Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

Disorders of sex development: Hormonal
management in adolescence
Silvano Bertelloni, Eleonora Dati & Giampiero I. Baroncelli
To cite this article: Silvano Bertelloni, Eleonora Dati & Giampiero I. Baroncelli (2008) Disorders
of sex development: Hormonal management in adolescence, Gynecological Endocrinology,
24:6, 339-346
To link to this article: http://dx.doi.org/10.1080/09513590802055708

Published online: 07 Jul 2009.

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The recommended sex of rearing for some 46. In addition. In fact. Via Roma 67.bertelloni@med. at adolescence. the development of secondary sexual characteristics. Italy Downloaded by [HINARI] at 23:01 10 December 2015 (Received 27 November 2007. height and weight throughout childhood with a significant gain during adolescence. ISSN 0951-3590 print/ISSN 1473-0766 online ª 2008 Informa UK Ltd. 24(6): 339–346 DISORDER OF SEX DEVELOPMENT Disorders of sex development: Hormonal management in adolescence* SILVANO BERTELLONI. Testosterone is the main hormone for treatment in males and estrogens in females.7]. 2nd Pediatric Unit. Fax: 39 050 993044. bone health Introduction Adolescence is a period of rapid developmental changes.XY DSD and related gonadal status are reported in Table II [4. yet. Thus. & GIAMPIERO I. bone mineral accrual increases with age. Ospedale Santa Chiara – AOUP. ELEONORA DATI. During adolescence. testosterone. June 2008. I-56125 Pisa. Individuals with disorders of sex development (DSD) (Table I) may experience some difficulties in progressing physiologically into adolescence [4. sex steroid substitutive therapy. Italy. to optimize bone mass accrual.it *This paper was presented at the II World Congress on Hypospadias and Disorders of Sex Development. usually defined as the period of life from the onset of puberty to the attainment of adult age [1].1080/09513590802055708 . 2007. revised 31 January 2008. Rome. definitive body proportions and adult fat mass/muscle mass ratio take place [1]. DOI: 10. The optimal regimens for sex steroid substitutive therapy in subjects with DSD should be better defined in multi-center prospective studies. The factors driving the increase of bone mass at adolescence are not fully understood.5]. For example.unipi.6]. adolescence. Pisa. BARONCELLI Adolescent Medicine. Bertelloni.XY DSD and intact gonads may emerge. E-mail: s. the need to remove gonads – to reinforce gender identity because of a mismatch between the assigned sex and the developing secondary sexual characteristics [4. but few sound data are available to guide clinical practice. Tel: 39 050 992743. Dipartimento Materno-infantile. but a crucial role is played by skeletal growth and sex steroid increase [3]. the need to reconsider gender assignment in subjects with 46. Gonadectomy during the prepubertal years may be an additional cause of hypogonadism [4]. Italy. and to promote physical and social well-being. November 16–18. or to reduce cancer risk [4] – may occur. when skeletal mass approximately doubles. Keywords: Disorders of sex development. normal sexual development should be assured to each adolescent for optimal body development and bone health status later in life. Bone health remains a crucial aspect in the management of these persons. The table shows that these subjects may need sex hormone substitutive treatment to progress normally into adolescence independently of Correspondence: S. estrogens. Department of Obstetrics. Azienda Ospedaliero–Universitaria Pisana. Hypogonadism in DSD people may be due to dysgenetic gonads or to defects in sex steroid biosynthesis or action. Gynecology and Pediatrics. and the achievement of adult height. accepted 10 March 2008) Abstract Hormonal treatment represents the principal aspect of clinical management of people with disorders of sex development (DSD) from adolescence onwards. individuals with DSD may require sex steroid replacement to induce secondary sex characteristics. with the attainment of reproductive function. adolescence may prolong into the third decade of life and expert care should be provided to address specific health problems during this period [1.Gynecological Endocrinology. Because chronic disorders may delay the attainment of an independent adult way of life.2].

