Turner syndrome through the lens of a gynaecologist

Abstract

Turner syndrome is a rare condition affecting 1 in 2500 female births and yet is the most common sex chromosome abnormality in women. Described as a cradle-to-grave condition, it requires life-long multidisciplinary management. Accelerated atresia of the primordial follicular pool leads to premature ovarian insufficiency, which is an almost inevitable feature of Turner syndrome, especially in 45XO karyotype. Many patients will have had their diagnosis made in childhood and require paediatric endocrinology management especially for induction of puberty. At the age of 18, patients may then be transitioned to an adult service. Continuation of multidisciplinary care for these women requires input from specialist services in menopause care, reproductive medicine and high-risk pregnancy, cardiology, endocrinology, bone health and psychosocial care. A gynaecologist may take on the mantle of lead clinician especially during the perceived reproductive years of a Turner syndrome patient’s life, hinging together management input from other disciplines. This review attempts to summarise an overview of the involvement of such a multidisciplinary team in the management of a single but complex condition, through the lens of a gynaecologist.

Keywords

Estrogen hormone replacement therapy menopause osteoporosis

Background

Generally considered to be a rare condition affecting 1 in 2500 female births, Turner syndrome (TS) is the most common sex chromosome abnormality in women. First described in 1930 by German paediatrician Otto Ullrich and in 1938 by American endocrinologist Henry Turner, TS has been described as a cradle-to-grave condition requiring life-long multidisciplinary management. Characterised by absent or part missing of an X chromosome, it can be inherited from the egg or the sperm but mostly a random event with similar prevalence across ethnic groups and countries. Unlike Down syndrome, it does not increase with maternal age. Phenotypic expression is intricately linked to the degree of mosaicism with mosaic karyotype having some albeit reduced ovarian reserve. A total of 15,000 females are affected in the UK.

Presentation

TS may present as premature ovarian insufficiency (POI) with secondary amenorrhoea as well as delayed or absence of puberty and primary amenorrhoea. Associated features include propensity to middle ear infections, sensorineural hearing loss, gastrointestinal and kidney disorders, coarctation of the aorta, hypertension, diabetes, hypothyroidism, osteoporosis, POI and infertility. At times overlooked but increasing in awareness, are specific cognitive and psychosocial phenotypes. Specific physical characteristics include webbed neck, short stature, deep forehead, low hairline, broad chest and widely spaced nipples and lymphoedema of hands and feet. These are just some of the physical features, perhaps helpful in suspecting the condition if the diagnosis was missed earlier.

The diagnosis of TS may be made at various stages of development, ranging from fetal diagnosis in utero by prenatal testing to diagnosis in childhood to a diagnosis when a girl gets investigated for primary amenorrhoea.

TS is typically represented as 45XO. Mosaic TS may have some cell lines with 45XO together with the presence of karyotypically normal cell lines 46XX. Turner’s variants include partial deletions of one X chromosome or a ring X chromosome. Turner’s variants may benefit from genetic counselling prior to conception as these women are at risk of passing an abnormal X chromosome to their offspring.

Accelerated atresia of the primordial follicular pool leads to POI, which is an almost inevitable feature of TS, especially in 45XO. In mosaic TS, the rate of follicular atresia tends to be influenced by the volume of cells which are karyotypically normal.

Multiple organ involvement necessitates a multidisciplinary approach.

We have a well-established Late Effects Clinic setup in our university affiliated tertiary referral hospital, which provides a multidisciplinary setup where we see patients with TS. Most of our patients in Sheffield have had their diagnosis made in childhood and have required Paediatric Endocrinology management especially for induction of puberty. At the age of 18, they are then transitioned to the adult service.

This review addresses the management of TS as viewed from the lens of an Obstetrician and Gynaecologist within a multidisciplinary clinic.

Multidisciplinary involvement

Endocrinology and otolaryngology

The endocrinologist plays a central role in the management of a woman with TS, having an input at paediatric level and throughout adulthood. The endocrinologist is often the Lead clinician, coordinating involvement of all the other specialists involved in management. It is vital to have a Lead clinician to take ownership of a case and be a point of reference of communication with other specialists and with primary care.

