Late onset of pituitary apoplexy following gonadotropin-releasing hormone agonist for prostate cancer treatment

Abstract

Pituitary apoplexy (PA) is a clinical condition characterised by a sudden increase in pituitary gland volume secondary to ischaemia and/or necrosis. Most cases occur in non-functioning pituitary adenoma but can also occur in functioning adenoma. Certain predisposing factors can result in PA and the use of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is one such condition. Once diagnosed, both surgical and conservative management has been used for the treatment of PA. We present a case of a man in his late 50s who developed PA following treatment of PCa with leuprolide. His symptoms developed insidiously and he presented 6 months after symptom onset. Anterior pituitary hormone workup along with pituitary MRI confirmed the diagnosis of PA and patient was subsequently treated with adequate replacement of pituitary hormone with significant improvement in his symptoms. It is very important to keep a high index of suspicion for PA, especially among elderly patients receiving GnRH agonist treatment for PCa.

Background

Pituitary apoplexy (PA) is a rare but potentially life-threatening condition with an estimated prevalence of 6.2 cases per 100 000 individuals.¹ It has a much higher prevalence ranging from 0.6% to 12% in patients with a known history of pituitary adenoma, however, it can also occur spontaneously in normal pituitary glands.^2–4 Several precipitating events are known to lead to PA and includes angiographic procedures, postpartum events (Sheehan syndrome), orthopaedic/cardiac surgeries, anticoagulation therapy, dopamine agonists, dynamic testing or medications such as gonadotropin-releasing hormone (GnRH) agonists.⁵ GnRH agonists (leuprolide, goserelin and triptorelin) are systemic therapy used in the treatment of advanced prostate cancer (PCa), suppresses luteinising hormone (LH) production and, therefore, the synthesis of testicular androgens. Very few cases of PA have been reported among patients receiving GnRH agonists for the treatment of PCa.^{5 6} Although previously PA was considered a neurosurgical emergency,⁷ recent evidence has suggested spontaneous clinical recovery with a conservative approach.^{8 9} Additionally, in the absence of classical sign and symptoms of PA, its diagnosis can get delayed and hence it is crucial that clinicians keep a very high index of suspicion for PA for the patients on GnRH agonists therapy for PCa treatment.^{3 5 6}

Case presentation

A man in his late 50s with a medical history of hypertension, dyslipidaemia and stage 4 PCa was referred to the endocrinology clinic for evaluation of pituitary enlargement found on MRI brain. Prior records failed to demonstrate any pituitary abnormalities on MRI and CT head done 9 months before (figure 1). Six months prior to the presentation, the patient noticed fatigue and anorexia which gradually worsened, and he also developed unintentional weight loss of 60 pounds (26.5 kg), diplopia and blurry vision. He denied headaches, photophobia, nausea, vomiting or eye pain but reported insidious onset and progression of all his symptoms in the last 6 months. He was diagnosed with stage 4 PCa (Gleason Score=8) with metastasis to the lymph nodes, ribs and pelvic bones 7 years prior to presentation and underwent palliative radiation for bone metastasis and androgen deprivation with intramuscular leuprolide 22.5 mg every 3 months. His last dose of leuprolide was 1 year prior to the presentation, when it was discontinued as prostate specific antigen and imaging were stable. On presentation to endocrinology clinic, his physical examination was unremarkable including visual field examination performed by neuro-ophthalmology.

Figure 1.

MRI of brain 9 months prior to presentation did not show any significant pituitary masses (sagittal view).

Investigations

Anterior pituitary hormone evaluation on presentation revealed low plasma adrenocorticotropic hormone, cortisol, thyroid-stimulating hormone, free thyroxine (FT4), LH, follicle stimulating hormone (FSH) and testosterone levels along with low normal insulin-like growth factor (IGF-1) (table 1). A dedicated pituitary MRI demonstrated subacute haemorrhage inside the pituitary gland confirming PA (apoplectic haemorrhagic event) (figure 2), which was not present in prior imaging (figure 1).

Table 1.

Anterior pituitary hormone evaluation on presentation

Laboratory test	Results (SI units)	Reference range (SI units)
Thyroid stimulating hormone (TSH)	0.53 mcIU/mL (0.53 mIU/L)	0.6–4.7 mcIU/mL (0.6–4.7 mIU/L)
Free thyroxine (FT4)	0.27 ng/dL (3.47 pmol/L)	0.58–1.76 ng/dL (7.46–22.65 pmol/L)
Cortisol	2.9 µg/dL (80 nmol/L)	5–15 µg/dL (137.9–413.8 nmol/L)
Plasma adrenocorticotropic hormone (ACTH)	5 pg/mL (1.10 pmol/L)	7.2–63.3 pg/mL (1.58–13.9 pmol/L)
Insulin-like growth factor 1 (IGF-1)	58 ng/mL (7.58 nmol/L)	54–258 ng/mL (7.06–33.73 nmol/L)
Growth hormone (GH)	0.6 ng/mL (0.6 µg/L)	0.4–10 ng/mL (0.4–10 µg/L)
Prolactin	32 ng/mL (32 µg/L)	2.1–17.7 ng/mL (2.1–17.7 µg/L)
Testosterone, total	<3 ng/dL (<0.104 nmol/L)	300–700 ng/dL (10.4–24.27 nmol/L)
Luteinising hormone (LH)	0.3 mIU/mL (0.3 IU/L)	1.5–9.3 mIU/mL (1.5–9.3 IU/L)
Follicle stimulating hormone (FSH)	1 mIU/mL (1 IU/L)	1.4–18 mIU/mL (1.4–18 IU/L)

Figure 2.

