Fig. 1
Simplified diagram of steroid hormone synthesis. (Coursiv letters mark enzymes; – OH = hydroxylase; e.g. 21, OH = 21-hydrohylase, if defect is the key enzyme for CAH)
In the case of salt-wasting 21-OHD, newborns develop vomiting, hyponatremia, weight loss, hypotension (salt-losing crisis) and hypoglycaemia and will die if not treated appropriately. While male newborns are clinically usually not conspicuous and may just present with pigmented, slightly enlarged genitalia, newborn females present with ambiguous external genitalia. The degree of virilisation may range from a mild clitoromegaly to a phallic transformation of the clitoris with varying degrees of fusion of the labia majora, which may give a scrotum-like appearance (classification according to Prader—stages I–V) (Prader, 1954). Urethra and vagina may thus end in a urogenital sinus. The inner part of the vagina as well as uterus and ovaries is however developed as in normal girls. Thus, once the diagnosis is established in these children, there is no doubt of their female gender and the rearing as girls. In cases of late-onset 21-OHD female’s tall stature with an advanced bone age, moderate clitoromegaly or hirsutism may lead the differential diagnosis.
Aside from the anatomical aspects in virilised girls with CAH, there is an ongoing discussion about the implications of elevated androgen levels during pre- and postnatal life on the brain and the personality of a female (Meyer-Bahlburg, 2001; Meyer-Bahlburg et al., 2008; Money and Ehrhartdt, 1972). Although there is no dissension that girls with CAH should be reared as girls and will function as females in any aspect, there is ample evidence that affected girls often tend to be attracted to activities previously thought to be more typically associated with boys (“rough and tumble play”) and to behave tomboyish. Although these categories are of lesser relevance in our Western societies, the fundamental role of hormonal imprinting on the brain is still not unravelled.
Treatment of CAH
Hormonal Replacement
The aims of treatment in CAH are to enable the affected children a normal development in terms of their metabolism, a normal growth process, a normal timing of puberty which ends in the ability to function sexually according to gender and to be fertile in adult life (Hindmarsh, 2009; Speiser et al., 2010). Under- and overtreatment with glucocorticoids and mineralocorticoids should be avoided at any time during development. Replacement with mineralocorticoids [e.g. fludrocortisone—orally 50–200 μg/day (or 150 μg/m2/day)]—potentially with sodium chloride supplementation—is relatively easy after infancy, when the monitoring of plasma rennin activity (PRA) and blood pressure shows stable results. Treatment with glucocorticoids, however, is difficult and less standardised. The main reason for this is the fact that blood glucocorticoid levels need not only be adequate in terms of mimicking the diurnal needs of the body but need to be given in such a mode that an excessive androgen production is avoided. This means that glucocorticoids need to be available for the feedback to the pituitary when the endogenous activity of the hypothalamus-pituitary is highest. Thus, the therapy can be oriented not only at the total daily cortisol production but also at its circadian distribution. Hydrocortisone is usually given in a daily dose of 10–15 mg/m2/day divided into three doses (morning 50 %, lunchtime and evening 25 % each). Given the fact that hydrocortisone has a biological half-life of only about 6 h, there may be periods of low glucocorticoid exposure. During childhood, this treatment can usually be done without avoiding under-treatment (virilisation, early puberty, loss of growth potential) or overtreatment (obesity, growth impairment, delayed puberty).
During adolescence, the standard therapy which was successful at a younger age is often no longer effective (Bonfig et al., 2009). There are several reasons for this: (1) in adolescent boys and girls, there is less control by parents, and often there is a higher degree of negation of rules. Adolescents find it difficult to adhere to frequent and fixed schedules. There is also the pubertal identity “crisis” which is aggravated by the recognition of the disease. (2) Some problems connected to elevated androgens in childhood such as growth problems or hirsutism are not easily recognisable during puberty. Particularly in boys an inadequate (irregular) replacement of glucocorticoids which may result in smaller testes or testicular adenoma is not obvious to the adolescent alongside normal pubertal development.
