Correspondence *Prince Henry's Institute, Level 3, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia

Email rob.mclachlan@princehenrys.org

The case

A 33-year-old man presented with secondary infertility of 24 months' duration. He had one child, aged 3 years, who was conceived 6 months after ceasing contraceptive use. He was later diagnosed with pulmonary tuberculosis and received triple therapy for 18 months. The patient reported increased libido over the past 12 months, and this was confirmed by his wife. General physical examination was unremarkable and no gynecomastia was noted. Both testes were scrotally placed; the volume of the right testicle was 10 ml and the volume of the left testicle was 12 ml. Semen volume was 4.7 ml with a sperm density of <100,000/ml. His karyotype was 46XY, with no Y chromosome deletions. Laboratory tests revealed that the level of serum luteinizing hormone (LH) was undetectable, the level of follicle-stimulating hormone (FSH) was low, and the level of testosterone was elevated (Table 1). These findings were confirmed by a second set of tests performed on a separate occasion. The gonadotropin suppression and elevated testosterone levels raised the possibility of androgen abuse, but the patient strenuously denied any intake. Dehydroepiandrosterone-sulfate levels were normal.

Table 1 Laboratory test results showing the patient's sperm density and hormone levels.

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Testicular ultrasound showed bilateral microlithiasis and a 2.5 cm hypoechoic homogeneous mass in the mid-to-lower portion of the left testis. Serum -fetoprotein and human chorionic gonadotropin (hCG) levels were within normal limits. CT scans of the abdomen and pelvis were normal. In view of these findings, a presumptive diagnosis of Leydig-cell adenoma was made. A left orchidectomy was performed and the diagnosis was confirmed histologically. Histologic examination of the seminiferous tubules showed that spermatogenesis predominantly progressed to the primary spermatocyte stage, with an occasional late spermatid seen. Examination of the intertubular areas revealed a paucity of mature Leydig cells (Figure 1). Mitotic activity was not increased.

Figure 1 The Leydig-cell tumor is characterized by typical Leydig cells, which show no unusual mitotic activity.

They are relatively homogeneous in morphology and a rich capillary network is present. On the edge of the tumor, seminiferous tubules show a marked decrease in the number of germ cells occupying the epithelium. The spermatogonial population is, however, well maintained. Primary spermatocytes and round spermatids are severely depleted and an occasional tubule shows a late spermatid.

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The patient's postoperative course was unremarkable. At 8 months postoperatively, his serum LH and testosterone levels were normal, while his serum FSH level was moderately elevated and his sperm density had increased to 3 million/ml with 50% total motility and 4% normal forms (Table 1). At 18 months postoperatively, no pregnancy had occurred, despite regular unprotected intercourse, although the patient's sperm density had increased to 9 million/ml with 53% progressive motility and 10% normal forms.

Discussion of diagnosis

Male-factor infertility accounts for 35% of infertile unions. Its main cause is primary seminiferous tubule failure, which is reflected in poor semen quality or azoospermia (e.g. in Klinefelter's syndrome, idiopathic and genetic spermatogenic disorders, and postchemoradiotherapy), testis atrophy, elevated gonadotropins, and variable androgen deficiency. The finding of low-to-undetectable serum gonadotropin levels with a low serum testosterone level suggests hypothalamopituitary disease, and should prompt MRI and assessment for other hormonal deficiencies or excesses, especially prolactinoma. These men are often undervirilized and usually complain of low libido and infrequent coital activity.

Azoospermia or severe oligospermia with hypogonadotropism and a normal-to-elevated serum testosterone level is a rare presentation. In an otherwise well man with no personal or family history of pubertal, growth or health disorders, most diagnoses can be readily excluded (Box 1). The primary differential diagnoses in the present case included the presence of an indolent, endogenous source of excessive testosterone secretion (e.g. the testes or adrenal glands) versus androgen abuse. The fact that his fertility had apparently been normal several years previously was not helpful in making this distinction.

Leydig-cell tumors (LCTs) account for 1–3% of testicular tumors; only 10% are malignant, and 10% are bilateral.¹ In adults, the key clinical features are a testicular mass (palpable or ultrasonographically detected) and endocrine manifestations, particularly feminization and gynecomastia, which can precede the testicular mass. In about half of all cases, small LCTs are detected incidentally on ultrasound, and do not result in hormonal excess. The natural history of LCTs, including the growth rate, endocrine profile, and propensity to malignant transformation, is variable. LCTs are usually sporadic and are of unknown etiology, although an activating mutation of the LH-receptor gene² and mutation of the fumurate hydratase gene³ have been associated with their occurence.

Endocrine evaluation should include tests of serum testosterone, estradiol and gonadotropin levels. Most often, excessive estrogen secretion (with or without clinical features such as gynecomastia) inhibits LH secretion and pulsatility,⁴with normal or reduced serum testosterone levels.⁵ In this regard, this case is unusual, as the serum testosterone level was elevated and was probably the cause of the low serum LH level. One could speculate that the tumor had reduced capacity for aromatization. Elevated serum inhibin and estradiol levels have been reported in LCT,⁵ and together would result in a marked inhibition of serum FSH. Unfortunately, neither hormone was measured in this patient.

