Preservation of ovarian cortex tissue in girls with Turner syndrome:
A multicenter exploratory intervention study

**Every once in a while, you know, when you*re holding a kid and they*re
snuggling up to your neck, I really thought: I wish I could have kids. I wish I
had the choice.** (31-year-old female diagnosed with Turner syndrome) (Sutton
et al., 2005). Infertility caused by premature ovarian insuffiency (POI) or
failure (POF) is a major concern for patients with Turner syndrome (TS) and
their parents (Sutton et al., 2005). Due to an accelerated loss of germ cells,
most girls with TS undergo ovarian failure at a very early age, starting as
early as 18 weeks fetal age. The timeline at which this occurs is less clear,
and may be different for each patient with TS. Spontaneous pregnancies are
rare, and occur in approximately 2-5% of women with TS (Bernard et al., 2016;
Bryman et al., 2011; Hadnott, Gould, Gharib, & Bondy, 2011). However, up to 30%
of females with TS have some pubertal development and up to 10% experience
spontaneous menarche (Pasquino, Passeri, Pucarelli, Segni, & Municchi, 1997). A
Swedish study group reported that primordial follicles can be found in the
ovaries of both mosaic and non-mosaic girls with TS up to 17 years of age
(Hreinsson et al., 2002). Due to this new insight, physicians are often asked
by patients with TS and their parents about the options of fertility
preservation (Grynberg et al., 2016). Fertility preservation includes the
cryopreservation of the patient*s own gametes, either by preserving mature
oocytes or ovarian tissue containing primordial follicles. Cryopreservation of
mature oocytes can be performed only in post pubertal females, since oocyte
maturation requires ovarian stimulation with exogenous FSH administration
followed by transvaginal ultrasound-guided oocyte retrieval (Oktay et al.,
2015). Ovarian tissue cryopreservation, however, appears to be a promising
technique to preserve the fertility of younger girls with TS and provides the
possibility to store a larger number of primordial follicles before their
disappearance (Borgstrom et al., 2009). Although still experimental,
cryopreservation of ovarian tissue has been well described in girls and young
women undergoing gonadotoxic cancer treatments, and over the past decades,
several clinical guidelines have been developed (Font-Gonzales et al., 2016;
Jakes et al. 2014). Retransplantation of cryopreserved-thawed ovarian cortical
tissue in cancer survivors has resulted in restoration of ovarian function and
follicular development (Oktay & Karlikaya, 2000; Radford et al., 2001), and at
present, more than 60 live births have been reported (Van der Ven et al., 2016;
Jensen et al., 2014; Andersen et al., 2014.; Demeestere et al., 2015; Dittrich,
Hackl, Lotz, Hoffmann, & Beckmann, 2015; Donnez et al., 2004; Donnez et al.,
2013; Meirow et al., 2005). Unfortunately, there are currently no
recommendations on fertility preservation in patients with TS. Although both
preservation procedures have been performed experimentally in girls and
adolescents with TS (Balen, Harris, Chambers, & Picton, 2010; Borgstrom et al.,
2009; Hreinsson et al., 2002; Huang et al., 2008), the promise of fertility
preservation is at present hypothetical, given that no girl with TS who has
undertaken these approaches thus far has returned for autotransplantation or
IVF. Further research is needed to provide supporting evidence for the
efficiency of both fertility preservation techniques in this specific patient
group. Furthermore, there is a need for reliable markers to assess the ovarian
reserve in girls with TS to offer fertility preservation services to those
patients who would benefit most.

To investigate the occurrence of live birth in women with TS after ovarian
tissue cryopreservation in childhood followed by auto transplantation in
adulthood.

A multicenter exploratory intervention study

1)Laparoscopic unilateral oophorectomy
2)Buccal Swab and one urine sample
3)1 Extra blood sample of 3.5mL will be collected during yearly blood check.
Hence, there will be no extra venipuncture performed.

It is important that the participant and her parents weigh the possible pros
and cons before participating in this research.

Benefits
The fertility of the participant could be saved with this procedure. In
addition, participation in this study will give her and her parents more
information about her fertility. The participant may also not benefit from
participation in this research. For example, if no follicles are found in her
ovary. Her participation contributes to more knowledge for other girls about TS
and (in)fertility.

Risks
A disadvantage of participating in this study is the potential risk of
complications related to the laparoscopic unilateral oophorectomy. and/or the
unknown effect on future fertility of these girls. Moreover, the procedure
might raise false hope in patients (and/or parents) about the chance of getting
pregnant after auto transplantation of cryopreserved-thawed ovarian tissue in
the future. However, we attempt to overcome this by extensive and honest
information provision by both written materials and face to face counseling.

Burden
Participation in this study also means:
- participation in this study takes time
- 3 additional hospital visits and 1 additional hospitalization
- (extra) controls;
- that the participant and her parents have appointments to which they must
comply

Due to a lack of evidence, it is not possible to predict the outcome for each
individual participant. All patients and their parents will be counseled about
the 3 possible scenario*s before participating in this study regarding their
benefit:

1) The participant belongs to the largest group of patients (95-98%) who are
infertile at the end of adolescence. OTC could be successfully performed (e.g.
follicles where found in the cortex strips).
Due to early menopause, this patient does not have any spontaneous chances of
getting pregnant. The removal of one ovary will not reduce her spontaneous
pregnancy chances (0% 0%). Her fertility might be saved for later.

2) The participant belongs to the largest group of patients (95-98%) who are
infertile at the end of adolescence. OTC was not successful (e.g. no follicles
where found in the cortex strips).
Due to early menopause, this patient does not have any spontaneous chances of
getting pregnant. The removal of one ovary will not reduce her spontaneous
pregnancy chances (0% -> 0%). Unfortunately, her fertility could not be saved.
The intervention does not have a personal benefit for this participant.

3) The participant belongs to the smallest group of patients (2-5%) who may
become spontaneously pregnant in the future. OTC could be successfully
performed (e.g. follicles where found in the cortex strips).
Due to a solid ovarian reserve in her remaining ovary, this participant still
has a chance of spontaneously becoming pregnant. Her fertility might be saved
for later if needed.