7.5 Transition in endocrinology

There is an increasing focus on improving adolescent healthcare and transition. Adolescents have particular healthcare needs, and these should be addressed to provide effective management in adolescence and young adulthood and transition to adult endocrine care.

Adolescence represents the process of becoming an adult. It involves significant biological, psychological and social change (Table 7.5.1). Growing up with any chronic condition can affect adolescent development, for instance, pubertal and growth delay and reduced bone mass, delayed social independence, poor body and sexual self-image, and educational and vocational failure. Conversely, normal adolescent development can make the management of a chronic condition problematic through poor adherence to medical regimens and risky health behaviours.

Much of endocrine care and research in adolescence focuses on optimizing hormone replacement therapy to try and normalize or maximize biological aspects of adolescence, growth and puberty in early and mid-adolescence, and bone mass and reproductive potential in late adolescence and young adulthood. Despite certain groups of young people with endocrine conditions having documented psychological and social consequences, current endocrine care does little to address these and there has been minimal research into possible therapeutic interventions. For healthcare professionals to engage and effectively manage young people, psychological and social as well as biological aspects need to be considered and studied.

Transition is an important part of adolescent healthcare. Transition has been defined as ‘a multi-faceted, active process that attends to the medical, psychosocial and educational/vocational needs of adolescents as they move from child-centered to adult-orientated health care’ (1). There is evidence in endocrinology as there are in other chronic conditions that young people suffer by not receiving appropriate follow-up or care in adulthood placing them at increased risk of morbidity and mortality as a consequence of poorly planned and organized transition. Despite many reviews stating the need for studies examining the outcomes of improved transitional care in endocrinology, these are not yet available. There is, however, an emerging evidence base of the benefits of improved transitional care in other chronic conditions.

Transition should be considered a process not an event (Box 7.5.1). The process should start in early adolescence to allow adequate preparation and education of the young person and their parent. The young person should be at the centre of the transition process and planning. Aspects that need to be covered during adolescence and therefore transition are disease knowledge and adherence, independence in health care and self advocacy, healthy living, education and vocation. The process should be individualized and therefore flexible. Young people should be considered ready for transfer based on a number of factors: chronological age, maturity, current medical status, adherence to therapy, independence in healthcare, preparation, readiness of the young person and availability of an appropriate adult endocrinologist.

A British Society of Paediatric Endocrinology and Diabetes (BSPED) audit of specialized and transitional care in paediatric endocrinology in the UK and Ireland identified that 56% of all paediatric endocrinology departments and 90% of specialist centres had a transition/transfer clinic (2). In the majority, the paediatric and adult endocrinologist consulted together. This has the advantage of meeting the adult team with the familiar paediatric team; in other chronic conditions, including diabetes, there is evidence that this improves attendance at the adult clinic. Although this audit is reassuring, further research is required to identify models and components of transitional care that improve both user satisfaction, and engagement with adult endocrine care, and whether there are groups of patients that require differing levels of support during the transition process.

All patients attending paediatric endocrine services during their adolescent years should receive age-appropriate healthcare and preparation for adult healthcare. The complexity and expected duration of the condition determines whether they will be transferred to secondary or tertiary adult endocrine care, or discharged to their family doctor. The main challenges are in young people with complex conditions, for instance, hypothalamic-pituitary disorders, adrenal disorders, particularly congenital adrenal hyperplasia, Turner's syndrome, Klinefelter’s syndrome, Prader–Willi syndrome, childhood cancer survivors. Young people with learning disabilities and behavioural problems need a more holistic approach involving professionals from education and social services.

