RBMO
ELSEVIER
RBMO
ARTICLE
Live birth after in-vitro maturation of oocytes in a patient with specific ovarian insufficiency caused by long-term mitotane treatment for adrenocortical carcinoma
BIOGRAPHY
Hélène Bry-Gauillard is a practitioner at the Centre of Reproductive Medicine, Creteil Hospital, and in the department of Reproductive Endocrinology, Bicêtre Hospital, University Paris- Saclay. Her clinical research focuses on reproductive endocrinology disorders and their fertility management. She has published several studies either in her own name or as co-author.
Hélène Bry-Gauillard1,*, Florine Belin1, Claire Vinolas2, Peggy Renoult-Pierre3, Nathalie Massin1, Jacques Young5,6,7, Christophe Sifer2,4, Michael Grynberg2,8,9,10
KEY MESSAGE
Persistent specific impaired ovarian function is reported 5 years after withdrawal of mitotane given at adjuvant therapy for 5 years, with the first live birth obtained after IVM in this situation. We raise the question of discussing fertility preservation in patients undergoing long-term mitotane treatments.
ABSTRACT
Research question: How should the fertility of a woman with persistent specific ovarian dysfunction after long-term mitotane exposure be managed?
Design: Case report. A 33-year-old woman who underwent surgery for adrenocortical carcinoma and treated with mitotane was referred for infertility. She rapidly became amenorrhoeic while taking mitotane, a condition that persisted for 5 years after cessation. Repeated serum hormone evaluation showed collapsed androgen levels, low oestradiol, high gonadotrophins (LH 69 and 63; FSH 23 and 43 IU/I), relatively high inhibin B level and slightly decreased anti-Müllerian hormone levels (1.4 and 0.7 ng/ml). An ultrasound scan revealed an antral follicle count of 13, contrasting with high serum gonadotrophin levels. After failure to obtain follicular growth after ovarian stimulation, in-vitro maturation (IVM) of immature oocytes aspirated from the antral follicles was carried out for microinjection with the spermatozoa of the patient’s partner.
Results: Two cycles of unstimulated egg retrieval were carried out, producing seven IVM oocytes, which were microinjected. A total of three cleavage-stage embryos were vitrified and unsuccessfully transferred after endometrial preparation using hormone replacement therapy (HRT). After a 20-month break, two new attempts were carried out under HRT with the aim of achieving a fresh embryo transfer. The last attempt succeeded after transfer of a single day-2 embryo, and the patient delivered a healthy baby.
Conclusion: Persistent specific impaired ovarian function 5 years after withdrawal of mitotane, and the first live birth after IVM in this situation, are reported. The question of fertility preservation before long-term mitotane treatment is raised.
1 Service de Médecine de la Reproduction et Gynécologie Obstétrique Centre Hospitalier Intercommunal de Créteil, 40 Avenue de Verdun 94010 Créteil Cedex
2 Department of Reproductive Medicine & Fertility Preservation, Hôpital Jean Verdier, avenue du 14 Juillet, 93140 Bondy, France
3 Department of Endocrinology CHU Bretonneau, 2bd Tonnelle 37044 TOURS Cedex 9
4 Department of d’Histology-Embryology-Cytogenetic-CECOS, Hôpital Jean Verdier, avenue du 14 juillet, 931440 Bondy 5 University Paris Saclay, F-91405 Orsay cedex, France
6 Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, F-94275, Le Kremlin-Bicêtre, France
7 INSERM UMR-U1185, Fac Med Paris Saclay, Le Kremlin Bicêtre, F-94276, France
8 Unité Inserm U1185, Université Paris-Sud, Le Kremlin Bicêtre, France
9 Department of Reproductive Medicine and Fertility Preservation, Hôpital Antoine Béclère, Hôpitaux Universitaires Paris Sud, Assistance Publique - Hôpitaux de Paris, Clamart 92140, France
10 Unité Inserm U1133, Université Paris-Diderot, 75013 Paris, France
KEYWORDS Adrenal cancer
Fertility preservation In-vitro maturation Mitotane
