Testicular adrenal rest tumours in congenital adrenal
H.L. Claahsen-van der Grinten, MD, PhDa,*, B.J. Otten, MD, PhDa,
M.M.L. Stikkelbroeck, MD, PhDb, F.C.G.J. Sweep, MD, PhDc,
A.R.M.M. Hermus, MD, PhDb
aDepartment of Paediatric Endocrinology, Radboud University Nijmegen Medical Centre, The Netherlands
bDepartment of Endocrinology, Radboud University Nijmegen Medical Centre, The Netherlands
cDepartment of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, The Netherlands
congenital adrenal hyperplasia
testicular adrenal rest tumours
In adult patients with congenital adrenal hyperplasia (CAH) the
presence of testicular adrenal rest tumours (TART) is an important
cause of gonadal dysfunction and infertility. In the last decade
several papers have focused on the origin and pathogenesis of
these tumours. In this paper we review the embryological, histo-
logical, biochemical and clinical features of TART and discuss the
treatment options. Furthermore, we propose a new five-stage
biochemical parameters, that may lead to a better follow up and
treatment of patients with TART.
? 2008 Elsevier Ltd. All rights reserved.
Congenital adrenal hyperplasia (CAH) is an inherited disorder of adrenal steroid synthesis. In more
than 90% of cases it is caused by 21-hydroxylase deficiency, leading to glucocorticoid deficiency and (in
most cases) mineralocorticoid deficiency.1,2The compensatory increase in adrenocorticotropic
hormone (ACTH) secretion by the pituitary gland leads to stimulation of the adrenals and consequently
overproduction of the adrenal androgenprecursors dehydroepiandrosterone and androstenedione and
subsequently of active androgens. The phenotype of 21-hydroxylase deficiency depends on the degree
of enzyme deficiency. Treatment of 21-hydroxylase deficiency consists of glucocorticoid supplemen-
tation and in case of aldosterone deficiency also of mineralocorticoid replacement.
* Corresponding author. Department of Pediatric Endocrinology, Radboud University Nijmegen Medical Centre, (833),
PO Box 9101, 6500 HB Nijmegen,
The Netherlands. Tel.: þ31-24-3619118; Fax: þ31-24-3668532.
E-mail address: firstname.lastname@example.org (H.L. Claahsen-van der Grinten).
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Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220
In the past, CAH was generally regarded as a paediatric endocrine disease, but nowadays nearly all
patients reach adulthood as a result of improved diagnosis and treatment. One of the most serious
problems in adult CAH patients is infertility.3–6It is known that fertility is significantly decreased in
male as well as in female CAH patients.4–15The most important cause of male infertility in CAH patients
is the presence of testicular tumours resulting in primary gonadal failure. These tumours were first
reported in 1940 by Wilkins et al.16Since then testicular tumours have been described in several
papers, mainly as case reports.17–21Because of the morphological and functional resemblance to
adrenal tissue, as described later in this chapter, they are called testicular adrenal rest tumours (TART).
They are always benign, although compression of the seminiferous tubules may lead to obstructive
azoospermia, irreversible damage of the surrounding testicular tissue, and consequently infertility.
Therefore, knowledge about the aetiology, pathogenesis and functional features of these tumours is
important to develop adequate treatment strategies.
The reported prevalence of TART in males varies between 0 and 94%, dependent on the selection of
the patients (age, hormonal control) and the method of tumour detection.4–8,22,23As usually only
tumours of >2 cm are detectable by palpation because of their location within the rete testis, the
tumours can be easily missed when additional imaging techniques such as ultrasound or magnetic
resonance imaging (MRI) are not performed. Ultrasound and MRI are equally good methods for
detection and monitoring of the tumours (Fig. 1), but ultrasound is preferable because it is quick and
cheap6,24, and even very small adrenal rests of onlya few millimetres in diameter are detectable. In our
own series, in 16 of the 17 patients (age 16–40 years) one or more testicular tumours were found. Most
of them were not detectable by palpation.6
Morphological aspects of TART
Macroscopically, longstanding TART are firm and multilobular with a yellow to tan colour on cut
surface and narrow bands of fibrous tissue (Fig. 2a). The typical location is within the rete testis, and in
most patients the tumours are present bilaterally.