XX DSD Ovotesticular DSD 46.9]. we do not discuss Downloaded by [HINARI] at 23:01 10 December 2015 Table I. hypogonadism and its treatment on bone health are also briefly summarized. and Table II. DSD*: revised nomenclature according to ESPE/LWPES consensus statement [4]. Hypogondadism due to dysgenetic gonads and possibly to gonadectomy Hypogondadism due to dysgenetic gonads . undervirilization of an XY male.8]. as congenital adrenal hyperplasia. undermasculinization of an XY male Female pseudohermaphrodite. potential for fertility (assuming consistent genitalia) is a major factor Male or female (dependent on degree of masculinization.XY complete gonadal dysgenesis Consider external genital development and fertility potential.XX DSD. optimizing the pubertal growth spurt.8. problems related to the management of adolescents affected by 46. gonadal location and parental input) Female DSD.XY DSD 46. In the present paper we review the indications for and the regimens of sex steroid substitutive treatment in individuals with DSD in adolescence.8. 12–13 years in males) [4.7] Gonadal status Complete androgen insensitivity syndrome Female Partial androgen insensitivity syndrome Male or female (depending on judgment of degree of masculinization and parental input) 5a-Reductase type II deficiency Strongly consider male assignment 17b-Hydroxysteroid dehydrogenase-3 deficiency Ovotesticular DSD Strongly consider male assignment Hypogonadism due to prepubertal or post-pubertal gonadectomy Hypogonadism due to inadequate estrogen levels for adult women (if gonadectomy is not performed) Hypogonadism due to prepubertal or postpubertal gonadectomy Hypogonadism due to inadequate androgen action for adult men (if gonadectomy is not performed in subjects raised as males) Hypogonadism due to impaired conversion of testosterone to dihydrotestosterone may be present Hypogonadism due to impaired conversion of D4-androstenedione to testosterone may be present Hypogonadism due to prepubertal or postpubertal gonadectomy may be present Mixed gonadal dysgenesis 46. overvirilization of an XX female. Bertelloni et al. No therapy should be initiated without the fully informed consent of both the patient and the parents [4]. prenatal androgen exposure. Current diagnosis-based recommendations for sex of rearing in some DSD and consequent gonadal status. The aims of sex steroid substitutive therapy are briefly summarized in Table III [4. Indications for hormonal substitutive treatment Substitutive sex steroid hormones should be administered in subjects with 46. European Society for Paediatric Endocinology/Lawson Wilkins Pediatric Endocrine Society. Our focus is mainly on individuals with 46. Disorder Recommended sex of rearing [4. gonadal or anatomic sex is atypical. Previous Proposed Intersex Male pseudohermaphrodite. disorders of sex development. masculinization of an XX female True hermaphrodite XX male or XX sex reversal XY sex reversal DSD 46.XY complete gonadal dysgenesis DSD. The sex steroid treatment should attempt to replicate the normal ‘tempo’ of puberty – i.XY DSD [4]. as Turner syndrome [4].XX testicular DSD 46. testicular function at and after puberty.340 S. the velocity of the progression from one stage of pubertal maturation to the following one – by inducing and then maintaining the development of sex-specific secondary sexual characteristics. disorders of sex development. body composition for the assigned sex and bone mineral accrual. or sex chromosome DSD. *Congenital conditions in which development of chromosomal.9]. doses should be individualized and adequate for age and sex [4. the effects of DSD. whether they are reared according to male or female phenotype.XY DSD and hypogonadism. Hormonal induction of puberty should be usually consistent with assigned sex of the child [9] and begin at an appropriate age for puberty onset (approximately 11–12 years in females.e. phallic development. given outcome uncertainties.

