Fertility in Turner Syndrome
Oocyte preservation involves a process of mature oocyte collection, incubation in cryoprotectant and vitrification – a rapid freezing technique to minimize ice formation. The ovulated oocyte is large and somewhat vulnerable to damage during cryopreservation and thawing; however, this procedure is now offered in many fertility clinics for adult cancer patients. Clinical pregnancy rates for this technique are similar to those attained from fresh oocytes, and over one thousand live births have been reported in the non-TS population. Oocyte preservation requires ovarian stimulation and ultrasound monitoring for 2 weeks beforehand to increase yield, with oocyte retrieval performed transvaginally under ultrasound guidance. Some degree of psychological and physical maturity is therefore required, with retrieval performed under general anaesthetic in the youngest reported patient, at age 14 years. This technique also offers the possibility of preserving oocytes with a view to surrogacy, if pregnancy is avoided due to associated risks.
Cryopreservation of mature oocytes with the aid of ovarian stimulation has previously seldom been considered a viable option in TS, as women requesting assisted fertility often have ovarian failure by the time of consultation. In adolescents with TS ovarian function may still be present; however, the majority of ovarian follicles found are immature primordial follicles, which require stimulated maturation prior to collection for storage.
There have been isolated case reports of mature oocyte preservation after gonadotropin stimulation in adolescents and young women with mosaic TS and positive indicators of ovarian reserve. Pregnancies have not been reported in this population.
There have been recent proposals that cryopreservation of ovarian cortical tissue could be offered to younger girls with TS, to preserve any viable primordial follicles for possible use in future fertility treatment. Of note in the wider population, ovarian tissue cryopreservation has a poorer success rate than oocyte preservation, due to difficulties associated with in vitro maturation of primordial follicles for oocyte retrieval. However, whole ovarian tissue transplantation has been shown to be robust, with a high success rate. Various methods have been described for tissue cryopreservation, including laparoscopic collection of ovarian cortical tissue containing immature oocytes and immediate vitrification, followed by thawing at the required time for fertilization, and autotransplantation of the ovarian tissue with in situ oocyte maturation. The tissue may be transplanted onto an orthoptic site (the ovarian fossa or pre-existing ovary) or onto a heterotopic site (such as abdominal wall). The aim of reimplantation onto an orthoptic site is reactivation of ovarian maturation and function within the graft followed by spontaneous conception. With heterotopic grafts, pregnancies may be achieved through hormonal stimulation, follicle aspiration and IVF. High rates of oocyte loss associated with freezing, thawing, maturation and graft ischaemia have been minimized with vitrification of ovarian tissue and microsurgery. Another technique described employs in vitro maturation of oocytes prior to freezing.
Precedent for use of this method in children has been established, with cryopreservation offered for a separate group of girls – those with cancer about to undergo gonadotoxic treatment. However, even in this group, the procedure is recommended only in specialized centres, using institutionally approved protocols and stringent consent. At the time of writing, over 30 live births have been reported using cryopreservation of ovarian tissue in adult women, none from tissue taken from adolescents or younger girls and none from 45,X individuals. Orthoptic transplantation appears to have higher success contributing to the live births reported, and there is a question whether some of these livebirths have arisen from unresected ovarian tissue which remained in situ, rather than the autotransplanted cryopreserved tissue. Spontaneous pregnancy has been observed after heterotopic transplantation of ovarian tissue in the subcutaneous anterior abdominal wall, suggesting that autotransplantation of cryopreserved ovarian tissue may restore function in residual, normally placed ovarian tissue.
Given the existence of the technical ability to perform cryopreservation but the lack of successful pregnancy outcomes for women with TS, the clinical question that arises is when, and from whom, should ovarian tissue be surgically removed for freezing and long-term tissue storage? Critical aims would be to ensure that children without follicles are not unnecessarily exposed to surgery, that any window of opportunity for oocyte preservation prior to complete follicle loss is utilized and that the amount of damage to the ovary is minimized during the harvest, in particular minimizing the risk of converting a functioning to a nonfunctioning ovary.
A large longitudinal study of 104 girls with TS using serial ultrasound found that in the minority of those with visible, nonstreak ovaries, there was apparent ovarian growth and follicular development from birth until puberty. This occurred in small dysgenetic ovaries as well as in ovaries of normal appearance. The authors suggested that the greatest period of follicle loss in females both with and without TS may be during the foetal and neonatal period, but that those with TS start with a reduced number.
A report of ovarian tissue sampling and storage in 57 girls with TS in Sweden has provided some data to aid identification of candidates for cryopreservation. Seven individuals had mosaic TS with complete X chromosomes (45,X/46,XX or 45,X/47,XXX) and 22 had structural anomalies including isochromosomes and ring chromosomes, with karyotypes including Y chromosome segments included in the structural anomaly group. Factors predictive of presence of healthy follicles included mosaic peripheral blood karyotype, normal range serum FSH, and normal range serum anti-Mullerian hormone (AMH, expressed in growing follicles), together with a history of spontaneous pubertal development. Negative predictive factors incl-uded monosomy or structurally anomalous karyotype, high serum FSH, low serum AMH and no evidence of spontaneous puberty. There was no difference between groups aged above and below 12 years regarding number of follicles. The authors suggested that girls with TS should be counselled about fertility options at age 13 or 14 and that the discussion should include cryopreservation of ovarian tissue in those with mosaic karyotype and spontaneous puberty in the absence of any elevation in FSH or reduction in AMH. It was noted, however, that if laparoscopic harvest of ovarian tissue was performed in this entire group of children, not all specimens would contain follicles (Table 4).