Histologically, TART resemble adrenocortical tissue.25,26The tumours are sharply demarcated but
not encapsulated, and consist of sheets or confluent cords of large polygonal cells with abundant
eosinophilic cytoplasm, separated by dense fibrous tissue strands (Fig. 2b). Within the tumour fields
there are regular thin fibrovascular septa, but a zonal arrangement is absent. The cytoplasm of the
Fig. 1. (a) Scrotal ultrasound of a 13-year-old male CAH patient showing a mostly hypoechogenic rounded lesion in the left testis
near the rete testis. (b) T2 weighted MR image of longstanding bilateral testicular adrenal rest tumour. Note that heterogeneous
low-signal-intensity tumours are displacing surrounding high signal normal testicular tissue.
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 210
tumour cells usually contains different amounts of lipofuscin pigment. The nuclei are round with
a central prominent nucleolus and show clear variation in size with frequent intranuclear cytoplasmic
A clear histological differentiation between TART and malignant Leydig cell tumours is difficult.
Some clinical features, however, can help to distinguish between these tumours: TART are bilateral in
more than 80% of cases, whereas Leydig cell tumours are bilateral in only 3% of cases. Reinke crystals,
which can be found in 25–40% of Leydig cell tumours, are absent. Malignant degeneration is seen in
10% of Leydig cell tumours but have never been described in patients with TART. Furthermore, the
typical location of the tumour in the rete testes can also help in the differentiation between these two
types of tumours.27,28
The origin and pathogenesis of TART
Several in vivo and in vitro studies, mainly in single patients, were performed to investigate the
aetiology and the functional features of TART in CAH patients. Clark et al described the presence of the
adrenal-specific enzyme CYP11B1 (11b-hydroxylase) in tumour tissue of a single CAH patient with
TART.29Bercovici et al demonstrated the presence of adrenal-specific steroids in TARTof one patient.30
The presence of adrenal-specific 11b-hydroxylated steroids such as 21-deoxycorticosterone (21DB) and
21-deoxycortisol (21DF) in blood taken from the gonadal veins is reported in three single cases.30–32
This indicates the presence of adrenal-like tissue in the testes of CAH patients with 21-hydroxylase
deficiency, because these steroids can only be synthesized by adrenal-specific 11-hydroxylation,
without the need for the deficient 21-hydroxylation step.
In our own study of seven male CAH patients with bilateral TART undergoing testis-sparing
surgery, we measured the concentrations of the adrenal-specific steroid 21DF and of 17-hydrox-
yprogesterone (17OHP) and androstenedione (A) in blood taken from the spermatic veins during the
operation.33In addition, the mRNA expression of the adrenal-specific enzymes CYP11B1 and
CYP11B2, as well as of ACTH and angiotensin II (AII) receptors in 16 testicular tumours of eight
patients, was measured by quantitative polymerase chain reaction (PCR). We showed that TART
contain adrenal-specific enzymes and produce adrenal-specific steroids, suggesting that these
tumours arise from adrenal-like cells. The presence of ACTH and AII receptors at mRNA level in the
adrenal rest tumours supports this hypothesis.
In the human adrenal gland CYP11B1 is expressed in high levels in the zona fasciculata/reticularis
where it catalyses the 11b-hydroxylation of 11-deoxycortisol to cortisol.34The presence of CYP11B1 in
the zona glomerulosa is controversial.35CYP11B2 is exclusively expressed in the zona glomerulosa
where it is responsible for the final step of the aldosterone synthesis pathway.36,37So, the presence of
CYP11B1 and CYP11B2 in tumour tissue of all patients in our study group suggests that the tumours
have functional features of both adrenal zona fasciculata and glomerulosa cells.
Fig. 2. (a) Macroscopic aspect of TART. Note the yellow colour and the bands of fibrous tissue. (b) Testicular adrenal rest tumour
growing into rete testis (RT) (HE, original magnification ?200).