During the transition period there is a shift of focus from growth and puberty to the implications of the condition in adulthood. Issues relating to reproductive health, for instance, sex and fertility, are more likely to engage the young person in consultations. As assisted reproductive techniques improve, there is a need to discuss options for fertility preservation in certain groups of patients during adolescence, for instance, in Turner’s and Klinefelter’s syndrome. Many endocrine conditions have a bone phenotype, which is potentially an important determinant of an individual’s risk of fracture in later life (3). The potential that there is a window of opportunity to optimize bone health in late adolescence and young adulthood is a focus of care and also research. Cardiovascular health also needs to be considered, as many endocrine conditions have an adverse cardiovascular risk profile in addition to increased morbidity and mortality from cardiovascular disease. There is evidence that the origins of this begin in adolescence or young adulthood.

These important management issues in the transition period will be discussed in the context of young people with growth hormone deficiency, congenital adrenal hyperplasia, and Turner's syndrome.

The primary role of growth hormone in children with growth hormone deficiency (GHD) is to promote linear growth. The metabolic benefits of growth hormone are considered only later in adulthood, often many years after paediatric growth hormone treatment has been discontinued. Studies have suggested that the discontinuation of growth hormone therapy at the achievement of final height in adolescents with persistent GHD may have detrimental consequences for the achievement of adult somatic development (i.e. muscle and bone). This deficit may not be entirely addressed by the recommencement of growth hormone later in adulthood. A consensus, therefore, is that growth hormone therapy should be restarted soon after final height has been achieved and continued into young adulthood in adolescents with persistent GHD (4).

Although it is during puberty that the most marked increase in muscle and bone mass occurs, peak levels are only reached in the middle of the third decade (3). The increase in gonadal steroid secretion during puberty is the most important hormonal regulator of somatic development, but growth hormone has also been shown to be an important factor. Growth hormone treatment in adults and children with GHD is associated with sustained increases in bone mineral density (BMD) as well as increases in lean body mass (LBM).

Attanasio et al. (5) compared body composition in 92 childhood-onset and 35 age-matched, untreated, adult-onset GHD patients. The mean age of those with severe GHD was 21 years; these patients had not been receiving growth hormone for a mean of 1.6 years. After adjusting for height, childhood-onset GHD patients had a lower bone mineral content (BMC) (2.1 vs 2.4 kg, p < 0.001) and LBM (38.5 vs. 50 kg, p < 0.001) than did adult-onset GHD patients. The closer childhood-onset GHD patients were to achieving their genetic target height, the higher their BMC and LBM. There is, therefore, a marked maturational deficit (16–20% less) in somatic development in childhood-onset GHD patients treated with growth hormone during childhood compared with adult-onset GHD (5). Although these deficits in body composition could be due to inadequate growth hormone in childhood, the absence of growth hormone for 18 months following discontinuation at final height may also be a factor.

The appropriate criteria for diagnosis of GHD in adolescence are unclear. Levels of IGF-1, spontaneous growth hormone secretion, and growth hormone to provocative testing reach peak values during late puberty and subsequently decline. The peak growth hormone response to provocative testing of 3 µg/l, below which severe GHD is diagnosed in an adult, is based on data from a cohort of 45-year-old patients with hypopituitarism. Therefore, adopting the adult criteria for severe GHD in adolescents is inappropriate. The first consensus organised by the European Society of Paediatric Endocrinology and Growth Hormone Research Society (ESPE/GRS) decided on a peak growth hormone of <5 µg/l as diagnostic of GHD in adolescence (4); however, a subsequent study examining retesting of adolescents with a high likelihood of persistent GHD, based on abnormalities on magnetic resonance imaging or the presence of multiple pituitary hormone deficiencies found that a peak growth hormone of <6 mcg/l during an insulin tolerance test (ITT) (Fig. 7.5.1) provided high sensitivity and specificity for the diagnosis of GHD (6). Consequently, the GRS consensus held in 2007 have adopted a peak growth hormone of <6 µg/l as diagnostic of GHD in adolescence (7).