14. Sex-specific secondary sexual characteristics and then maintain them in adulthood . Testosterone implants (pellets. Puberty induction in phenotypic females with 46.XY disorders of sex development In hypogonadal subjects raised as males with normal sensitivity to androgens. Sex-specific psychosocial and psychosexual maturation .5–5. but the use of DHT gel in adolescents with 5a-reductase deficiency raised as males to improve virilization at puberty remains to be addressed. polycytemia.XY DSD. low doses of testosterone should be used to induce pubertal development and they should be increased regularly to adult doses (Table IV) [8–12]. requires small incision): ! puberty induction: 8–10 mg/kg at 6-month intervals ! adult dose: 600–1200 mg/every 4–6 months improve phenotypic virilization [16. adult dose): 15–30 mg/day . if a uterus is present. DHT gel has been used successfully in prepubertal children with 5a-reductase deficiency to increase penile length [18].XY disorders of sex development In patients raised as females.8.0 mg/day .9]. However. In some androgen target tissues. then 80 mg/day for 6–12 months. Sex steroid replacement therapy in males [8–12]. adult doses): Testosterone ! non-scrotal patch: 5–10 mg/day ! gel: 5–10 g/day Dihydrotestosterone ! gel: 2.4. are also lacking in phenotypic adolescent males with 46. disorders of sex development. the 5a-reduced metabolite of testosterone. Trials with more recent formulations. represents the active androgen [4]. Transdermal androgens (topical. aggressiveness. improving the sense of well-being and social relationships [3. treatment burden and cost [12]. Oral testosterone undecanoate and transdermal preparations of testosterone are available (Table IV). Optimal bone mineral mass accumulation . however. Anecdotal case reports demonstrate that patients with partial androgen insensitivity syndrome (AIS) may benefit from supraphysiological doses of testosterone esters (e. they are designed mainly to provide full adult male testosterone levels. Thus. no evidence-based data from large trials are available on the hormone formulations.11]. several data are derived from observations in adolescents or adults with other forms of hypogonadism [9]. 150–250 mg/2–4 weeks) Testosterone enanthate (100 and 250 mg): see testosterone esters Long-acting testosterone: testosterone undecanoate (intramuscular): 1000 mg/12 weeks (adult dose) . then double dose for 6–18 months. A tentative scheme of follow-up during testosterone substitutive therapy is shown in Table V. Oral testosterone: Testosterone undecanoate: 40 mg/day for 6–12 months. Normal social/sexual life and well-being (in adolescence and adulthood) Downloaded by [HINARI] at 23:01 10 December 2015 DSD. Main indications for sex steroid substitutive treatment in persons with hypogonadal DSD [4. priapism.11. excessive stimulation of libido.XY DSD [4]. 250 mg/week) that are able to 341 Table IV. Adequate uterine growth and maturation (if present) in females or adequate penile growth and internal genitalia (if present) in males . Adequate free-fat (muscle) mass and fat mass development according to assigned sex . leading to impaired adult height. Intramuscular testosterone: Testosterone ester combinations (100 and 250 mg)*: 50 mg/ 4–6 weeks intramuscularly for 6–12 months. then dose should be increased to adult one (75–100 mg/week.9]. Genetic deficiency of 5a-reductase type II is a well-established cause of 46. such as transbuccal testosterone or long-acting (3 months) injectable testosterone undecanoate (Table IV). route of administration and doses for puberty induction in subjects with 46. Puberty induction in phenotypic males with 46. sex steroid replacement is necessary to induce: .17].11. dihydrotestosterone (DHT). recent guidelines suggest to achieve testosterone levels in the mid–normal range during treatment with any of the approved formulations. administration of estrogens and progesterone. Intramuscular depot injections of testosterone esters are commonly used in pediatric practice [10.15] and data are lacking for pubertal induction in DSD [8. Normal pubertal growth spurt and body proportions . Possible adverse effects of androgen supplementation are premature closure of the epiphyses in prepubertal boys. then the adolescent should be switched to classical intramuscular or transdermal androgen therapy . In hypogonadal individuals with DSD. Adverse effects of androgen treatment are uncommon.XY DSD [4]. while few experiences have been published in adolescents [11.8. However. In the same table reference values for testosterone in the various pubertal stages are also reported [19].13].12].g. prospective studies in homogeneous selected series of adolescent patients have been not performed. In adults.Hormonal management of DSD in adolescence Table III. but they are affected by some pharmacokinetics pitfalls [10. emotional lability may be associated with marked variations in serum testosterone related to the use of injectable ester formulations [9. . is . obstructive sleep apnea (mainly in older men) and gynecomastia. Buccal testosterone (transbuccal.9]. in addition. chosen on the basis of the patient’s preference and consideration of the pharmacokinetics.

