ORIGINAL ARTICLE
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia: prevalence and impact on testicular function M. Chihaoui1, F. Kanoun1, F. Chaker1, M. Yazidi1, K. Bouchrit1, H. Mizouni2, M.Feki3, M. Kharrat4 & H. Slimane1 1 2 3 4
Department Department Department Department
of of of of
Endocrinology, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Radiology, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Biochemistry, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Genetics, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
Keywords Congenital adrenal hyperplasia—semen analysis—testicular adrenal rest tumours— testicular sonography Correspondence Melika Chihaoui, Endocrinology Department, La Rabta Hospital, Jabbari, 1007 Tunis, Tunisia. Tel.: 0021698647327; Fax: 00216 71 570867; E-mail: [email protected] Accepted: February 17, 2015 doi: 10.1111/and.12416
Summary Testicular adrenal rest tumours (TARTs) have been described in patients with congenital adrenal hyperplasia (CAH). The aim of the study was to determine the prevalence of TARTs in patients with CAH, the associated factors and their impact on gonadal function. It is a prospective study concerning six young adult men with CAH, four cases with 21-hydroxylase deficiency and two cases with 11-hydroxylase deficiency. All patients were under glucocorticoid therapy. The mean age was 25 years (range: 20–31). All patients underwent a physical examination with testicular palpation, scrotal ultrasonography, a blood sample for serum testosterone, FSH, LH, inhibin B, Δ4-androstenedione and 17-OH-progesterone measurements and a semen analysis. Ultrasound revealed TARTs in four patients; three were bilateral. The mean tumour size was 6.3 ml (range: 0.02–14.1). The tumours were palpable in two cases. 17OH-progesterone was G IVS 2-13 A/C>G Q318X Q318X G379V Q356X
NN NN NN NN 12 m 22 m
SW SW SW SW PP PP
HC : 1.5 + 0 + 3 HC: 2 + 2 + 2 HC: 2 + 2 + 1 HC: 1.5 + 1 + 2 DEX: 0 + 0 + 0.5 HC: 1 + 0 + 2
0 100 50 50 0 0
a
Type of CAH: 21-OHD or 11-OHD, b9a-fluoro-hydrocortisone acetate, NN: neonatally, m: months, SW: salt wasting, PP: precocious puberty, HC: hydrocortisone, DEX: dexamethasone.
at night (Table 1). The mean height was 168.5 cm (range: 155–176), and the mean body mass index was 24.7 kg m2 (range: 22.4–29.4). Age at diagnosis, circumstances of diagnosis, genotype and treatment are detailed in Table 1. Methods The study protocol was approved by our hospital ethics committee. Informed consent was obtained from each patient. All patients underwent a physical examination with a testicular palpation by the same experienced endocrinologist. They had a fasting blood sample for the measurement of 17-hydroxyprogesterone (17-OHP), delta 4androstenedione, testosterone, inhibin B, follicle-stimulating hormone (FSH) and luteinising hormone (LH). The treatment was unchanged before the blood sampling. Adrenal and scrotal ultrasonographies were performed in all patients to detect the presence of an adrenal mass, to evaluate the testicular size and to detect the presence of TARTs, their location and size. All ultrasound examinations were performed by the same radiologist using a Philips iU22 xMATRIX ultrasound system equipped with a 12 MHz linear transducer probe for testicles and a 3– 5 MHz probe for adrenals. Testicular volume (V) was calculated using the formula: V (ml) = length (cm) 9 width (cm) 9 depth (cm) 9 0.52. The normal range for testicular volume in young adults is 6.0–31.8 ml. The volumes of testicular rests were calculated using the same formula. A semen sample was collected after 3–7 days of ejaculatory abstinence. The analysis included assessment of the semen volume, sperm concentration, motility and morphology. The results were evaluated according to the WHO criteria (World Health Organization, 2010). Hormone assays The plasma testosterone, FSH and LH levels were measured by the chemiluminescent microparticle immunoas46
say (CMIA) method on an architect i2000 analyzer using the Architect/Abbott kit. The normal testosterone range is 3.5–11 ng/ml. The normal ranges for FSH and LH are, respectively, 1-20UI/l and 2-20UI/l. Δ4-androstenedione and 17-OH-progesterone were measured using a specific radioimmunoassay (RIA; Immunotech, Beckman Coulter, France). The normal Δ4-androstenedione range is 20– 290 ng/dl. The adequate control of CAH was defined as a serum level of 17-OH-progesterone ≤10 ng/ml. The serum inhibin B was measured by enzyme-linked immunosorbent assay (ELISA) using a commercial ELISA kit (Immunotech, Beckman Coulter, France). The normal inhibin B range in adult men is >100 ng/l. Results Two patients (no. 1 and no. 2) had palpable testicular tumours, which were bilaterally palpable (Table 2). Testicular ultrasonography (Table 2) showed ten testicular adrenal rest tumours in four patients. TARTs were bilateral in three cases and multiple in one case. The mean tumour volume was 6.31 ml, ranging between 0.02 and 14.1 ml. In two patients, the nodules were not palpable; their total volumes were 0.02, 0.55 and 1.18 ml. All Table 2 Physical and ultrasonographic examination of the testes Ultrasonography Testis volume (ml)
Number of TARTs
Total TARTs volume (ml)
Patient no.