Height

A paediatric endocrinologist usually takes charge of administration of growth hormone and estrogen in childhood and adolescence. Short stature is a characteristic feature and TS girls may be up to 20 cm shorter in final height than their unaffected counterparts. Recombinant human growth hormone (r-hGH) is administered sometimes in combination with oxandrolone and has been demonstrated to increase height velocity and final height. Safety of growth hormone treatment is monitored using IGF-1 levels and success of treatment is assessed by measurement of height every six months. In a recent meta-analysis, the mean height increase was 7.22 cm with r-GH alone and an additional 2.46 cm in combination with oxandrolone, compared with untreated controls.¹ It is recommended that growth hormone be started at the age of 4–6 and preferably before 12–13 years.²

Pubertal induction

The second role played by the Paediatric endocrinologist in managing TS patients is induction of puberty. TS women have hypergonodotropic hypogonadism due to POI. Usually pubic and axillary hair growth is maintained as the ovaries are not the only source of androgens, which are also produced by the adrenal glands. Breast and uterine development together with achievement of an acceptable growth spurt and achievement of peak bone mass is the aim of estrogen therapy in TS women. Delayed puberty generally is defined as the start of puberty at a chronological age older than +2 SD of average. For girls this occurs when breast development is not present at the age of 13 or menarche did not occur at the age of 15.³ Estrogen may be given as ethinylestradiol, a synthetic estrogen or 17β-oestradiol, a natural estrogen. When 17β-oestradiol is given transdermally, it avoids hepatic first pass metabolism and has a better cardiovascular risk profile. Oral 17β-oestradiol is available as a 1mg preparation at its minimum strength roughly equivalent to 10 mcg of ethinyl estradiol. Tablets either therefore need to be cut or dissolved to reach lower induction doses. 17β-oestradiol is also available as a transdermal patch that requires to be cut to obtain lower induction doses. The normal pubertal development process is mimicked by using low dose estrogen at the start of the induction process and monitoring clinical response by reviewing linear growth rate and breast development. High-dose estrogen early in the development process or escalating the dose of estrogen too quickly, results in reduced final height with normal nipple but poor breast development. Progestogen is introduced for endometrial protection and this may be done sequentially or in a continuous fashion to avoid withdrawal bleeding.⁴ The European Society of Human Reproduction and Embryology (ESHRE) advises the sequential method especially if pregnancy is desirous in the future. Progestogen is added at puberty stage 4 or if vaginal bleeding occurs with estrogen only⁴ or if estrogen has been given for 2 years.²

There is an increased risk of developing autoimmune disorders such as hypothyroidism, celiac disease, type 1 diabetes, alopecia areata, juvenile rheumatoid arthritis, uveitis and inflammatory bowel disease. Hypothyroidism due to Hashimoto thyroiditis is the most prevalent autoimmune disorder found in patients with TS and its prevalence increases with age. Screening for hypothyroidism at diagnosis and then annually with (free) T4 and TSH measurements is recommended.²

Hearing loss has been observed in one third of patients with TS. Sensorineural hearing loss is the predominant type of auditory impairment but conducting hearing loss may be seen together with early presbycusis. Suggested mechanisms of hearing loss include unusual middle ear anatomy and estrogen deficiency. Prompt and aggressive treatment of otitis media with antibiotics will prevent complicated sequelae. Periodic audiometric evaluation throughout lifespan and institution of hearing aids early in life are crucial to avoid hearing related speech pathology, risk of isolation, depression and possibly dementia.²

Cardiovascular health

Congenital heart disease is the most frequent cause of early mortality in TS women, occurring with a prevalence of 23–50%, with a higher incidence in 45XO compared to X mosaicism.^5–7 Bicuspid aortic valve and coarctation are two such common lesions and newly discovered lesions in a neonate should necessitate screening for TS. In addition, an aortopathy with concomitant risk of aortic dissection (AoD) and a generalised arteriopathy is observed.⁸

AoD occurs in approximately 40 per 100,000 person-years in TS compared to 6 per 100,000 person-years in the general population,⁹ most of which occur in the ascending aorta. Aortic size index (ASI) has been used to predict the risk of AoD. This is the absolute aortic diameter in cm divided by body surface area in m². An ASI of ≥2.5 cm/m² has been shown to increase the risk of AoD. In some cases, an absolute ascending aorta diameter of 4 cm may be used to determine risk of AoD.

