterone (n = 309).
As shown in Table IV, the pregnancy rate was statistically significantly higher with dydrogesterone than
with micronized progesterone in group D (39.1% vs. 26.7%; p
Table II. Pregnancy rates in phase I.
Table III. Patients included in phase II.
Table IV. Pregnancy rates in phase II.
Discussion
For mammalian pregnancy to succeed substantial physiological adjustments are required in the mother;
these changes result from signals passing between the conceptus (especially the trophoblast) and the
mother throughout pregnancy. Every system in the body is affected, including the immune system,
which is part of a complex signaling procedure between cells that has developed the ability to recognize
self and non-self. Data from inbred mice, and less adequate evidence from human pregnancy, suggest
that the maternal immune response may be modulated away from cellular responses and toward
humoral immunity, not all of which depends on recognition of major histocompatibility complex
antigens [5]. For example, antibody production during pregnancy tends toward the immunoglobulin G
(IgG) 1 isotype and away from the complementfixing IgG2a isotype, particularly for antibodies against
fetal alloantigens. In addition, cytotoxicity mediated by non-specific natural killer cells seems to be
dampened by inhibition of Thl cells, which produce cytokines such as IL-2 and interferon-gamma
(IFN^sub 7^). Activation of natural killer cells in pregnant mice is known to result in fetal resorption. This
suggests that the bias towards the production of Th2 cells in pregnancy may be a protective mechanism
to promote fetal survival (Figure 1). Dudley and colleagues have observed that the cytokines produced
by activated lymphocytes during murine pregnancy tend to favor antibody production over cytotoxic
responses [6]. This effect is most prominent in the uterine decidua, but is also seen systemically. These
authors also contend that the regulation of cytokine production during normal pregnancy changes as a
result of the pregnancy itself, and not in response to specific fetopaternal antigens [6]. It has been
shown that, in women with recurrent spontaneous abortion, dydrogesterone inhibits the production of
the Thl cytokines IFNy and tumor necrosis factor- alpha (TNFalpha) from lymphocytes and upregulates
production of the Th2 cytokines IL-4 and IL-6, thereby inducing a Thl to Th2 cytokine shift [4] (Figure 2).
The effect of dydrogesterone can be blocked by the progesterone-receptor antagonist mifepristone,
indicating that dydrogesterone acts via the progesterone receptor. Dydrogesterone also induced PIBF
production [4]. Thus, as well as having progestogenic properties, dydrogesterone has been shown to
have immunomodulating effects that are favorable for pregnancy (Figure 3). In the current trial we
therefore incorporated dydrogesterone into ART cycles in order to evaluate its role in luteal-phase
support.
Figure 1. Immunological reactions during pregnancy.
Figure 2. Immunological reactions in recurrent/spontaneous abortion.
Figure 3. Immunological reactions during successful pregnancy.
In phase I of the trial, we included dydrogesterone in our standard post-pickup protocol for in vitro
fertilization (IVF)/ embryo transfer. The patients receiving a long protocol were divided into those
without and those with a risk of OHSS, while the third group comprised patients who were enrolled in a
donor oocyte program. The pregnancy rates in the first two groups were somewhat higher in patients
receiving micronized progesterone plus 20 mg dydrogesterone than in those given micronized
progesterone plus placebo, although the differences were not statistically significant. In contrast, in
patients enrolled in a donor oocyte program, the pregnancy rate was statistically significantly higher in
those treated with dydrogesterone than in those given placebo. Thus, after confirming that
dydrogesterone does not reduce the pregnancy rate, phase II of the study was initiated.
In phase II, the patients were divided into three groups similar to those used in phase I and were
randomized to receive either micronized progesterone or 30 mg dydrogesterone only. In all three
groups, the pregnancy rates were statistically significantly higher in patients treated with
dydrogesterone than in those given micronized progesterone. Belaisch-Allart and associates have also
evaluated the effect of dydrogesterone supplementation in an IVF program [7]. In a double-blind study
comparing dydrogesterone (125 transfers) with placebo (133 transfers), the pregnancy rate was 21.6%
vs. 15.0% per transfer cycle with dydrogesterone and placebo, respectively. Although there was no
statistically significant difference between the groups, taking into account the usual success rate in IVF
programs of 15-20%o, a difference of 5% would be significant only with two groups of 1500 subjects
each.
In conclusion, dydrogesterone is an orally active and effective drug for use in luteal-phase support in
ART cycles. The optimal dose of dydrogesterone in luteal-phase support would appear to be 30 mg/ day,
although further studies are necessary to confirm this. Dydrogesterone is superior to micronized
progesterone as it resulted in a higher pregnancy rate and patient compliance is generally better with an
orally administered than with a vaginally administered drug. Multicenter, randomized, placebocontrolled studies are, however, necessary to confirm these findings.
References
1. Chakravarty BN, Shirazee HH, Dam P, Goswami SK, Chaterjee R, Ghosh S. Oral dydrogesterone versus
intravaginal micronized progesterone as luteal phase support in assisted reproductive technology cycles:
results of a randomised study. J Steroid Biochem Mol Biol 2005;97:416-420.
2. Gidley-Baird AA, O’Neill C, Sinosich MJ, Porter RN, Pike IL, Saunders DM. Failure of implantation in
human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/ estrogen
ratios in humans and mice. Fertil Steril 1986;45:69-74.
3. Daya S, Gunby J. Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev
2004;(3):CD004830.
4. Raghupathy R, Almutawa E, Makhseed M, Azizieh F, Szekeres- Bartho J. Modulation of cytokine
production by dydrogesterone in lymphocytes from women with recurrent miscarriage. Br J Obstet
Gynaecol 2005;112:1096-1101.
5. Wegmann TG, Lin H, Guilbert L Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal
relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353- 356.
6. Dudley DJ, Chen C-L, Mitchell MD, Daynes RA, Araneo BA. Adaptive immune responses during murine
pregnancy: pregnancy- induced regulation of lymphokine production by activated T lymphocytes. Am J
Obstet Gynecol 1993;168:1155-1163.
7. Belaisch-Allart J, Testart J, Fries N, Forman RG, Frydman R. The effect of dydrogesterone
supplementation in an IVF programme. Hum Reprod 1987;2:183-185.
AMEET PATKI & VIJAY C. PAWAR
ReGenesis, Centre for Assisted Reproduction, Endoscopy & Foetal Medicine, Reliance Life Sciences,
Worli, Mumbai, India
(Received 17 May 2007; accepted 5 September 2007)
Correspondence: A. Patki, ReGenesis, Reliance Life Sciences, 3rd Floor Sadhana House, 570 Pandurang
Budhkar Marg, Worli, Mumbai 400018, India. Tel: 91 22 66120804/09. Fax: 91 22 66120800. E-mail:
[email protected]
Copyright Taylor & Francis Ltd. Oct 2007
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