not estradiol precursors.0).4). follicle-stimulating hormone. . . prostate-specific antigen.342 S. ethinyl estradiol. . suggesting a clinically advantageous.13. disorders of sex development. DEXA. {If prostate is present. Low doses of depot 17b-estradiol have been employed in the USA with good results in girls with Turner’s syndrome [25]. Again. FSH.0–10. 3. blood pressure. Oral estrogen formulations: Ethinyl estradiol: 2. then 0. very little is known about the effects of testosterone therapy on prostate growth or pathology in adolescents and men with 46. protected from hepatic inactivation. The optimal dose of estrogen for substitutive therapy in young adulthood is not well known [9]. 0. Measurement of testosterone should be: midway between injections for testosterone cypionate or enanthate. there is no evidence that cyclic/continuous progesterone administration is beneficial in women without a uterus. xLumbar spine and femoral neck should be assessed. . . 0. . Parameter Downloaded by [HINARI] at 23:01 10 December 2015 Full clinical evaluation with Tanner staging Bone age Testosterone* LH (FSH) Hematocrit{ Examination of the prostate plus PSA{ DEXAx Baseline 3 months 6 months 12 months 18 months 24 months Then yearly . . the dose should be increased gradually to adult dose (20–25 mg/day) Micronized 17b-estradiol: 5 mg/kg/day. . At any rate. . dual-energy X-ray absorptiometry. .25 mg/day{ . some data indicate that the growth hormone–insulin-like growth factor-I system is markedly affected by oral but not by transdermal estrogen administration. 0. then 0.XY DSD. Table VI. few changes in clinical practice have likely occurred in recent years (Table VII). or after 1–2 weeks of transdermal testosterone gel application [12]. . . 2 mg/day) Conjugated equine estrogens: *0.3 mg/day.3–9. in addition.625 to 1. Progestins{ (cyclic therapy. Therapy should restore serum testosterone levels to the mid–normal range (subjects with partial androgen insensitivity may require supranormal testosterone levels).XY DSD. .11). they are similar to those obtained by use of a fractionated transdermal patch regimen [10.5 mg every 6 months (maximum. Beneficial effects of the transdermal route of administration over oral preparations have been demonstrated for other biological systems (bone tissue. . LH. .21–24].20]. Transdermal estrogen formulations (adult dose): 17b-Estradiol ! patch: 25–100 mg/24 h ! gel: 25–100 mg/24 h . . .7 (0. natural form and natural binder for estrogen receptor (ER) in humans. route-dependent benefit of transdermal estradiol therapy [10]. { Unavailable in some countries. . the dose should be increased gradually to adult dose (minimum effective adult dose. Mean (range) testosterone levels (ng/ml) according to Tanner stage [19]: Tanner stage I. .13]. . . . . luteinizing hormone. Minimal tentative scheme to monitor androgen substitutive therapy in males with 46. .0).7–10. . Tanner stage II. .9–8.5 (0. *Total testosterone by a reliable assay for the investigation of hormone levels in children and adolescents.1 (0.20]. . conjugated equine estrogens. immediately before the application of the new buccal testosterone tablet. {If hematocrit is greater than 54% then therapy should be stopped until hematocrit decreases to a safe level [12]. no data are available for females with 46. . Estrogen therapy should begin with low doses. low-dose transdermal formulations should be encouraged for puberty induction in hypogonadic individuals with DSD who are raised as females [9].5 mg/day Levonorgestrel: 60–90 mg/day *Equivalence among different estrogen formulations and notes: 17b-estradiol. . bone mineral density data must be given as standard deviation score for age and sex according to normative values for the DEXA machine used. 10–14 days/period): Medroxyprogesterone acetate: 5–10 mg/day Dydrogestrone: 10–20 mg/day Norethisterone: 0.2 (0.5 (2.{ . inflammatory markers) [10. binds to ER as 17b-estradiol but retained for a longer time. insulin sensitivity. . Tanner stage IV. . Every 1–2 years .XY DSD [9].5–5 mg/day ( ¼ 50–100 ng/kg/day). 1. required to induce full pubertal changes and menses [4]. {To be added after 12–24 months from the start of estrogen substitutive therapy or after breakthrough bleeding. 3–12 h after application of transdermal testosterone patch. Tanner stage V.3 mg/day. Bertelloni et al.03–0. 0. . increasing 0.13.25].01 mg/day. Large differences persist among pediatric endocrinologists regarding the preferred estrogen formulation and the route of administration for pubertal induction [10.1). However. Tanner stage III. Depot estrogen formulations: 17b-Estradiol: 0. protected from hepatic inactivation.2 mg every 6 months until 1. .2 mg/month. should be individualized and should be increased slowly based on the observed rate of clinical (secondary sexual characteristics) and bone maturation (Table VI) [8–10. 3. synthetic analogue. .13].02–3. . Table V.0 mg. a progestin is usually added after breakthrough bleeding develops.0 mg/month) . oral estrogens are used more often than transdermal estrogens to induce puberty by pediatric endocrinologists in Europe as well as in the USA (Table VII) [10. ineffective orally (hepatic inactivation). In DSD women with a uterus. 0. Sex steroid replacement therapy* in females [8–10. . DSD. PSA. So. 1 mg/day. {Until the attainment of adult height and epiphyseal closure.