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 211
It is known that AII has a strong trophic effect on the adrenal gland, especially on the zona
glomerulosa.38–41These trophic effects were studied in detail by Chatelain et al in adult rats
showing that water deprivation resulted in high AII levels without affecting ACTH levels and in an
increase of adrenal zona glomerulosa weight.38Inhibition of AII production by angiotensin-con-
verting enzyme inhibitors significantly decreased adrenal weight, suggesting that AII is an
important factor in the stimulation of adrenal growth. AII markedly increases levels of both
CYP11B1 and CYP11B2 mRNA, whereas ACTH causes an acute increase in CYP11B1 mRNA levels
without an effect on CYP11B2 transcription.38Therefore it can be speculated that tumour growth
in CAH patients may not only be stimulated by elevated ACTH concentrations but also by elevated
AII levels, as present in salt-wasting CAH patients with poor hormonal control. Interestingly, in
late-onset CAH patients without clearly elevated ACTH or AII levels, testicular tumours have never
Embryology of TART
The adrenal glands develop in the immediate vicinity of the gonads, and cells destined to become
adrenocortical cells may nestle within the rete testis.42,43In the literature a prevalence of up to 15% of
such so-called adrenal rest cells in the testes of healthy neonates is reported.44,45However, this
prevalence is probably underestimated because single adrenal-like cells or small cell groups are very
difficult to detect.
It is thought that poor hormonal control, leading to high blood levels of ACTH (and/or AII), is an
important factor in the pathogenesis of TART inducing hypertrophy and hyperplasia of adrenal-like
cells within the testis.19,29However, TARTare also found in adequately treated patients, whereas some
poorly controlled male CAH patients never develop TART despite chronically elevated ACTH levels.5,6
The most plausible explanation for this observation is that in the embryological period aberrant
adrenal cells do not nestle in the testes in all males. The presence of these aberrant adrenal cells within
the testis is a prerequisite for the development of TART, explaining the often observed discrepancy
between the development of TARTand hormonal control. It is likely that CAH patients without adrenal
rest cells within their testes will never develop TART.
Our observation that TART can already be detected in early childhood, even in adequately treated
patients, suggests that when adrenal rest cells are present within the testis even mildly or intermit-
tently increased ACTH (and AII) concentrations may induce proliferation of these cells within the testis.
Poor hormonal control with high ACTH levels may accelerate this process. It has to be realized that
adrenal cells may already be stimulated in utero when there are elevated levels of ACTH.
So, both the concentrations of and the duration of exposure to growth-promoting factors are
probably important in the pathogenesis of tumour growth. Furthermore, it can be hypothesized that
the pubertal rise of luteinizing hormone (LH) may give an additional stimulation of tumour growth as
LH receptors are found in TART46, which may explain the increased prevalence of TART in pubertal and
post-pubertal CAH patients even when there is good hormonal control. Detailed studies focusing on
the effects of ACTH, AII and LH in young male CAH patients are needed to determine the role of these
factors in the development of TART.
The natural history of adrenal rest cells in healthy neonates is insufficiently known, but it is sug-
gested that spontaneous regression occurs within the first years of life.5,6It can be hypothesized that
spontaneous regression of these adrenal rest cells will also occur in male CAH children when growth-
promoting factors such as ACTH (and AII) are effectively suppressed in the first years of life. However,
this treatment strategy conflicts with the negative effect of high doses of glucocorticoids on growth
velocity in the first years of life. Therefore, the optimal medical treatment strategy in the first years of
life is still not clear.
