A 25-year-old male presented to the endocrine clinic in November 2011 with a history of tiredness, reduced libido and bilateral large testicles, which he wanted surgically removed
Q Define Marcoorchidism ?
Macroorchidism is defined as testis size twice the norm for the age ?
Q How do you measure testicular volume ?
- Prader’s orchidometer
- Ultrasound- using formula L x B x W x 0.71
Q What are causes of Macroorchidism ?
- Untreated primary hypothyroidism
- Testicular rest tumors in Congenital adrenal hyperplasia
- Fragile X syndrome
- Pituitary tumor secreting FSH
- Testicular malignancy
- Aromatase deficiency
He had been diagnosed with salt-losing CAH during his antenatal period and commenced on steroid replacement therapy soon after birth. However, he stopped taking all medications in 2000 because of family issues and although his testicles were felt to be lumpy in 2002, further investigation was hampered by poor compliance to treatment and follow-up. He did see the urologist in 2007 but failed to attend follow-up appointments and scans thereafter. He reappeared in the urology clinic in 2010 and again in 2011, after which he was re-referred to the endocrinology department by the urologist in readiness for testosterone replacement therapy after the proposed orchidectomy
Q What is the clinical presentation of Congenital Adrenal hyperplasia in males ?
- Classical 21 hydroxylase deficiency presents with salt wasting, hyponatremia, hypokalemia and shock at birth
- Simple virilizing forms of 21 hydroxylase deficiency can present as early puberty in boys
- Males with StAR deficiency, 3 beta HSD and 17 hydroxylase deficiency present with ambiguous genitalia
Q What is the diagnosis at the end of history ?
We are probably dealing with presence of Testricular adrenal rest tumors (TART)in a patient who is a known case of congenital adrenal hyperplasia.
Q Which hormone is responsible for growth of TART ?
Q How common are TART in male patients with CAH ?
They are present in as much as 94% of male patients with CAH
On examination he was well with normal secondary sexual features, but his testicles felt hard and three times the normal size.
- What is the physical examination points to be looked for while dealing with a male with reproductive endocrinological disorder ?
- Secondary sexual characteristics
- Body proportions and configuration
- Hair growth
- Hair distribution.- face, trunk, axilla and pubic
- Tanner staging
- Palpate for Gynecomastia
- If Hypogonadism found then do the following
- Visual field testing (for Hemianopia)
- Test for smell sensation (rule out Anosmia which is seen with Kallmann’s syndrome)
- Not palpable
- Not palpable
- Vas deferens
- Not palpable
- Scrotal swelling
- Hydrocele, lymphocele
- Valsalva positive- grade I
- Palpable- grade II
- Visible- grade III
- Inguinal region
- Rectal examination
- Seminal vesicle
His serum testosterone level was 50.4 nmol/l. After the baseline investigations and multiple non-attendances, he finally had bilateral orchidectomy and prosthesis replacement in October 2012. Further follow-up was difficult, and compliance with steroid replacement was again very poor.
Q What is your interpretation of the lab results ?
This patient has a salt wasting form of 21 hydroxylase deficiency.
- The impaired response of cortisol to Short synacthen suggest Adrenal insufficiency. The high ACTH confirms it.
- The high 17 OHP and DHEAS level suggest the CAH is not controlled
The short Synacthen test demonstrated impaired adrenal gland function. The raised serum 17-hydroxyprogesterone, testosterone and dehydroepiandosterone levels were in line with the unsuppressed raised serum ACTH levels. Previous serum tumour markers (alphafetoprotein, lactate dehydrogenase and beta human chorionic gonadotrophin) were normal in 2010.
An ultrasound scan performed initially in 2010 confirmed large testicles (the right testis measured 6.2×4.7×2.6 cm, the left testis measured 6.6×3.9×3.6 cm and epididymis could not be visualised).
Pathological examination after orchidectomy demonstrated large testicles measuring 8.5×5×4 cm in size with no recognisable testicular parenchyma (stage 5). The histology comprised sheets of cells separated by delicate fibrous septa with polygonal tumour cells with abundant oeosinophilic cytoplasm, round, variably sized nuclei and prominent central nucleoli. This histology report is the characteristic of TARTs. The report also mentioned the possible presence of some Reinke crystals.
Q What is the ultrasound appearance of TART ?
They are often seen bilaterally on ultrasound. TART appear to be hypoechoic on Ultrasound with perilesional flow commonly seen. They are generally well rounded in appearance.
Q Which is an important differential diagnosis of TART and what are the difference between the two ?
Leydig cell tumor of testis is an important differential of TART. It is differentiated in the following way :
|Testicular adrenal rest tumor (TART)||Leydig cell tumor|
|Background||Congenital adrenal hyperplasia||Not specific|
|Echogenecity on Ultrasound||Hypoechoic||Hyperechoic|
|Vascularity on Doppler||Perilesional||Central|
|Reinke’s crystal||Generally absent||Prominent|
|Location||Close to hilum of testis||Close of interstitium of testis|
|Response to Corticosteroids||Regresses after giving corticosteroids||Fails to regress|
Q Which tumor marker is sensitive for Leydig cell tumor ?
- What is the treatment you would consider for this patients ?
- Optimize the management of CAH- I would start the patient on Oral hydrocortisone (HISONE) 10 mg (8am), 5 mg (12 noon) and 5 mg (5 pm) with dose adjustment based on clinical response. Some people would also advocate nighttime low dose dexamethasone to suppress the ACTH.
- I would also add Fludrocortisone in dose of 0.1 mg per day
- After optimal Glucocorticoid replacement, I would start the patient on Testosterone undecanoate (inj CERNOS 1 gram every 3 months)
- I would regularly monitor the 17 OHP, testosterone and ACTH for the patient.
His initial treatment (restarted in 2011) was hydrocortisone 5 mg twice a day for steroid replacement therapy with the addition of dexamethasone 0.25 mg at bedtime for ACTH suppression.
Q What are the 5 stages of TART ?
- Stage 1 – presence of adrenal rest cells
- Stage 2- enlargement of adrenal rest cells
- Stage 3- compression on Rete testis
- Stage 4- Fibrosis
- Stage 5- Irreversible damage to testicular parenchyma
Q How common are TART in patients without CAH ?
It can be present in upto 15% of newborn and 1.5 % of adults.
Learning points from this case
- Testicular adrenal rest tumors (TART) are found in majority of male patients with CAH. They can present as testicular mass in such patients.
- TART are ACTH dependent and treatment with dexamethasone at bedtime can normalize the ACTH and can lead to reduction in size of TART.
- Leydig cell tumor is an important differential of TART.