Hypergonadotrophic hypogonadism due to testicular adrenal rest tumours presenting with hypogonadotrophic hypergonadism

Abstract

Primary testicular failure is characterized by low serum testosterone with appropriately high serum gonadotrophins, that is hypergonadotrophic hypogonadism. We report on a 27-year-old man with congenital adrenal hyperplasia (CAH) and infertility due to testicular adrenal rest rumours (TART) resulting in primary testicular failure but presenting with azoospermia, elevated serum testosterone and very low serum gonadotrophins. Hypergonadotrophic hypogonadism was unmasked by increasing glucocorticoid dosage. It is important to recognise the limitations of follicle-stimulating hormone, luteinising hormone and testosterone in assessing testicular function in men with CAH. Abnormal semen analysis may be the best indicator of testicular dysfunction in men with CAH.

Introduction

Adults with classical congenital adrenal hyperplasia (CAH) have an increased incidence of infertility. ^1–3 Although well described, it is not widely appreciated that benign testicular adrenal rest tumours (TART) are a frequent cause of infertility in men with CAH. ^1,2 Compression of the seminiferous tubules by TART may lead to reversible obstructive azoospermia. TART may also cause irreversible damage to the surrounding testicular tissue, resulting in primary hypogonadism and permanent infertility. ^1,2

We present a case of infertility due to primary testicular failure in a 27-year-old man with CAH and TART presenting with azoospermia in the presence of elevated serum testosterone with low serum follicle-stimulating hormone (FSH) and suppressed serum luteinising hormone (LH). Hypergonadotrophic hypogonadism was unmasked by increasing glucocorticoid dosage. This, to our knowledge, has not been previously reported.

Case report

A 27-year-old man, with known CAH, and his wife were investigated for primary infertility. He was found to have azoospermia in the presence of an elevated serum testosterone concentration and very low serum gonadotrophins (Table 1).

Table 1

Biochemical data at presentation with infertility and following an increase in corticosteroid dosage

	At presentation	At urological review	At endocrine review	Reference intervals
Prednisolone	1.5 mg mane	1.5 mg mane	2.5 mg mane
	4.0 mg pm	4.0 mg pm	5.0 mg pm
Fludrocortisone	0.2 mg od	0.2 mg od	0.2 mg od
Testosterone (nmol/L)	34.3	29.9	2.9	9.9–27.8
SHBG (nmol/L)		18.7		18.0–84.0
LH (U/L)	<0.1	<0.1	12.7	1.7–8.6
FSH (U/L)	0.3	0.4	15.0	1.5–12.4
17β-oestradiol (pmol/L)		223		28–156
ACTH (ng/L)		>1250	28.3	<46.0
17-OHP (nmol/L)		276	10	0.9–4.1
Androstenedione (nmol/L)		26.5	1.3	2.8–10.5
DHAS (μmol/L)		1.68	<0.8
Alphafetoprotein (KIU/L)		2.6		<10
β-HCG (IU/L)		<0.1		0.1–2.0

SHBG, sex hormone-binding globulin; LH, luteinising hormone; FSH, follicle-stimulating hormone; ACTH, adrenocorticotrophic hormone; 17-OHP, 17-hydroxyprogesterone; β-HCG, β human chorionic gonadotrophin; DHAS, dehydroepiandrostenedione sulphate

He was, therefore, referred to the urologists who palpated non-tender discrete masses in both testicles, which were confirmed on ultrasound and magnetic resonance imaging (MRI) to be multiple complex nodules throughout both testes predominantly surrounding the mediastinum testis. The MRI scan also showed bilateral adrenal gland enlargement. Repeat investigations confirmed hyperandrogenaemia with very low serum gonadotrophins and also showed elevated plasma adrenocorticotrophic hormone (ACTH), hyperoestrogenaemia and raised 17-hydroxyprogesterone (17-OHP) indicating inadequate control of his CAH (Table 1). Normal vasography at scrotal exploration excluded obstructive azoospermia. Histology of testicular biopsies was reported as bilateral TART with peritubular fibrosis and loss of spermatogenesis. The couple were referred for in vitro fertilisation using donor sperm.

On endocrine review, the patient stated that he was largely compliant with medication prescribed for his CAH, which was due to salt-wasting 21-hydroxylase deficiency diagnosed at the age of two weeks. The prednisolone dosage was, therefore, increased from 5.5 mg to 7.5 mg in daily divided dosages, which led to improved control of his CAH and unmasking of typical primary testicular failure (hypergonadotrophic hypogonadism) (Table 1).

There is little information in the literature regarding management of hypergonadotrophic hypogonadism in TART. We have agreed with the patient to continue to control CAH with adequate glucocorticoid suppression of ACTH to prevent progression of TART and to replace with testosterone in order to correct androgen deficiency and associated co-morbidity.