A safe level of exercise is important. Regarding sports participation, intense weight training is best avoided if the ASI ≥ 2.0 cm/m². Those with ASI 2.0–2.3 cm/m² participation in low and moderate static and dynamic competitive sports may be advised and if the ASI <2.0 cm/m² it is reasonable to participate in all sports. If the ASI >2.3 cm/m² she should be advised not to participate in any competitive sports.²

Up to 60% of TS adults have been reported to have systemic hypertension. This may be a consequence of renal abnormalities, coarctation of the aorta or may be idiopathic.^10–12 Strict BP control is recommended (135/85 mmHg) to lessen the risk of AoD.²

Cerebrovascular accidents (strokes) are more common than the general population. This may be as a result of underlying hypertension or an underlying thrombophilia, some of which such as factor V Leiden have been reported to be more prevalent in TS patients (13%) compared to the background population (2%).¹³

Overall management of cardiovascular risk should be geared at lowering morbidity and mortality by instituting lifestyle measures such as smoking cessation, moderating alcohol intake, adequate and measured exercise, management of ideal body weight, regular monitoring and early recourse to treatment of raised blood pressure, hypercholesterolaemia and diabetes.

Psychosocial care

In a review of the literature on cognitive and psychosocial development for girls with TS, Culen et al.¹⁴ discuss that while in infancy TS girls show no psychological development differences from non-affected girls, as a TS girl grows older, her psychosocial and intellectual development is seen to more clearly diverge from her normally developing peers.¹⁴ TS girls have been shown to have normal vocabulary with reduced oral fluency skill,¹⁵ cognitive deficits¹⁶ and impaired social function¹⁷ with phenotypical variations, which may persist throughout life. They may also have some traits on the autistic spectrum; however, a fundamental difference with TS is that girls with TS desire social interaction.¹⁸ Most would agree that a reasonable quality of life is a desirable outcome in managing women with TS, and provision of support to these women to be well equipped to deal with future challenges of professional and social life cannot be overemphasised. This must be continual support throughout life, first for the parents as they digest their child’s diagnosis the first time and then for the patient herself as she transitions from adolescence into and throughout adulthood. This is largely provided for by healthcare professionals and support groups but calls for more specialised professional support for this complex condition.

Genetic testing and diagnosis

A diagnosis of TS should be considered in phenotypic females with one X chromosome and a complete or partial absence of the second X chromosome, associated with one or more typical clinical manifestations, unless the deletion in the second X chromosome is distal to Xq24. Females with deletion distal to Xq24 frequently have primary or secondary amenorrhoea without features of TS and should be regarded as having POI and not TS. Also excluded are women > 50 years of age with less than 5% 45,X mosaicism as this may develop as part of the ageing process.¹⁹

There is a broad spectrum of physical features of TS and for this reason, a diagnosis may be made across the lifespan. The karyotype may range from complete 45,X to forms of mosaicism in which there may be a normal or more than one abnormal cell line. The specific karyotype does not always predict the phenotype; however, mosaicism 45,X/46,XX is often associated with a milder phenotype and a ring X chromosome is sometimes associated with intellectual disability to a variably degree.^20,21 It is therefore recommended that general surveillance management is applied to all TS women regardless of karyotype.²

Sex chromosome abnormalities may be detected when prenatal diagnosis, either chorionic villous sampling or amniocentesis is undertaken for situations such as advanced maternal age, abnormal first trimester screening for autosomal trisomies or if abnormalities are picked up on a 20-week fetal anomaly ultrasound scan. An amniocentesis karyotype relies on fetal fibroblasts for analysis. Mosaicism may exist and so chromosome analysis should always be repeated after birth whenever a diagnosis of 45,X is made antenatally. Management should include pre and post-test genetic counselling. It is recommended that a formal karyotype is repeated in the following situations: (1) infants diagnosed prenatally; (2) diagnosis based on buccal swab only; (3) karyotype performed in the distant past; (4) historical diagnosis with no formal report available² and (5) in case of high clinical suspicion and negative initial testing.

A Y chromosome detected on chromosomal analysis is associated with an increased risk of gonadoblastoma,²² ranging from 4% to 60% but quoted as 10% as an overall figure among TS women. At least 10% of women with TS carry Y chromosome sequences. Newer molecular methods have made it possible to increase the detection rate of Y chromosome sequences. However overall as the risk of gonadoblastoma in TS patients, including those with Y chromosome sequences, is only 1%, molecular screening to detect Y-chromosomal sequences is currently recommended only in TS women with masculine features or virilisation who test negative for Y material by conventional cytogenetic and FISH analysis methods.² Cryptic Y material may exist in some tissues and not generally, such as in buccal cells but not in peripheral blood. When virilisation is present, it may become essential to test more than 1 tissue for cryptic Y material.²³