Physical examination Palpable nodule
Right
Left
Right
Left
Right
Left
1 2 3 4 5 6
Yes Yes No No No No
23 23.1 8.3 12.7 8.3 7.5
18.4 20.9 10.2 0.8 9.2 7.4
1 1 0 0 1 2
1 1 0 0 0 3
11.25 14.1 – – 0.02 1.18
8 9.1 – – – 0.55
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
M. Chihaoui et al.
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
tumours detected by palpation were confirmed by ultrasonography, and they were located adjacent to the mediastinum testis. Eight TARTs were hypoechoic and two were hyperechoic. The TARTs were hypervascular on colour doppler. Figures 1–3 illustrate different sonographic appearances of TARTs. The mean testicular volume was 12.5 7.2 ml, ranging from 0.8 to 23.1 ml. One patient (no. 4) had a small testicle; he was operated on for ectopia. Adrenal ultrasonography was normal in all cases. All patients were under tight hormonal control with 17-OHP2 cm are detected by palpation (Claahsen-van der Grinten et al., 2009; Falhammar et al., 2012). On the other hand, TARTs can be the first presentation of CAH. This was reported in 18% of cases of TARTs (Rutgers et al., 1988). TARTs may be misdiagnosed as Leydig cell tumours and can lead to orchiectomy. Unnecessary testicular surgery for presumed 47
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
M. Chihaoui et al.
Table 3 Plasma levels of 17-OH-progesterone, Δ4-androstenedione, testosterone, inhibin B, FSH and LH
Patient no.
17-OH-progesterone (ng/ml)
Δ4-androstenedione (N: 20–290 ng/%)
Testosterone (3.5–11 ng/ml)
Inhibin B (N: >100 ng/l)
FSH (N: 1–20UI/l)
LH (N: 2–20UI/l)
1 2 3 4 5 6
2.86 3.3 1.77 0.93 4.87 4.55
939 224 64.7 90.1 – 430
9.25 7.86 3.95 4.16 3.97 2.15
143 – 140 89 75 150
6.1 5 4.3 6.5 2.9 2.5
8.2 2.3 3.2 4.3 2.8 5.7
Table 4 Semen analysis Patient no.
Volume (ml)
Concentration (9106/ml)
Motile spermatozoa (%)
Normal morphology (%)
Classificationa
1 2 3 4 5 6
8 5.5 2.2 3.6 1.4 1.9
0 1.2 68 28 16 29
0 21 47 36 14 15
0 15 40 31 8 7
Azoospermia Oligo-asthenozoospermiab Normal Asthenozoospermia Hypo-asthenozoospermiab Asthenozoospermia
a
WHO criteria (2), bcontrolled.