Ovarian cyst Ovarian failure
CrossMark
INTRODUCTION
M itotane is an adrenolytic drug widely used to treat adrenocortical malignancies. It is also used as an anticortisolic agent in the treatment of adrenocorticotropic hormone-dependent Cushing’s syndrome associated with pituitary corticotropic adenomas or with ectopic adrenocorticotropic hormone secretion (Kamenický et al., 2011). Although this treatment has been used for decades, the mechanisms of its action on adrenal steroidogenic cells are only beginning to be elucidated (Hescot et al., 2013). The inhibitory effect of this drug on steroidogenesis does not seem to be specific to the adrenal cortex, but can also affect other steroidogenic glands, such as the gonads. Research into the ovarian effects of mitotane has been limited, even though Cushing’s disease and adrenocortical carcinomas are more common in women and can occur before the menopause. (Salenave 2015) described for the first time the ovarian hormonal and gonadotrophic effect of mitotane in 21 premenopausal patients, and discussed the unexpected occurrence of ovarian macrocysts in the women studied. This effect was followed by a dramatic decrease in serum levels of androgens and an increase in serum gonadotrophin values, suggesting impairment of the theca interna, adding to the inhibition of adrenal androgen secretion. The side- effect was found to be reversible in two patients 4 months after discontinuing mitotane, but was not mentioned in the other patients, probably because the treatment was ongoing. Another recent study (Abrahamsson et al., 2020) also reported ovarian cyst formation in women of reproductive age receiving mitotane, with four women among five studied becoming amenorrhoeic during the treatment period. After mitotane cessation, the ovarian cysts disappeared, and normal menstrual cycles resumed in all the patients except one, who had undergone a hysterectomy. Therefore, one important unresolved question is whether the effect of mitotane is reversible after discontinuing the drug. Indeed, the life expectancy of patients with adrenocortical carcinoma has improved when this adjuvant treatment has been given for a minimum of 5 years (Amodru et al., 2021). The issue of pregnancy after remission or cure of an adrenocortical carcinoma, and that of fertility preservation, need further investigation.
To the best of our knowledge, we describe for the first time the persistent elective impairment of thecal function 5 years after discontinuing mitotane delivered for 5 years, after adrenocortical carcinoma surgery, in a patient who was given permission to attempt pregnancy in the context of long-term remission.
The management of infertility is discussed in this specific context. After failure to obtain follicular growth under ovarian stimulation, despite the persistence of small antral follicles within the ovaries, it was hypothesized that in- vitro maturation (IVM) might constitute a useful approach for fertility treatment in a patient experiencing persistent ovarian dysfunction caused by mitotane treatment.
MATERIALS AND METHODS
Patient
The 33-year-old woman underwent surgery for right adrenocortical carcinoma in 2009 and then treated with Lysodren® (mitotane) until November 2013. After a few regular cycles after surgery in 2009, the patient rapidly became amenorrhoeic when taking mitotane, a condition that persisted after cessation. Mitotane concentration was controlled and undetectable during regular follow-up after stopping the drug, including during the basal ovarian evaluation at the end of 2015. The patient had persistent adrenal insufficiency and persistent remission of the disease after stopping mitotane. She was allowed to attempt pregnancy after the end of 2015.
The patient provided informed consent for the publication of this case report, which was approved by the Hospital Ethics Committee on 23 June 2021 (reference number 2021-06-05).