MRI of pituitary on presentation showed findings consistent with subacute blood, likely related to apoplectic haemorrhagic event (arrow) in the pituitary gland. No significant mass effect on the optic chiasm (sagittal view).

Differential diagnosis

Based on laboratory workup showing secondary adrenal insufficiency and central hypothyroidism, as well as in presence of pituitary MRI suggestive of apoplectic event, he was diagnosed with PA secondary in the setting of GnRH agonist use (leuprolide).

Treatment

The patient was initially treated with prednisone 10 mg daily for the first 3 days following which dose of prednisone reduced to 5 mg daily and levothyroxine 75 µg daily was added.

Outcome and follow-up

He had significant improvement in his symptoms over the next few weeks along with complete resolution of visual symptoms except for mild left eye visual problem, which was present prior to his presentation for PA. A repeat thyroid function test a month later showed low-normal FT4 (0.7 ng/dL or 9.0 pmol/L). Dose of levothyroxine was increased to 100 µg daily to achieve a mid to high-normal FT4 levels and a repeat FT4 level 6 weeks later was 1.01 ng/dL or 13.0 pmol/L.

Discussion

PA is a rare condition characterised sudden onset of neurological symptoms, such as headache, visual impairment, ocular palsy and/or loss of consciousness, associated with an ischaemic or haemorrhagic lesion within the pituitary, typically occurring within pituitary adenomas.¹ Although PA commonly happen in setting of known pituitary tumours, in over 60% of cases, the underlying lesion can be diagnosed at the time of apoplectic event.¹⁰ GnRH agonists are commonly used in the management of patients with PCa and can rarely lead to PA.^{6 11} In a systematic review by Raj et al, authors reported 21 such cases between 1990 and 2020 with only three cases happening in previously known pituitary adenoma.⁶ In this case, the patient did not have any known pituitary adenoma as suggested by previously normal pituitary imaging and was only found to have abnormal imaging at the diagnosis of PA.

Although the exact mechanism of PA following GnRH agonists remain unclear, several mechanisms have been suggested and include: increased tumour vascularity,⁶ blood supply mismatch,¹² increased tumour size resulting in compression of surrounding structure^{13 14} and cytoskeletal structure changes in gonadotroph cells.¹⁵ Majority (up to 62%) of the patients with PA presents within 24 hours of GnRH agonists administration, few cases has been described with presentations up to 6 months after receiving GnRH agonist.^{6 11} Our patient presented with PA approximately 12 months after receiving leuprolide none the less, he started having symptoms of pituitary hormone deficiency at least 6 months prior to his presentation. This suggests an insidious and delayed presentation of our patient’s clinical symptoms of PA, which is extremely uncommon. The most common presentation of PA following GnRH agonist include headache (100%), followed by nausea, vomiting, ophthalmoplegia, visual changes and altered mental status.^{1 6 11} Few cases of blindness associated with PA in patients receiving GnRH agonist have also been reported.^{14 16 17} Our patient developed few symptoms/signs to suggest underlying pituitary hormone deficiency (fatigue, weight loss, anorexia) and mass effect (visual field defects). Endocrine hormone evaluation at the onset of PA is important to determine the management.⁹ In our patient, patient was found to have low cortisol, thyroxine, IGF-1 and testosterone suggestive of panhypopituitarism.

Studies have shown high prevalence of previously undiagnosed gonadotrophinomas to be the underlying pathology for PA. Very few cases have been reported on functioning pituitary adenomas. In one systemic review, 10 out of 12 patients who underwent surgical treatment for PA were found to have gonadotroph adenoma on histopathology.⁶ However, our patient had low LH and FSH, which could be explained by leuprolide mediated effect to suppress testosterone levels. Consensus regarding appropriate management of PA is unclear and considering course of PA to be variable, management should be individualised. Another systematic review showed that 71% of patient with PA following GnRH were managed surgically while the rest 29% were managed conservatively and found variable clinical and hormonal outcomes following either surgical or conservative management, with none showing superiority over the other.^{6 11}

Patient’s perspective.

My energy level and tolerated activity significantly improved after starting Synthroid and prednisone. My weight loss has also stopped, with slight gain (6–8 pounds) in weight as well. No recurrence of double or blurred vision, although left eye vision is still decreased. Tolerance of chemotherapy also improved with the new medications, less weakness, less recovery time.

Learning points.

• Given high prevalence of prostate cancer and increase use of gonadotropin-releasing hormone (GnRH) agonists, it is likely that more patient will develop pituitary apoplexy (PA), which was once thought to be extremely rare.

• It is of utmost importance that patients receiving GnRH agonist should be evaluated for possible PA in the setting of new-onset symptoms, even in the absence of acute symptoms typically seen in PA.

• By early diagnosis and treatment of these patients, clinicians could prevent adrenal crises episode and death.

• Multidisciplinary approach at the earliest should be used or guiding appropriate and individualised management.

Ethics statements

Patient consent for publication

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