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The Luteal Phase and Ovarian Stimulation
How to Define a Luteal-phase Defect? How to Support the Luteal Phase
Although LPDs have been clearly described in research settings, the The Role of Progesterone in the Luteal Phase
diagnosis remains controversial.
12
A defective luteal phase in a Csapo et al. demonstrated the importance of progesterone during
natural cycle was defined as the serum mid-luteal progesterone the first few weeks of a pregnancy. In their initial study, the removal
levels being below 10ng/ml.
12
However, mid-luteal progesterone of the corpus luteum before seven weeks’ gestation led to
levels do not always reflect the endometrial maturation.
13
Therefore, pregnancy loss.
29
However, the authors found that pregnancy could
in the literature the most reasonable consensus of a defective luteal be maintained even after removal of the corpus luteum by external
phase is a lag of more than two days in endometrial histological administration of progesterone.
30
Progesterone also promotes local
development compared with the expected day of the cycle.
14,15
vasodilatation and uterine musculature quiescence by inducing
nitric oxide synthesis in the decidua.
31
Inadequate uterine
Ovarian Stimulation and the Luteal Phase contractility may lead to ectopic pregnancies, miscarriages,
With the advent of ovarian stimulation for in vitro fertilisation (IVF), retrograde bleeding with dysmenorrhoea and endometriosis.
31
The
it has been established that the luteal phase of all stimulated IVF uterine-relaxing properties of progesterone were supported by a
cycles are abnormal.
16
The aetiology of LPD in stimulated IVF cycles study of IVF embryo transfer outcomes by Fanchin et al.
32
This study
has been debated for more than two decades. Initially, it was investigated the consequences of uterine contractions (UC) as
thought that the removal of large quantities of granulosa cells visualised by ultrasound (US) during embryo transfer. Results
during oocyte retrieval (OR) might diminish the most important indicated that a high frequency of uterine contractions on the day
source of progesterone synthesis by the corpora lutea, leading to a of embryo transfer hindered transfer outcome, possibly by expelling
defect of the luteal phase. However, this hypothesis was disproved embryos out of the uterine cavity. A negative correlation between
when it was established that the aspiration of a pre-ovulatory UC frequency and progesterone concentrations was detected,
oocyte in a natural cycle neither diminished the luteal phase steroid underlining the benefits of progesterone in IVF.
32
secretion nor shortened the luteal phase.
17
Luteal-phase Support
Another proposal suggested that the prolonged pituitary recovery Progesterone
that followed the gonadotropin-releasing hormone (GnRH) agonist Currently available formulations of progesterone include oral,
co-treatment designed to prevent spontaneous LH rise in stimulated vaginal and intramuscular (IM).
3
Progesterone administered orally is
cycles, resulting in a lack of support for the corpus luteum, would subjected to first-pass pre-hepatic and hepatic metabolism. This
cause an LPD.
18
It was also suggested that the hCG administered for metabolic activity results in progesterone degradation to its 5α and
the final oocyte maturation in stimulated IVF cycles could potentially 5α-reduced metabolites.
3
Parenteral administration (vaginal, rectal
cause an LPD by suppressing LH production via a short-loop and IM) of progesterone surpasses the metabolic consequences of
feedback mechanism.
19
However, the administration of hCG did not orally administered progesterone.
33
downregulate LH secretion in the luteal phase of normal,
unstimulated cycles in normo-ovulatory women.
20
Oral Progesterone
Oral micronised progesterone was used for luteal support in IVF
The introduction of GnRH antagonists in IVF raised speculations with poor results until the end of the 1980s.
34
Devroey et al.
35
and
that a rapid recovery of pituary function
21
would obviate Bourgain et al.
36
reported an absence of the secretory
the need for luteal-phase supplementation.
22
However, various transformation of the endometrium in patients with premature
studies of GnRH antagonist co-treatment in IVF have since found ovarian failure (POF) who had been treated with oral micronised
different results. Luteolysis is also initiated prematurely in progesterone compared with patients treated with IM injections or
antagonist-co-treated IVF cycles, resulting in a significant reduction vaginal micronised progesterone. This finding suggests that oral
in the luteal-phase length and compromising the chances administration reduced the hormone’s bioavailibility. To overcome
for pregnancy.
23,24
Despite the rapid recovery of pituitary function this problem, dydrogesterone (DG) was introduced to support the
in GnRH antagonist protocols,
25
luteal-phase supplementation luteal phase of stimulated IVF cycles.
37
DG, a retroprogesterone with
remains mandatory.
26
good oral bioavailability, is a biologically active metabolite of
progesterone and has an anti-oestrogenic effect on the
It appears that the main cause of LPD observed in stimulated IVF endometrium, achieving the desired secretory transformation.
38,39
cycles is related to the multifollicular development achieved during Recently, Chakravarty et al.
39
undertook a prospective, randomised
ovarian stimulation, which completely alters the hormonal study (n=430) that compared the efficacy, safety and tolerability of
environment.
27
It can be postulated that one of the main causes of oral DG with vaginal micronised progesterone as luteal-phase
the LPD in stimulated IVF cycles is supra-physiological levels of support after IVF. Both DG and progesterone were associated with
steroids secreted by a high number of corpora lutea during the similar rates of successful pregnancy (24.1 versus 22.8%,
early luteal phase, which directly inhibits LH release via negative respectively; p=0.81).
feedback actions at the hypothalamic–pituary axis level.
27
Prior to the initiation of a large randomised controlled trial to
The hCG administered for final oocyte maturation covers the luteal compare these two treatment schemes for IVF cycles, our group
phase for a maximum of eight days.
27
Under normal circumstances, performed a pilot study in patients with premature ovarian failure
thereafter LH would stimulate the corpora lutea, but due to the (POF) who were on the waiting list of our oocyte donation
suppressed LH levels in IVF cycles there is no stimulus of the programme. Patients were treated with oral DG and vaginal
corpora lutea. The LH levels measured during the luteal phase of progesterone in consecutive cycles as progestins in protocols of
stimulated cycles are below the detection limit.
28
cyclic steroid replacement after endometrial priming with E
2
.
40
The
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