malignancy has been performed in 6% of the CAH males in large series (Falhammar et al., 2012; Arlt et al., 2010). Ultrasonography is considered as the method of choice for detection and follow-up of TARTs. The lesions are typically located adjacent to the mediastinum testis and are generally hypoechoic (Stikkelbroeck et al., 2003), as in our study. The nodule can be unique or multiple. It was multiple in one of four cases in our study and in 16% in Kang’s study (Kang et al., 2011). The nodule can be unilateral or bilateral as in three of four cases in our study and in 87% in Kang’s study (Kang et al., 2011). The prevalence of TARTs also depends on the type of CAH, as TARTs do not occur in patients with nonclassic or late-onset CAH, probably because ACTH level is not high enough (Claahsen-van der Grinten et al., 2009). Similarly, the size of a TART can differ according to the type of CAH (Reisch et al., 2009). Severe forms of CYP21, with deletion or conversion of the CYP21 gene, were associated with larger TARTs (White & Speiser, 2000; Stikkelbroeck et al., 2001; Mouritsen et al., 2010). This can be explained by the very high levels of ACTH in severe CAH during early prenatal life that contribute to the development of TARTs. The hypothesised pathophysiology of TARTs is an over stimulation of ACTH (and angiotensin II in SW) receptors of testicular adrenal rests in CAH patients under poor hormonal control (Claahsen-van der Grinten et al., 2007b). These testicular adrenal rests are aberrant adrenal cortical tissue that has descended with the testes during embryogenesis (Stikkelbroeck et al., 2001), (Clark et al., 48
1990). TARTs have also been seen in other conditions associated with high ACTH levels such as Nelson’s syndrome (Johnson & Scheithauer, 1982). In our series, all patients were considered well controlled with 17-hydroxyprogesterone less than 10 ng/ml. However, the long-term adequate hormonal control is not easy to prove. A short stature and a higher lean body mass can suggest insufficient hormonal control. Height was 155 cm in patient no. 3, but he had no TARTs. Corrected final adult height was significantly lower in patients with TARTs in Kang’s study concerning 48 post-pubertal 21-OHD patients (Kang et al., 2011). Two studies suggested a positive correlation between ACTH and 17-OH-progesterone and the frequency of TARTs (Nermoen et al., 2011; Pierre et al., 2012). Similarly, in the large Kang’s study, under treatment was significantly correlated with the size of TARTs even after controlling for the type of CAH (SW or simple virilising form), hydrocortisone equivalent dose and age at the time of ultrasonography (Kang et al., 2011). However, a recent large (50 cases) retrospective longitudinal study demonstrated no association between long-term parameters of disease control and the presence of TARTs (Reisch et al., 2013). Similarly, other studies did not provide evidence that hormonal control was correlated with TART volume (Reisch et al., 2010). The mean daily dose of hydrocortisone equivalent was higher in our patients without TARTs than in patients with TARTs (47.5 vs 38.75 mg/day). In other studies, neither the daily dose of glucocorticoid nor the time of taking the medication was associated with the size of © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
M. Chihaoui et al.
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
TARTs (Stikkelbroeck et al., 2001). All these data show that under treatment is not the only cause of TARTs. Testosterone was low in one patient (no. 6). He had elevated Δ4-androstenedione and normal gonadotropins indicating a possible suppression of the hypothalamic– pituitary–testicular axis by the excess of adrenal androgens that are aromatised to oestrogens. Another mechanism of low testosterone level has also been described: a local effect of the tumours by a mechanical way and/or by local androgen production that may have a paracrine toxic effect on testicular tissue. Decreased plasma testosterone was found in 35% of cases in Stikkelbroeck’s study (Stikkelbroeck et al., 2001). Abnormal semen parameters were present in 5 of 6 patients. It was an azoospermia in one case (no. 1). This patient had normal testosterone and gonadotropins ruling out hypogonadism as the cause of testicular exocrine dysfunction. The presence of bilateral palpable TARTs in this patient suggests a mechanical effect of TARTs on spermatogenesis. Large tumours, especially when located in the mediastinum, can compress the seminiferous tubules and cause obstructive azoospermia (Claahsen-van der Grinten et al., 2007c). Patient no. 4 had an asthenozoospermia, but he had neither TARTs nor hypogonadism, suggesting other possible causes of the abnormal semen. Impaired semen quality was noted in 43 to 100% of cases in the other studies (Reisch et al., 2009; Delfino et al., 2012; Falhammar et al., 2012; Aycan et al., 2013). The recommended treatment of TARTs consists of an intensification of glucocorticoid therapy. This should reduce ACTH levels that might lead to a decrease in the tumour size and even a disappearance of the tumour (Cunnah et al., 1989; Bayhan et al., 