These proposed indicators of the presence of follicles were the basis of an analysis in a series of 28 TS girls, of whom 4 (14%) were identified as candidates for fertility preservation. Of note in this Canadian study, serum FSH concentration increased with age, and girls with levels below 40 IU/l were younger than those with levels above 40 IU/l (11·5 ± 2·4 years vs 14·3 ± 2·0 years, respectively). In those with a mosaic karyotype, elevation of serum FSH > 40 IU/l occurred at approximate age 16 years. Serum inhibin A has also been proposed as an indicator of ovarian reserve in girls with TS.
Although these authors suggest using selection criteria of mosaic karyotype, normal range serum FSH and AMH to reduce the chance of any girls who may have had follicles to harvest being missed, there are case reports of women with TS who have conceived despite failing to fulfil these criteria. Recent work in the general population has demonstrated that although AMH may be indicative of quantitative ovarian reserve, it does not predict the chance of a live birth, as similar live birth rates per mature follicle produced occur irrespective of AMH quartile.
Further research is required to ascertain whether harvesting ovarian tissue prior to puberty would increase the chance of preserving viable oocytes. Currently, no evidence exists for this proposal, although a benefit cannot be excluded. Of note, it is also theoretically possible that ovarian harvest for cryopreservation may actually decrease the chance of a pregnancy occurring, for example, if nests of 46,XX cells are removed and subsequently lost in the process of cryopreservation and autografting.
The chromosome complement of retrieved oocytes may be affected in a similar way to spontaneous TS pregnancies, carrying the same risk for chromosomal problems in the offspring, thus genetic counselling and pre-implantation/prenatal diagnosis are warranted.
Cryopreservation of embryos has not been thought suitable in children and young women as it requires sperm for fertilization. It is an established form of fertility preservation in the general population. The majority of good quality embryos survive cryopreservation and thawing, and perinatal outcomes are normal. This technique requires retrieval of mature oocytes through superovulation and immediate fertilization.
Fertility Preservation
Oocyte Preservation
Oocyte preservation involves a process of mature oocyte collection, incubation in cryoprotectant and vitrification – a rapid freezing technique to minimize ice formation. The ovulated oocyte is large and somewhat vulnerable to damage during cryopreservation and thawing; however, this procedure is now offered in many fertility clinics for adult cancer patients. Clinical pregnancy rates for this technique are similar to those attained from fresh oocytes, and over one thousand live births have been reported in the non-TS population. Oocyte preservation requires ovarian stimulation and ultrasound monitoring for 2 weeks beforehand to increase yield, with oocyte retrieval performed transvaginally under ultrasound guidance. Some degree of psychological and physical maturity is therefore required, with retrieval performed under general anaesthetic in the youngest reported patient, at age 14 years. This technique also offers the possibility of preserving oocytes with a view to surrogacy, if pregnancy is avoided due to associated risks.
Cryopreservation of mature oocytes with the aid of ovarian stimulation has previously seldom been considered a viable option in TS, as women requesting assisted fertility often have ovarian failure by the time of consultation. In adolescents with TS ovarian function may still be present; however, the majority of ovarian follicles found are immature primordial follicles, which require stimulated maturation prior to collection for storage.
There have been isolated case reports of mature oocyte preservation after gonadotropin stimulation in adolescents and young women with mosaic TS and positive indicators of ovarian reserve. Pregnancies have not been reported in this population.
Ovarian Tissue Cryopreservation
There have been recent proposals that cryopreservation of ovarian cortical tissue could be offered to younger girls with TS, to preserve any viable primordial follicles for possible use in future fertility treatment. Of note in the wider population, ovarian tissue cryopreservation has a poorer success rate than oocyte preservation, due to difficulties associated with in vitro maturation of primordial follicles for oocyte retrieval. However, whole ovarian tissue transplantation has been shown to be robust, with a high success rate. Various methods have been described for tissue cryopreservation, including laparoscopic collection of ovarian cortical tissue containing immature oocytes and immediate vitrification, followed by thawing at the required time for fertilization, and autotransplantation of the ovarian tissue with in situ oocyte maturation. The tissue may be transplanted onto an orthoptic site (the ovarian fossa or pre-existing ovary) or onto a heterotopic site (such as abdominal wall). The aim of reimplantation onto an orthoptic site is reactivation of ovarian maturation and function within the graft followed by spontaneous conception. With heterotopic grafts, pregnancies may be achieved through hormonal stimulation, follicle aspiration and IVF. High rates of oocyte loss associated with freezing, thawing, maturation and graft ischaemia have been minimized with vitrification of ovarian tissue and microsurgery. Another technique described employs in vitro maturation of oocytes prior to freezing.
