Key words
Cryoconservation of oocytes - early pregnancy - breast cancer - midluteal protocol
- aromatase inhibitor
Schlüsselwörter
Kryokonservierung von Eizellen - Frühschwangerschaft - Mammakarzinom - mittluteales
Protokoll - Aromataseinhibitor
Introduction
As the survival rates of younger patients with oncological disease have continued
to improve, there has been an increased awareness of the importance of maintaining
fertility and fulfilling the wish of patients to have children. Preservation of fertility
is particularly suitable for women with breast cancer, as hysterectomy is an essential
part of surgical therapy to treat cervical, uterine corpus and ovarian cancer – except
in younger patients with early stage disease and the wish to conceive. Around 5 %
of women carry a pregnancy to term after breast cancer. To what extent cytostatic
therapy induces amenorrhea largely depends on patient age (</>40 years) and the cumulative
dosage of cyclophosphamides [1].
There are a number of options available to protect fertility prior to starting chemotherapy:
one option consists of ovarian stimulation with cryoconservation of fertilised or
unfertilised oocytes. As it is highly effective and IVF and ICSI are extremely well
researched technologies, this method is the option advocated by the fertility preservation
network FertiPROTEKT. A number of different protocols can be used for stimulation.
Another option consists of cryoconserving ovarian tissue after laparoscopic removal.
However, experience with this technique is very limited and only a few children have
been born after re-transplantation [2]. The risk of metastasis after re-transplantation cannot be entirely excluded, even
if there are as yet no reports of metastasis in humans after re-transplantation. In
vitro maturation allows immature oocytes to be retrieved without or with only limited
stimulation and the oocytes are then cultured to maturation prior to being cryopreserved.
However, the reported fertility and pregnancy rates to date are distinctly lower.
GnRH analogues can have a protective effect during chemotherapy [3]. However, it is possible that GnRH analogues may reduce the impact of chemotherapy
due to reduced tumour cell growth in hormone-dependent carcinomas. Outside clinical
studies, the administration of a GnRH analogue for ovarian protection together with
chemotherapy should only be done after discussing the option with patients with hormone
receptor-negative tumours [4], [5].
Case Report
A 38-year-old gravida ll, para 0 was advised on fertility preservation after being
newly diagnosed with invasive ductal breast cancer. The patientʼs previous history
included 1 miscarriage, 1 termination and adnexitis. The patient reported that her
cycles were regular (29–30/4) and that until the diagnosis of breast cancer she had
used Cerazette® for contraception. The first meeting with the patient took place after
mastectomy for invasive ductal breast carcinoma, stage pT2, pN2 (6/12), G2, L1, R0,
M0, ER 10/12, PR 10/12, Her2neu 1+. Adjuvant chemotherapy was planned to start within
two weeks.
The patientʼs hormonal status on the 13th day of her menstrual cycle showed normal
gonadotropin levels, and she was normo-androgenaemic and euthyreotic. Anti-Müllerian
hormone levels were 4.04 ng/ml (normal range: 1.0–2.5 ng/ml), indicating a good ovarian
reserve. The patient was informed in detail about all options for fertility preservation
(cryoconservation of fertilised/unfertilised oocytes, ovarian tissue banking, in vitro
maturation, GnRH analogues). Because IVF/ICSI has been tested over many years and
currently has the best prognosis for a successful future pregnancy, the patient opted
for cryoconservation of oocytes. As the patient was not in a long-term relationship
the plan was to cryoconserve unfertilised oocytes. As there was only a very short
interval before starting chemotherapy, stimulation was started in the second half
of the cycle on the 26th day of the patientʼs cycle. The patient received 300 IE hMG
s. c. daily and a GnRH antagonist (cetrorelix
0.25 mg s. c.) as well as an aromatase inhibitor (letrozole 5 mg p. o.) during the
first 5 days of stimulation. Ovulation was induced on the 11th day of stimulation
using hCG (10 000 IE s. c.) and a GnRH agonist (triptorelin 0.2 mg s. c.) ([Table 1]). Surprisingly, no luteolysis occurred during stimulation despite the administration
of a GnRH antagonist, and a pregnancy test was done on the 11th day of stimulation.
The test was positive (β-hCG 3493 mIU/ml, E2 1848 pg/ml, prog 19 ng/ml). Sonography showed an intrauterine pregnancy. It was calculated
that the patient was in gestational week 5 + 0.
Table 1 Stimulation chart.
|
Day of stimulation
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
8
|
9
|
10
|
11
|
12
|
13
|
|
Letrozole (5 mg)
|
✓
|
✓
|
✓
|
✓
|
✓
|
|
|
|
|
|
|
|
|
|
hMG (IE)
|
300
|
300
|
300
|
300
|
300
|
300
|
300
|
300
|
300
|
300
|
|
|
|
|
Cetrorelix (Amp.)