. DEXA. one study showed a male pattern for skeletal maturation [30]. breast cancer and thromboembolic disease with oral estrogen replacement therapy has been reported in adult menopausal women [27].4 + 0.7 – 16. A small increase in the risk of myocardial infarction. Reference values for uterine volume during adolescence are reported in the same table [26]. .40].9 cm. Minimal tentative scheme to monitor estrogen substitutive therapy in females with 46.6 cm.8{ Year of survey Number of pediatric endocrinologists Estrogen use (%) Oral ethinyl estradiol Oral 17b-estradiol Oral conjugated estrogens Transdermal 17b-estradiol Oral estradiol valerate Oral estrogen/progestin combination* Other 343 *Oral contraceptive pill. {no preference for a single estrogen.8 7 80. Tanner stage 4. disorders of sex development.8 7 9. uterine length ¼ 6.5 + 0. Parameter Full clinical evaluation with Tanner staging* Bone age Uterine size{ and endometrial thickness LH Liver enzymes Blood pressure DEXA{ Baseline 3 months 6 months 12 months 18 months 24 months Then yearly . . Bone mineral density (BMD) has been assessed mainly individuals with AIS [29. fundal/cervical ratio ¼ 1. . .5.5 27.29. Too high estrogen doses lead to premature closure of the epiphyses and impaired adult height [9. some authors have also reported BMD in individuals with 5a-reductase deficiency [39. reassuring and emphasizing the positive effects of hormonal therapy on several somatic and neuropsycholocal aspects [10. .2 10. Every 1–2 years . The majority of the papers reported reduced BMD in women with complete AIS.x . but the ‘best’ progestogen is not known [9].7 7 – 1.3. it has been suggested that neither of these two patterns can be used to estimate bone age development in complete AIS [32]. xUntil the attainment of adult height and epiphyseal closure. . . Tanner stage 2. but use of a different formulation.5 + 1.5 cm. There is no clear evidence of adverse events related to estrogen treatment in young females with 46. Tanner stage 3.33–39]. {If uterus is present.3 50.28]. Data on bone development are limited to bone age. bone mineral density data must be given as standard deviation score for age and sex according to normative values for the DEXA machine used.XY DSD. intramuscular or intrauterine. Table VIII. . .7 + 0. .XY DSD disorders of sex development A special issue in the management of hypogonadal individuals with DSD is bone development and health [3. .0 7. while BMD was normal or low–normal in Table VII. . . .9 + 0. uterine length ¼ 5. the absolute risk is likely small and these results must be considered in the appropriate context. uterine measures (mean + standard deviation) according to breast pubertal stage [26]: Tanner stage 1. . the overall message should be positive. . Practices of estrogen use among pediatric endocrinologists for puberty induction in females. . dual-energy X-ray absorptiometry. DSD. A recent review concluded that long-term sex steroid deficiency carries a health risk more than hormone replacement in young women with hypogonadism [28]. uterine length ¼ 3. . . mainly obtained in females with complete AIS [30–32].0 4.2. .0 cm. . another study confirmed that the bone age corresponded better to the standards of boys than to the standards of girls [31]. . . . uterine length ¼ 3.10. . LH. There is no evidence that the addition of cyclic progesterone is beneficial for wellbeing in women without a uterus [4. In fact. uterine length ¼ 5.9].5 mm or within 1–2 years of a continuous estrogen regimen (Table VI) [9. Additional long-term studies are required on this matter. .5 + 0. . luteinizing hormone. transdermal.2.3 7 7.Downloaded by [HINARI] at 23:01 10 December 2015 Hormonal management of DSD in adolescence when endometrial width 40.10.30]. *Likely the main aspect to monitor therapy. . The main results are summarized in Table IX. .13]. data in aging women should not be extrapolated to adolescent and young adult subjects. .2. . . Europe [17] USA [13] Italy [11] 2000 229 2004 41 2007 18 39. .0 7 5. fundal/cervical ratio ¼ 0. for example Italy [13].3 + 0. stroke. . .9 12. fundal/cervical ratio ¼ 0.20]. More recently. { Lumbar spine and femoral neck should be assessed. .8 + 0. Bone health in 46. fundal/cervical ratio ¼ 1. but this practice is adopted by the majority of pediatric endocrinologists in some countries. Thus.3. A tentative scheme of follow-up during estrogen substitutive therapy is shown in Table VIII. .3 31. . Tanner stage 5. fundal/cervical ratio ¼ 1.XY DSD.9 + 0. however. but very few data have been published on the skeletal consequences of these disorders.8 + 0. In these children. Administration can be oral.7 cm.