2010; C ß akir et al., 2012; Delfino et al., 2012; Aycan et al., 2013). This will also reduce adrenal androgen production improving the pituitary–gonadal axis function and testosterone production. The result should be an improvement in the semen quality (Cunnah et al., 1989). However, if the tumour does not respond to steroid therapy, surgical therapy using a testis-sparing procedure should be considered. In 2009, Claahsen-van Der Grinten suggested a classification of TARTs (Claahsen-van der Grinten et al., 2009). According to this classification, tumours at/or higher than stage III must be surgically removed. However, it has been shown that testicular sparing tumour enucleation did not improve testicular function, suggesting the presence of irreversible testicular damage caused by a longstanding mechanical obstruction (Claahsen-van der Grinten et al., 2007c). Because of the high risk of infertility in CAH male patients, sperm cryopreservation should be considered. The major limitation of this study is the small number of patients. This is explained by the rarity of the disease. © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
Large studies are limited (Kang et al., 2011; Falhammar et al., 2012; Aycan et al., 2013). In conclusion, this study confirms the high prevalence of TARTs in patients with CAH. The semen production is often impaired in these patients. Testosterone secretion may also be impaired. The early screening of TATRs by ultrasonography and intensification of glucocorticoid therapy may prevent testicular dysfunction. References Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ (2010) United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: A cohort study of 203 patients. J Clin Endocrinol Metab 95:5110–5121. Aycan Z, Bas VN, Cetinkaya S, Yilmaz Agladioglu S, Tiryaki T (2013) Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 78:667–672. Bayhan GI, Cetinkaya S, Cinar HG, Aycan Z (2010) Testicular adrenal rest tumor in a patient with 11beta-hydroxylase deficient congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 23:729–732. C ß akir ED, Mutlu FS, Eren E, Pasßa AO, Saglam H, Tarim O (2012) Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia. J Clin Res Pediatr Endocrinol 4:94–100. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, Hermus AR, Otten BJ (2007a) Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 157:339–344. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, Span PN, Ross HA, Meuleman EJ, Hermus AR (2007b) Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue. J Clin Endocrinol Metab 92: 3674–3680. Claahsen-van der Grinten HL, Otten BJ, Takahashi S, Meuleman EJ, Hulsbergen-van de Kaa C, Sweep FC, Hermus AR (2007c) Testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia: evaluation of pituitary-gonadal function before and after successful testissparing surgery in eight patients. J Clin Endocrinol Metab 92:612–615. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, Sweep FC, Hermus AR (2009) Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23:209–220. Clark RV, Albertson BD, Munabi A, Cassorla F, Aguilera G, Warren DW, Sherins RJ, Loriaux DL (1990) Steroidogenic
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Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia. J Clin Endocrinol Metab 70:1408–1413. Cunnah D, Perry L, Dacie JA, Grant DB, Lowe DG, Savage MO, Besser GM (1989) Bilateral testicular tumours in congenital adrenal hyperplasia: a continuing diagnostic and therapeutic dilemma. Clin Endocrinol (Oxf) 30:141–147. Delfino M, Elia J, Imbrogno N, Argese N, Mazzilli R, Toscano V, Mazzilli F (2012) Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. J Ultrasound Med 31:383–3818. Falhammar H, Nystr€ om HF, Ekstr€ om U, Granberg S, Wedell A, Thoren M (2012) Fertility, sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. Eur J Endocrinol 166:441–449. Johnson RE, Scheithauer B (1982) Massive hyperplasia of testicular adrenal rests in a patient with Nelson’s syndrome. Am J Clin Pathol 77:501–507. Kang MJ, Kim JH, Lee SH, Lee YA, Shin CH, Yang SW (2011) The prevalence of testicular adrenal rest tumors and associated factors in postpubertal patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Endocr J 58:501–508. Martinez-Aguayo A, Rocha A, Rojas N, Garcıa C, Parra R, Lagos M, Valdivia L, Poggi H, Cattani A; Chilean Collaborative Testicular Adrenal Rest Tumor Study Group (2007) Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 92:4583–4589. Mouritsen A, Jørgensen N, Main KM, Schwartz M, Juul A (2010) Testicular adrenal rest tumours in boys, adolescents and adult men with congenital adrenal hyperplasia may be associated with the CYP21A2 mutation. Int J Androl 33:521– 527. Nermoen I, Rørvik J, Holmedal SH, Hykkerud DL, Fougner KJ, Svartberg J, Husebye ES, Løv as K (2011) High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clin Endocrinol (Oxf) 75:753–759. Pierre P, Despert F, Tranquart F, Coutant R, Tardy V, Kerlan V, Sonnet E, Baron S, Lorcy Y, Emy P, Delavierre D, Monceaux F, Morel Y, Lecomte P (2012) Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients. Ann Endocrinol (Paris) 73:515–522.