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
|
|
|
Predalone (IE)
|
|
|
|
|
|
|
|
|
|
|
10 000
|
|
|
|
Triptorelin (mg)
|
|
|
|
|
|
|
|
|
|
|
0.2
|
|
|
|
E2 (pg/ml)
|
|
|
|
|
|
88
|
|
543
|
|
|
1 848
|
|
|
|
LH (IU/l)
|
|
|
|
|
|
0.72
|
|
1.3
|
|
|
3.8
|
|
|
|
PGN (ng/ml)
|
|
|
|
|
|
16
|
|
13
|
|
|
19
|
|
|
|
β-HCG
|
|
|
|
|
|
|
|
|
|
|
3 493
|
|
|
|
Sonography right ovary
|
|
|
|
|
|
3 × 8
|
|
14
4 × 8
|
|
|
23
21
19
18
2 × 16
|
|
|
|
Sonography left ovary
|
|
|
|
|
|
3 × 8
|
|
2 × 14
4 × 6
|
|
|
18
17
3 × 14
|
|
|
|
Endometrium
|
8
|
|
|
|
|
8
|
|
8
|
|
|
9
|
|
|
Oocyte retrieval was done on the 13th day of stimulation. Seventeen oocytes were aspirated.
Most of the aspirated oocytes had a normal morphology, and the majority were metaphase
II (11 × MII; 2 × MI; 4 × GV). Cryoconservation was done using Boriniʼs slow freezing
method [6]. Treatment was carried out with the help of the FertiPROTECT network. The patient
took the decision to terminate the pregnancy after intensive discussions with the
oncologist. Adjuvant chemotherapy (3 × FEC, 3 × paclitaxel) was then started as planned.
Discussion
Various protocols can be used for ovarian stimulation with subsequent cryoconservation
of fertilised or unfertilised oocytes. Usually a conventional antagonist protocol
is used, with gonadotropin stimulation started on the 2nd day of the cycle. In this
case hMG was used for stimulation at the patientʼs request to reduce costs. A GnRH
antagonist is administered from the 6th day of stimulation onwards to prevent early
ovulation. Modified stimulation protocols have been developed specifically for oncological
patients so that chemotherapy can be started within 14 days. With these protocols
stimulation can be initiated in every phase of the cycle using recombinant follicle
stimulating hormone (FSH) with simultaneous administration of an antagonist from the
start of stimulation [4], [5], [7]. Onset of luteolysis is important for successful stimulation in the 2nd half of
the menstrual cycle. The goal
of stimulation is maturation and retrieval of oocytes, as endometrium transformation
in preparation for pregnancy is not required. ln this case there was the additional
goal of maintaining relatively low estradiol levels to minimise any potentially negative
impact on the hormone receptor-positive breast carcinoma. The combination of gonadotropins
with an aromatase inhibitor allows estradiol levels to be maintained at or just over
the levels present in the natural menstrual cycle [8]. No increased risk of recurrence has been reported to date [9].
There is only limited data on the safety of ovarian stimulation in patients with receptor-positive
breast cancer, and a careful risk-benefit analysis in close consultation with the
patient and the oncologist is necessary. Theoretically, higher estradiol levels could
trigger increased tumour cell growth. However, it is questionable whether a short-term
elevation of estradiol levels will actually result in a relevant worsening of prognosis.
Moreover, it is important to bear in mind that even without stimulation patients can
have relatively high endogenous estradiol levels prior to chemotherapy (300–400 pg/ml
estradiol in the middle of the cycle). No negative effect on prognosis was found in
a study of 91 patients with localised disease [5], [6], [10].
We describe here an unusual case of a pregnancy conceived spontaneously within the
same cycle immediately prior to the start of stimulation in the second half of the
cycle. Apart from the problem of an early pregnancy and the urgent necessity of adjuvant
chemotherapy another factor also had to be discussed with the patient: the 5-day administration
of an aromatase inhibitor in early pregnancy meant that it was not possible to exclude
potential teratogenic effects on the foetus. An adverse effect of gonadotropin stimulation
and administration of a GnRH antagonist on the pregnancy is probably negligible. Administration
of an aromatase inhibitor is commonly done over the entire course of stimulation until
the induction of ovulation. We deviated from this protocol in our case because non-onset
of luteolysis indicated a possible early pregnancy.
We decided in favour of a combination of hCG (10 000 IE) and a GnRH agonist (triptorelin
0.2 mg) to induce ovulation. We considered that the standard use of hCG, which induces
ovulation through binding to the LH receptor, was not appropriate as the patient was
already producing hCG due to her pregnancy. As there are no reports in the literature
on the induction of ovulation in pregnancy, we opted for this “safe” combination of
both preparations.
There was also a risk that the oocytes would not be able to reach metaphase II or
that they had already reached the stage due to endogenous production of hCG and might
have become atretic. Due to the continuous high progesterone levels we initially had
to assume that oocyte maturation might be impaired. Surprisingly, morphological examination
of the oocytes did not confirm this.
It should be noted critically that a pregnancy test could have been done a few days
earlier. Moreover, after discussing it with the patient, it would have been possible
to administer the aromatase inhibitor for a longer period to ensure an optimal decrease
of estradiol levels as the concerns about teratogenicity are probably speculative.
Conclusion
We report an unusual case of spontaneous pregnancy conceived shortly before the start
of stimulation in the 2nd half of the menstrual cycle. Stimulation was done in the
shortest possible time, starting in the 2nd half of the cycle with gonadotropins and
GnRH antagonists in combination with an aromatase inhibitor to ensure relatively low
estradiol levels. Surprisingly, morphological examination of the oocytes showed no
impairment due to the pregnancy. We cannot draw any definitive conclusions about the
future potential of the oocytes to be fertilised.
There is not sufficient data about the risk of ovarian stimulation in patients with
receptor-positive breast cancer. Treatment should be done in centres integrated in
the FertiPROTEKT network.