The most appropriate test to diagnose GHD in adolescence is also an area of debate. The ESPE/GRS consensus guidelines on retesting stratifies patients into high or low likelihood of persistent GHD (4). Those who are low likelihood (idiopathic isolated GHD with no hypothalamic pituitary abnormalities on MRI) require confirmation of GHD on both a serum IGF-1 of (<–2 SDS) and a growth hormone provocative test, while those with high likelihood undergo screening with serum IGF-1 and progress to a growth hormone provocative test if IGF-1 SDS of greater than –2. The use of IGF-1 as a screening tool in those with high likelihood of persistent GHD is similar to the recommendations in the diagnosis of GHD in adulthood (8). The ESPE/GRS consensus recommended the use of the ITT, with arginine stimulation test (AST) or glucagon stimulation test (GST) as alternatives (4). However, only the ITT has been validated in adolescence and more recently the GHRH-AST, defining a peak growth hormone of <19 µg/l as diagnostic of GHD (8). However, there should be caution when relying on the test in irradiated patients (8). Further studies are required validating other provocative tests and also the effect of increasing BMI in this age group.

However, Tauber et al. (9) examined the outcome of adolescents with partial GHD (peak growth hormone: 3–11.8 µg/l) 1 year after discontinuing growth hormone at the completion of growth. At baseline, body composition was adversely affected in adolescents with partial GHD (higher FM, reduced LBM) compared with those with normal growth hormone status, and this deteriorated over the year of the study with no change in adolescents with normal growth hormone status (9). This study suggests that partial GHD in the transition period may also have adverse consequences on body composition. Further longitudinal evaluation of the clinical implications of partial GHD are required.

Studies have examined whether continuation or early recommencement of growth hormone after final height in the transition period in GHD adolescents is necessary to achieve normal somatic development and to maintain a reduced cardiovascular risk. Table 7.5.2 summarizes the effect on bone health and body composition in studies of discontinuation, continuation, and recommencement of growth hormone therapy in the transition period (reviewed in (10)).

Studies (reviewed in (10)) comparing the effect of ‘seamless’ continuation with discontinuation of growth hormone on bone have reported contrasting results. In a 1-year study, a greater increase in total body BMC (6%) and lumbar spine BMD (5%) in GHD subjects receiving growth hormone compared with those not receiving growth hormone was reported. The increase in BMC of 6% is similar to the increase in healthy adolescents over a similar time period. However, in a similarly designed 2-year study, no effect of growth hormone was found on total or lumbar spine BMD. When considering these results, one needs to consider that the patients in the second study had less severe GHD (peak growth hormone <5 µg/l) and were treated with higher doses (42 µg/kg/day) up to final height, compared with patients in the first study. The higher growth hormone dose may have resulted in increased accrual of bone mass during linear growth.

Studies (reviewed in (10)) examining the effect of recommencement of growth hormone have demonstrated improvement in total body and lumbar spine BMC and BMD. However, the increase in total body BMC and lumbar spine BMD after 2 years of treatment was of similar magnitude to the increase seen after 1 year of ‘seamless’ continuation. This supports the notion that a period of discontinuation of growth hormone in adolescent GHD patients delays progression towards peak bone mass, partly because of an initial reduction in BMC and BMD when growth hormone is restarted after a period of discontinuation, with bone resorption being at first greater than bone mineralization.

In the ‘seamless’, placebo-controlled, continuation studies (reviewed in (10)), two studies demonstrated a modest improvement in body composition, with a 4–6% increase in LBM and a 6–8% decrease in fat mass (FM) over 1–2 years, consistent with normal changes in body composition. One study found no statistically significant differences in body composition changes (increasing percentage FM and reducing LBM) between the three groups of adolescents assessed (GHD treated with growth hormone, GHD off growth hormone, and retesting normal for growth hormone status). The studies demonstrating benefit in body composition on continued growth hormone therapy had no alteration in IGF-1 levels compared with a reduction in IGF-1 levels seen in the study that did not show a benefit, the latter being consistent with the reduction in growth hormone dosage (42–20 µg/kg per day). The decrease in IGF-1 levels may have influenced the apparent lack of effect of continued growth hormone therapy on body composition.

