Pituitary hyperplasia with Sertoli cell-only and 47,XYY syndromes: an uncommon triad

Background

Infertility is identified as a global public health issue by the WHO and an estimated 48.5 million couples worldwide are affected by infertility.1 In the UK, around one in seven couples have difficulty conceiving.2 Infertility can lead to personal distress for those affected3 4 and there are often significant treatment costs.5 We report the case history of a patient with Sertoli cell-only (SCO) and 47,XYY syndromes associated with pituitary gland hyperplasia, which required collaborative input from various specialists. This case report demonstrates the patient journey in uncovering the causes of infertility and highlights the importance of multidisciplinary teamwork, especially in complex cases encompassing numerous diagnoses.

Case presentation

A 32-year-old patient was referred to our endocrinology clinic after being unable to conceive with his partner for 4 years. Over these years, he experienced gradual reduction in libido and impaired erectile function. The patient went through puberty at 12 years of age. His sense of smell was normal. There was no history of headaches or visual problems. He had no history of mumps orchitis, testicular trauma, exposure to radiation, chemotherapy, tuberculosis or other granulomatous conditions. One of his half-brothers also experienced fertility problems.

Our patient’s height was 205 cm with an arm span of 202 cm. Upper and lower segments were 99 and 106 cm, respectively, with a ratio of 0.93. The patient’s biological mother and father were 163 cm and 178 cm tall and the mid-parental height was 175.5 cm. His two half-brothers were 193 cm tall. On examination, the patient weighed 98.4 kg with a body mass index (BMI) of 23.2 kg/m² and normal muscle mass.

He was normally virilised with normal phallic length. The testicular volume was 15 mL bilaterally with normal testicular consistency. There were no palpable testicular nodules and no evidence of varicocele was found. Facial, body and axillary hair were normal and pubic hair was Tanner stage 5. He appeared euthyroid and did not have stigmata of hypercortisolism or growth hormone excess. There was no gynaecomastia.

Investigations

Blood tests revealed elevated gonadotropins with compensated hypogonadism; follicle-stimulating hormone (FSH) level was 39.0 U/L and luteinising hormone (LH) level was 23.6 U/L. Early morning testosterone levels ranged between 9.6 and 15.9 nmol/L. Sex hormone binding globulin (SHBG) was normal at 43 nmol/L and the free androgen index (FAI) was mildly low at 28.8. Prolactin level was mildly elevated at 375 mU/L. Prolactin level was repeated with adequate precautions in non-stressful circumstances; it measured 370 mU/L. We did not perform the polyethylene glycol (PEG) precipitation test as our biochemistry laboratory performs PEG precipitation tests when prolactin levels are >600 mU/L. We use Roche immunoassays which use monoclonal antibodies which have low reactivity to macroprolactin. Our patient’s renal function was normal with creatinine of 86 µmol/L and estimated glomerular filtration rate (eGFR) of 90 mL/min/1.73 m². Thyroid function tests (TFTs) and short Synacthen test were normal. Semen analyses revealed azoospermia.

• FSH: 39.0 (1.0 – 12.0 U/L).

• LH: 23.6 (2.0 – 9.0 U/L).

• Early morning testosterone: 9.6–15.9 (10.0–28.0 nmol/L).

• SHBG: 43 (12–78 nmol/L).

• FAI: 28.8 (30–150).

• Prolactin: 370–375 (<350 mU/L).

• Serum creatinine: 86 (59–104 µmol/L); eGFR 90 (>90 mL/min/1.73 m²).

• TFTs: thyroid-stimulating hormone (TSH) 0.56 (0.3–3.5 mU/L); free triiodothyronine (FT3) 5.3 (3.1–7.0 pmol/L); free thyroxine (FT4) 13.8 (11.5–22.7 pmol/L).

• Insulin-like growth factor 1 (IGF1): 29.8 (10–32.5 nmol/L).

• Short Synacthen test: baseline cortisol 298 nmol/L and 30 minute cortisol 577 nmol/L.

• Semen analyses: azoospermia.

Scrotal ultrasound revealed a 1.5 cm focal rounded area of ill-defined abnormality in the left testis (see figure 1A,B). The uroradiologist was of the opinion that the ill-defined abnormality was consistent with focal testicular atrophy, with malignancy and previous inflammation as differentials. Left radical orchidectomy was performed.

Histology showed well-vascularised, hyalinised fibrous tissue, containing scattered sclerotic seminiferous tubules and patchy chronic inflammation. The background testis contained tubules with thickened basement membranes and a ‘wind-swept’ appearance, which contained only Sertoli cells with prominent nucleoli. Spermatogenesis was not identified in any of the tubules. The interstitium contained numerous prominent clusters of Leydig cells. The features were in keeping with those of SCO syndrome. There was no active spermatogenesis in either testicle (see figure 1C–E). A biopsy of the contralateral testis excluded carcinoma in situ. Sperm retrieval was unsuccessful.

Alongside these investigations, an MRI of the pituitary was performed to establish if there was a pituitary cause for the mild hyperprolactinaemia. This revealed a diffusely enlarged pituitary gland measuring 14×11×10 mm with a superior convexity with extension into the suprasellar cistern and compression of the central portion of the optic chiasm (see figure 2A). The patient’s visual fields were normal. Karyotyping revealed 47,XYY syndrome (see figure 2B).

Differential diagnosis

Considering the tall stature and the history of infertility, our initial clinical differential diagnosis was Klinefelter syndrome (KS), which is the most common genetic cause of male infertility found in around 1 in every 600 men.6 The diagnosis of SCO syndrome in our patient also pointed towards KS as it is the most common chromosomal abnormality seen in patients with SCO syndrome.7 However, the patient’s testes were larger and softer than would be expected in KS. These findings led us to arrange a chromosomal analysis, which revealed 47,XYY. The differential diagnoses considered for the enlarged pituitary gland included pituitary hyperplasia and pituitary macroadenoma. Although distinguishing between pituitary hyperplasia and macroadenoma can be challenging, pituitary MRI scan revealed symmetrical, diffuse pituitary enlargement which was isointense to grey matter and homogeneously enhancing with a convex superior margin, and these findings are in favour of pituitary hyperplasia.

Treatment

Cabergoline 250 µg once a week normalised the mildly raised prolactin level. Material was sent from the right testicular biopsy for an attempt at sperm extraction, which was unsuccessful. Sildenafil improved erectile function to some extent.

Outcome and follow-up

The pituitary surgical opinion was that surgical intervention was not necessary due to the lack of visual symptoms. The patient received a 6-month pituitary surgical review for 2 years and was seen annually for 2 years thereafter. There was no change in pituitary size on serial MRI pituitary scans. The patient attends biannual visual field examination and is being followed-up by the endocrinology team. After careful consideration, the patient and his partner opted for in vitro fertilisation with donor sperm. The wife gave birth to a healthy baby. Referral to the erectile dysfunction clinic has been made.