Turner syndrome is associated with a wide spectrum of gonadal dysfunction up to POF and sterility, but little is known about the best FP strategy to offer before complete follicle pool depletion. We think that ovarian tissue cryopreservation (OTC) removing the entire ovary is highly debatable in women with TS. Alternatively, oocyte vitrification after COS does not reduce the spontaneous ovarian lifespan, but this technique can be only offered to post-menarchal girls after spontaneous puberty. COS procedure was successful for all three women referred to our centre despite various karyotypes, even in case of 45,X monosomy.
Specificities in our Group Facing General TS Women
Characteristics at Baseline. The three women who underwent COS presented few typical manifestations of TS, suggesting that they had a mild phenotype. All of three had spontaneous menarche, which generally occurs in about 20% of TS adolescents.[5,8] Serum AMH level has been established as a marker of ovarian reserve in women with TS, but in the study of Talaulikar et al, no correlation was found between AMH and the number of oocytes retrieved for seven patients with TS. In our work, AMH was increased in the woman with complete 45,X monosomy that was not in accordance with the correlation between AMH and TS karyotype previously described.
Referral Delay. There is a narrow window of opportunity to discuss FP options for women with TS. Yet, our study highlights a significant time-period between TS diagnosis (before the age of 20 for the three patients) and the referring to a FP centre (almost 10 years). The FP process should be advised at the earliest to avoid time-related DOR, which occurs for most patients before adulthood. Referral delay to FP Center should be shortened thanks to accurate information from paediatricians during transition to adulthood. In our centre, two patients were referred for counselling before the occurrence of menarche. Therefore, we advised a regular medical follow-up for puberty evolution and ovarian reserve evaluation (AFC, AMH and FSH follow-up) to not miss the window of FP opportunity.
Ovarian Response to Stimulation. In our study, the mature oocyte retrieval rate was higher than usually described in women with TS.[18,19] Repeated cycles of COS allowed patient 1 who already had a DOR to bank 9 vitrified oocytes. Once spontaneous puberty and menarche occurred, karyotype did not predict response to COS: 17 oocytes were cryopreserved despite 45,X monosomy for patient 2 who had a normal/high AMH serum level with normal FSH level. Independently of karyotype, antral follicular count, AMH and FSH levels seemed to be reliable predictive markers of oocyte cryopreservation success. The theory of 'cryptic mosaicism' with a rescue cell line in 45,X women has been exposed. Another plausible explanation is that mosaicism may fluctuate between tissues with different karyotype patterns within blood and ovaries: Balen et al performed ovarian tissue biopsies in a mosaic TS women, showing higher proportion of 46,XX cells in the gonads.
According to the non-TS cohort study of Cobo et al, the number of oocytes needed to hope a live-birth should be at least 15. Among our three patients, two only needed one cycle of stimulation to achieve this goal, making COS a relevant option for FP in selected post-pubertal TS women.
Literature Review on Oocyte Vitrification for FP in TS Women
At our knowledge, only a few cases have been described to support that oocyte cryopreservation could be offered to TS women before POF occurrence, when AMH is above 14.3 pmol/L (2 ng/mL) and baseline FSH below 20 UI/L. Table 3 summarizes all oocyte vitrification cases for patients with TS reported in literature so far.[18,19,23,26–28] Oktay et al recommended oocyte cryopreservation as soon as possible when the TS adolescent initiates pubertal development.
What About TS Oocyte Quality and Quantity?
Oocyte Quality. Little is known about TS oocyte quality since no pregnancy with frozen-thawed oocytes has been described in women with TS. Balen et al assessed oocyte quality and genetics for 11 mature oocytes retrieved from a girl with TS: FISH technique did not detect any aberration on chromosomes 13, 18, 21, X and Y. However, an higher miscarriage rate (twice as much as the general population) and an increased risk of aneuploidy in the offspring are reported in TS spontaneous pregnancies: preimplantation genetic testing has therefore been recommended.[8,29] Besides, a recent study showed high rate of abnormal follicle morphology in TS ovaries. With those controversial facts and the lack of data, the live-birth rate per oocyte cannot be predicted but is likely lower for women with TS. In women with TS, the ideal number of vitrified oocytes to obtain a live-birth is yet to be determined.
Oocyte Quantity. Ovarian tissue biopsies performed in women with TS led to the description of positive predictive factors for the existence of intra-ovarian follicles: spontaneous puberty, mosaic blood karyotype, age from 12- to 16-year-old, normal baseline FSH (<11 UI/L) and AMH levels (>2 μg/L or 14.3 pmol/L). An option would be to monitor every year serum AMH level to determine the time of indicating a FP when AMH starts declining. However, in the study of Borgström et al, some follicles were observed in girls without spontaneous puberty and in others with high serum gonadotrophins concentrations associated with low AMH: interpretation of ovarian reserve markers in women with TS can be challenging, especially for peripubertal girls.
Alternative Option Available for FP
OTC prior POF could also be discussed, but no pregnancy has been described in women with TS after autologous autograft with frozen-thawed ovarian tissue. A recent study exposed biopsy results from fifteen girls with TS and young women after OTC; the authors highlight the fact that benefits of OTC may be limited to a highly selected group of patients. Due to the lack of data, we think that OTC is still debatable for prepubertal TS women since it implies amputation of the follicular ovarian reserve and consequently a decrease in spontaneous pregnancy chances.
FP Hopes Facing High Pregnancy Complications in Women With TS
Pregnancy may be at high risk in TS women with risks of severe hypertensive disorders, lethal aortic complications, foetal morbidity and mortality. In case of cardiovascular comorbidities with future pregnancy contraindications, oocyte vitrification can be discussed if gestational surrogacy is legislated in the country of residence.
Clin Endocrinol. 2019;91(5):646-651. © 2019 Blackwell Publishing