Basal hormonal evaluation
Basal hormonal evaluations were carried out at the Department of Endocrinology and Reproductive Medicine at Bicetre Hospital. In December 2015 and 2018, and during ovarian monitoring for assisted reproductive technologie. FSH, LH, oestradiol, total testosterone, delta4 androstenedione (ADIONE), inhibin B, anti-Müllerian hormone (AMH) and dehydroepiandrosterone sulphate evaluations were carried out at baseline. Serum FSH and LH were measured using a sensitive immunoradiometric assay (Cisbio International, Gif-sur
Yvette, France). Oestradiol, ADIONE and testosterone were measured after extraction and derivatization, as described in detail by Giton et al. (2015). The lower limits of detection and the intra-assay and inter-assay coefficients of variation were 0.05 ng/ ml and 2.2/3.1% for testosterone using quality-control sera measuring 0.48 ng/ml and 0.049 ng/ml; and 4.6/5.2% for ADIONE using quality-control sera measuring 0.15 ng/ml. Serum inhibin B levels were measured with the Beckman Coulter 8 GenII assay (Beckman Coulter, Marseilles, France), with a detection limit of 3 pg/ml and intra- and inter-assay coefficients of variation of 6% and 11%, respectively, at 15 pg/ml. Serum AMH was measured using an enzymatically amplified two- site immunoassay (AMH Gen II ELISA) (Beckman Coulter, Marseilles, France) according to the manufacturer’s recommendations. The detection limit was 0.1 ng/ml. The mean inter-assay coefficient of variation was 8.6% at 3 ng/ ml, and the mean intra-assay coefficient of variation was 4.0%.
Morphological evaluation
Transvaginal ultrasound scans were carried out with probes by experienced gynaecological radiologists using a Voluson E8 Expert device (Voluson E8 EXP BT13, 3D-4D) (General Electric Systems, Velizy, France) equipped with a 9-12-MHz transvaginal transducer.
Assisted reproductive technology cycles
Standard ovarian stimulation with exogenous FSH for IVF was attempted before the first oocyte retrieval. As attempts at inducing follicle growth with exogenous FSH were unsuccessful, the subsequent attempts were carried out without exogenous FSH treatment.
Our IVM of oocytes protocol was based on a routine technique (Chian et al., 1999). Immature oocyte retrieval was scheduled 35-36 h after HCG priming using 6500 IU recombinant HCG administered subcutaneously (Ovitrelle, Merck Serono, France). Oocytes were retrieved under transvaginal ultrasound guidance, using a 16-gauge needle (K-OPS-7035-RWH-ET) (Cook Medical, Charenton-le-pont, France), with a reduced aspiration pressure of 7.5 kPa. Follicular fluids were collected in tubes with 5 ml of pre-warmed heparinized saline (100 ul in 250 ml NaCl).
In-vitro maturation technique and embryo vitrification
Oocyte-cumulus complexes were washed and matured in 1 ml of IVM medium (Origio, Lyon, France), supplemented with 20% of the patient’s own serum, which had previously been heat-inactivated, as well as with 0.75 IU/ml of FSH and 0.11 IU/ml of HCG (HP-hMG Menopur) (Ferring, Gentilly, France) for 24 h. Thereafter, oocytes were denuded of cumulus cells with hyaluronidase (SynVitro Hyadase®) (MediCult, Lyon, France) and mechanical pipetting, and checked for maturity (the first polar body visible). After examination, immature oocytes remaining at the germinal vesicle or metaphase I stage were further cultured in the same medium, and their meiotic status was re-examined 24 h later. The oocytes that had reached the metaphase II stage were then inseminated by intracytoplasmic sperm injection (ICSI) using the partner’s spermatozoa. Fertilization was assessed 17-19 h after insemination for the appearance of two distinct pronuclei and two polar bodies. The zygotes were cultured in embryo maintenance medium (CooperSurgical, Inc., Trumbull, USA). Embryo development was assessed on days 2 (41-43 h) and 3 (65-67 h) after ICSI vitrification for cryopreserving the embryos.
Endometrial preparation
Endometrial preparation was required in this patient, who was unable to produce sufficient steroids. Hormone replacement therapy (HRT) was used before vitrified- warmed embryo transfer and fresh embryo transfer.