Discussion

Until recently, treatment of adult men with CAH had often been limited to mineralocorticoid and glucocorticoid replacement in doses to manage the clinical and biochemical features of adrenal failure. However, it is now apparent that long-term control of CAH in men may be essential to preserve gonadal function and fertility. ^1,2

The reported prevalence of TART in male individuals, in studies usually involving small numbers of patients, varies between 0% and 94% dependent on patient selection and the method of tumour detection. ¹ Although well described, it is not widely appreciated that TART, even though benign, are a frequent cause of infertility in men with CAH. ^1–3 By compressing the seminiferous tubules, TART may lead to reversible obstructive azoospermia but may also cause irreversible damage of the surrounding testicular tissue, resulting in hypogonadism and permanent infertility. ¹ TART are usually associated with poor control of CAH, ¹ and high ACTH levels are considered to be a prerequisite for development of TART. However, this is unclear as TART have been reported in men with adequate control of CAH. ³ TART, however, may develop in other conditions of chronic ACTH hypersecretion such as Nelson's syndrome, ^4,5 and regress when ACTH levels are reduced by the introduction or intensification of glucocorticoid therapy, ^1,2 supporting the notion that these tumours are ACTH-dependent.

The biochemical hallmarks of primary testicular failure, hypergonadotrophic hypogonadism, are a low testosterone with elevated FSH and LH. This classical biochemical picture of primary testicular failure is unusual in TART, which are often accompanied by normal testosterone along with normal or low gonadotrophins. ^1,2 The normal (or elevated as in this report) testosterone is usually attributed to oversecretion of adrenal androgens which are peripherally aromatised to oestrogens. ^1,2 The elevated androgens and oestrogens then suppress the hypothalamic-pituitary release of FSH and LH and hence spermatogenesis. ^1,4 It should be noted, however, that the hyperandrogenaemia associated with TART in men following bilateral adrenalectomies ^5,6 can only be testicular and not adrenal in origin, supporting an alternative notion that TART may originate, at least in part, from ACTH-sensitive testosterone-secreting foetal Leydig cells, ⁷ rather than solely from remnants of adrenocortical tissue that have descended with the testes into the scrotal sac during embryological development. ¹ Caution should, therefore, be exercised in interpreting testosterone, FSH and LH in men with CAH and suspected testicular dysfunction. Circulating inhibin B may be low in Sertoli cell failure, but offers no advantage over serum FSH in the investigation and management of male infertility. ^8,9 Data on inhibin B in male patients with CAH is limited. A low inhibin B in young boys with CAH may be a prepubertal marker of Sertoli cell dysfunction, ¹ but this remains unclear. ¹⁰ Data from a small study indicated that 57% of men with TART and abnormal spermatogenesis have a normal serum inhibin B, ³ suggesting that they may have obstructive azoospermia. This, however, is unlikely, because inhibin B does not distinguish between obstructive and non-obstructive azoospermia. At present, therefore, inhibin B appears to have little or no role in the investigation and management of TART. Abnormal semen analysis, therefore, appears to be the most reliable marker of testicular dysfunction in men with CAH. ³

This case was unusual because of the unequivocally elevated serum testosterone at presentation. The raised testosterone, azoospermia and suppressed LH and low FSH raised the possibility of an androgen-secreting tumour. ¹¹ Bilateral, rather than unilateral, testicular masses situated near the mediastinum testis ^12–14 in a patient with poorly controlled CAH favoured TART. TART, however, may be unilateral and as Leydig cell cancer has been reported in CAH, ^15,16 a testicular biopsy may be necessary to exclude malignancy. Bilateral testicular biopsy and vasography were undertaken in this case to assess the severity of TART and the presence or absence of spermatogenesis, and to exclude a surgically correctable cause of obstructive azoospermia. Histology indicated TART with irreversible testicular damage, indicative of permanent testicular failure and infertility with no evidence of Leydig cell cancer.

The high ACTH, 17-OHP, androgens and oestrogens and MRI-proven bilateral adrenal hyperplasia in this patient indicated either non-compliance with, or inadequate, glucocorticoid therapy. As the patient reported compliance, his glucocorticoid dosage was increased and this, by reducing ACTH, controlled the CAH and unmasked hypergonadotrophic hypogonadism. Optimal management of CAH in men from diagnosis and throughout adulthood may be essential to prevent testicular dysfunction and infertility, ^1,2 but this has to be balanced against the adverse effects of glucocorticoid overtreatment. ² Management of TART depends on its severity. In the early stages, TART may be successfully treated by intensifying glucocorticoid therapy, which reverses hyperandrogenaemia and hyperoestrogenaemia-induced suppression of gonadotrophins, and/or improves testicular function by reducing tumour size. ² In the later stages, increasing the dose of glucocorticoids may be ineffective in decreasing tumour size and improving testicular function, ² but we speculate that control of CAH may prevent further growth of TART and testicular damage. Testis-sparing surgery has been proposed for the treatment of TART, ¹⁷ but this should be limited to pain relief as it does not improve testicular function. ¹⁸ It has been recommended that male patients with CAH should be screened for TART from puberty, with either annual ultrasound of the testes, ¹⁰ semen analysis ¹⁹ or palpation of the testes. ²⁰ It has also been suggested that male patients with CAH be counselled from an early age about potential infertility and, if appropriate, be offered cryopreservation of semen. ¹

In conclusion, TART must be considered in men with CAH, especially in those presenting with infertility. It is important to recognise the limitations of LH, FSH and testosterone in assessing testicular function in men with CAH. Abnormal semen analysis is the best indicator of testicular dysfunction in men with CAH. ³

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not applicable. Written consent was obtained from the patient.

Guarantor: RG.

Contributorship: RMG conceived the case report. RMG, HLA and HS researched the literature. RMG and HLA wrote the first draft of the manuscript. JI, HS, RG and CF contributed to data. All authors reviewed and edited the manuscript, and approved the final version of the manuscript.