In a recent paper Val et al describe the presence of cells with mixed adrenal and Leydig cell
properties within the mouse testis.47These cells express adrenal markers such as CYP11B1 and CYP21
and respond to ACTH and human chorionic gonadotropin (HCG) incubation. These investigators
hypothesize that adrenal rest cells may develop from a different population of adrenal-like cells. Of
course these findings have to be translated with caution tothe humanpopulation, as mouse fetal testes
also express the ACTH receptor, in contrast to the developing human testes.47
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 212
Long-term consequences of TART
TART have no malignant features, and therefore there seems to be no need to remove them at an
early stage. However, because of the central localization of the tumours near the mediastinum testis,
compression of the seminiferous tubules finally may lead to obstructive azoospermia and irreversible
damage of the surrounding testicular tissue. In a recent study we showed a decreased tubular diameter
and a varying degree of peritubular fibrosis and tubular hyalinization in the testicular biopsies of seven
male CAH patients with longstanding bilateral TART and clinical infertility25(Fig. 3). Furthermore, we
found a severe decrease in the number of germ cells in all patients. In the literature, obstructive
azoospermia is described mainly as a result of extra-testicular obstruction due to infections or surgical
interventions mostly located at the epididymis or vas deferens.48–51In these cases, adverse effects of
the obstruction on the germinal epithelium or Leydig cells were not reported.49,51This can be
explained by the ability of the epididymis to become enlarged, to accommodate the sperm cells, and to
phagocytose and resorb spermatozoa.49It can be speculated that in the case of large TART located in
the mediastinum testis proximal to the epididymis, the efferent flow in the seminiferous tubules is
chronically obstructed without the possibility of compensatory dilatation of the epididymis. Long-
standing obstruction of the seminiferous tubules could then lead to hypospermatogenesis and peri-
In addition to the mechanical effects the tumours may also have a paracrine effect on the
surrounding tissue. Steroids produced by the tumour cells may be toxic to the Leydig cells and/or germ
The irreversible end-stage of longstanding TART is tubular hyalinization with obstruction of the
lumen and complete loss of germ cells and Sertoli cells. In contrast to ischaemic hyalinization, where
a reduced number of Leydig cells are expected, the interstitium of our patients contained a normal or
only slightly reduced number of Leydig cells.25Therefore, TART represent a very specific cause of
obstructive azoospermia, commonly not mentioned in the literature, and with more severe clinical
consequences than other forms.
TART in childhood
The presence of TART in children is described mostly in case reports53–56, and onlya limited number
of studies describe its prevalence in larger populations of children and adults.17,22,57Avila et al detected
TART by ultrasound in eight of 38 male CAH patients (age 6–31 years).22The mean age of the patients
was 14.8 years, and sevenof the eight patients with TART were <18 years old. Theyoungestpatient was
6.2 years old. The total numberof investigated patients <18 years of agewas not reported. Vanzulli et al
Fig. 3. Testicular biopsy of a patient showing seminiferous tubules with hypospermatogenesis and prominent peritubular fibrosis
with increased number of peritubular fibroblasts (arrows), as well as tubular hyalinisation (arrow-head; original magnification
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 213
described a prevalence of 27% of TART in a group of 30 CAH patients 9–32 years old.57In the 24
investigated patients <18 years old, seven (29%) had TART. However, these studies did not focus on
childhood age and did not present information on gonadal function.
Shanklin et al studied autopsy material of patients with CAH and detected TART in three of seven
patients <8 weeks old.17
In our own patient population we found that in 34 male CAH children (age 2–18 years) TART were
already present in childhood with a prevalence of 24%.59The prevalence increased with age. None of
the tumours was detectable by palpation, and none of the children with testicular tumours showed
signs of gonadal dysfunction. In another study of 19 male CAH patients, age 2–10 years old, a similar
prevalence of 21% was found.60The investigators found significantly lower inhibin B values in the CAH
group compared with a healthy control group, suggesting that gonadal dysfunction is already present
in prepubertal CAH children.60
Proposed classification of TART
Based on the histological appearance of the TART and the surrounding testicular parenchyma, and
the clinical observations described above, we propose that the development and growth of TARTcan be
divided into five different stages (Fig. 4).
? Stage 1: This stage can be defined as the presence of adrenal rest cells within the rete testis, not
detectable by scrotal ultrasound. In healthy boys these cells probably regress in utero or in the first
years of life.
? Stage 2: In CAH patients, the adrenal rest cells may proliferate in the presence of increased
concentrations of growth-promoting factors such as ACTH (and possibly also of AII). In this stage
the adrenal rest cells may become visible by ultrasound as one or more small hypoechogenic
lesions. The age of onset of cell growth may depend on the cumulative exposure to ACTH (and AII)
concentrations over time and the number of ACTH (and AII) receptors on the adrenal rest cells.
? Stage 3: Further growth of the adrenal rest cells will compress the rete testis. In pubertal or
postpubertal CAH patients, oligo- or azoospermia may already be found due to obstruction of the
seminiferous tubules. Signs of gonadal dysfunction such as decreased inhibin B and increased
follicle-stimulating hormone (FSH) and LH levels may also be present. At this stage tumour size
may still be reduced by high dosages of glucocorticoids. However, because it is expected that
tumour growth will restart after decreasing the dose of glucocorticoids, this is only a temporary
? Stage 4: Further hypertrophy and hyperplasia of the adrenal rest cells with progressive obstruction
of the rete testis may lead to induction of fibrosis within the tumour and focal lymphocytic
infiltration. Several small tumours within the rete testis will conflate, forming a single lobulated
structure separated from the residual testicular tissue by fibrous strands. In this stage high doses of
glucocorticoids are probably no longer effective in decreasing tumour size because parts of the
tumours contain fibrous tissue and/or because the adrenal rest cells may dedifferentiate in time
with loss of ACTH and AII dependency. Furthermore, peritubular fibrosis can be found in the
surrounding testicular tissue, indicating early testicular damage.
