Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment

Abstract

Gonadotropin-releasing hormone agonists, used widely in the treatment of metastatic prostate cancer and hormone receptor-positive breast cancer, are associated with a rare but potentially fatal outcome of pituitary apoplexy (PA). An 85-year-old man presented with sudden onset of headache, left eye pain, sensitivity to light, nausea and vomiting. The symptoms started 4 hours after initiation of leuprolide therapy for treatment of recently diagnosed metastatic prostate carcinoma. Radiological imaging of the brain demonstrated a heterogeneously enlarged pituitary gland measuring 19×16×13 mm and T1-hyperintense signal compatible with pituitary haemorrhage. Hormone function tests were indicative of panhypopituitarism, confirming the diagnosis of PA. Due to age, the patient was started on hormonal replacement therapy and eventually symptoms improved.

Background

Physicians should be aware of the rare association of pituitary apoplexy (PA) with the use of Gonadotropin-relasing hormone (GnRH) analogue. Though our patient was fortunate, lack of recognition of this condition has the possibility of a life-threatening outcome to patients. PA has been well documented with usage of various medications including oestrogen, bromocriptine, anticoagulants, carbamazepine and isosorbide dinitrate. There are a few case reports of GnRH agonist-induced PA. Extensive literature review revealed only 15 previously documented cases to date.^1–17 There are no recommendations on pretreatment evaluation of the patients receiving hormonal therapy. Thus, it is important to recognise this condition because if left untreated, it can have long-term implications.

Case presentation

An 85-year-old man, recently diagnosed with prostate cancer (Gleason score=9), presented with a sudden onset of severe, dull and pulsating frontal headache that started 4 hours after administration of the first dose of leuprolide, 45 mg subcutaneously. The patient complained of left eye pain, photophobia, nausea and vomiting. His medical history was significant for diabetes, hypertension, coronary artery disease, benign prostate hypertrophy and migraine headaches. His home medications included: amlodipine, isosorbide dinitrate, fosinopril, promethazine, finasteride, tamsulosin and sumatriptan. On physical examination, the patient seemed to be in apparent distress with normal vital signs. The physical examination was unremarkable with normal extraocular movements, normal visual field confrontation and an insignificant neurological examination.

Investigations

Laboratory workup was significant for thyroid-stimulating hormone (TSH) 0.131 mcIU/mL (0.46–4.6 mcIU/mL), cortisol 2.5 µg/dL (4.5–22.7 µg/dL), blood glucose 141 mg/dL (75–110 mg/dL), adrenocorticotrophic hormone 6.2 pg/mL (7.2–63.3 pg/mL), insulin-like growth factor (IGF) ­78 ng/mL (37–182 ng/mL), free testosterone 3.33 ng/dL (5–21 ng/dL), prolactin 2.7 ng/mL (4–15.2 ng/mL), arginine vasopressin <0.8 pg/mL (0.0–4.7 pg/mL), sodium 129 mEq/L (135–145 mEq/L) with normal follicle-stimulating hormone (FSH), luteinising hormone (LH), growth hormone and free T4. CT of the head demonstrated a 9 mm soft tissue is visualised in the suprasellar cistern. MRI of the pituitary confirmed the presence of an enlarged gland measuring 19×16×13 mm, with a suprasellar component that abuts and slightly uplifts the optic chiasm, and a heterogeneous partially T1-hyperintense signal compatible with pituitary haemorrhage, probably within a pre-existing adenoma (figure 1).

Figures 1.

Sagittal (A) and coronal (B,C) sections: Non-contrast pituitary MRI illustrates enlarged pituitary gland (white arrow) measuring 19x16×13 mm, T1-hyperintense signal compatible with pituitary haemorrhage indicative of pituitary apoplexy.

Differential diagnosis

Our initial differentials included subarachnoid haemorrhage, optic neuritis, aneurysmal rupture, bacterial meningitis, stroke and PA. Based on the imaging studies, laboratory workup and clinical presentation, a diagnosis of PA was established.

