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Published in final edited form as: J Pediatr Adolesc Gynecol. 2022 Mar 8;35(4):429–434. doi: 10.1016/j.jpag.2022.02.002

The Care of Adolescents and Young Adults with Turner syndrome: A Pediatric and Adolescent Gynecology Perspective

Tazim Dowlut-McElroy 1,2, Roopa Kanakatti Shankar 1,3,4
PMCID: PMC9288983  NIHMSID: NIHMS1802301  PMID: 35272055

Abstract

Turner syndrome (TS) is caused by the absence of a part or whole X-chromosome in a phenotypic female and has an estimated prevalence of 25-50/100,000 liveborn females. The primary gynecologic manifestation of TS is Primary Ovarian Insufficiency (POI) and the resulting hypoestrogenism and infertility are experienced by most individuals with TS. In this review, we summarize the recommendations for the care of adolescents and young adults (AYA) with TS, with a focus on primary ovarian insufficiency in TS, hormone replacement therapy, fertility preservation and pregnancy in TS.

Keywords: Turner syndrome, DSD, pubertal induction, POI, hormone replacement therapy, fertility preservation, pregnancy complications

Introduction

Turner syndrome (TS) is caused by the absence of a part or whole X-chromosome in a phenotypic female and has an estimated prevalence of 25-50/100,000 liveborn females 1. The primary gynecologic manifestation of TS is Primary Ovarian Insufficiency (POI) and the resulting hypoestrogenism and infertility are experienced by most individuals with TS 2. In this review, we summarize the recommendations for the care of adolescents and young adults (AYA) with TS, with a focus on primary ovarian insufficiency in TS, hormone replacement therapy, fertility preservation and pregnancy in TS.

Primary Ovarian Insufficiency

Sexual infantilism was described by Henry Turner in 1938 as one of the cardinal features of the syndrome 3. The prevailing theory regarding the etiology of POI in TS is accelerated apoptosis of ovarian follicles beginning in-utero after the 14th week of gestation which continues after birth 4,5. As a result, only approximately 30 to 40 % of girls with TS undergo spontaneous pubertal development6,7 and only approximately 16% undergo spontaneous menarche 8. The prevalence of spontaneous pregnancy in women with TS is as low as 2 to 7% and the majority experience infertility and early menopause 9-11. Two distinct loci on Xq (Xq13.3-Xq21.1 and Xq26-qter) and one on Xp11.2 (BMP15 gene) have been implicated in the etiopathogenesis of POI 12.

The presence of Y-chromosome material (as with 45,X/46, XY mosaicism) is clinically significant in that it confers an increased risk at 12 to 30% of gonadoblastoma , a benign germ cell tumor with the propensity to develop into malignant neoplasm13,14. In girls with Turner syndrome with Y chromosome material, gonadoblastoma has been reported as early as 5 months and dysgerminoma at 10 years15,16. Although risk-reducing prophylactic bilateral gonadectomy is typically recommended at the time of diagnosis, gonadal function is possible as evidenced by reports of spontaneous puberty, menarche, and pregnancies in these individuals17 18 19. However, current imaging modalities including pelvic ultrasound and magnetic resonance imaging (MRI) cannot reliably identify gonadal tumors on these individuals 20. Given the difficulty in making a decision that results in infertility, an approach including referral to a center with expertise in the care of individuals with TS with Y chromosome material and shared decision-making is recommended for optimal timing of gonadectomy in these individuals.

In AYA with TS, spontaneous puberty and ongoing ovarian function are positively correlated with higher Anti-Mullerian Hormone (AMH) levels and negatively correlated with follicle-stimulating hormone (FSH), luteinizing hormone (LH) and 45,X karyotype 21,22. In addition, AMH < 4 pmol/L (0.56ng/ml) has been reported as predictive of absent puberty in prepubertal girls and POI in adolescents and adult patients 23. Care should be taken in the generalization of these results, however, as the evaluation of AMH as a predictor of spontaneous puberty was based only on 15 patients before pubertal onset (5 with spontaneous puberty and 10 with puberty induced by hormone replacement therapy). Girls with TS remain at risk of POI despite spontaneous puberty and/or menarche.