Gynaecology, sexual health and genitourinary function

Gonadectomy is recommended for all women with TS, diagnosed to have a Y chromosome on karyotyping because of a higher risk of developing a gonadoblastoma. ²

Uterine growth and endometrial development require estrogenic stimulation and rely on underlying ovarian function. Spontaneous menarche is a prognostic indicator of normal underlying uterine development. Natural pregnancy occurs in 2–8% of women with TS but high rates of miscarriages, stillbirths and a risk of fetal chromosomal abnormalities may occur.^24,25

Sexual debut tends to be later in life compared with the general population with reported sexual impairment and problems with arousal. TS women may require topical vaginal estrogen or androgen support, the latter especially to be used with caution, in the absence of specific guidance for routine use.

While many women with TS will have POI and not require contraception, some mosaic TS women will have reduced or preserved fertility and require contraception. Reference is made to the UK MEC FSRH guideline (2016) with specific reference to existing co-morbidities.²⁶

If combined hormonal contraception (CHC) is used, preparations containing 20 μg of ethinyl estradiol are preferred as they have a lower risk of venous thrombo-embolism (VTE) compared with the higher dose preparations.

Hormone replacement therapy

Introduction and types of estrogen/progestogen therapy

TS women tend to have POI. The British Menopause Society (BMS) have published a consensus statement on the management of women with POI. Hormone replacement types, containing physiological estradiol such as in conventional HRT or synthetic ethinylestradiol such as in CHC both provide a beneficial role in preventing long-term complications of estrogen deficiency. Hormone replacement therapy (HRT) is recommended for women with POI to maintain bone and cardiovascular health and potentially maintain cognitive function. In addition to estrogen, a progestogen must be added for endometrial protection in women with an intact uterus to avoid endometrial hyperplasia and minimise the risk of endometrial cancer.

Cardiovascular and thrombotic implications

While both HRT and CHC containing ethinylestradiol may be beneficial, HRT may be more beneficial in improving bone health and cardiovascular markers compared with the CHC. This would be particularly relevant to TS patients, who are already at risk of hypertension and dyslipidaemia. The risks of HRT quoted in the Women’s Health Initiative (WHI) and other studies apply to women in their 50’s and should not be extrapolated to women with POI.

There is limited evidence to inform the best route, dosage, or regime of HRT in POI women. Transdermal (TD) HRT avoids first pass metabolism and for naturally menopausal women, in vitro data have shown a neutral impact on thrombin generation for TD estrogen and that TD HRT does not increase the risk of stroke or thrombosis compared to women not taking HRT. It is likely that the same advantage would be conferred to POI women and the TD route should be considered in women with risk of VTE or raised BMI.

In the PEPI trial (1995), oral micronised progesterone resulted in higher HDL cholesterol levels than the MPA group suggesting a more favourable effect on blood lipids.²⁷

Progestogens have also shown differential effects on the risk of VTE. In the ESTHER study, a retrospective case-control study, current users of oral HRT but not TD HRT were at increased risk of VTE compared with non-users. There was no significant association of VTE with micronised progesterone and pregnane derivatives but a four-fold increased risk with norpregnane-derived progestogens (OR, 3.9; 95% CI: 1.5–10).²⁸

From the E3N French prospective cohort study, oral but not TD estrogens were associated with increased thrombotic risk. The thrombotic risk also differed by concomitant progestogen type. There was no significant association of VTE with progesterone, pregnanes and nortestosterone-derived progestogens but an increased VTE risk was seen with norpregnane-derived progestogens.²⁹

Overall, it appears therefore that if we were to extrapolate the findings from these studies to POI women, the best adverse effect profile would be from a TD HRT with either micronised progesterone or dydrogesterone.

We suggest an inclination towards offering a TD method as a first choice with either micronized progesterone or dydrogesterone as these are a group of women with significant risk factors for ischaemic heart disease, hypertension, renal disease and many will have a BMI >30, which would also put them into a category for whom TD HRT is recommended.

Utrogestan is a micronised progesterone that can be given as follows off licence: 100mg orally each evening continuously or 200 mg each evening orally for 12–14 days out of four weeks sequentially. For women requiring contraception, the Mirena IUS or the progesterone only pill or a progesterone implant may be used alongside if required.

Tailored treatment regimens to stages of life

The aim of estrogen replacement is to try and achieve physiological levels of serum oestradiol. HRT administration should aim to achieve estradiol levels within physiological range (180–370 pmol/L) and is generally recommended until the average natural age of the menopause of 50/51 years as is the recommendation for POI patients in general.