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Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M, Beuschlein F, Reincke M (2009) High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J Clin Endocrinol Metab 94:1665–1670. Reisch N, Scherr M, Flade L, Bidlingmaier M, Schwarz HP, M€ uller-Lisse U, Reincke M, Quinkler M, Beuschlein F (2010) Total adrenal volume but not testicular adrenal rest tumor volume is associated with hormonal control in patients with 21-hydroxylase deficiency. J Clin Endocrinol Metab 95:2065–2072. Reisch N, Rottenkolber M, Greifenstein A, Krone N, Schmidt H, Reincke M, Schwarz HP, Beuschlein F (2013) Testicular adrenal rest tumors develop independently of long-term disease control: a longitudinal analysis of 50 adult men with congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. J Clin Endocrinol Metab 98:1820–1826. Rutgers JL, Young RH, Scully RE (1988) The testicular “tumor” of the adrenogenital syndrome. A report of six cases and review of the literature on testicular masses in patients with adrenocortical disorders. Am J Surg Pathol 12:503–513. Shanklin DR, Richardson A Jr, Rothstein G (1963) Testicular hilar nodules in adrenogenital syndrome; the nature of the nodules. Am J Dis Child 106:243–250. Stikkelbroeck NM, Otten BJ, Pasic A, Jager GJ, Sweep CG, Noordam K, Hermus ARJ (2001) High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab 86:5721–5728. Stikkelbroeck NM, Suliman HM, Otten BJ, Hermus AR, Blickman JG, Jager GJ (2003) Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features. Eur Radiol 13:1597–1603. White PC, Speiser PW (2000) Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245–291. Wilkins L, Fleishmann W, Howards JE (1940) Macrogenitosomia precox associated with hyperplasia of the androgenic tissue of the adrenal and death from corticoadrenal insufficiency. Endocrinology 26:358–395. World Health Organization (2010) WHO Laboratory Manual for the Examination and Processing of Human Semen, 5th edn. Cambridge University Press, New York, NY.
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia: prevalence and impact on testicular function M. Chihaoui1, F. Kanoun1, F. Chaker1, M. Yazidi1, K. Bouchrit1, H. Mizouni2, M.Feki3, M. Kharrat4 & H. Slimane1 1 2 3 4
Department Department Department Department
of of of of
Endocrinology, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Radiology, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Biochemistry, University Hospital La Rabta, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia; Genetics, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
Keywords Congenital adrenal hyperplasia—semen analysis—testicular adrenal rest tumours— testicular sonography Correspondence Melika Chihaoui, Endocrinology Department, La Rabta Hospital, Jabbari, 1007 Tunis, Tunisia. Tel.: 0021698647327; Fax: 00216 71 570867; E-mail: [email protected] Accepted: February 17, 2015 doi: 10.1111/and.12416
Summary Testicular adrenal rest tumours (TARTs) have been described in patients with congenital adrenal hyperplasia (CAH). The aim of the study was to determine the prevalence of TARTs in patients with CAH, the associated factors and their impact on gonadal function. It is a prospective study concerning six young adult men with CAH, four cases with 21-hydroxylase deficiency and two cases with 11-hydroxylase deficiency. All patients were under glucocorticoid therapy. The mean age was 25 years (range: 20–31). All patients underwent a physical examination with testicular palpation, scrotal ultrasonography, a blood sample for serum testosterone, FSH, LH, inhibin B, Δ4-androstenedione and 17-OH-progesterone measurements and a semen analysis. Ultrasound revealed TARTs in four patients; three were bilateral. The mean tumour size was 6.3 ml (range: 0.02–14.1). The tumours were palpable in two cases. 17OH-progesterone was G IVS 2-13 A/C>G Q318X Q318X G379V Q356X
NN NN NN NN 12 m 22 m
SW SW SW SW PP PP
HC : 1.5 + 0 + 3 HC: 2 + 2 + 2 HC: 2 + 2 + 1 HC: 1.5 + 1 + 2 DEX: 0 + 0 + 0.5 HC: 1 + 0 + 2
0 100 50 50 0 0
a
Type of CAH: 21-OHD or 11-OHD, b9a-fluoro-hydrocortisone acetate, NN: neonatally, m: months, SW: salt wasting, PP: precocious puberty, HC: hydrocortisone, DEX: dexamethasone.