Female infants experience a transient surge of gonadotropins starting a few weeks after birth known as the ‘mini-puberty of infancy’ followed by gradual dampening and quiescence of the hypothalamic-pituitary-gonadotropin axis during childhood with a rise again in the peripubertal period. In patients with TS, this biphasic gonadotropin elevation appears to be exaggerated and the early and sustained gonadotropin elevations may predict future POI 24. In the presence of elevated gonadotropins, estrogen replacement therapy (ERT) for pubertal induction is recommended to begin at age 11 to 12 years 1. In addition to the psychosocial advantage of reaching puberty concurrently with peers, using physiological age as a guide to the initiation of HRT supports normal bone mineral accrual 25,26. While an elevated FSH level is valuable in defining POI in girls with TS, an actual cut-off level at which ERT should be initiated remains debatable. Although FSH levels can remain low prior to age 10 years even in girls with POI, in girls with TS, an FSH level of > 6.7 IU/L between the ages of 6 and 10 years is predictive of the need for future ERT 27. Some clinicians choose to initiate ERT for pubertal induction with FSH ≥ 10 IU/L to prevent a delay in pubertal development 28.

The goals of ERT are to replicate the progression of sexual maturity as seen in girls with intact ovarian function including breast development and uterine maturation and, to optimize peak bone mineral density (BMD) in young adults. Estrogen also appears to improve cognitive function in individuals with TS 29. A randomized control trial of very low dose prepubertal estrogen supplementation showed improvement in growth velocity, memory and executive function but current guidelines do not recommend ERT routinely for pre-pubertal TS patients to promote growth 1,30. Since growth hormone is routinely used now to improve height outcomes, delaying ERT to improve height prediction is no longer recommended 1. To date, no studies have meticulously evaluated outcomes of pubertal induction in relation to different estrogen preparations, the optimal starting dose, and rate of dose increase of ERT. Starting with lower doses of estrogen preserves height potential whether or not GH is used concurrently, as higher doses of estrogen are known to advance epiphyseal maturation 1. Various ERT options are recommended by the current international guidelines for the care of girls with TS. Dose increments every 6 months by 25-100% until adult-dosing is reached in 2 to 3 years, is felt to best mimic the cadence of pubertal progression in girls with functional ovaries 2.

Transdermal 17β-estradiol (TDE) is preferred as it is a more physiologic mode of delivery, is measurable in serum, and avoids the liver first pass effect of oral estrogen which would decrease the accumulation of non-physiologic estrogens and avoid a pro-coagulable state 31-33. Various regimens have been proposed including beginning with nocturnal application to achieve a diurnal rhythm as is seen with spontaneous puberty and at reduced weight-based dosing of 0.05–0.07 μg/kg and monitoring serum estradiol (E2) levels with an ultrasensitive E2 assay 34. The low doses (equivalent of 3-7 mcg/day of 17-β-estradiol) are practically achieved by cutting the lowest dose of commercially available matrix TDE patches (14 or 25 mcg/24h) in 1/4 to 1/8th. Only matrix patches and not reservoir-type patches are recommended to be fractionated. Some clinicians suggest application of the patch for one week of the month with no patch for the other 3 weeks of the month, but the comparative effectiveness of these regimens is unknown 2. A typical progressive dose increase for ERT is shown in Figure 1. Patient and family preference and compliance should be considered, and pubertal induction should be carefully individualized.

Figure 1:

Figure 1:

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Practical Approach to incremental Hormone replacement for Pubertal induction in Turner Syndrome

Oral estradiol can be offered as an alternative if there is difficulty in cutting patches, or in the case of skin reactions or an aversion to a visible patch. Both weight-based (from 5 to 15 μg/kg/day for the first 2 years) and fixed doses (0.25 mg/day in the first year followed by 0.5 mg/day in the second year) of oral micronized 17β-estradiol have been proposed 35-37 with recommended adult dosing of 1-4 mg/day (Figure 1) 1. Pubertal development is adequate with fixed dosing and does not appear to affect height outcomes 37. Conjugated equine estrogen (CEE) is no longer recommended for pubertal induction. When compared with transdermal estrogen, CEE results in slower bone and uterine maturation in girls with TS 38. The higher doses of ethinyl estradiol contained in oral contraceptive pills may have negative effects on growth and are not recommended for pubertal induction 39. In most girls, breast buds develop within 6 months of the initiation of ERT and Tanner 4 breast development occurs at an average duration of 2.25 years, a similar rate as that of girls with TS who have spontaneous puberty as well as girls without gonadal dysfunction 36,38,40-42.