Signs of androgen excess such as acne, hirsutism and hair loss of the scull (male-pattern balding) are alarming symptoms for female adolescents. Such a development should be documented systematically with a scoring system (Ferryman-Gallwey Score) (Ferryman & Gallwey, 1961). In addition to treating the hormonal basis (see below), it may also be required to involve a dermatologist for the treatment of acne (James, 2005) and the optical (bleaching) or physical (epilation) removal of hirsutism (Rosenfield, 2005). Today both aspects of treatment are multifaceted and may require an expertise, which is beyond the paediatric and adult endocrinologist. In adolescent girls, the processes starting and maintaining regular ovulation require a higher degree of optimisation of glucocorticoid replacement. Therefore, adolescents may need a more frequent control by the paediatric endocrinologist and repeated and more personalised information about the nature of the disease. It is inadequate to believe that everything is clear to the adolescent (and its parents) only because the family has been coming to the office for years. In my experience additional interventions by experienced psychologists are however only needed in rare cases.
When impaired adherence to the regimen of hydrocortisone is the cause of an inadequate control of the disease, the use of more potent glucocorticoid derivates ought to be considered, and this will reduce the frequency of medication during the day. Prednisone/prednisolone with a potency about five times higher than hydrocortisone may be given twice daily [total dose 4–5 mg/m2/day (morning to evening—1/3 to 2/3)]. Dexamethasone is even more potent (30–100 times) and may be given at the end of the growth phase (50–150 μg in the evening). Changes in treatment patterns should always be guided by experienced endocrinologists.
Growth
Already at birth, children with CAH tend to be slightly larger. Children whose disorder is discovered in childhood are tall and have an advanced bone age, which impairs the growth potential. On average the adult height in children treated is impaired compared to the population (Hargitai et al., 2001) by about one standard deviation (about 6–7 cm). A reduction in height is more pronounced in cases with salt wasting, which probably reflects a greater difficulty to control the disorder. It is the rule that any growth impairment is more likely to be the result of insufficient treatment with glucocorticoids rather than its excess. The latter however may occur subtly and slowly and may be accompanied with a gain in weight, which may be misinterpreted as simple obesity in times when this is exploding in incidence particularly among juveniles and adolescents. Any gain in weight (BMI) with a slowing down of the height velocity and a subnormal progression of the bone age should stimulate to search for further signs of hypercortisolism. The potentially positive psychotropic effect of glucocorticoids holds the risk of an addiction with higher than recommended doses in adolescents.
The onset of puberty in children with CAH tends to be in the normal age range, provided that the hormonal treatment has been optimal. In a small number of cases, central puberty may be precocious, which may then require treatment with gonadotropin-releasing hormone analogues for psychological reasons and for the preservation of a normal growth potential (Carel et al., 2009). In cases of a poor adult height, prognosis at puberty onset of treatment with growth hormone is a discussed option.
Genitalia and Sexuality
Issues related to sexuality should, in general, always be addressed openly, sensitively and with competence, since they are an essential element of human life and in particular a major concern of adolescents (Casteras et al., 2009; Frisen et al., 2009; Otten et al., 2005). In girls with virilised genitalia at birth, surgical correction needs to be performed by experienced surgeons after counselling of the parents about all aspects relevant to the disorder. The goals of surgery are (1) genital appearance compatible with gender, (2) unobstructed urinary emptying without incontinence or infection and (3) good adult sexual and reproductive function (Speiser et al., 2010). When there is only minimal virilisation (Prader stage I–II), surgery may not be required at all, since the clitoris will reduce in size relative to the growth of the child’s body and with proper medical care. Clitorectomy should never be performed. Any reduction of clitoral size needs to be performed with the greatest care to preserve its sensitivity. Today the correction of the vaginal opening using up-to-date surgical technology is recommended during the first year of life (2–6–[12] months). Such early procedures are supposed to ensure good sexual functionality. However, experience shows that many girls now in their adolescence have not been treated surgically under optimal conditions in infancy, thus necessitating a second surgery in adolescence. Aside from technical aspects of the procedure, the most important issue is its timing (Vidal et al., 2010).