at night (Table 1). The mean height was 168.5 cm (range: 155–176), and the mean body mass index was 24.7 kg m2 (range: 22.4–29.4). Age at diagnosis, circumstances of diagnosis, genotype and treatment are detailed in Table 1. Methods The study protocol was approved by our hospital ethics committee. Informed consent was obtained from each patient. All patients underwent a physical examination with a testicular palpation by the same experienced endocrinologist. They had a fasting blood sample for the measurement of 17-hydroxyprogesterone (17-OHP), delta 4androstenedione, testosterone, inhibin B, follicle-stimulating hormone (FSH) and luteinising hormone (LH). The treatment was unchanged before the blood sampling. Adrenal and scrotal ultrasonographies were performed in all patients to detect the presence of an adrenal mass, to evaluate the testicular size and to detect the presence of TARTs, their location and size. All ultrasound examinations were performed by the same radiologist using a Philips iU22 xMATRIX ultrasound system equipped with a 12 MHz linear transducer probe for testicles and a 3– 5 MHz probe for adrenals. Testicular volume (V) was calculated using the formula: V (ml) = length (cm) 9 width (cm) 9 depth (cm) 9 0.52. The normal range for testicular volume in young adults is 6.0–31.8 ml. The volumes of testicular rests were calculated using the same formula. A semen sample was collected after 3–7 days of ejaculatory abstinence. The analysis included assessment of the semen volume, sperm concentration, motility and morphology. The results were evaluated according to the WHO criteria (World Health Organization, 2010). Hormone assays The plasma testosterone, FSH and LH levels were measured by the chemiluminescent microparticle immunoas46
say (CMIA) method on an architect i2000 analyzer using the Architect/Abbott kit. The normal testosterone range is 3.5–11 ng/ml. The normal ranges for FSH and LH are, respectively, 1-20UI/l and 2-20UI/l. Δ4-androstenedione and 17-OH-progesterone were measured using a specific radioimmunoassay (RIA; Immunotech, Beckman Coulter, France). The normal Δ4-androstenedione range is 20– 290 ng/dl. The adequate control of CAH was defined as a serum level of 17-OH-progesterone ≤10 ng/ml. The serum inhibin B was measured by enzyme-linked immunosorbent assay (ELISA) using a commercial ELISA kit (Immunotech, Beckman Coulter, France). The normal inhibin B range in adult men is >100 ng/l. Results Two patients (no. 1 and no. 2) had palpable testicular tumours, which were bilaterally palpable (Table 2). Testicular ultrasonography (Table 2) showed ten testicular adrenal rest tumours in four patients. TARTs were bilateral in three cases and multiple in one case. The mean tumour volume was 6.31 ml, ranging between 0.02 and 14.1 ml. In two patients, the nodules were not palpable; their total volumes were 0.02, 0.55 and 1.18 ml. All Table 2 Physical and ultrasonographic examination of the testes Ultrasonography Testis volume (ml)
Number of TARTs
Total TARTs volume (ml)
Patient no.
Physical examination Palpable nodule
Right
Left
Right
Left
Right
Left
1 2 3 4 5 6
Yes Yes No No No No
23 23.1 8.3 12.7 8.3 7.5
18.4 20.9 10.2 0.8 9.2 7.4
1 1 0 0 1 2
1 1 0 0 0 3
11.25 14.1 – – 0.02 1.18
8 9.1 – – – 0.55
© 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
M. Chihaoui et al.
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
tumours detected by palpation were confirmed by ultrasonography, and they were located adjacent to the mediastinum testis. Eight TARTs were hypoechoic and two were hyperechoic. The TARTs were hypervascular on colour doppler. Figures 1–3 illustrate different sonographic appearances of TARTs. The mean testicular volume was 12.5 7.2 ml, ranging from 0.8 to 23.1 ml. One patient (no. 4) had a small testicle; he was operated on for ectopia. Adrenal ultrasonography was normal in all cases. All patients were under tight hormonal control with 17-OHP2 cm are detected by palpation (Claahsen-van der Grinten et al., 2009; Falhammar et al., 2012). On the other hand, TARTs can be the first presentation of CAH. This was reported in 18% of cases of TARTs (Rutgers et al., 1988). TARTs may be misdiagnosed as Leydig cell tumours and can lead to orchiectomy. Unnecessary testicular surgery for presumed 47
Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
M. Chihaoui et al.
Table 3 Plasma levels of 17-OH-progesterone, Δ4-androstenedione, testosterone, inhibin B, FSH and LH
Patient no.