[40] DSD form Genetic analysis n SRT status Lumbar BMD Femoral BMD RV cAIS cAIS cAIS cAIS cAIS cAIS pAIS cAIS pAIS cAIS pAIS 5a-D 5a-D no no no no yes no no yes yes y/n F/M M yes 6 1 1 2 10 22 6 5 6 12 2 16 4 þ bg no bg bg/þ þ þ yes yes bg/þ bg/þ no* no* ## ## # LN/# ##{ # N{ #{ #{ ## N{ N{ N{ ## ## # N – N N N N # N N N F F F F F/M F F F/M F/M F/M F/M M M Downloaded by [HINARI] at 23:01 10 December 2015 DSD. introducing difficulties in data interpretation. cAIS. In such patients skeletal phenotype may be not affected. M ¼ male. # ¼ low. Moreover. complete androgen insensitivity syndrome. partial androgen insensitivity syndrome. In this regard. few sound data are available on the impact of the different substitutive regimens on bone health in adolescence and adulthood. on adult women with complete AIS proved by the presence of mutations in the androgen receptor.33–39]. in women who were not gonadectomized or who started sex steroid substitutive therapy soon after the surgery and reported good compliance with treatment. the findings shown in Table IX and our preliminary data suggest that bone health represents a main issue of hypogonadal subjects with 46.9]. performed in collaboration with the Italian support group for AIS (AISIA).XY DSD. data on BMD were collected in a small number of patients [29. Taken together. 5a-reductase deficiency. mainly in those affected by complete AIS. suggesting that partial activity of the androgen receptor may be sufficient for bone mineralization when sex steroid supplementation is adequate. We are currently involved in a study. lumbar BMD was usually more affected than femoral BMD (Table IX). in comparison with those poorly compliant [41]. Therefore. ## ¼ very low. with the diagnosis often based only on clinical and/or endocrine features [29. subjects with partial AIS or 5a-reductase deficiency (Table IX). [29] Marcus et al. LN ¼ low–normal. Sex steroid substitutive therapy for such individuals remains to be better defined. reference value to evaluate BMD status. patients with phenotypes resembling AIS but affected by other 46. [37] Danilovic et al. þ ¼ variable compliance. Future well-designed studies need to be done to address these issues. mutational analysis of the androgen receptor was not performed in all of the studies (Table IX). [35] Munoz-Torres et al. Acknowledgement The authors wish to thank the Italian support group for AIS (AISIA) for constructive collaboration and . F ¼ female. age 19–42 years) show better BMD. at both lumbar spine and femoral neck. as suggested by sparse data in subjects with 5a-reductase deficiency [39. [36] Vered et al. the doses of estrogens that are recommend for the prevention of impaired BMD are derived from studies in postmenopausal women rather than in adolescents and young women aiming to achieve their optimal peak bone mass [3. In some studies. In fact. [34] Bertelloni et al. {corrected for body weight.344 S.34. Bertelloni et al. However. even if defective androgen receptor action at bone level may contribute per se to the altered bone mineralization [29. SRT.39] or obtained by cumulating results from different machines [37]. BMD data have been obtained in heterogeneous populations regarding gonadal status and/or substitutive therapy. BMD. Preliminary data (n ¼ 9. data on bone status in other forms of 46. To our knowledge. [33] Mizunuma et al. Table IX. In addition.XY DSD. bg ¼ before gonadectomy. RV. Author Soule et al. 5a-D. pAIS. The efficacy of estrogen administration at the usual regimens in normalizing BMD in women with complete AIS and removed gonads remains a debated issue [33–39] (Table IX). sex steroid replacement therapy.33–39]. y/n ¼ in some patients. Bone mineral status in individuals with 46.XY DSD are not available. but larger series of more homogeneous patients should be investigated to obtain conclusive data and clear indications for clinical practice. *Intact testes. [38] Sobel et al. disorders of sex development. due to the relatively low prevalence of DSD. Sex steroid substitutive therapy seems to be able to determine a better bone status. a multi-center network exploring these issues will have to be developed. N ¼ normal. {corrected for apparent bone volume by mathematical formulas.40]. Impaired BMD has been related to gonadectomy not followed by appropriate sex steroid substitutive treatment.38. Subjects with partial AIS did not show a large impairment of BMD [37]. bone mineral density.XY DSD might be included. Conclusions DSD are rare conditions: in total about one person in 5500 is affected [42]. [39] Costa et al. mainly regarding the regimens for optimal puberty induction in subjects with prepubertal onset of hypogonadism.33.