When puberty has started it must be investigated whether the genital situation is likely to allow a normal intercourse. This investigation should be done after explaining the reasons and potential consequences to the girls with utmost sensitivity. The issue often needs to be put forward by the treating paediatrician. An examination should only be done by the team qualified for the potentially necessary surgery. The procedure should then be done not too early before the first intercourse can be expected. At the same time it should be done at a time point sufficiently before the cohabitarche is imminent in order to provide time for healing and the feeling of normality to the female adolescent. Thus, the timing of genital surgery in adolescence also depends on the personal and social settings. In the author’s experience a practical timing is when menarche is imminent. In conflicts between parents and the adolescent, the physician needs to find compromises in the interest of the affected girls and must respect their privacy within the legal frameworks. Manipulations with devices to widen a narrow vaginal introitus by the adolescents themselves, as was recommended previously, are considered obsolete today.
Like any other adolescent girls with CAH also need to be counselled about conception and its prevention. In the case of a pregnant adolescent, monitoring needs to be done in an experienced centre. Treatment with hydrocortisone or prednisone should be guided so that serum testosterone remains in the upper normal range. Dexamethasone treatment should be avoided. The problems of prenatal therapy of CAH in an affected fetus are beyond the scope of this article. If reconstructive surgery has been performed, primary caesarean section should be advised to avoid further damage to the genital tract.
The issues of genital development and sexuality also need to be discussed with adolescent boys. They should be taught that their sexual functioning and fertility is absolutely normal as long as the management of the disorder is appropriate. They should also be advised that non-compliance may result in the development of adrenal and/or testicular adenoma (adrenal rest tumours) (Mouritsen et al., 2010).
Hypogonadism
Hypogonadism is a term describing the inability to develop functioning gonads which leads to normal organic and functional development enabling normal reproduction. Hypogonadism usually becomes apparent when puberty does not occur timely or does not progress according to its natural pattern. In a strict sense disorders of puberty which are of transient nature (see Chapter of Rogol) are distinguished from those with permanent hypogonadism. The causes of hypogonadism vary (see Table 1). In principle disorders with the cause located in the gonads (testes, ovaries) are termed “primary or peripheral hypogonadism” (e.g. Turner syndrome, Klinefelter syndrome), and disorders with the cause located in the regulating centres hypothalamus and pituitary are termed “secondary or central hypogonadism” (e.g. gonadotropin deficiency, combined pituitary hormone deficiency). In the case of a delay in the pubertal development, there are several tasks: (1) to establish a diagnosis and to find out whether the condition is transient or permanent, (2) to ensure a normal phenotypical and psychological development of the affected adolescent and (3) to ensure fertility. Since there is a high degree of complexity depending on the cause of hypogonadism, this chapter will only deal with selected aspects of the topic taking specific disorders as models to discuss the relevant issues.
Table 1
Classification of hypogonadism
Affected area | Example | |
|---|---|---|
Impaired hypothalamus-pituitary function | ||
“Secondary hypogonadism” | Congenital anomalies | Septo-optic dysplasia |
CNS tumours | Craniopharyngioma | |
CNS irradiation | Post-X-ray | |
Trauma/surgery | Head injury | |
Defects of GnRH, LH, FSH | Kallman’s syndrome | |
Impaired gonadal function | ||
“Primary hypogonadism” | Loss of the gonads | Torsion on gonads |
Irradiation damage | Post-X-ray | |
Chemical damage | Cyclophosphamide | |
Syndromes | Prader-Willi S. | |
Chromosomal disorders | Turner S. Klinefelter S. | |
Turner Syndrome
Background
Turner syndrome (TS) or Ullrich-Turner syndrome (UTS) may be defined as the combination of characteristic physical features—short stature, gonadal dysgenesis, typical visible dysmorphic stigmata and abnormalities in organs—which is present in individuals with a female phenotype and is caused by the complete or partial absence of one of the X chromosomes (Bondy, 2007; Ranke and Saenger, 2001). The main topics discussed here will be sexual development and fertility, growth promotion and psychosocial aspects.