? Stage 5: Chronic obstruction subsequently will lead to destruction of the surrounding testicular
parenchyma with irreversible damage of the testis.
Further studies are necessary to validate this proposed classification of TART.
Diagnosis of TART
Scrotal ultrasound and biochemical analysis may help to determine the presence and stage of TART
in individual CAH patients. Because of their location within the rete testis, TARTare difficult to palpate.
Usually, only tumours with a size >2 cm are detectable by palpation. Until now verysmall adrenal rests
(stage 1) cannot be detected, not even with radiological techniques. Nowadays, ultrasound seems to be
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 214
Adrenal rest cells
Adrenal rest cells present within the rete testis
Hyperplasia and hypertrophy of adrenal
Further growth of the adrenal rest cells
with compression of the rete testis
the rete testis
Induction of fibrosis and focal
Irreversible damage of testicular parenchyma
within the tumour
Fig. 4. Schematic view of the proposed classification of testicular adrenal rests.
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220
the best method for detection and follow-up, especially in the case of small non-palpable tumours. In
stage 2 testicular tumours can be visible as small hypoechogenic lesions. From stage 3 onwards fibrous
strands can be visible as hyperechogenic reflections.
Evaluation of gonadal function by determining blood LH, FSH, inhibin B and testosterone concen-
trations can help to determine the degree of gonadal failure as is expected from stage 3 onward. It
should be realized that LH and FSH are of limited value to evaluate gonadal function in CAH patients
because the gonadotrophins may be suppressed due to elevated adrenal androgens, which are partly
aromatized to oestrone and oestradiol.61In contrast to other causes of hypogonadotropic hypo-
gonadism, CAH patients have generallynormal oronlyslightlydecreased testosteronelevels because of
elevated adrenal androgens. Inhibin B is a better marker for the evaluation of Sertoli cell function and
mayalso be used in the evaluation of gonadal function inprepubertal children.62Semen analysis can be
performed in (post-)pubertal and adult patients when the patient is willing to collect semen for
Because tumour growth may be related to hormonal control as discussed earlier it is important to
monitor plasma ACTH, renin, 17-hydroxyprogesterone and androstenedione concentrations.
In the case of longstanding tumours in infertile CAH patients, a testicular biopsy may be helpful to
evaluate the quality of residual testicular parenchyma (stage 4 or 5).25Such a biopsy is stronglyadvised
before surgical treatment is offered. However, one should realize that a testicular biopsy only gives
information about a limited area of the testis.
Because only patients in whom aberrant adrenal cells have been nestled in the testes in the
embryological period are supposed to be at risk for developing TART, it would be very important to
identify these patients as early as possible. Nowadays, adrenal rests can only be detected after
substantial growth. In the future, new sensitive imaging techniques may help to detect these adrenal
rests in the first years of life. If this is possible, patients with adrenal rests within their rete testis could
be monitored and treated more intensively, whereas in patients without adrenal rests unnecessary
ultrasound follow up and aggressive treatment strategies could be avoided.
Treatment of TART
The proposed classification of TART may help in the decision on which treatment option is
useful in individual patients. TART stages 2 and 3 may be successfully treated by increasing the
dose of glucocorticoids. Intensifying glucocorticoid therapy may lead to reduction of the tumour
size by suppression of ACTH secretion, thereby improving testicular function. Although case
reports with successful pregnancy of partners of male CAH patients have been published63, some
studies report failure of intensified glucocorticoid treatment and serious side-effects after long-
standing dexamethasone treatment, and therefore some patients will not accept this treatment
option.18–20,63–65Furthermore, it may be that this treatment leads only to temporary improve-
ment of the obstruction because tumour growth may start again after lowering the glucocorticoid
dose. However, optimizing glucocorticoid medication, especially in patients with poor hormonal
control, is important to determine whether tumour growth is reversible (stage 3). Probably, in
the future, new types of glucocorticoids – such as slow-release hydrocortisone or selective ACTH
inhibitors – may help to suppress ACTH more effectively without the risk of adverse events.