Endometrial proliferation was obtained by administration of 6 mg of 17-B oestradiol (Provames) (Sanofi Aventis, Paris, France)
| November 2015 | December 2018 | Normal range in EFPa | |
|---|---|---|---|
| Menstrual cycles | Amenorrhoea | Amenorrhoea | |
| FSH, mIU/l | 23 | 43 | 3.2-10 |
| Oestradiol pg/ml | 35 | 24 | 34-100 |
| LH, mIU/l | 69 | 63 | 2.6-9.5 |
| Testosterone, ng/ml | 0.02 | 0.03 | 0.2-0.6 |
| Inhibin B, pg/ml | 257 | 224 | 60-125 |
| AMH, ng/ml | 1.4 | 0.65 | 2-6.8 |
| ADIONE, ng/ml | 0.11 | 0.05 | 0.4-2 |
| DHEAS, ng/ml | <30 | ND | 350-4000 |
To convert the values for testosterone in ng/ml to nanomoles/l, multiply by 3.467. To convert the values for day-4 an- drostenedione in ng/ml to nanomoles/l, multiply by 3.492. To convert the values for oestradiol to picomoles per litre, multiply by 3.671. To convert the values for anti-Müllerian hormone (AMH) to picomoles per litre, multiply by 7.1. a Lower and upper limit of normal range indicated are the mean of values obtained with the different assays used in the reference centres.
ADIONE, delta4 androstenedione; EFP, early follicular phase; DHEAS, dehydroepiandrosterone sulphate.
orally for 14 days. On day 14 of oestradiol intake, a transvaginal ultrasound scan was carried out to confirm that endometrial thickness was 7 mm or wider. Administration of 800 mg/day of micronized progesterone (Progestan) (Besins Healthcare, Brussels, Belgium) vaginally was started in combination with 17-ß oestradiol treatment. Embryos were transferred after 2 days of progesterone luteal support. The associated 17-B oestradiol and micronized progesterone were continued at the same doses at least until the pregnancy test.
RESULTS
Basal evaluations
Basal evaluations were carried out at 3 years’ follow-up (TABLE 1). It revealed collapsed testosterone levels (0.02 and 0.03 ng/ml), low oestradiol (35 and 24 pg/
ml), high LH (69 and 63 IU/l), increased FSH (23 and 43 IU/l), slightly increased inhibin B (257 and 224 pg/ml) and slightly decreased AMH levels (1.4 and 0.7 ng/ ml). The second ovarian check-up showed mild degradation of the ovarian phenotype, as hormone levels showed decreased AMH and increased FSH compared with the first evaluation.
The initial ultrasound carried out in January 2016 showed the presence of five macro cysts with an antral follicle count (AFC) of 5, possibly impaired by the presence of multiple cysts. In the follow-up in January 2019, the cysts had disappeared, and AFC was 13 (FIGURE 1).
Assisted reproductive technology outcome
Standard IVF was initially attempted in February 2017. Despite high doses
A
B
C
D
| Cycles | IVM1 | IVM2 | Vitrified-warmed embryo transfer | IVM3 | IVM4 |
|---|---|---|---|---|---|
| Date | March 2017 | May 2017 | July 2017 | May 2019 | July 2019 |
| Priming | 250 µg Ovitrelle | 250 μg Ovitrelle | NA | 250 µg Ovitrelle | 250 µg Ovitrelle |
| Oocytes retrieved, n | 7 | 2 | NA | 6 | 5 |
| MII oocytes after IVM, n | 5 | 2 | NA | 4 | 4 |
| Day-2 embryos, n | 2 | 1 | NA | 2 | 1 |
| Embryos cryopreserved, transferred, or | both, n Two vitrified | One vitrified | Three from IVM1 and IVM2 | Two in fresh transfer | One in fresh transfer |
| Clinical outcome | NA | NA | No pregnancy | No pregnancy | Delivery of a healthy boy |
IVM, in-vitro maturation; NA, not applicable.
of recombinant FSH and then urinary FSH (300 IU/day) for 20 days, follicular growth was deficient: about 15 follicles were visible on ultrasound, but remained under 9 mm. The oestradiol level also remained low, under 50 pg/ml. In the absence of follicular maturation, it was decided that IVM of immature oocytes aspirated from immature follicles should be carried out. Outcomes of IVM treatment cycles are presented in TABLE 2. After IVM, five mature oocytes were microinjected, whereas two embryos were vitrified on day 2.