Turner syndrome affects approximately 1:2,000 live-born females. In about 50 % of cases, the karyotype analysis of peripheral lymphocytes reveals the complete loss of one X chromosome (karyotype 45, X), while the remaining patients display a multitude of chromosomal abnormalities. The wide range of somatic features in TS indicates that a number of different X-located genes are responsible for the complete phenotype. Short stature in TS has been associated with haploinsufficiency of a critical chromosomal region (distal of Xp22.2), which escapes inactivation (pseudoautosomal region of X and Y) and in which the short stature homeobox (SHOX) gene resides (Xp22.33) (Rao et al., 1997). Skeletal defects in TS include mesomelia, micrognathia, cubitus valgus, high-arched palate, short metacarpals and Madelung deformity. SHOX defects are known to cause mesomelic short stature associated with varied phenotypical features. Thus, haploinsufficiency of SHOX may explain a major part of short stature in TS, but does not entirely clarify this issue. To date, there is neither conclusive genetic data available which would explain the soft tissue and visceral stigmata in TS, such as lymphoedema, webbing of the neck and congenital heart failure, nor a firm knowledge about the genetic basis of the defect of ovarian function (gonadal dysgenesis).
Sexual Development and Fertility in TS
A consistent feature documented in TS is the unambiguous identification with the female gender. The completion of female development may, however, be thwarted by certain factors during adolescence and in adult life: ovarian failure occurs in the majority of patients, and up to 30 % experience late but spontaneous puberty (Pasquino et al., 1997). Puberty and the menstrual cycle will however only continue in a fraction of these patients. We now know that ovarian failure in TS results from premature ovarian senescence which, in several patients, ends during infancy as it progresses at a faster pace than normal. External genitalia, vagina and uterus are normally developed at birth and may grow normally on oestrogens.
Due to their short stature, young as well as adolescent TS patients are likely to be overprotected by adults and possibly rejected by their peers. Growth-promoting therapy with recombinant human growth hormone (rhGH) is an accepted method for attempting to normalise height during childhood and adult life (see below). Its aims are not only to achieve a normal height during childhood and in adult life but also to assure that measures to induce puberty can be initiated within the normal developmental window for girls. A delay of oestrogen replacement resulting in the postponement of feminisation may affect the process in which the role of the mature female is learned, as primary deficits involving cognition hinder the development of appropriate social relations and interaction with the opposite sex (Burnett et al., 2010; McCauley et al., 1987). However, patients with partners tend to develop normal sexual relationships (Sheaffer et al., 2008).
The ultimate biological goal of women is childbearing. As a rule ovarian failure and infertility are major features of TS. It is extremely rare for a TS patient to experience a spontaneous pregnancy and delivery of a healthy baby. The almost uniform prospect of infertility is by far the most existential threat to patients with TS, particularly during adolescence. In women with TS, like in any other women with ovarian failure, recent endeavours to alleviate this situation include in vitro fertilisation of donated oocytes or embryos. The success of such attempts depends, to a great extent, on the maturity of the uterus. The fact that this approach entails a higher-than-normal risk of spontaneous abortion possibly indicates that an optimal developmental window is required in order to ensure complete anatomical and functional uterine development (Bryman et al., 2011). Cryopreservation of oocytes makes it possible for the patient’s own cells to be used at a suitable time point after the technical difficulties of this procedure are completely resolved (Lau et al., 2009). Finally, the maintenance of ovarian function may possibly be a further mean of resolving the problem of infertility in UTS (Simpson and Rajkovic, 1999).
It also needs to be kept in mind that in part of the girls with TS, puberty will start but will progress incompletely due to remnant ovarian function. The fact that spontaneous fertility is reported means that potentially fertile adolescents need to be identified and contraception may be advised in time.
Oestrogen Replacement in TS
In a large study of 566 adults with TS, it was documented that the timely induction of puberty was extremely important for the self-esteem, for the development of social relations to the peers and for the initiation of sexual activities (Carel et al., 2006). Given that the mean onset of puberty in girls visible through breast budding (Tanner stage B2) occurs at about 10 years with a natural variation of about 2 years, the induction of puberty should ideally not be delayed much beyond an age of 12 years. Of course the intentions of the adolescents, their parents and the overall circumstances will eventually decide the time point. The principal problem related to oestrogen replacement during puberty is that oestrogens fasten the tempo of growth but do not augment it and lead to the closure of the epiphyses of the long bones, thus bringing the growth process to an end. Any therapy with oestrogen should therefore be conducted in a way that does not impair the growth potential. At a chronological age of 12 years at which the bone age in TS is about 10 years, it can be expected that an adolescent on GH will still grow—even very conservatively estimated—10 cm (Ranke and Lindberg, 2011). Thus, when a child with TS has reached about 140+ cm at puberty onset, it can be assumed that she is likely to reach an adult height of more than 150 cm. Timely and appropriate oestrogen replacement is also considered important for the lifelong bone health of adult women.