Recommencement of growth hormone therapy (reviewed in (10)) results in a marked improvement in body composition, with an increase in LBM (13–14%), regardless of the duration off therapy. This increase in LBM equates to 65–85% of the deficit observed in young adults with childhood-onset compared with age-matched adult-onset subjects (5). A less consistent effect (1–25%) was seen for reduction in FM, probably due to a gender effect.

Despite evidence that growth hormone treatment in adults improves lipid profiles, results from studies in adolescents are inconsistent (reviewed in (10)). Reassuringly, there are only reports of subtle effects from stopping growth hormone replacement on cardiac morphology and function, which improved with recommencement, and no effect has been observed on intima-media thickness in the common carotid arteries. With more prolonged discontinuation of growth hormone, negative effects on the cardiovascular system may occur.

Growth hormone therapy in the transition period has minimal effect on quality of life (reviewed in (10)). One study examined the effect of seamless continuation of growth hormone compared with discontinuation and found no effect on quality of life at baseline or after 2 years off growth hormone therapy. In a study on recommencement of growth hormone replacement therapy, although quality of life was lower than in normal controls, no change in overall score was identified with growth hormone despite substantial improvement in individual parameters that were low at baseline, including sexual arousal and body shape.

In all growth hormone studies, evidence of safety is a priority. No differences in short-term adverse effects, such as fluid retention and arthralgia, were found among placebo, adult, and paediatric doses of growth hormone. With regards to medium-term adverse effects, studies have demonstrated a reduction in insulin sensitivity and an increase in fasting glucose levels, but no impairment in glucose tolerance, on recommencement of growth hormone, and no change in insulin sensitivity or glucose homeostasis when growth hormone was continued. Surveillance programmes are required to monitor long-term safety in relation to the risk of malignancy and other causes of increased morbidity and mortality in patients with GHD.

There is a consensus of opinion that growth hormone should be continued after final height is achieved, to enable patients to achieve adult somatic development. Recommendations have been made, based on biochemical criteria, for the diagnosis of GHD in the transition period, and for the dosing and duration of growth hormone replacement therapy. Strategies for the reassessment of growth hormone status, and for the management of growth hormone therapy in adolescents in the transition period are detailed in Fig. 7.5.2 a and b (4). Furthermore, the completion of linear growth in patients diagnosed with GHD in childhood is an ideal time for the re-evaluation of the underlying hypothalamic-pituitary condition and for assessing the need for other hormone replacement treatments.

During adolescence maintaining adequate biochemical control in congenital adrenal hyperplasia is challenging. Their current health status needs to be assessed, therapy altered and an interdisciplinary team involved if necessary. Reproductive and psychosexual health should be prioritized at this time, but cardiovascular and bone health should also be considered.

Patients with classical CAH are managed with glucocorticoid therapy and, if salt-wasting, mineralocorticoid replacement throughout life.

The challenge of treatment with glucocorticoids is to control hyperandrogenism without inducing hypercortisolism with a focus on the clinical outcomes. Monitoring should involve both biochemical measures and clinical assessment of glucocorticoid under- or over-replacement.

During puberty management of CAH may become more difficult with failed suppression of adrenal androgen precursors. From a physiological perspective, there is a recognized increase in cortisol clearance (11) and glucocorticoid dose adjustment may be necessary. From a psychological perspective, adolescents with chronic illness will often test boundaries, and with that may omit or forget to take their medication regularly. In this situation, it is important to work with the young person to identify what makes it easy for them to take their medication regularly and identify what they recognize as benefits of regular glucocorticoid therapy.

During childhood hydrocortisone is the glucocorticoid of choice because of concerns that the more potent glucocorticoids have an adverse effect on growth (12). In late adolescence there is no consensus on the choice of glucocorticoid (13). A longer-acting glucocorticoid may provide improved biochemical control and also has the benefit of being taken once, rather than three times a day. In adults, after hydrocortisone, dexamethasone is the most popular glucocorticoid of choice (13). However, dexamethasone is not suitable for sexually-active females who are not using contraception, and either hydrocortisone or prednisolone should be considered. In the event of pregnancy these steroids are inactivated by placental 11 beta hydroxysteroid dehydrogenase. If there is a risk of an affected pregnancy then counselling is required for early maternal dexamethasone therapy to prevent virilization.