A new attempt was made in May 2017 to accumulate vitrified embryos in a fertility preservation strategy: two oocytes aspirated and matured in vitro were microinjected, and one embryo was vitrified. The patient underwent a transfer of the three vitrified embryos from the two IVM cycles without achieving pregnancy.
After a long break, the patient returned at the end of 2018. A new attempt with IVM was carried out under HRT to achieve a fresh embryo transfer: six immature oocytes were collected and matured in vitro. These produced two embryos, which were transferred on day 2, without pregnancy. A last attempt was carried out in July 2019: five immature oocytes collected and matured in vitro produced one embryo; this was transferred on day 2 and succeeded. The patient delivered a healthy boy at 37 weeks of gestation.
In each transfer (fresh or vitrified-warmed) the endometrium was at optimal thickness between 7 and 8 mm under HRT.
DISCUSSION
To the best of our knowledge, this is the first report of persistent impaired ovarian
function after withdrawal of mitotane and successful management of this unusual infertility by using IVM.
This patient, without recurrence at 8 years after surgical treatment of adrenocortical carcinoma, presented an ovarian profile consistent with mitotane treatment, which persisted for 5 years after the withdrawal of mitotane. She had persistent amenorrhoea. Initial ultrasound revealed multiples cysts, as usually observed while taking mitotane. The presence of multiple cysts probably led us to underestimate the AFC, which was found to be low at the initial exploration (FIGURE 1A-1B). The cysts disappeared the following year without any medication, allowing for improved visibility of the antral follicles in the following ultrasound examination (FIGURE 1C-1D).
Basal hormonal evaluation found atypical ovarian failure with collapsed androgen levels, low oestradiol and increased FSH levels. The latter were, however, lower than the LH levels, which were constantly high. Inhibin B concentrations were slightly increased, whereas AMH concentrations were not markedly low, which would be expected with the high FSH concentrations reported. This profile suggests selective damage to the thecal cells, with preserved follicles and granulosa cells.
This ovarian profile described under mitotane remained in our patient despite drug removal, which has not been previously reported. In fact, in rare studies, all the young patients (fewer than 10) reported resumption of the normal cycle after discontinuing the drug (Salenave et al., 2015; Abrahamsson et al., 2020). Mitotane may, through its deleterious effect on mitochondria, inhibit gonadal steroidogenesis, in
addition to its established effect on the adrenal cortex (Hescot et al., 2013). Evidence of an effect on testicular steroidogenesis has indeed been reported, thereby strengthening this hypothesis (Bry-Gauillard et al., 2014). Before menopause, circulating testosterone is derived from androgenic precursors produced by the reticulate region of the adrenal cortex and by the theca interna cells of large antral ovarian follicles (Labrie et al., 2003). The massive decline in 4-androstenedione and testosterone suggests that ovarian androgen biosynthesis ensured by cells of the theca interna has been affected by mitotane, as have reticular adrenal cells. This hypothesis is supported by the significant concomitant increase in circulating LH, which could be secondary to the removal of negative feedback exerted by the ovaries. Similar increases in gonadotrophin levels, and particularly LH levels, have indeed been described in situations in which ovarian androgen biosynthesis is affected by genetic disorders, such as mutations in the LH receptor (Latronico et al., 1996), StAR (Fujieda et al., 1997), 17 hydroxylase (ten Kate-Booij et al., 2004) or cytochrome P450 oxidoreductase (T. Zhang et al., 2020a) or by ovarian autoimmune disease, which selectively damages thecal function at the beginning of the disease (La Marca et al., 2009). To date, no other treatments are known to be responsible for this specific type of ovarian profile.