As girls with TS typically have a normal uterus, progesterone is added 2 years after initiation of ERT or once breakthrough bleeding occurs to minimize the risks of irregular bleeding, endometrial hyperplasia and carcinoma associated with prolonged unopposed estrogen 1,43. Another suggested approach is the introduction of progesterone if ultrasound shows a mature uterus with endometrial thickening 28. The optimal regimen of progesterone delivery in girls and women with TS remains unknown 1. Both oral medroxyprogesterone acetate and micronized progesterone for 10 days each month protect against endometrial hyperplasia. The use of micronized progesterone in combination with estrogen for greater than 5 years has been associated with a 2-fold increase in endometrial cancer 44-46 but others still prefer micronized progesterone based on data showing a lower risk of breast cancer and venous thromboembolism in adult women without TS 47. Some clinicians offer the levonorgestrel intrauterine device (LnG IUD) to AYA with TS with a mature uterus for endometrial protection. Although not approved for use in postmenopausal women in the U.S., the LnG IUD is effective at minimizing endometrial cancer risk and can be safely used in nulliparous individuals 48,49. When benefits outweigh risks, hormone replacement therapy (HRT) is recommended to be continued until the average age of menopause although there is no data in TS to inform duration of therapy 1.

After completing pubertal induction, maintenance of hormone replacement therapy in AYA with TS is important for continued uterine development as evidenced by several studies that report poor uterine growth in TS despite appropriate HRT 50-52. The use of oral ethinyl estradiol also often leads to insufficient uterine development 53.In addition, transdermal estrogen results in better blood pressure profiles and has a more positive effect on bone mineral density than oral contraceptive pills (OCPs) 54,55. Despite this, several clinicians switch to combined hormonal contraceptives at the completion of pubertal induction due to patient preference, irregular bleeding, cost, or compliance. The guidelines are unclear and provide a range of adult dosing from the equivalent of 25 to 100 mcg/24h TDE 1.

Sexual function is impaired in women with TS with only 50-55% report being sexually active compared to women of similar ages 25,56. The onset of sexual debut is significantly later among women with TS with mean age of first intercourse of 23 years 57. Although women with TS are less likely to be married or in relationships as compared to women of the same age, women with TS in a partner relationship report relatively normal overall sexual function 25,56,58. There remains a paucity of data on impact of HRT on sexual function in individuals with TS.

Fertility Preservation and Pregnancy

For individuals with TS, uncertainty about future fertility begins at a young age and is a major concern for their parents as well 59. The inability to have genetically related children is a painful challenge experienced by most individuals with TS, especially when their peers begin to have children 59,60. Individuals with TS should be counselled that their ability to conceive spontaneously decreases rapidly with age and may not be present during adulthood 1 Consideration should be given to offering fertility preservation at a young age 1.

There is no consensus on an optimal approach to fertility preservation for individuals with TS. The efficacy of fertility preservation in individuals with TS, whether by controlled ovarian stimulation and vitrification of mature oocytes (oocyte cryopreservation, OC) or ovarian tissue cryopreservation (OTC), is unknown due to the lack of long-term follow-up and outcomes data. An approach to fertility preservation counselling in TS based on 1) karyotype of peripheral lymphocytes (monosomy vs mosaic or structural anomaly), 2) AMH concentration, and 3) health risk of later pregnancy has recently been proposed 61. However, this approach may not be predictive given the possibility of non-congruence of karyotype in lymphocytes and ovarian tissue 62 and the lack of correlation between ovarian follicular density and AMH in prepubertal children 63. OC is an option only for the limited number of adolescents with TS who undergo spontaneous menarche and are emotionally mature enough to undergo the procedure 64. Since 2008, there have been 18 reported cases of OC in girls as young as 13 years with TS, most of whom had a mosaic (45,X/46,XX) karyotype 65. There are no published reports of pregnancy after OC in individuals with TS. OTC may be an option for prepubertal girls with TS and post-pubertal girls who cannot undergo OC. Unlike OTC in patients undergoing gonadotoxic therapy, OTC is still considered experimental in TS 66. OTC has been performed experimentally in > 80 children and AYA with TS 10,67-70. It is unknown if auto transplantation after OTC has been performed in individuals with TS and there are no published data of pregnancy after OTC in TS.