Reports of hypogonadotropism and resultant spermatogenic failure are uncommon. In addition, increased intratesticular estradiol concentrations could potentially impair spermatogenesis. A recent meta-analysis of impalpable lesions detected on ultrasound and characterized histologically, found that 31% were LCTs and that these were significantly associated with infertility.⁶ Two cases of azoospermia and LCT were reported in 1999 by Fallick et al.;⁷ one of these cases showed germ-cell maturation arrest—a pattern not associated with secondary hypogonadotropism.⁸ Spermatogenic recovery after LCT removal was not mentioned. The 5-year period between the appearance of suggestive endocrine data and the development of a palpable scrotal lesion seen in the above case⁷ emphasizes the potentially indolent course of LCTs. Mostafid et al.⁹ reported the case of a man presenting with azoospermia and testicular atrophy whose gonadotropin levels were suppressed, but whose serum testosterone and estrogen levels were normal. A small LCT tumor was removed by orchidectomy, and gonadotropin levels and sperm density subsequently normalized.

In patients with LCTs, baseline serum testosterone levels are usually in the normal range or slightly reduced. The serum estradiol level tends to be high, and an exaggerated and prolonged estradiol response to hCG is apparent (but not diagnostic).¹⁰ Our case was unusual in that serum testosterone was clearly elevated and gynecomastia was not apparent (although estradiol was not measured), suggesting that the patient's tumor was predominantly androgen-secreting.

Testicular ultrasound has a key role in the diagnosis of benign LCTs. In particular, and even in the absence of a palpable lesion, attention must be given to cases of apparently idiopathic infertility with serum gonadotropin levels at or below the lower limit of assay detection.

The differentiation of Leydig cells is usually normal, but the presence of pleomorphism and increased mitotic activity suggest the possibility of malignancy. In some cases, spermatogenesis is well maintained in the vicinity of the tumor, where testosterone levels are highest, but suppressed in tubules further away from the tumor. In this case, however, spermatogenesis was profoundly suppressed throughout the testis, although the spermatogonial complement was well maintained, suggesting that spermatogenesis might have the potential to recover.

The elevated FSH level seen 8 months after surgery raises two possibilities: it could reflect continuing restimulation of spermatogenesis; alternatively, it could be the result of the presence of an underlying defective spermatogenic process. While the patient's sperm density was continuing to rise at 18 months postoperatively, it remained subnormal, supporting the latter conclusion.

Differential diagnosis

Adrenal tumors

Benign adrenal tumors can be indolent and present similarly to benign LCTs. Detection requires a screen for adrenal androgens (androstenedione, 17-OH progesterone, dehydroepiandrosterone sulfate), imaging, and, possibly, confirmatory venous sampling, given the high incidence of 'incidentalomas'. Hyperestrogenism leads to feminization and suppressed LH, testosterone, and FSH levels (inhibin-B secretion augmenting the latter).¹⁶ Malignant lesions can feature rapid growth, florid endocrine and systemic features, and early metastases.

An algorithm for the assessment of the man presenting with severe infertility, normal or reduced testicular size without palpable masses, and markedly suppressed gonadotropin levels is presented in Figure 2.

Figure 2 An algorithm for the investigation and management of the infertile male presenting with oligoazoospermia, suppressed serum gonadotropin levels, and no evidence of testicular tumor on clinical exmaination.

Abbreviations: E2, estradiol; EpiT, epitestosterone; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; HH, hypogonadotropic hypogonadism; LH, luteinizing hormone; T, testosterone.

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Treatment and management

LCT requires surgical management. In this patient, an orchidectomy was undertaken for his presumed LCT. Alternatively, as a means of preserving fertility and avoiding androgen deficiency, a testis-sparing procedure (lesion excision) has been proposed for bilateral LCTs.¹⁷ Furthermore, frozen section followed by testis-sparing surgery has been performed without complication in a range of testicular tumors up to 25 mm in diameter, including LCTs (both bilateral and unilateral).¹⁸ Follow-up includes monitoring of serum testosterone and gonadotropin levels and semen analysis, if the patient is concerned about fertility.

Conclusion

Confirmed suppression of serum gonadotropins is unusual in infertility practice and suggests HPT disease or suppression by exogenous or endogenous sex steroids. Clinical features of androgen deficiency, such as low libido and poor virilization, and biochemical features of androgen deficiency, such as low testosterone, demand exclusion of HPT disease, but synthetic-androgen abuse must also be considered. Normal-to-elevated serum testosterone levels are uncommon, and detection of androgen abuse requires a good clinical history and biochemical screening. Although rare, extragonadal tumors (especially adrenal tumors) that secrete sex steroids or hCG must be considered. LCTs are the most common neoplasia in this setting. This case emphasizes the key role of testicular ultrasonography in the evaluation of the infertile male, especially its capacity to detect small lesions, the removal of which could restore reproductive function.

Acknowledgments

RI McLachlan is supported by an Australian National Health and Medical Research Council Fellowship #169020 and Program Grant #241000, DM de Kretser is supported by National Health and Medical Research Program Grant # 334011.

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Subject areas under which this article appears: Male factor infertility