In addition to the timing of the initiation of oestrogens, the choice of the hormone preparation, the dose and the dose progression play a major role. This is relevant in all adolescents irrespective of the cause of hypogonadism. Oral oestrogen preparations which are most convenient in daily life are available as 17ß-estradiol (=E2), estradiol valerate (=E2val), ethinyl estradiol (EE) and conjugated oestrogens. Ethinyl estradiol is no longer recommended for oestrogen replacement. Oestrogen valerate and oestrogen cypionate are given i.m., a mode which is rarely indicated. Transdermal estradiol can be given as an ointment or as matrix patches, which release E2 in a standardised mode. The medicaments and the equivalent therapeutic doses of the different preparations are listed in Table 2. The choice of the oestrogen used obviously also depends on its availability, the experience of the physicians and habits in the medical environment (Drobac et al., 2006; Kiess et al., 2002). The dose increments over time are chosen in such a way that the normal pubertal course (about 3 years from the onset to menarche) is mimicked. Unfortunately oestrogen measurements in blood during replacement cannot be used for the guidance of treatment. Therefore, clinical parameters (e.g. breast staging), sonography of the uterus, body growth and bone age development need to guide treatment. Usually we start with about 1/6 of the adult oestrogen dose and increase the dose by this amount every 6 months. We give oestrogens unopposed with gestagens until the pubertal development (including uterine size) is equivalent to Tanner stage 4. Then derivates of progesterone (progestagens) are added in a cyclic mode (e.g. 10–14 out of 28–30 days) in order to induce a menstruation. The phenotypical feminisation of girls with TS and in other disorders with hypogonadism is usually very satisfying. Unfortunately neither the treatment with oestrogens “for the induction of puberty” nor “treatment of oestrogen deficit in adolescents” is a licensed indication but constitutes formally an “off label use”.
Table 2
Medication available for oestrogen replacement therapy
Substance | Mode of application | Medicament (availability may vary from country to country) | Dose (daily) for adult women | Use in Europe (%) | Use in the USA (%) |
|---|---|---|---|---|---|
17ß-estradiol | t.d. | 25/37.5/50/75/100 μg—release/24 h (patches) | 50–100 μg | 10 | 5 |
17ß-estradiol | p.o. | 1.0/2.0/4.0 mg (tablets) | 1.0–2.0 mg | 32 | |
Estradiol valerate | p.o. | 1.0/2.0 mg (tablets) | 1.0–2.0 mg | 5 | |
Ethinyl estradiol | p.o. | 25 μg (tablets) | 25 μg | 39 | 12 |
Conjugated estrogens | p.o. | 0.3/0.6/1.25 mg (tablets) | 1.25 mg/day | 12 | 78 |
Male Hypogonadism
In the male Klinefelter syndrome (karyotype 47,XXY) (Rogol and Tartaglia, 2010; Ryan, 2010) and testicular insufficiency due to the treatment of malignancies (Edgar et al., 2009) are probably the most frequent causes of peripheral hypogonadism, while congenital or acquired pituitary deficits with combined loss of hypothalamus-pituitary hormone secretion are the most frequent causes of central hypogonadism (Table 1). In Klinefelter syndrome boys are tall (they have three active SHOX loci) and have minor intellectual deficits. Since the disorder affects predominantly the Sertoli cells, thus impairing fertility, the Leydig cells, which produce testosterone, are less affected. Therefore, puberty often begins less conspicuous with low-normal testosterone levels and moderate penile growth but smaller testes. With time progressing the testicular abnormality becomes more evident. Treatment for malignancies frequently involves exposure of gonads (in males and females) to chemotherapeutically or X-rays. This leads more often to infertility than to complete loss of sex steroids since Leydig cells are also more resistant to these factors than Sertoli cells. Since during adolescence masculine physical development (growth, muscular development and strength, secondary sex characteristics such as pubic and facial hair growth, deepening of the voice) and penile growth rather than testicular size and fertility are the major concerns for adolescent boys, treatment of hypogonadism in adolescence means basically adequate replacement of testosterone.
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