Congenital adrenal hyperplasia, infertility and testicular masses
A 29-year-old man was seen 2 years ago to transfer his care from pediatric to adult endocrinology. He was diagnosed at birth with classic congenital adrenal hyperplasia from 21-hydroxylase deficiency with glucocorticoid and mineralocorticoid deficiencies.
The patient reported compliance with taking once-daily fludrocortisone and prednisone 7.5 mg, but had several episodes of adrenal crises each year. He had new-onset breast tenderness with reduced libido. On exam, he was an obese male with normal secondary sexual characteristics; weight 247 lb; BMI 35; blood pressure of 128 mm Hg/82 mm Hg without orthostatic change; and pulse of 90 beats per minute. He had bilateral gynecomastia without galactorrhea. His testes were normal in volume and texture, without masses.
Initial laboratory testing (see Table) showed a very elevated 17-hydroxyprogesterone (17-OHP) but with normal prolactin, gonadotrophin (luteinizing hormone, follicle-stimulating hormone) levels, thyroid function tests and electrolytes. The elevated 17-OHP suggested inadequate glucocorticoid replacement with prednisone 7.5 mg, and the patient was switched to dexamethasone 1 mg daily because of the long half-life of more than 24 hours and better adrenocorticotropic hormone (ACTH) suppression. A baseline testicular ultrasound was performed that demonstrated normal-sized testes with small bilateral nodules near the rete testes (Figures 1 and 2). These nodules were compatible with testicular adrenal rest tumors (TART) of congenital adrenal hyperplasia (CAH). After the switch to dexamethasone 1 mg daily, his gynecomastia resolved with a reduction in the 17-OHP, suggesting adequate glucocorticoid therapy. Eventually, his daily dose of dexamethasone was reduced to 0.5 mg daily with good control of the 17-OHP (see Table). A repeat testicular ultrasound performed after 1 year demonstrated complete resolution of the small nodules. Despite the resolution of the testicular masses, his testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) remained mildly low, but the patient feels his libido and sexual function has returned to normal. Because he desires fertility, testosterone therapy was not started, which would reduce his spermatogenesis.
Photos courtesy of: Stephanie L. Lee, MD, PhD
CAH is diagnosed as failure to thrive and salt-wasting at birth, and is caused in 90% of cases by varying degrees of 21-hydroxylase, glucocorticoid and mineralocorticoid deficiencies. The lack of suppression of the negative feedback loop results in an increase in ACTH that stimulates the adrenal gland to overproduce dehydroepiandrosterone, androstenedione and 17-OHP, which accumulates before the enzymatic block.
TART, described by Wilkins in 1940, is the most important cause of infertility in men with CAH. Histological TART resembles adrenocortical tissue and contains adrenal-specific steroidogenesis enzymes and steroid hormones. This tumor originates from ectopic adrenal cortical tissue in the testes. Both the adrenal gland and the testes derive from the urogenital ridge, and some adrenal cortical cells can migrate into the testes in the early embryonic period. Adrenal tissue can be found in the testes of 7.5% to 15% of normal neonates, but usually regresses with time. In the situation of chronically high ACTH, the small adrenal remnants in the testes become hyperplastic and develop the benign TARTs. TART occurs in up to 95% of men with classical CAH, but not non-classic or late-onset CAH because the ACTH is not sufficiently elevated. The tumors are always benign but compress the seminiferous tubules and lead to obstructive azoospermia, peritubular fibrosis and irreversible damage to the surrounding tissue, resulting in infertility.
The tumors cannot be detected with palpation until they are bigger than 2 cm because of the location within the rete testes. The best imaging techniques are ultrasound or MRI. The preferred imaging technique is sonography because of low cost, ease of exam and sensitivity to detect even very small rests of tissue a few millimeters in size. The scrotal ultrasound frequently shows a hypoechoic rounded lesion near the rete testes (Figures 1 and 2).
Gonadal function may be tested with serum LH, FSH, inhibin B and testosterone levels. It is important to understand that LH and FSH are of limited value because the gonadotrophins may be suppressed due to elevated adrenal androgen levels, as in our patient, that results in a normal or slightly low testosterone level (see Table). Inhibin B is a better marker for evaluation of Sertoli cell function, but semen analysis in the adult is preferable if fertility is being evaluated. In addition, testicular biopsy in a patient with longstanding infertility may be helpful to evaluate the quality of the residual testicular tissue.
The size of the TART has been associated with glucocorticoid undertreatment. It is suggested that regular examination of lab tests, including ACTH, renin, 17-OHP and androstenedione, and ultrasound of the testes is recommended in men with 21-hydroxylase CAH. Tumor regression in early disease with improved testicular function may occur with good hormone control, as shown with this patient (Figure 2). In more advanced stages of tumor with obstruction and fibrosis, increased glucocorticoid therapy is unlikely to shrink the TART, but there are several reports of testis-sparing surgery to remove these moderate size tumors to prevent further testicular obstruction or damage and to preserve fertility. In advanced, long-standing tumors, testis-sparing surgery has not been shown to reverse infertility but may improve pain.
Stephanie L. Lee, MD, PhD, is director of the Thyroid Health Clinic at Boston Medical Center and associate professor of medicine at Boston University School of Medicine. She is also an Endocrine Today Editorial Board member.
For more information:
- Claahsen-van der Grinten HL. J Clin Endocrinol Metab. 2007;92:612-615.
- Claahsen-van der Grinten HL. Best Pract Res Clin Endocrinol Metab. 2009;23:209-220.
- Kang MJ. Endocr J. 2011; [Published online ahead of print April 27, 2011].
Disclosure: Dr. Lee reports no relevant financial disclosures.