The challenge in TS is to identify girls with residual ovarian follicles during childhood and adolescence prior to the onset of POI. Patients should be referred to centers with expertise in fertility preservation counselling, OC and/or OTC in the setting of TS.

Additionally, options for future parenthood including fostering, adoption, donor egg, and donor embryo should be discussed. Gestational surrogacy should be discussed because pregnancy is associated with greater risk in women with TS. Women with TS have traditionally been counselled against pregnancy due to early reports of a 2% risk of maternal death due to aortic dissection (AoD) or rupture 71,72, a risk 100 times higher than the risk for women in general population 73-75. However, given advances in fertility therapy, more women with TS are contemplating pregnancy. Over the last decade, a recognition of the need for improved risk stratification, and a multi-disciplinary approach to preconceptual assessment, intrapartum and post-partum monitoring including mandatory cardiac and aortic magnetic resonance imaging of in women with TS has resulted in improved outcomes 76-78. In 2018, the American Heart Association adopted a more moderate stance on pregnancy in individuals with TS stating that pregnancy can be undertaken safely by women with TS, even in some with known risk factors 79. Risk factors for AoD include bicuspid aortic valve, aortic dilation, elongation of the transverse aorta, and coarctation of the aorta 1. Hypertension, which occurs in about 50% of individuals with TS, also increases the risk of AoD 1. Aortic root dilation imparts an increased risk of aortic complications such as AoD and the aortic size index (ASI), defined as ascending aortic diameter divided by body surface area, has been the primary parameter used to assess AoD risk in TS 79. In individuals with TS greater than 15 years of age, an ASI ≥ 2.5 cm/m2 is associated with an increased risk of AoD 79. According to current international guidelines, women with TS and a history of AoD, ASI ≥ 2.5 cm/m2 , or an ASI 2.0 to 2.5 cm/m2 with associated risk factors for AoD (bicuspid aortic valve, elongation of transverse aorta, hypertension) should be counselled against pregnancy 1.

The standardization of guidelines including strict blood pressure control and serial cardiac and aortic imaging has resulted in improved perinatal outcomes for women with TS. In a retrospective study of 14 French centers that incorporated the use of standardized guidelines for the care of 103 women with TS with 170 pregnancies, there were no maternal cardiovascular events, marked improvement in the control of hypertension and a decreased prevalence of preeclampsia 77. In a more recent study evaluating outcomes in 10 centers in Canada, the U.S. and the Netherlands, 60 women with TS 20% of whom had structural heart disease including bicuspid aortic valve and coarctation of the aorta, management during pregnancy by dedicated maternal cardiovascular/adult congenital heart teams resulted in no cardiovascular events during pregnancy or 6 months postpartum 78. These studies suggest that there may be no increased risk of cardiovascular outcomes amongst women with TS without structural heart disease and that the risk is not as prohibitive as previously described among women with TS with structural heart disease.

Role of Gynecologists in Transition to Adult Care

Mortality in TS is increased 3-fold over the general population, with a higher mortality amongst individuals with 45,X monosomy as compared to other karyotypes 80,81. TS is associated with an increased occurrence type 1 and type 2 diabetes (DM), thyroid disorders, autoimmune diseases, osteoporosis, fractures, ischemic heart disease, and aortic dissection as well as congenital heart disease such as coarctation of the aorta, abnormal anatomy of the coronary arteries, and bicuspid aortic valve 1. Appropriate gynecologic care, with HRT, contributes to improved health in TS. Although the use of HRT does not decrease mortality in TS, among HRT-treated individuals with 45,X there is a lower use of antihypertensives, antidiabetics and thyroid hormones and reduced hospitalization rates for stroke and osteoporotic fractures 81. Gynecologists can play a lead role in the continuity of care for AYA with TS, as they transition to adulthood.

Conclusion

Primary ovarian insufficiency is a cardinal feature of TS and gynecologic and reproductive care are critical to the health and wellbeing of children and AYA with TS. Pediatric and adolescent gynecologists and adolescent medicine providers can become skilled collaborators in a multidisciplinary approach to the care of individuals with TS and lead the transition team for AYA in TS.

Acknowledgements

This work is supported by NICHD grant Z1A HD008985.

Footnotes

Conflict of Interest/Disclosure Statement

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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