The BMS suggest the following regime: 75–100 μg of a TD oestradiol patch or 2 mg equivalent of oestradiol gel or 2 mg of oral oestradiol a day.³⁰ The advantage of using an estrogen gel is flexible dosing and has the advantage to provide for top-up dosing. Sandrena gel is available in 0.5 mg and 1mg sachets. Estrogel is available in a metered dose pump. Each pump actuation of 0.06% estrogel delivers 1.25g of gel, which contains 0.75 mg of 17β-oestradiol.

Cyclical HRT is the preferred regime when commencing HRT in adolescents with primary amenorrhoea in order to establish normal endometrial development and to stimulate active functional regular endometrial proliferation and withdrawal bleeding especially, in women aiming to conceive a pregnancy by oocyte donation.³¹ The CHC has an atrophic effect on the endometrium and may be a reason for avoiding this. Younger women on continuous combined HRT are also more likely to get breakthrough bleeding. If a bleed-free type of HRT is desired, women may benefit from using the levonorgestrel intrauterine system (mirena IUS) with appropriate estrogen replacement. This has the additional benefit of providing contraception to those women who may not have POI and require contraception. If a cyclical regime is used, progestogen should be administered for 12–14 days a month.

A continuous combined regime may be an option for women who have not had a menstrual period for over two years. The levonorgestrel intrauterine system (LNG IUS) provides endometrial protection in women receiving oral or TD estrogen and has a licence for this indication for four years. However, the Faculty of Sexual and Reproductive Health (FSRH) endorse a five-year use out of licence as there is evidence to show efficacy of endometrial protection. This would be standard practise. We recommend that the LNG IUS is fitted by an experienced fitter in case the uterus is not well developed, with a concomitant higher risk of uterine perforation.

There is, however, limited evidence comparing different progestogen uses in POI women.

All progestogens have progestational activity, inducing a secretory endometrium to support gestation but also stimulate other receptors translating into different clinical effects.³² Progestogens are either natural or synthetic, the latter being structurally related to either progesterone (further classified into pregnane or nor pregnane derivatives) or structurally related to testosterone (further classified into 19-nortestosterone and spironolactone derivatives). Medroxyprogesterone and dydrogesterone are pregnane derivatives. Norpregnane derivatives are not in common use in the UK. Norethisterone and levonorgestrel are 19-nortestosterone derivatives and drosperinone is a spironolactone derivative also present in the CHC Yasmin. Micronised progesterone has a more selective effect on progesterone receptors with less stimulatory effect on androgenic and mineralocorticoid receptors compared with other progestogens and so produce fewer progestogenic side-effects.

Among naturally menopausal women, progestogens have exhibited differential effects on the risk of breast cancer. In the French E3N Cohort study, women who had used estrogen only or estrogen/progestogen combinations excluding progesterone and dydrogesterone, had a higher breast cancer risk than never users of HRT. However, compared to never users of HRT, there was no significant increase in breast cancer risk in women who had used estrogen–progesterone or estrogen–dydrogesterone combinations of HRT.³³

At the age of 50/51 years, a review of risks versus benefits should be undertaken with available information on risks of HRT. Should a woman choose to remain on HRT, she may not require the same dose of estradiol and a lower dose may be more appropriate.

Bone health

Osteoporosis is the most common cause of fragility fractures. One of the main purposes of HRT is the protection of bone health. The National Osteoporosis Guideline Group (NOGG) recommends that fracture probability should be assessed in postmenopausal women, using FRAX® (Fracture Risk Assessment Tool) launched by the University of Sheffield in 2008. In individuals at intermediate risk, bone mineral density (BMD) measurement should be performed using dual-energy X-ray absorptiometry (DEXA) and fracture probability re-estimated using FRAX®. However, the lower age at which this tool may be used is 40 years and so for TS women who are often diagnosed and managed at a much younger age, BMD measurement would be the tool of choice to assess for osteoporosis. Advice on lifestyle and dietary measures recommended are as follows:

A daily calcium intake of between 700 and 1200 mg should be advised, if possible, achieved through dietary intake, with the use of supplements if necessary.

800IU cholecalciferol daily.

Regular weight-bearing exercise should be advised, tailored according to the needs and abilities of the individual patient. With TS patients, it is imperative that advice about correct exercise intensity and type is done in conjunction with the patient’s cardiologist as patients at risk of aortic dissection may be advised to avoid weight bearing exercises.