Precedent for use of this method in children has been established, with cryopreservation offered for a separate group of girls – those with cancer about to undergo gonadotoxic treatment. However, even in this group, the procedure is recommended only in specialized centres, using institutionally approved protocols and stringent consent. At the time of writing, over 30 live births have been reported using cryopreservation of ovarian tissue in adult women, none from tissue taken from adolescents or younger girls and none from 45,X individuals. Orthoptic transplantation appears to have higher success contributing to the live births reported, and there is a question whether some of these livebirths have arisen from unresected ovarian tissue which remained in situ, rather than the autotransplanted cryopreserved tissue. Spontaneous pregnancy has been observed after heterotopic transplantation of ovarian tissue in the subcutaneous anterior abdominal wall, suggesting that autotransplantation of cryopreserved ovarian tissue may restore function in residual, normally placed ovarian tissue.
Given the existence of the technical ability to perform cryopreservation but the lack of successful pregnancy outcomes for women with TS, the clinical question that arises is when, and from whom, should ovarian tissue be surgically removed for freezing and long-term tissue storage? Critical aims would be to ensure that children without follicles are not unnecessarily exposed to surgery, that any window of opportunity for oocyte preservation prior to complete follicle loss is utilized and that the amount of damage to the ovary is minimized during the harvest, in particular minimizing the risk of converting a functioning to a nonfunctioning ovary.
A large longitudinal study of 104 girls with TS using serial ultrasound found that in the minority of those with visible, nonstreak ovaries, there was apparent ovarian growth and follicular development from birth until puberty. This occurred in small dysgenetic ovaries as well as in ovaries of normal appearance. The authors suggested that the greatest period of follicle loss in females both with and without TS may be during the foetal and neonatal period, but that those with TS start with a reduced number.
A report of ovarian tissue sampling and storage in 57 girls with TS in Sweden has provided some data to aid identification of candidates for cryopreservation. Seven individuals had mosaic TS with complete X chromosomes (45,X/46,XX or 45,X/47,XXX) and 22 had structural anomalies including isochromosomes and ring chromosomes, with karyotypes including Y chromosome segments included in the structural anomaly group. Factors predictive of presence of healthy follicles included mosaic peripheral blood karyotype, normal range serum FSH, and normal range serum anti-Mullerian hormone (AMH, expressed in growing follicles), together with a history of spontaneous pubertal development. Negative predictive factors incl-uded monosomy or structurally anomalous karyotype, high serum FSH, low serum AMH and no evidence of spontaneous puberty. There was no difference between groups aged above and below 12 years regarding number of follicles. The authors suggested that girls with TS should be counselled about fertility options at age 13 or 14 and that the discussion should include cryopreservation of ovarian tissue in those with mosaic karyotype and spontaneous puberty in the absence of any elevation in FSH or reduction in AMH. It was noted, however, that if laparoscopic harvest of ovarian tissue was performed in this entire group of children, not all specimens would contain follicles (Table 4).
These proposed indicators of the presence of follicles were the basis of an analysis in a series of 28 TS girls, of whom 4 (14%) were identified as candidates for fertility preservation. Of note in this Canadian study, serum FSH concentration increased with age, and girls with levels below 40 IU/l were younger than those with levels above 40 IU/l (11·5 ± 2·4 years vs 14·3 ± 2·0 years, respectively). In those with a mosaic karyotype, elevation of serum FSH > 40 IU/l occurred at approximate age 16 years. Serum inhibin A has also been proposed as an indicator of ovarian reserve in girls with TS.
Although these authors suggest using selection criteria of mosaic karyotype, normal range serum FSH and AMH to reduce the chance of any girls who may have had follicles to harvest being missed, there are case reports of women with TS who have conceived despite failing to fulfil these criteria. Recent work in the general population has demonstrated that although AMH may be indicative of quantitative ovarian reserve, it does not predict the chance of a live birth, as similar live birth rates per mature follicle produced occur irrespective of AMH quartile.
Further research is required to ascertain whether harvesting ovarian tissue prior to puberty would increase the chance of preserving viable oocytes. Currently, no evidence exists for this proposal, although a benefit cannot be excluded. Of note, it is also theoretically possible that ovarian harvest for cryopreservation may actually decrease the chance of a pregnancy occurring, for example, if nests of 46,XX cells are removed and subsequently lost in the process of cryopreservation and autografting.
The chromosome complement of retrieved oocytes may be affected in a similar way to spontaneous TS pregnancies, carrying the same risk for chromosomal problems in the offspring, thus genetic counselling and pre-implantation/prenatal diagnosis are warranted.
Embryo Cryopreservation
Cryopreservation of embryos has not been thought suitable in children and young women as it requires sperm for fertilization. It is an established form of fertility preservation in the general population. The majority of good quality embryos survive cryopreservation and thawing, and perinatal outcomes are normal. This technique requires retrieval of mature oocytes through superovulation and immediate fertilization.
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