Treatment

Considering our patient’s age and symptoms, a conservative non-surgical approach was adopted. The patient was started on hormonal replacement treatment including hydrocortisone, 100 mg intravenously one dose followed by 100 mg every 6 hours. On discharge, he was instructed to take hydrocortisone 20 mg in the morning and 10 mg in the evening along with dexamethasone 4 mg/mL intramuscular injection for symptoms suggesting adrenal insufficiency, acute drop in blood pressure, nausea, weakness or fatigue.

Outcome and follow-up

On follow-up in the endocrinology clinic, our patient reported to be doing well. The hydrocortisone dose was decreased to 15 mg in the morning and 5 mg in the evening. He was educated to continue using dexamethasone injection in situations indicative of adrenal insufficiency. An MRI of the brain had been scheduled in 6 months.

Discussion

Prostate cancer is the most frequently diagnosed cancer in men and is the second leading cause of cancer death preceded by lung cancer.¹⁸ Prostate cancer has an incidence of affecting one in seven men, which has increased in the early 1990s as result of the introduction of prostate-specific antigen (PSA) testing. Additionally, the mortality rate in the USA has diminished by 3.5% per year from 2003 to 2012. Various treatment modalities may be attributing to this diminished mortality rate, including observation, surgery, radiation, hormonal therapy, chemotherapy and the recent introduction of sipuleucel-T immunotherapy.¹⁹ Hormonal therapy including LH-releasing hormone (LHRH) agonists or antagonists are an important modality of treatment for advanced prostate cancer. They are used when surgery or radiation therapy is not possible or preceding radiation in metastatic disease.

Leuprolide acts as an agonist that binds to pituitary GnRH receptors. It acts via desensitisation, downregulating FSH and LH production and ultimately decreasing testicular and ovarian steroidogenesis.²⁰ Initial administration leads to transient stimulation of the pituitary which leads to elevated FSH and LH levels and increased production of oestrogen and testosterone in the first week, with eventual downregulation of the overall pathway.²⁰ Major side effects of these agents include impotence, hot flashes, reduced or absent libido and osteoporosis. A rare complication is the development of apoplexy in a pre-existing pituitary adenoma. Per extensive literature review, there have only been 15 reported cases of PA in patients undergoing treatment for prostate cancer since its implementation.^1–17 The first case of PA was reported in 1995 by Ando et al in a patient receiving a GnRH analogue for treatment of prostate cancer.⁷

LHRH agonists such as leuprolide are not exclusively in use for men with prostate cancer. These agents have also been commonly used in premenopausal women with hormone receptor-positive breast cancer, where it reduces the risk of early-stage breast cancer recurrence after surgery or other treatments. Adjuvant GnRH analogue treatment has demonstrated a survival benefit in premenopausal patients with endocrine responsive breast cancer.^{21 22} Male breast cancer is relatively rare and there is less known about the optimal treatment for male hormone receptor-positive breast cancer, though cases have been reported of leuprolide use in these men.²³ About 40 610 women in the USA are expected to die in 2017 from breast cancer, though death rates have been decreasing since 1989.²⁴ These decreases are thought to be the result of earlier detection in combination with advancements in treatment, such as leuprolide. It is therefore necessary to report the uncommon complication of PA associated with GnRH analogue administration for prostate cancer therapy given the additional concern for the development of this side effect in all utilisations of GnRH analogue class drugs.