Falls history should be obtained in individuals at increased risk of fracture and further assessment and appropriate measures undertaken in those at risk.

There is no specific evidence-based guideline on the frequency of BMD assessment for TS patients. However, non-specific to TS women but more generally in women with POI, a five-year interval has been suggested from European guidance.

Fertility

The options for parenthood for TS patients with infertility are fertility preservation for women with ovarian reserve and for women with POI – donor egg IVF, surrogacy or adoption.

Fertility preservation may be done as oocyte or embryo freezing for later use for post pubertal girls. Embryo freezing is usually the option of choice for a woman in a stable relationship as embryos are more likely to survive the freeze–thaw process than frozen oocytes. At the present time, and with vitrification techniques available for oocyte cryopreservation, 5% of frozen oocytes result in a live birth. This is data from oocyte cryopreservation in general and not TS patients. The first case report on oocyte retrieval and freezing for fertility preservation in a TS patient was published in 2008.³⁴ Oocyte freezing requires that a woman is post pubertal with an adequate ovarian reserve to respond to FSH/LH ovarian stimulation combined with an oocyte retrieval procedure, usually but not exclusively carried out under transvaginal ultrasound control. This technique is no longer considered experimental but with low reported live-birth rates per frozen oocyte, more than 1 cycle may be required to achieve a satisfactory number of eggs to freeze.^35,36 Live birth rates have not been reported exclusively from frozen oocytes in TS patients and may be less than expected for patients who have had oocytes frozen for other reasons.

For pre-pubertal girls, ovarian cortex cryopreservation is undertaken but is still at the present time regarded as an experimental technique. This means it is largely offered as part of research projects rather than routinely. Segments of ovarian cortex have been surgically excised and then re-transplanted back into the pelvis (autologous transplantation) resulting in live-births in women without TS. Whole ovary freezing is currently being undertaken experimentally. In vitro maturation (IVM) is a technique where immature oocytes are extracted from the ovarian cortex and matured in vitro as opposed to in-vivo which occurs with controlled ovarian stimulation and oocyte retrieval carried out in IVF. To date, no pregnancies have yet been reported after whole ovary freezing or IVM, as at the time of writing this review.

Donor egg IVF requires the presence of a developed uterus. An egg donor may be an altruistic donor or be part of a widely practised egg sharing programme in the UK or be a known donor such as a friend or a relative. She donates some or all her eggs to the TS recipient patient. The eggs are then fertilised with sperm from the partner of the TS patient and fertilised embryos are transferred into the uterus ideally one at a time as a single embryo transfer. It is best to avoid multiple pregnancy because of the associated obstetric risks, in particular, a higher risk of aortic dissection that already exists in TS patients despite a normal aortic root index. Any excess good quality embryos may be frozen for later use either if the first embryo transfer was unsuccessful or to extend the family. Prior to embryo transfer, high-dose estrogenic therapy is given for at least 14 days to cause endometrial growth to an endometrial thickness (ET) of at least 7 mm. One regime in use is 6 mg oral oestradiol daily for one week followed by 8 mg oral oestradiol daily for a further week. After two weeks of oestradiol therapy, a transvaginal ultrasound scan measures the ET and if the desired 7 mm is not yet reached, a further few days of oestradiol is continued and the ET rechecked. An alternative to the regime is to use 100 mcg oestradiol patches every third day for a week followed by 200 mcg oestradiol patches every third day for a further week. Once the desired ET is reached, progestogen supplementation is commenced. Various regimes are in current use worldwide. One such regime that we use in our Assisted Conception Unit is Cyclogest pessaries 400 mg twice daily commenced on the equivalent egg collection day and continued through embryo transfer to eight weeks of gestation if there is a pregnancy. A pregnancy test is done two weeks after embryo transfer and if the pregnancy test is negative, the progestogen pessaries are stopped.

Some TS women fail to develop an endometrium to the desired thickness with oestradiol therapy because of an undeveloped uterus. Some TS women have an undeveloped uterus to start with while some may have an adequately developed uterus, but pregnancy may be contraindicated because of risk of aortic dissection. For such women, the options available are either surrogacy or adoption. The following section on surrogacy refers to the process in general and not specifically to TS patients who form a small cohort of the larger cohort of intended patients accessing surrogacy arrangements.

Surrogacy

There are two types of surrogacy:

Traditional surrogacy, where the surrogate donates the use of her uterus and her eggs to intended parents (IP).