17-OH-progesterone (ng/ml)
Δ4-androstenedione (N: 20–290 ng/%)
Testosterone (3.5–11 ng/ml)
Inhibin B (N: >100 ng/l)
FSH (N: 1–20UI/l)
LH (N: 2–20UI/l)
1 2 3 4 5 6
2.86 3.3 1.77 0.93 4.87 4.55
939 224 64.7 90.1 – 430
9.25 7.86 3.95 4.16 3.97 2.15
143 – 140 89 75 150
6.1 5 4.3 6.5 2.9 2.5
8.2 2.3 3.2 4.3 2.8 5.7
Table 4 Semen analysis Patient no.
Volume (ml)
Concentration (9106/ml)
Motile spermatozoa (%)
Normal morphology (%)
Classificationa
1 2 3 4 5 6
8 5.5 2.2 3.6 1.4 1.9
0 1.2 68 28 16 29
0 21 47 36 14 15
0 15 40 31 8 7
Azoospermia Oligo-asthenozoospermiab Normal Asthenozoospermia Hypo-asthenozoospermiab Asthenozoospermia
a
WHO criteria (2), bcontrolled.
malignancy has been performed in 6% of the CAH males in large series (Falhammar et al., 2012; Arlt et al., 2010). Ultrasonography is considered as the method of choice for detection and follow-up of TARTs. The lesions are typically located adjacent to the mediastinum testis and are generally hypoechoic (Stikkelbroeck et al., 2003), as in our study. The nodule can be unique or multiple. It was multiple in one of four cases in our study and in 16% in Kang’s study (Kang et al., 2011). The nodule can be unilateral or bilateral as in three of four cases in our study and in 87% in Kang’s study (Kang et al., 2011). The prevalence of TARTs also depends on the type of CAH, as TARTs do not occur in patients with nonclassic or late-onset CAH, probably because ACTH level is not high enough (Claahsen-van der Grinten et al., 2009). Similarly, the size of a TART can differ according to the type of CAH (Reisch et al., 2009). Severe forms of CYP21, with deletion or conversion of the CYP21 gene, were associated with larger TARTs (White & Speiser, 2000; Stikkelbroeck et al., 2001; Mouritsen et al., 2010). This can be explained by the very high levels of ACTH in severe CAH during early prenatal life that contribute to the development of TARTs. The hypothesised pathophysiology of TARTs is an over stimulation of ACTH (and angiotensin II in SW) receptors of testicular adrenal rests in CAH patients under poor hormonal control (Claahsen-van der Grinten et al., 2007b). These testicular adrenal rests are aberrant adrenal cortical tissue that has descended with the testes during embryogenesis (Stikkelbroeck et al., 2001), (Clark et al., 48
1990). TARTs have also been seen in other conditions associated with high ACTH levels such as Nelson’s syndrome (Johnson & Scheithauer, 1982). In our series, all patients were considered well controlled with 17-hydroxyprogesterone less than 10 ng/ml. However, the long-term adequate hormonal control is not easy to prove. A short stature and a higher lean body mass can suggest insufficient hormonal control. Height was 155 cm in patient no. 3, but he had no TARTs. Corrected final adult height was significantly lower in patients with TARTs in Kang’s study concerning 48 post-pubertal 21-OHD patients (Kang et al., 2011). Two studies suggested a positive correlation between ACTH and 17-OH-progesterone and the frequency of TARTs (Nermoen et al., 2011; Pierre et al., 2012). Similarly, in the large Kang’s study, under treatment was significantly correlated with the size of TARTs even after controlling for the type of CAH (SW or simple virilising form), hydrocortisone equivalent dose and age at the time of ultrasonography (Kang et al., 2011). However, a recent large (50 cases) retrospective longitudinal study demonstrated no association between long-term parameters of disease control and the presence of TARTs (Reisch et al., 2013). Similarly, other studies did not provide evidence that hormonal control was correlated with TART volume (Reisch et al., 2010). The mean daily dose of hydrocortisone equivalent was higher in our patients without TARTs than in patients with TARTs (47.5 vs 38.75 mg/day). In other studies, neither the daily dose of glucocorticoid nor the time of taking the medication was associated with the size of © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
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Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia
TARTs (Stikkelbroeck et al., 2001). All these data show that under treatment is not the only cause of TARTs. Testosterone was low in one patient (no. 6). He had elevated Δ4-androstenedione and normal gonadotropins indicating a possible suppression of the hypothalamic– pituitary–testicular axis by the excess of adrenal androgens that are aromatised to oestrogens. Another mechanism of low testosterone level has also been described: a local effect of the tumours by a mechanical way and/or by local androgen production that may have a paracrine toxic effect on testicular tissue. Decreased plasma testosterone was found in 35% of cases in Stikkelbroeck’s study (Stikkelbroeck et al., 2001). Abnormal semen parameters were present in 5 of 6 patients. It was an azoospermia in one case (no. 1). This patient had normal testosterone and gonadotropins ruling out hypogonadism as the cause of testicular exocrine dysfunction. The presence of bilateral palpable TARTs in this patient suggests a mechanical effect of TARTs on spermatogenesis. Large tumours, especially when located in the mediastinum, can compress the seminiferous tubules and cause obstructive azoospermia (Claahsen-van der Grinten et al., 2007c). Patient no. 4 had an asthenozoospermia, but he had neither TARTs nor hypogonadism, suggesting other possible causes of the abnormal semen. Impaired semen quality was noted in 43 to 100% of cases in the other studies (Reisch et al., 2009; Delfino et al., 2012; Falhammar et al., 2012; Aycan et al., 2013). The recommended treatment of TARTs consists of an intensification of glucocorticoid therapy. This should reduce ACTH levels that might lead to a decrease in the tumour size and even a disappearance of the tumour (Cunnah et al., 1989; Bayhan et al., 2010; C ß akir et al., 2012; Delfino et al., 2012; Aycan et al., 2013). This will also reduce adrenal androgen production improving the pituitary–gonadal axis function and testosterone production. The result should be an improvement in the semen quality (Cunnah et al., 1989). However, if the tumour does not respond to steroid therapy, surgical therapy using a testis-sparing procedure should be considered. In 2009, Claahsen-van Der Grinten suggested a classification of TARTs (Claahsen-van der Grinten et al., 2009). According to this classification, tumours at/or higher than stage III must be surgically removed. However, it has been shown that testicular sparing tumour enucleation did not improve testicular function, suggesting the presence of irreversible testicular damage caused by a longstanding mechanical obstruction (Claahsen-van der Grinten et al., 2007c). Because of the high risk of infertility in CAH male patients, sperm cryopreservation should be considered. The major limitation of this study is the small number of patients. This is explained by the rarity of the disease. © 2015 Blackwell Verlag GmbH Andrologia 2016, 48, 45–50
Large studies are limited (Kang et al., 2011; Falhammar et al., 2012; Aycan et al., 2013). In conclusion, this study confirms the high prevalence of TARTs in patients with CAH. The semen production is often impaired in these patients. Testosterone secretion may also be impaired. The early screening of TATRs by ultrasonography and intensification of glucocorticoid therapy may prevent testicular dysfunction. References Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ (2010) United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: A cohort study of 203 patients. J Clin Endocrinol Metab 95:5110–5121. Aycan Z, Bas VN, Cetinkaya S, Yilmaz Agladioglu S, Tiryaki T (2013) Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 78:667–672. Bayhan GI, Cetinkaya S, Cinar HG, Aycan Z (2010) Testicular adrenal rest tumor in a patient with 11beta-hydroxylase deficient congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 23:729–732. C ß akir ED, Mutlu FS, Eren E, Pasßa AO, Saglam H, Tarim O (2012) Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia. J Clin Res Pediatr Endocrinol 4:94–100. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, Hermus AR, Otten BJ (2007a) Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 157:339–344. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, Span PN, Ross HA, Meuleman EJ, Hermus AR (2007b) Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue. J Clin Endocrinol Metab 92: 3674–3680. Claahsen-van der Grinten HL, Otten BJ, Takahashi S, Meuleman EJ, Hulsbergen-van de Kaa C, Sweep FC, Hermus AR (2007c) Testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia: evaluation of pituitary-gonadal function before and after successful testissparing surgery in eight patients. J Clin Endocrinol Metab 92:612–615. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, Sweep FC, Hermus AR (2009) Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23:209–220. Clark RV, Albertson BD, Munabi A, Cassorla F, Aguilera G, Warren DW, Sherins RJ, Loriaux DL (1990) Steroidogenic
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