Because AII may also stimulate tumour growth the mineralocorticoid treatment has to be
In stage 4, increasing the dose of glucocorticoids is probably no longer effective in decreasing
tumour size, but removal of the tumour may prevent further testicular damage. Because of the
benign character of the tumours, testis-sparing surgery has been proposed for the treatment of
TART. Walker et al performed testis-sparing surgery in three CAH patients.55Postoperatively, there
was good vascular flow and no recurrence of the tumour. Tiryaki et al reported two CAH patients
with steroid-unresponsive testicular tumours, who were also treated by testis-sparing surgery.66In
neither study was information about pituitary–gonadal function before and after surgery reported.
In a recent study we showed that in patients with longstanding TART (stage 5), gonadal dysfunction
did not improve, suggesting irreversible damage to the surrounding testicular tissue.62Further-
more, additional damage from surgery could not be excluded. From our experience we now
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 216
conclude that in this stage the only indication for surgery is the relief of pain and discomfort caused
Therefore, mainly in longstanding TART with signs of gonadal dysfunction, testicular biopsies are
advised to evaluate the quality of the surrounding testicular parenchyma before surgery is considered.
Further studies in childhood are needed to investigate whether surgery in stages 2, 3 and 4
may prevent irreversible damage to the testes. Hopefully, in order to prevent destruction of
residual testicular parenchyma, introduction of new surgical techniques may facilitate the surgical
treatment of the tumours already in childhood. As long as medical and surgical treatments of
TART are far from perfect, patients should be informed about the negative effects of TART on
fertility and cryopreservation of semen should be offered as soon as possible. Because adrenal rest
cells are already present in the embryological period it is clear that prevention of TART is not
Ovarian adrenal rest tumours in female CAH patients
Interestingly, in contrast toTART in male CAH patients, ovarian adrenal rest tumours in female CAH
patients seem to be very rare and have been described in only three case reports.67–69Stikkelbroeck
et al searched for aberrant adrenal tissue in the gonads of female CAH patients with ultrasonography
and MR.70In none of the 13 female patients could ovarian adrenal rest tumours be detected.
To explain the striking difference between male and female CAH patients in the prevalence of
gonadal adrenal rest tumours, we propose the following hypothesis: in the fifth week of the
embryological period the gonadal ridge has the potential to develop into either a male or a female
gonad, depending on the karyotype of the migrating primordial germ cells. In both male and
female embryos the mesonephric duct forms primary sex cords (Fig. 5). In the male embryo these
primary sex cords penetrate into the medulla of the developing testis, becoming the rete testis and
seminiferous tubules. In these primary sex cords aberrant adrenal cells from the nearby devel-
oping adrenal cortex may easily nestle. In contrast, in the female embryo, the primary sex cords
regress and secondary (cortical) sex cords will develop together with thickening of the surface
epithelium. Therefore, in females aberrant adrenal cells nestled in the primary sex cords will also
Fig. 5. Development of the female gonads. Note the presence of adrenal rest cells within the primary sex cords. It can be
hypothesized that in the female gonad the adrenal rest cells will regress together with the primary sex cord.
H.L. Claahsen-van der Grinten et al. / Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 209–220 217
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? TART is the most important cause of infertility in male CAH patients
? the incidence of TART in adult CAH patients, detected by ultrasound as the method of choice,
is high (up to 94%)
? TART are also detectable in children with CAH; gonadal dysfunction in childhood is
? TARTare not malignant, but longstanding TARTcan result in irreversible damage to testicular
? TART have histological and functional features of adrenocortical tissue, and growth can be
stimulated by elevated ACTH concentrations
? intensifying glucocorticoid therapy is the first step in the treatment of TART; before testis-
sparing surgery is considered, testicular biopsies are advised to evaluate the quality of the
surrounding testicular parenchyma
? evaluation of the natural history of TART and validation of the proposed classification
? early detection methods for TART
? role of angiotensin II and LH as growth-promoting factors
? medical and surgical treatment options
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