There is also no consensus on optimal goals for biochemical control in this age group and it has been suggested that this could be tailored (14). For example, for a young female interested in fertility early morning and before medication 17α hydroxyprogesterone (17OHP) levels should be maintained at levels lower than 24 nmol/l, whereas the adult male with no evidence of testicular adrenal rests on ultrasound could be maintained at a higher 17OHP level at lower than 75 nmol/l. As in childhood, androstenedione levels should be within the normal range.

Studies are ongoing to design a long-acting hydrocortisone preparation, however, in the mean time, more studies are required to identify the advantages and disadvantages of different available glucocorticoid preparations on biochemical control and other biological endpoints

In contrast to glucocorticoid therapy, the requirements for mineralocorticoid therapy are often lower during adolescence compared with those during childhood. The dose of fludrocortisone should be altered, based on maintaining renin levels at the upper end of the normal range and a normal blood pressure.

The risk of addisonian crises is present throughout life. As young people with CAH become increasingly independent and spend more time away from home, their education about what to do during illness and emergency situations, in terms of increasing their glucocorticoid therapy or seeking medical help, is essential. They should be encouraged to wear medic alert jewellery and carry a steroid replacement card at all times.

In late adolescence, after the completion of growth, sex and fertility issues become a focus for the majority of young people.

There are several reasons that reproductive and psychosexual health can be affected in females (reviewed in (14)). These can be divided into structural, endocrinological, or psychological reasons. An interdisciplinary approach is essential. From a structural perspective, genital malformations, and suboptimal surgical reconstruction may result in impaired self-image and decreased sexual activity. 50% of young women with salt-wasting CAH report experiencing pain on vaginal penetration and sexual function was reduced compared with controls. From an endocrinological perspective irregular menstrual periods are common, anovulation may occur due to hyperandrogenaemia with inadequate glucocorticoid therapy and elevated follicular phase progesterone due to abnormal gonadotrophin dynamics may affect implantation and, therefore, fertility. Evidence that polycystic ovaries are more common is unclear.

In the transition period, young women with CAH should be offered referral to surgical/urological/gynaecological teams for genital examination and further surgery, if necessary, with or without vaginal dilatation. Psychosexual counselling should play an important part in their management during this time. Longer-acting glucocorticoids are often successful in regulating the menstrual cycle and optimizing fertility. However, as discussed previously dexamethasone may not be suitable for sexually active females. Women can be reassured that with appropriate therapy young women with CAH can achieve pregnancy. All CAH patients hoping to achieve pregnancy should be offered genetic counselling to ascertain whether their partner is a carrier and the fetus is at risk.

Although most young men with CAH are fertile, reproductive health can be affected if biochemical control is not adequate. The development of testicular adrenal rest tumours (TARTs) may result in oligo- or azoospermia or Leydig cell failure. At least one third of males with CAH have evidence of TART on ultrasound (reviewed in (14)). As the ‘tumours’ are frequently impalpable, a screening testicular ultrasound is recommended. Excess adrenal androgen production can impact upon the hypothalamic–pituitary–gonadal axis leading to hypogonadotrophic hypogonadism and reduced gonadal testosterone production, which is required for spermatogenesis.

To assess reproductive health in males, testicular ultrasound is recommended and monitoring of luteinizing hormone levels. In men who require a more accurate assessment sperm analysis can be offered. By improving control using higher doses of glucocorticoids infertility can be reversed (reviewed in (14)). As in females male CAH patients hoping to achieve pregnancy should be offered genetic counselling to ascertain whether their partner is a carrier and the fetus is at risk.