In the present case, as the patient intended to achieve pregnancy with her partner, we proposed ICSI, but attempted to accumulate vitrified embryos first to give the couple a cumulative chance to achieve pregnancy. In fact, this specific ovarian failure is potentially an indication for fertility
preservation. It is not clear to what degree this ovarian failure is reversible after drug withdrawal and the time frame. If it occurs, the patient may be too old to obtain an ongoing pregnancy at that point. Second, the profile of dissociated ovarian failure described in this case report may also move to complete ovarian failure within a few years, with the extinction of the follicle reserve initially present, as has been described in cases of autoimmune ovarian insufficiency (La Marca et al., 2009; Komorowska, 2016). This ultimate stage of ovarian failure would then make fertility preservation impossible.
The state of follicular resistance to FSH prevents the possibility of mature oocyte retrieval after ovarian stimulation and has led us to carry out IVM of immature oocytes retrieved from antral follicles. In-vitro maturation has recently been reported as a successful technique in a woman with autoimmune ovarian insufficiency (Grynberg et al., 2020). All other situations described above, which are responsible for dissociated ovarian failure, including genetic disorders such as P450 oxidoreductase mutation, may benefit from IVM.
Insufficient mature oocytes and embryos were retrieved after the first two attempts, and the transfer of the three vitrified embryos obtained did not achieve pregnancy. When the patient returned after a 20-month break, she was still amenorrhoeic, with a similarly impaired ovarian profile and mild degradation of the ovarian reserve. As she did not want to undergo cumulative oocyte retrieval with embryo vitrification, we proposed carrying out a fresh embryo transfer under HRT. The woman achieved a pregnancy after the second fresh embryo transfer, resulting in the delivery of a healthy child. In any case (for fresh or vitrified embryo transfer) we had to prepare the endometrium with exogenous hormone, as the endogenous secretion of oestradiol and progesterone is deficient in this specific ovarian failure. Moreover, mitotane is responsible for persistent adrenal insufficiency. In our case, the pregnancy was uneventful when the woman was undergoing standard glucocorticoid replacement therapy, appropriately increased during stressful situations. Patients with well-managed adrenal insufficiency have generally uneventful pregnancies with favourable outcome, if substitutive treatment is
carefully adjusted during the pregnancy to avoid acute adrenal insufficiency. Patients need to be educated about the prevention of adrenal crisis and the necessity of increasing glucocorticoid dose during intercurrent illness, as well as the necessity of using intramuscular or subcutaneous hydrocortisone when oral intake is not possible (Bensing et al., 2020)
Persistent ovarian damage in such patients should lead the oncologist, endocrinologist and reproductive teams to propose mature oocyte cryopreservation before starting mitotane in patients of childbearing age. In fact, as adrenocortical carcinoma is a severe disease, the adjuvant therapy is maintained for at least 5 years to prevent recurrence and to improve survival rate, and pregnancy is authorized only after long-term remission of the malignancy. Indeed, pregnancy in the case of a malignant adrenal tumour has a poor prognosis, as patient and fetal survival rates are low; however, information is limited (Y. Zhang et al., 2020b). This can explain the delayed intent to become pregnant among those patients who may then be too old to have successful pregnancies and may be ineligible for the use of the assisted reproductive technology techniques owing to follicle depletion and age.
In conclusion, we report persistent specific impaired ovarian function after withdrawal of mitotane given as adjuvant therapy for adrenocortical carcinoma for 5 years. In this case, mitotane seems to be responsible for persistent damage of thecal cells, whereas granulosa cells and antral follicles are relatively preserved. This present case study shows that IVM of oocytes represents the only option for achieving a pregnancy at this stage of the disease.
Persistent ovarian damage in this patient, and the time limit imposed by this severe disease, indicate that, if possible, teams should propose mature oocyte cryopreservation obtained after FSH ovarian stimulation in patients of childbearing age before starting mitotane for adrenal carcinoma.
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Received 7 July 2021; received in revised form 14 September 2021; accepted 4 October 2021.