11(Suppl 3):891– 900. Orbak Z. Bhasin S. Cappa M.68:578–584. 31. inflammation and serum lipids and lipoproteins in postmenopausal women. Linglart A. Ital J Pediatr 2007. 21. Bertelloni S.91:1995–2010. Trabucco S. Orr DP. Horm Res 2006. Leggio S. Swerdloff RS. Stefanick ML. Hayes FJ. Ahmed SF. 345 17. J Pediatr Endocrinol Metab 1998. Robins DG. JAMA 2002. Appropriate use of estrogen replacement therapy in adolescents and young adults with Turner syndrome and hypopituitarism in light of the Women’s Health Initiative. Peters B. Zajac JD.19:55–64. De Sanctis V. Treat Endocrinol 2005. Romalo G. Puberty and bone development. Lala R. Hormonal therapies for individuals with intersex conditions: protocol for use. 2. Saggese G. 29. Kreipe RE. p167. et al. Downloaded by [HINARI] at 23:01 10 December 2015 References 1. J Pediatr 1986. Silveira A. Clin Genet 1986. Kaya D. O’Sullivan AJ. Freund J. Montori VM. Cunningham GR. Devine N. . Hovatta O. Acquafredda A. Effects of different oral oestrogen formulations on insulin-like growth factor-I. Grover S. Pearl KN. Navari S. Houk CP. 26. van Pareren Y. Rubin K.Hormonal management of DSD in adolescence encouragement to improve the care of individuals with DSD. Rossouw JE.55(5 Suppl 1):58–62. Taskinen MR. Expert Opin Pharmacother 2005. Vullo C. Age limits of adolescence and health care system for adolescents: a position paper of the Italian Society for Adolescent Medicine. J Clin Invest 1998. Crigler JF Jr. Rigolin F. 20.67:720–723. 14. Drobac S. Consensus statement on management of intersex disorders. Ho KK.102:1035–1040. Hughes IA. J Bone Miner Res 2004. Arch Dis Child 1994. Lee PA. 46. Yigit S. Bertelloni S. Comerci GD. Holterhus PM. Hakala-Ala-Pietila¨ T. Prentice RL. Hamsten A. Papadimitriou DT. Houk C. Mauras N. Raiola G. Chiavetta S. Effect of transdermal versus oral estradiol on growth factors and markers of bone turn-over in young adults with Turner syndrome. Alp H. Arch Dis Child 2006. Ritzen M. 23. Urso L. Chua A. Rubin K. Cochran W. McAnarney ER. Weidemann W. Spindler KD. Smith PJ.71:315–317. Baroncelli GI. 19. Prader A. Early diagnosis and management of 5a-reductase deficiency.39:561–567. Virkama¨ki A. Warne GL. Root AW.11:525–530. Textbook of adolescent medicine.57:66–71. Gendreau P. Warren MP. Rajkovic IA. Bourguignon J-P.83:1173–1176. Oral treatment for constitutional delay of growth and puberty in boys: a randomized trial of an anabolic steroid or testosterone undecanoate. Skeletal maturation in the XY female syndrome. Saggese G. Caramelli K. XVI Congresso Nazionale SIEDP. Wilson JD. 7. Arch Dis Child 1992. 27. New facets of androgen replacement therapy during childhood and adolescence. Ho KK. Kelly JJ. de Muinck Keiser-Scharama SMPF. 22. J Pediatr Endocrinol Metab 2006.XY DSD caused by a rare mutation of the 17bhydroxysteroid dehydrogenase type 3 gene. Clinical experience using the Androderm testosterone transdermal system in hypogonadal adolescents and young men with b-thalassemia major. growth hormone and growth hormone binding protein in post-menopausal women. Matsumoto AM. Baroncelli GI. De Simone M.4:19–29. Kiess W. Morel Y. Lee PA. 4. 11–13 ottobre 2007.288:321–333. Scho¨n D. 32. Best Pract Res Clin Endocrinol Metab 2002. Philadelphia (PA): WB Saunders.23: 33–39. 18. Jackson RD. Bertelloni S. Ju¨rgensen M. Clin Endocrinol (Oxf) 1993. 16. LWPES Consensus Group. Ital J Pediatr 2007. 15.108:694– 697. Neonate with ambiguous genitalia: medical therapy after the first weeks of life. Ritzen EM. Long A. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. 11. Crampton LJ. Johnson KC. Hunold JJ. Albanese A. 12. Ferrandez A. ESPE Consensus Group. Giordani L. 28. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.33:13–16.90:6424–6430. Rosenfield RL. Kewley GD. Garofalo P. Schweikert HU. Rosenfield R. Donaldson MD. Faienza MF. Grino PB.16:53–64. Altered bone mineral density in patients with complete androgen insensitivity syndrome. Cavallo L. Sobel EH. Lerer T. Federico G. 1992. Bernasconi S. Rogol AD. Ranieri L. J Clin Endocrinol Metab 2006. LaCroix AZ. Thyen U. 10. Reinecke S. 13.65:126–131.85:619–625. 