Obesity is a particular problem, the origins of which appear to be in the first years of life (reviewed in (15)), and are possibly related to the high doses of glucocorticoid therapy used in the past. Reduced insulin sensitivity has been observed in CAH patients compared with matched BMI controls. Patients with CAH also have a higher incidence of hypertension. One study of 19 classical CAH adults demonstrated evidence of early arterial disease with increased intima media thickness in all major arteries (16). There is no evidence yet available of increased incidence of cardiovascular events in adults with CAH. Further studies are necessary to understand the pathogenesis of increased cardiovascular risk.

Young people should undergo regular assessment of cardiovascular risk (blood pressure, fasting glucose, and lipids) and be encouraged to adopt a healthy lifestyle. If appropriate, the dose or type of glucocorticoids, and dose of mineralocorticoids could be altered to help reduce either obesity or hypertension.

Long-term glucocorticoid therapy is associated with osteopaenia. In patients with CAH, studies of prepubertal children have failed to demonstrate significant difference, while those in adolescents and young adults report a reduced BMD (reviewed in (14)). There is a clear association in some of the studies between osteopaenia and glucocorticoid exposure, longer duration of glucocorticoids, higher doses of glucocorticoids, and longer-acting glucocorticoids. One study identified that osteopaenia was present in 48% of young people under the age of 30, compared with 73% of those over 30 years (17). The same study also found more osteoporotic fractures in patients compared with controls (p = 0.058). Larger studies are required to examine this in more detail and, in particular, long-term fracture risk.

In young people with CAH the improvement of biochemical control to improve reproductive health may compromise bone health. The use of DEXA scanning can allow the situation to be monitored and appropriate advice to be given.

Girls and women with Turner's syndrome (TS) are at an increased risk of morbidity (18) and mortality (19) compared with the general population. It is not known if this is due to inadequate transition to adult care leading to suboptimal follow-up (20) and/or lack of optimization of hormone replacement therapy (HRT). Fertility options are also increasing and need to be discussed at this time.

Morbidity is considerably increased in TS, including an increased relative risk of endocrine conditions, hypothyroidism, type 1 and 2 diabetes, cardiovascular conditions, congenital and acquired and hypertension, gastrointestinal conditions, cirrhosis, inflammatory bowel disease and coeliac disease, osteoporosis, and fractures (18). Although in childhood conductive hearing loss is common following otitis media, sensorineural hearing loss is extremely common in adulthood. Mortality in a British cohort was increased with a standardized mortality ratio of 3, which is increased at all ages and from conditions affecting all systems (19). Health screening should therefore be performed to identify problems early. During childhood many of these elements of screening will not have been performed on a regular basis, the end of growth provides an ideal opportunity to restart health screening and allows discussion with the young person about the implications of the condition in adulthood, and the need for regular checks.

The most significant health problems are related to the cardiovascular system. Girls and women with TS have an increased risk of congenital heart malformations, hypertension, and coronary heart disease.

Aortic dilatation is common and greatly increases the risk of aortic dissection, which is often fatal. Aortic dilatation is observed in 3–42% of randomly selected TS women (21). Aortic dissection occurs in 40 per million TS years versus 6 per million years in the general population, at the earlier median age of 35 compared with 71 years in the general population (22). Risk factors for developing aortic dilatation and, therefore, dissection are bicuspid aortic valve, aortic coarctation, and hypertension.

During adolescence hypertension becomes common, in childhood and adolescence 30% are mildly hypertensive increasing to 50% in adulthood on 24-h ambulatory blood pressure with 50% displaying abnormal circadian blood pressure profiles (reviewed in (23)). It is thought to be the main explanation for women with TS having an increased risk of dying from coronary artery disease compared to the general population (19).

Abnormalities in glucose homeostasis are common (reviewed in (23)). Fasting glucose levels are often normal but fasting hyperinsulinaemia and impaired glucose tolerance has been found in 25–78% of adults. This is secondary to decreased insulin sensitivity and reduced first phase insulin response. Reduced insulin sensitivity is more likely because of the altered body composition and sedentary lifestyle. There is also an increased relative risk of both type 1 and type 2 diabetes.