PA is a syndrome characterised by sudden severe headache mimicking subarachnoid bleeding associated with visual impairment, headache, vomiting and ophthalmoplegia, which per literary review has been consistent in previous case reports. Acute multihormonal pituitary failure results when the anterior lobe is destroyed, leading to serious medical conditions including adrenal failure, hypothyroidism, diabetes insipidus and rarely death.²⁵ PA has been associated with a wide range of pathologies from sudden head trauma, major surgery (especially coronary artery bypass grafting), arterial hypertension, transient elevation of intracranial pressure, diabetes mellitus, thyrotropin-releasing hormone, anticoagulation, bromocriptine, isosorbide dinitrate, chlorpromazine, oestrogen, pregnancy, obstetrical haemorrhage, dynamic pituitary function testing, radiotherapy and GnRH analogues.^{25 26}

The mechanism relating GnRH analogue administration with PA is not clearly understood. It is believed that the initial pituitary stimulation by leuprolide administration causes increased metabolic activity of the underlying adenoma which outgrows its blood supply, thus developing ischaemic necrosis and subsequent haemorrhage. A second hypothesis is compression of the superior hypophyseal and infundibular vessels against the diaphragm sellae may explain infarction in the non-adenomatous gland.^{4 25} Our patient received the intramuscular form of leuprolide that reaches maximum serum concentration in 4 hours, coinciding with the onset of symptoms. This is consistent with 12 out of the 15 previous cases documented, as shown in table 1 summarising all previous case reports.

Table 1.

Summary and organised current and all previously reported cases of pituitary apoplexy induced by GnRH analogues

Year	Author	Age of patient	GnRH agonist	Drug dose	Time of onset	Pathological findings	Signs/symptoms	Ultimate treatment
1995	Ando et al 7	83	Goserelin	3.6 mg	9 days	No biopsy, CT imaging showed suprasellar mass	Headache, nausea, vomiting, altered mentation, hyponatraemia, diplopia	Medical management
1995	Chanson et al 13	78	Triptorelin	3.75 mg	<4 hours	No biopsy, CT imaging showed suprasellar mass	Headache, dizziness, partial ophthalmoplegia	Medical management
1996	Morsi et al 6	74	Leuprolide	7.5 mg	<4 hours	Pituitary adenoma, Stain FSH+, LH+	Headache, nausea, vomiting, generalised weakness, altered mentation, ophthalmoplegia	Surgical removal
1997	Reznik et al 12	62	Leuprorelin	?	<4 hours	Pituitary adenoma, Stain LH+, FSH+	Sudden intracranial hypertension	Surgical removal
2001	Eaton et al 11	67	Goserelin	3.6 mg	4 hours	Pituitary adenoma, Stain LH+, FSH+	Headache, nausea, vomiting, visual disturbances, altered mentation, hypertension	Medical management
2003	Hernandez et al 5	69	Leuprolide	?	<4 hours	Pituitary adenoma, Stain FSH+	Headache, visual disturbances, diabetes insipidus	Surgical removal
2006	Blaut et al 10	68	Goserelin	3.6 mg	4–6 hours	Pituitary adenoma	Headache, nausea, vomiting, altered mentation, diplopia, ptosis	Surgical removal
2006	Davis et al 4	61	Leuprolide	30 mg	<4 hours	Pituitary adenoma	Headache, nausea, vomiting, ptosis, diplopia, ptosis, CNIII palsy	Surgical removal
2006	Massoud et al 9	70	Leuprolide	11.25 mg	10 day	Pituitary adenoma	Visual disturbances, diplopia, intracranial hypertension, ptosis	Surgical removal
2007	Hands et al 3	60	Leuprolide	22.5 mg	4 hours	Pituitary adenoma, Stain LH+, FSH-, PRL-	Headache, nausea, vomiting, altered mentation, ptosis, CNIII,IV,VI paralysis, diplopia	Surgical removal
2010	Guerra et al 2	60	Leuprolide	?	<4 hours	Pituitary adenoma, Stain LH+	Headache, blurry vision, ptosis, ophthalmoplegia	Surgical removal
2013	Huang et al 8	77	Leuprorelin	3.75 mg	<4 hours	Necrotic debris	Headache, nausea, vomiting, ophthalmoplegia	Surgical removal
2015	Sasagawa et al 15	62	Leuprolide	11.25 mg	<4 hours	Pituitary adenoma, Stain LH+, FSH+	Headache, nausea	Surgical removal
2016	Keane et al 16	67	Triptorelin	?	10–14 days	Pituitary adenoma, Stain LH+, FSH+	Headache, ptosis, CNIII palsy	Surgical removal
2016	Fabiano et al 17	63	Leuprolide	11.25 mg	3 days	No biopsy, MRI showed haemorrhage	Headache, blurry vision, loss of consciousness	Medical management
2017	Tanios et al	84	Leuprolide	45 mg	<4 hours	Pituitary adenoma	Headache, photophobia, nausea, vomiting	Medical management