Gestational surrogacy, where the surrogate donates the use of her uterus only. The egg comes from the intended parent or an egg donor. Treatment invariably involves IVF and embryo transfer.

A surrogacy arrangement is an agreement between the IP and a surrogate. In a surrogacy agreement, expectations are agreed between the IP and the surrogate. These include not just financial arrangements but also agreements on assisted conception treatment, antenatal screening, agreement on termination of pregnancy in case of fetal abnormality, frequency of communication, attendance for antenatal appointments, place and mode of delivery, extent of involvement of other members of the surrogate’s family, expectations of the surrogate on mode of travel, diet and social habits among other things.

UK law permits surrogacy but does not recognise a surrogacy agreement as an enforceable contract in a court of law. However, UK law does provide for completion of legal processes at the end of the surrogacy arrangement.

Surrogacy laws vary internationally, and while the information contained in this write up relates primarily to surrogacy taking place in the UK, it is well worth being aware that there are established surrogacy destinations such as USA and Canada as well as emerging destinations such as Greece and Russia where UK residents are tending to access surrogacy arrangements.

For surrogacy to take place there must be a genetic link between at least one of the IP and the offspring. This means that the intended parents must provide at least one set of gametes, that is provide either the egg or the sperm or both. The surrogate provides an egg and/or her uterus and carries the pregnancy for the IP. At the end of the gestation period, the surrogate hands over the baby to the IP. UK law recognises that the birth mother is the legal mother of the baby and if married, her spouse becomes the other legal parent on the birth certificate. If the surrogate is single, then the male partner of the IP, who would have normally provided the sperm, would become the legal second parent on the child’s birth certificate. Within six months of birth and being handed over the child, the IP apply to the family court for a parental order. After a parental order is granted, a revised birth certificate is issued with the IP as the legal parents on the new birth certificate. By granting a parental order, the court is not ratifying the original agreement which the family court does not recognise but is ratifying that the baby has been born and handed over. Disputes are rare. There have been five so far (as at writing this review), compared to over 1000 successful surrogacy completions in the UK. Contrary to a commonly held misconception that the court would automatically hand over parental responsibility to the surrogate in case of dispute, the family court will decide based on the best interests of the child. Most of the time, albeit based on the few cases on record, the court has handed over parental responsibility to the IP.

UK law makes it a criminal offence for a third party to be paid a fee to negotiate a surrogacy arrangement. Solicitors therefore will commit a criminal offence if they negotiate a surrogacy arrangement on a professional basis. Patients may seek legal advice on the laws surrounding legal parenthood and parental responsibility or immigration advice if having surrogacy overseas, however a solicitor or any other third party based in the UK, is not permitted to draw up a contract between the IP and the surrogate for a fee. Patients would well be advised to access such support from a non-profit organisation such as Surrogacy UK or Hope Surrogacy which could provide a template for such an agreement to be drawn between the IP and the surrogate.

A surrogate may be an independent surrogate or be affiliated with a non-profit organisation, with the intention of providing the service altruistically, but with the expectation of being reimbursed reasonable expenses. Strict vetting rules apply in the US but in the UK, there is much greater flexibility on who can be a surrogate. For example, the age limits in the US are 21–39 years, potential surrogates must hold a clean driver’s licence, have a clean credit record, not have a criminal record, not be poor, be of sound physical and mental health and must go through a process of psychological evaluation before being accepted as a surrogate. In the UK, there is a lower age limit of 21 years but no upper age limit. Individuals with mental health problems are not barred from being potential surrogates. A non-profit organisation would then match a registered surrogate with an IP based on what each other’s expectations are from the entire surrogacy journey.

The IP and surrogate then meet, establish a relationship, and agree on an arrangement before proceeding with treatment.

Pregnancy

Obstetric complications

The spectrum of adverse pregnancy outcome associated with high risk pregnancies in general and donor egg IVF pregnancies in POI women in particular consists of first trimester miscarriage, intra-uterine fetal death mid trimester onwards, intra-uterine growth restriction, preterm delivery, low birth weight, pre-eclampsia and stillbirth. Studies have shown such pregnancy complication in TS women notwithstanding natural or assisted conception.