Cardiac imaging should be performed in the transition period and then every 3–5 years if normal. Although echocardiography is widely available the use of cardiac MRI is also recommended as abnormalities not detected on echocardiography may be identified (24), an electrocardiograph is also useful. There should be a regular clinic assessment of blood pressure including the appropriate use of 24-h ambulatory blood pressure. In addition, fasting lipids, glucose, and in some patients an oral glucose tolerance test should be checked annually. Healthy lifestyle advice about maintaining a healthy weight and not smoking should be provided.

The majority of adolescents with TS will not undergo menarche; however, as with the TS phenotype, there is also a variation in gonadal function. In a large Italian study of 522 girls who were 12 years and older, 16% underwent spontaneous pubertal development and menarche (9% of girls with 45,X and 41% of those mosaic for a 46,XX line) (25). Menstrual dysfunction occurred relatively soon after menarche with 23% developing irregular menses within 0.9 ± 1.8 years and 14% developing secondary amenorrhoea after 1.6 ± 2.0 years. Measurements of gonadotrophins in childhood (26) or at the onset of puberty (25) may prove useful in predicting who may go on to develop ovarian failure or who may be suitable for ovarian preservation. This would allow counselling of the young person.

The majority of adolescents require oestrogen replacement. There is no consensus on how to optimize HRT in adolescents with TS. Initial focus in the literature around oestrogen replacement and particularly timing of pubertal induction was related to height. The role of oestrogen replacement in TS is now considered much wider and includes secondary sex characteristics, cardiovascular and bone health, cognitive function, and uterine size and shape.

It is unclear how oestrogen deficiency impacts on cardiovascular health (reviewed in (27)). There is evidence of positive benefits of oestrogen on vascular structure and function, HDL cholesterol, fasting glucose and insulin, and blood pressure. However, oral HRT in interventional studies did not reduce total risk of cardiovascular disease in postmenopausal women. Emerging evidence is suggestive that the early introduction of HRT may reduce cardiovascular disease risk–the ‘so-called’ timing hypothesis.

Bone mass is dependent on a multitude of factors with puberty and oestrogen secretion providing a critical period of bone mass accumulation. Individuals with TS have a low BMD throughout life and are at increased risk of fracture (18, 28). The implication that oestrogen deficiency is a significant factor is supported by longitudinal studies demonstrating that young people with TS who have spontaneous menstruation have normal BMD where as young people with ovarian failure have reduced BMD. Adequate HRT is required to avoid a rapid decrease in BMD and to maximize bone mass in adolescents and young adults. A 3-year longitudinal study of 21 women with TS (20–40) who underwent bone biopsies demonstrated the marked anabolic effect of oestrogen on bone (29).

Adolescence is a key time for brain maturation and the development of higher cognitive functions and social and emotional behaviour. The potential effects of puberty and oestrogen on this are difficult to ignore (reviewed in (27)). Individuals with TS often have intellectual functioning within the normal range, but impaired nonverbal skills. There are deficits in visual perception, selected executive functions, and social skills. Variations in oestrogen through the menstrual cycle or after the introduction of HRT at the menopause alter cognitive function and mood. Two studies in girls with TS have also suggested positive effects. Delayed induction of puberty had a long-lasting effect on self-esteem, social adjustment, and initiation of a patient’s sex life (30).

Maximizing uterine size and function by the hormonal excursions during the menstrual cycle is considered to be the best preparation for reproduction. Current oestrogen replacement protocols for pubertal induction and maintenance fail to develop a fully mature uterus in many TS girls (31). Two cross-sectional studies examining uterine development in patients with TS aged between 18 and 45 years identified that between 18–25% had adult size and shape uterus (32, 33). In one study, the size of the uterus correlated positively with daily oestrogen dose and negatively with age at artificial menarche in one study (32). In the other, spontaneous puberty, duration (but not age at start) and type of HRT, with oestradiol-based treatments being more effective, were associated with an adult size and shaped uterus (33).