5. Howard BV. J Clin Endocrinol Metab 2005. J Pediatr Endocrinol Metab 1998. Daugherty C. O’Sullivan AJ. Trattamento dell’ipogonadismo in eta’ evolutiva: indagine conoscitiva SIEDP. J Pediatr Endocrinol Metab 2003. Chaussain JL.16 (Suppl 2): 297–306.91:554–563. J Clin Endocrinol Metab 1989. Juul A. Saggese G. Zecchino C. Tan H. Geraci S. Balsamo A. Sa!gso¨z N. fibrinolysis. Horm Res 2002. 6. Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor. 3. Bertacca L.369:1057–1058. Onyirimba M. Beresford SA.30:199–201. van Gelderen HH. In: Rappresentanza dei Gruppi di Studio SIEDP di Fisiopatologia della Puberta` & Complicanze Endocrine nelle Malattie Croniche. Wallace AM. Writing Group for the Women’s Health Initiative Investigators. Isidro-Gutierrez RF.33:128–131. Parma. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation.19:S320. Kleinert S.16(Suppl A):S98–102. 30. Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy. Minerva Pediatr 2003. Growth Genet Horm 2007. Practices and attitudes of pediatric endocrinologists in Europe. Abstract book. Moshang T Jr. Atares M. Cavallini A. Stanhope R. Disorders of sex development: making ambiguity less ambiguous. Rosenfield RL. Todarello O. Griffin JE. Govoni MR. Sernia C. D’Aniello M. 24. Richter-Appelt H. 25. Hiort O. 8. Anderson GL. Snyder PJ. A workshop on pubertal hormone replacement options in the United States. Conway G. Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome. 9. Puberty in disorders of somatosexual differentiation. Lancet 2007. Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. Adolescent health: an opportunity not to be missed. Rogol AL. Bertelloni S. Pelvic ultrasound measurements in normal girls: relation to puberty and sex hormone concentration. Horm Res 1998. J Clin Endocrinol Metab 1998. Odame I. de Sanctis V. Bertelloni S. Zachmann M. Yildirim H. Delvecchio M. Induction of puberty in the hypogonadal girl. Kooperberg C. Vehkavaara S.50:309–314. Mazer N.6:1319–1336. Thromb Haemost 2001. Yki-Ja¨rvinen H. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women. Puberty in subjects with complete androgen insensitivity syndrome.Growth Horm IGF Res 2006.

37. J Clin Endocrinol Metab 1997. Leary D. Favus M. J Sex Res 2002. Danilovic DL. 36. Miyamoto S.43:671–675. Dati E. 39. Sela BA. J Clin Endocrinol Metab 2006. Ginsburg J. Bertelloni et al. Jodar E. Munoz-Torres M. Normal bone density in male pseudohermaphroditism due to 5areductase 2 deficiency. Vered I. Sobel V.24(Suppl 1):222 (abs).18:369–374. Simi P. Soule SG. Rev Hosp Clı´n Fac Med S Paulo 2001. Shane E. Changes in bone mineral density after orchidectomy and hormone replacement therapy in individuals with androgen insensitivity syndrome. Cross genotype sex hormone treatment in two cases of hypogonadal osteoporosis. Correa PH. Schwartz B. Ibuki Y. Quesada M. Arnhold IJP. 41. Quigley CA. 42.56:139–142. Baidinotti F. Erba P. Calcif Tissue Int 1995. Osteoporos Int 2007. Mendonca BB.85:1032–1037. Sax L. Osteopenia as a feature of the androgen insensitivity syndrome. Bone mineral density in the complete androgen insensitivity and 5a-reductase-2 deficiency syndromes. Okano H. Bertelloni S. Mizunuma H. Clin Endocrinol Oxf. Kagami I. Sack J. Ohsawa M. 40. Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene. Inacio M. Zhu YS. Hum Reprod 1998.39:174–178.57:94– 96. The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. Mendonca BB. Kaiserman I. Prelevic GM. 38. Costa EMF. 34. Prentice M. Fogli A.13:2816–2818. . How common is intersex? A response to Anne FaustoSterling. Soda M. Escobar-Jimenez F. 35. J Clin Endocrinol Metab 2000. Bone mass in androgen-insensitivity syndrome: response to hormonal replacement therapy. Marcus R. Arnhold IJ. The AISIA study: preliminary data.346 S. Downloaded by [HINARI] at 23:01 10 December 2015 33. Jacobs HS. Bone mineral density (BMD) in young women with complete androgen insensitivity syndrome (CAIS). Melo KF. Cordero JJ. ImperatoMcGinley J. Costa EM. Ginecol Endocrinol 2008. 1995. Baroncelli GI.91:3017–3023. Conway G. Schneider Dl.82:576–578.