Spontaneous pregnancies have been reported in upto 40% of turner mosaic, mainly in women with 45XO/46XX mosaicism³⁷ and 2% of monosomy X women.³⁸ Miscarriage rates are higher than the general population, in the region of 31% versus 15% after natural conception, presumed to be due to poor oocyte quality²⁴ but uterine factors may play a role.³⁹

A Swedish population-based study of 115 TS women showed that the Obstetric outcome was generally favourable but not without risk and TS pregnancies ought to be regarded as high-risk pregnancies with close obstetric and fetal monitoring. Compared with 56,000 women in the general population, TS women had a higher rate of pre-eclampsia (6.3 vs. 3.0%, P = 0.07), marginally lower gestational age at delivery (−6.4 d, P = 0.0067), lower median birth weight (-208 g, P = 0.0012), a higher Caesarean section rate (35.6% vs. 11.8%, P < 0.0001) but no difference in congenital birth defects.⁴⁰ Results obtained from a French audit showed considerably higher rates of pre-eclampsia (37.8%), prematurity (38.3%) and intrauterine growth restriction (27.5%).⁴¹

Compared with autologous IVF, donor egg IVF is associated with a higher risk of pre-eclampsia, small for gestational age, preterm delivery and Caesarean section in both singleton and twin pregnancies.⁴² Elective single embryo transfer is therefore advocated for TS patients who have IVF to avoid multiple pregnancy as obstetric complications tend to be higher for multiple than singleton pregnancies.

National Institute of Health and Care Excellence (NICE) guidelines recommend low dose aspirin once a day from the second trimester onwards for prevention of pre-eclampsia.⁴³

Non-obstetric complications

Specific to donor egg IVF pregnancies among 106 TS women, pre-eclampsia complicated 20.5% of all pregnancies with a preterm birth rate of 8.0% and LBW rate of 8.8% in singletons. One woman developed aortic dissection. In this particular cohort, the karyotype was 45,X in 44% of the women with TS.⁴⁰

The risk of maternal death from aortic dissection/rupture during pregnancy in women with TS has been estimated to be 2%.^41,44 Pregnancy carries a higher risk of aortic dissection in TS women than in the general obstetric population and this risk is even higher with a dilated ascending aorta or other additional risk factors. Pregnancy management should therefore be undertaken by a specialist in maternal medicine and in a joint Obstetric Cardiology clinic in conjunction with a cardiologist. A transthoracic echo (TTE) or cardiac CT/MRI should be undertaken within two years of planned pregnancy or assisted conception. Pregnancy should be avoided in case of an ascending aortic size index (ASI) of >2.5 cm/m² or an ASI 2.0–2.5 cm/m² with associated risk factors for aortic dissection. Risk factors include bicuspid aortic valve, elongation of the transverse aorta, coarctation of the aorta and hypertension. Women with a history of aortic dissection should be advised to avoid a pregnancy. If a woman is already pregnant, she should have close follow up and be delivered by Caesarean section. Vaginal delivery may be undertaken for women with ASI under 2.0 cm/m². For women with ASI 2.0–2.5 cm/m², a vaginal delivery with an epidural and an expedited second stage is preferable, or a Caesarean section may be considered. For women with ASI >2.5cm/m², a Caesarean section is preferable but vaginal delivery with an epidural and an expedited second stage may be considered. For women without aortic dilatation or other risk factors described above, a TTE should be performed in pregnancy at approximately 20 weeks gestation. The risk of aortic dissection is five times higher in multiple pregnancy compared with a singleton pregnancy.²

Renal tract abnormalities described in TS include horseshoe, total or partial duplication, absent, multicystic or ectopic kidneys. Collecting duct and ureteral abnormalities also occur and urinary tract infections (UTIs) are thought to be more frequent as a result of obstruction or reflux.⁴⁵ This is to be monitored for attentively in pregnancy which itself is a condition that predisposes to UTIs.

Useful websites

https://tss.org.uk/

https://www.nhs.uk/conditions/turner-syndrome/

https://www.turnersyndrome.org/

www.britspag.org

Sources of recommendations for Best Practice

Gravholt CH, Andersen NH, Conway GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.

FSRH UK Medical Eligibility Criteria for Contraceptive Use. UKMEC (2016).

Management of women with Premature Ovarian Insufficiency (POI). ESHRE (2015).

The British Menopause Society consensus statement on the management of women with premature ovarian insufficiency. (2017).

Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY, Scientific Advisory Board of the European Society for C, Economic Aspects of O, Osteoarthritis, the Committee of Scientific Advisors of the International Osteoporosis F. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013; 24: 23–57.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

SJ.

Contributorship

SJ wrote the first draft of the manuscript. SS reviewed and edited the manuscript and both authors approved the final version of the manuscript.

ORCID iD

Shehnaaz Jivraj

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