The impact of different HRT preparations, including what type of oestrogen and progestin, what dose at different ages and what route of delivery, on the range of biological endpoints is largely unknown. Although many recommend the administration of E2 (oestradiol) via a transdermal route, as the only way to achieve natural levels of E2 in the blood, prescribing patterns in the US and Europe favour the oral preparations, premarin, conjugated equine oestrogen, and ethinyloestradiol, a potent synthetic oestrogen used in many oral contraceptive pills. The usual adult dose is 100–200 µg of transdermal oestradiol, 2–4 mg of micronized oestradiol, 20 µg of ethinyloestradiol or 1.25–2.5 mg of conjugated equine oestrogen. The dose required in adolescence is not known. Studies have shown that 2 mg of oestradiol or equivalent may be too low for normalizing the cardiovascular system and growth of the uterus (32, 34), but that no advantage has been demonstrated with different routes of administration (35–37). To allow for normal breast and uterine development it seems advisable to delay the addition of progestin for at least 2 years after starting oestrogen therapy or until breakthrough bleeding occurs (23).

More longitudinal studies are required in the transition period to evaluate different types of HRT preparations, what type of oestrogen and progestin, what dose at different ages, and what route of delivery is necessary to optimize cardiovascular and bone health, cognitive function, or uterine size.

In adolescents with gonadal failure, the primary focus is in the development of secondary sexual characteristics. However, it is at this age that issues relating to fertility should also be discussed.

Infertility is rated as the most significant problem in adults with TS (38). In those with ovarian failure oocyte donation offers a real option for child-bearing with comparable results with other groups of patients. Improved uterine size and function with high doses of oestrogen should improve outcome (39).

Due to the variation in gonadal function, the presence of follicles in adolescents with TS (40) and the rapid development of assisted reproductive techniques, there is potential for women with TS to become pregnant with their own oocytes. Spontaneous pregnancy occurs in 2–5% of women who undergo spontaneous menarche without medical intervention (25). Of those that undergo a spontaneous menarche, it is now possible to offer them oocyte cryopreservation. Even if spontaneous menarche has not yet occurred, the presence of follicles has suggested that ovarian tissue could be cryopreserved (40); however, this approach remains experimental (41). Spontaneous puberty, mosaicism, and normal hormone concentrations were statistically significant, but not exclusive prognostic factors as regards to finding follicles (42). In the future understanding the process of follicular apoptosis in TS may lead to a treatment sparing the follicles and maintaining fertility.

When fertility preservation is a possibility there may be a window of opportunity in which it could take place. Adolescents should be carefully counselled and encouraged to make their own decisions, supported by their family and healthcare team.

Regardless of whether a woman with TS is undergoing a spontaneous or assisted pregnancy she should be considered at high risk of complications. In a large survey of patients undergoing donor oocyte treatment, a 2% or higher maternal mortality was estimated. Only 50% had been screened adequately. Therefore, in a woman with TS, who is considering a pregnancy, screening of the cardiovascular system is imperative.

Around 20–25% of individuals with TS are diagnosed in adolescence or later (43). This delay in diagnosis was found in one study to be 7.7 years and was due in part to lack of awareness by health professionals (43). For these individuals this delay represents a missed opportunity for early introduction of growth hormone with optimization of final height, normalization of timing of pubertal development, and the other potential benefits of hormone replacement therapy, and early detection and management of comorbidities. To maximize height, the use of higher doses of growth hormone and consideration of the introduction of oxandrolone has been recommended. Patients diagnosed with TS in adolescence should be counselled about the timing of pubertal induction and the potential advantages for growth compared with the potential disadvantages if delayed. It is important to act in concordance with the patient’s wishes.

Transition is an important part of adolescent healthcare. Getting transition right is thought to give young people with endocrine conditions the best chance of engaging with adult endocrine services. More studies are required to examine the impact of growing up with an endocrine condition on the biological, psychological, and social aspects of adolescence and young adulthood to allow improved management during this time.