Juniper Publishers : Customized Assisted Reproduction Enhancement (CARE) for Women with Extremely Poor Ovarian Reserve (EPOR)
JUNIPER PUBLISHERS- JOURNAL OF GYNECOLOGY AND WOMEN’S
HEALTH
Journal of Gynecology and Women’s Health-Juniper
Publishers
Authored by Jan Tesarik*
Abstract
The ovarian reserve is usually evaluated by
determining serum levels of anti-Mullerian hormone (AMH) and ovarian
antral follicle count. It is widely accepted that women with moderately
impaired ovarian reserve (AMH levels between 0.2ng/ml and 1.1ng/ml) have
a poor chance of having a child by in vitro fertilization (IVF) because
of a low response to ovarian stimulation. However, conflicting data
have been published as to predicting the chances of women with extremely
poor ovarian reserve (AMH ≤0.2ng/ml). In many clinics in the world
women with extremely poor ovarian reserve (EPOR) are not admitted for
IVF assuming that their chance of success is zero.
This report shows that a relatively high clinical
pregnancy rate (23%) and delivery rate (18%) can be achieved in this
category of women by using customized assisted reproduction enhacement
(CARE). In the CARE protocol the patient treatment is personally
tailored during the pre-stimulation phase, ovarian stimulation, the
embryological laboratory work and the patient follow-up after embryo
transfer.
Introduction
Ovarian reserve is a term that refers to the quantity
and quality of the pool of ovarian non-growing follicles (NGF) which
can be recruited for growth and yield viable oocytes [1].
The ovarian reserve, represented by several million NGF at birth,
diminishes progressively with the age, mainly due to follicle death by
apoptosis until menopause is reached at an average age of 50-51 years,
with approximately 1,000 NGF left. Even though the reduction of the
ovarian reserve is age-related, there is significant interindividual
variability in its timing. Consequently, the actual size of the NGF pool
cannot be accurately predicted by the woman’s age.
Several predictors of the ovarian reserve have been
suggested. Recently, serum levels of anti-Mullerian hormone (AMH) are
used as the most common marker. The consensus meeting of the European
Society of Human Reproduction and Embryology (ESHRE) working group on
poor ovarian reserve (POR), held in 2011 in Bologna, suggested the serum
AMH level of 1.1ng/ml as cutoff to be used for POR diagnosis [2]. Within the group of POR women, those with AMH levels ≤0.2 ng/ml are considered to have extremely poor ovarian reserve (EPOR) [3].
There are controversial opinions about the chance of
women with EPOR in an eventual IVF attempt. In spite of the fact that
one study has reported that women with EPOR still have 4.4% ongoing
pregnancy rates per treatment cycle and 16% cumulative ongoing pregnancy
rates after repeated cycles, other authors could not establish any
pregnancies in 26 women up to 44 years of age with AMH concentrations
≤0.15ng/ml using a range of different treatment approaches [4]. In many European countries women with EPOR are not admitted for IVF by infertility clinics, in particular in public hospitals.
The present report describes a high ongoing pregnancy
and delivery rate in women with EPOR achieved with the use of a series
of rules and measures, named "Customized Assisted Reproduction
Enhancement” (CARE). According to the CARE protocol, the treatment of
EPOR patients is systematically adapted to the individual condition of
each of them at different phases of the treatment, including the period
preceding the beginning of ovarian stimulation, the ovarian stimulation,
embryological laboratory work, and the patient follow-up after embryo
transfer.
Patients and Methods
This study involves 78 treatment cycles, performed in
78 women with AMH levels ≤0.2 ng/ml in the period between January 2012
and March 2016. The Women's mean age was 37 years, ranging between 32
and 40 years. If a treatment attempt was repeated in the same woman,
only the first attempt is included in this study, and cumulative success
rates are not presented. Among the women actually treated with CARE
protocol in this period, those over 40 years of age and those with
endometriosis are not included in this report.
Previously described methods for ovarian stimulation,
oocyte and embryo handling and embryo transfer [5] were used with small
modifications, as described below. The GnRH antagonist protocol was
used in all cases. IVF was performed by intracytoplasmic sperm injection
(ICSI).
CARE Protocol
The customization of the treatment protocol for women
with EPOR concerns different subsequent phases of the treatment,
starting 1-3 months before the beginning of ovarian stimulation, the
ovarian stimulation itself, laboratory work related to IVF, embryo
culture and handling, and the period after embryo transfer including the
first three months of pregnancy (Table 1).
The special measures adopted in the CARE protocol are of two types: (1)
those related to the condition of EPOR, and thus applied to all
patients in this condition, and (2) those tailored to each individual
patient, and thus variable from patient to patient.
The common measures in the pre-stimulation phase
included the treatment with dehydroepiandrosterone (DHEA), at the daily
dose of 75mg split in three 25mg doses, during 6-8 weeks preceding the
onset of ovarian stimulation, one cycle of contraceptive pill before the
stimulation, and 3-5 days oral estradiol priming (1mg estradiol daily)
from day one of the cycle following the pill until the beginning of the
stimulation. The uterine cavity was evaluated in each woman by
conventional or virtual hysteroscopy, and eventual pathologies were
corrected when necessary [6].