CN, cranial nerve; FSH, follicle-stimulating hormone; LH, luteinising hormone; PRL, prolactin.

Underlying gonadotroph adenomas are the most common adenomas associated with the occurrence of PA because the hormonal stimulation accelerates the growth of the adenoma and perpetuates infarction that causes apoplexy.^{3 6} The prevalence of pituitary adenomas has been reported to be 16.7%, with prevalence of macroadenomas being 1 in 600.²⁷ There is a high likelihood that these functional or non-functional adenomas will not be recognised until they are detected by imaging or autopsy. However, 65% of cases of PA occur in patients with previously undiagnosed non-functioning pituitary adenomas with 17% of the cases occurring in patients with a known pituitary adenoma.²⁸ Although potentially fatal, this complication remains rare; thus, pretreatment evaluation is not necessary especially when the majority of these adenomas are non-functioning.²⁹

MRI is currently the gold standard for diagnosing PA; therefore, an urgent MRI or dedicated pituitary CT if MRI is contraindicated or unavailable should be performed in all patients with suspected PA. Empiric steroid therapy of 100 mg intravenous bolus, followed by 2–4 mg/hour continuous infusion or 500–100 mg every 6 hours via intramuscular route should be initiated once blood work for the baseline endocrine, kidney and renal function has been collected.²⁶ Pituitary function should be evaluated via Free-T4 (FT4), TSH, LH, FSH, IGF1, cortisol, growth-hormone (GH), estradiol in women and testosterone in men at the time of admission then 4–8 weeks after the event plus annual evaluation if required.²⁶ The decision to manage conservatively or with surgical intervention should be made carefully through a multidisciplinary team composed of an endocrinologist, ophthalmologist and pituitary surgeon. Preferably, a pituitary surgeon should perform a trans-sphenoidal surgery within 7 days of onset of symptoms in patients with visual problems, altered consciousness or cranial nerve involvement.²⁶ All these factors combined will potentially improve the outcome of this possibly life-threatening condition. Patients without neuro-ophthalmic signs or mild and stable signs can be considered for conservative management with close monitoring.³⁰

All patients with PA should have an endocrine evaluation at 4–8 weeks following the event. Both conservatively and surgically treated patients require close radiological follow-up and, if residual tumour or recurrence is detected, additional treatments such as radiotherapy or additional surgery should be considered.³⁰ It is important that patients are educated about the various side effects of leuprolide therapy in order to recognise the signs and symptoms of pituitary failure. Healthcare professionals additionally must be vigilant regarding the rare but possibly fatal consequence of GnRH analogue administration in prostate and breast cancer patients. Early recognition could be life altering and would result in a better prognosis.

Learning points.

• Pituitary apoplexy (PA) is a rare but potentially fatal medical emergency associated with use of Gonadotropin-releasing hormone (GnRH) analogues in a patient with advanced prostate cancer and hormone receptor-positive breast cancer.

• PA can mimic subarachnoid haemorrhage.

• No pretreatment evaluation is indicated in non-functioning pituitary adenomas.

• MRI or dedicated pituitary CT should be performed in all patients with suspected PA.

• Clinicians should be familiar with this complication that could prevent a delay in diagnosis and thus help in a better outcome.