The injection of 10,000 IU HCG was done in cases with very low plasma
testosterone levels (<0.3ng/ml) during the cycle preceding ovarian
stimulation (Table 1).
In the ovarian stimulation phase, growth hormone (GH)
and low-dose aspirin were used, together with gonadotropins, in all
patients as described [7].
Other aspects of the stimulation regimen were flexible, adapted to the
patient's response to treatment. The ratio of FSH and LH activities in
the exogenous gonadotropin formulas used for ovarian stimulation was
continuously adapted during stimulation according to repeated measures
of serum estradiol and LH levels, and the part of the LH component was
increased when the LH values fell below 1 IU/l [8].
The timing of the HCG trigger with respect to the time of ovarian
puncture was decided individually, and ranged between 36h and 37h,
according to the size of the antral follicles on the day of trigger.
When one or more medium-sized follicles were present, in addition to a
large follicle, a second HCG trigger was applied approximately 24h
before ovarian puncture in order to facilitate the release of
cumulus-oocyte complexes from these smaller follicles.
As to the laboratory work for ICSI, the deformation
of the oocyte zona pellucida under the pressure of the injection needle
was evaluated while the first oocyte was being injected. In case of
excessive deformation, without needle penetration, the injection
procedure was halted and all available oocytes were subsequently
injected by laser-assisted ICSI [9].
Particular attention was paid to the period after
embryo transfer with frequent hormonal controls throughout the whole
first trimester Serum concentrations of estradiol and progesterone were
determined on the day of embryo transfer and then every 3 days until the
pregnancy test. Hormonal supplementation of the luteal phase [5]
was continuosly adapted according to the last hormone measures, with
daily doses of orally administered estradiol and vaginally administered
progesterone going up to 6 mg and 800 mg, respectively, in cases in
which the serum concentrations of these hormones tended to decrease. In
addition, GnRH agonist was used for luteal phase support in all cases [5,10].
Results and Discussion
The results of IVF obtained with the CARE protocol are summarized in Table 2.
Out of the 78 started treatment cycles, 2 were canceled before ovarian
puncture because of the lack of response to stimulation, and no oocytes
were recovered by ovarian puncture in other 2 women. In one case the
cycle had to be canceled because of fertilization failure. In the
remaining 73 cases embryo transfer was performed (Table 2).
The treatment resulted in 18 clinical pregnancies and 14 deliveries,
corresponding to clinical pregnancy rate of 23% and delivery rate of 18%
per started treatment cycle. All deliveries resulted in the birth of a
single child, corresponding to live birth rate of 13% (Table 2).
Out of the 78 women included in this study, 41 had previously been
denied IVF treatment in other clinics in Spain, France and Italy,
claiming that egg donation was the only way they can get pregnant. The
present results demonstrate the feasibility of childbirth with one's own
eggs in this condition, although the probability of birth is low (23%)
as compared to 80% in our current egg donation program.
The success rates achieved with the CARE protocol are
relatively high for this patient condition, as compared with other
studies dealing with women in a similar situation [3,11].
CARE puts together different treatments and measures, some of which,
when applied alone, have been shown previously to improve IVF results in
women with POR.
[12].
Steroid hormone priming is believed to help synchronize the population
of recruitable follicles before the start of stimulation [13].
We also observed an improvement of endometrial growth with this
treatment, especially in women whose serum estradiol levels increased
slowly in response to ovarian stimulation. HCG priming has been shown to
improve the response to ovarian stimulation in patients with previous
IVF failures [14]. With the use of conventional or virtual hysteroscopy [6]
we have also detected different anomalies of the uterine cavity in many
patients of this group. Consequently, these anomalies were corrected
before the start of ovarian stimulation.
During the ovarian stimuation, co-treatment with GH improves success rates in women aged >40 years [7] and in younger women with multiple IVF failures [15], whereas low- dose aspirin alone does not appear to have any beneficial effect [16].
Tailoring the FSH/LH ratio in the formula of the mix of gonadotropins
used for ovarian stimulation according to the current serum LH levels is
known to improve oocyte yield and quality [8].
During ICSI we have often observed unusually high zona pellucida
resistance in this group of patients. We have reported previously that
laser-assisted ICSI reduces oocyte damage in this condition [9].
Moreover, the hole created in the zona pellucida during this procedure
may facilitate the subsequent hatching of the respective embryos.
The follow-up of women after embryo transfer is very
important in the condition of EPOR, since we often observed abnormally
low levels of progesterone, and to a lesser extent estradiol, just a few
days after transfer. These abnormalities were corrected immediately by
enhancing the luteal phase support with higher doses of exogenous
hormones. Most of the patients who needed this early correction of the
luteal phase support would probably never get pregnant without this
early intervention. Some patients showed unexpected falls in
progesterone level even later during the first trimester of pregnancy.
We believe that frequent hormonal controls, carried out short after
embryo transfer and during early pregnancy, can avoid implantation
failure and abortion in many cases. The importance of adequate early
luteal phase support, including the use of GnRH agonist [5], has been highlighted recently [10].
Conclusion
CARE is a protocol with which acceptable success
rates can be obtained in women with EPOR, considered to be one of the
conditions with the worst prognosis for IVF treatment at present. The
possibility of using CARE in other, less severe cases of female
infertility in order to improve IVF outcomes is a challenge for future
clinical research.
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