GnRH agonist-associated pituitary apoplexy: a case series and review of the literature.

PURPOSE: To examine the clinical presentation and longitudinal outcome of Pituitary Apoplexy (PA) after gonadotropin-releasing hormone agonist (GnRHa) in a series of patients and compare to prior reports. METHODS: A retrospective chart review was performed on seven patients receiving GnRHa who developed PA. Prior reported cases were analyzed. RESULTS: Six men (median age 72 years) with prostate cancer and one woman (aged 22 years) undergoing oocyte donation presented with PA between 1990 and 2020. Most presented with within 24 h of the first dose, but two developed PA 1 to 5 months after GnRHa initiation. The main clinical manifestations were headache (100%), nausea and vomiting (86%). While no patients had a previously known pituitary tumor, all had imaging demonstrating sellar mass and/or hemorrhage at presentation. Among those surgically treated (5/7), 80% (4/5) of patients had pathologic specimens that stained positive for gonadotropins; the remaining patient's pathologic specimen was necrotic. At the time of PA, the most common pituitary dysfunction was hypocortisolism. Central adrenal insufficiency and central hypothyroidism were reversible in a subset. Pituitary imaging remained stable. CONCLUSIONS: This is the first report of a case series with PA after GnRHa administration with longitudinal follow-up. Although infrequent, PA can be life-threatening and should be suspected among patients receiving GnRHa, with or without a known pituitary adenoma, who develop acute headache, nausea and/or vomiting. Since hypopituitarism was reversible in a subset, ongoing pituitary function testing may be indicated.

Pituitary adenoma and apoplexy during GnRH agonist treatment for IVF - case report.

In vitro fertilization is commonly used for treating infertility. One stage of this process is controlled hyperstimulation of the ovaries, achieved by administering gonadotropins. There are several stimulation protocols utilized that increase the number of ovarian follicles during IVF. The most common protocol employs desensitization - the inhibition of follicle-stimulating hormone and luteinizing hormone secretion by the pituitary gland. This is achieved by administering a gonadotropin-releasing hormone (GnRH) analog that is agonistic for the GnRH receptor. However the use of a this drug during therapy carries a risk of complications. This case report deals with a rare case of a woman who underwent pituitary tumor growth as a result of the treatment of GnRH analog.

A Case of Pituitary Apoplexy Following Leuprolide Injection for Prostate Cancer.

Pituitary apoplexy is a rare but potentially life-threatening complication of androgen deprivation therapy for prostate cancer. We present a case of a 70-year-old African American male with prostate cancer who developed symptoms of pituitary apoplexy, including hot flashes, nausea, vomiting, and cranial nerve III palsy, following the initiation of leuprolide therapy. Imaging revealed a pituitary adenoma with hemorrhage, and prompt multidisciplinary management was initiated. The patient was managed conservatively with improvement in symptoms. This case highlights the importance of recognizing the potential for pituitary apoplexy in patients receiving GnRH agonist therapy. We discuss the clinical presentation of GnRH agonist induced pituitary apoplexy, emphasizing that clinicians should maintain a high index of suspicion and promptly investigate any new neuro- ophthalmic symptoms in this group of patients. Ultimately, prompt diagnosis and treatment are crucial to mitigate the severity of this complication in patients with prostate cancer undergoing androgen deprivation therapy.

Pituitary apoplexy induced by Gonadotropin-releasing hormone agonists for treating prostate cancer-report of first Asian case.

We present the first Asian case of a 77-year-old man who developed pituitary apoplexy (PA) soon after gonadotropin-releasing hormone agonist (GnRHa) (leuprorelin) injection to treat prostate cancer. Headache, ophthalmoplegia, visual field deficit, nausea, and vomiting are the typical characteristics of pituitary apoplexy. Though the occurrence rate is rare, the consequence of this condition can vary from mild symptoms such as headache to life-threatening scenarios like conscious change. Magnetic resonance imaging is the best imaging modality to detect PA and sublabial trans-sphenoid pituitary tumor removal can resolve most of PA symptoms and is so far the best solution in consensus. We also review 11 previous reported cases receiving GnRHa for androgen deprivation therapy of prostate cancer, and hope to alert clinicians to use GnRHa with caution.

Pituitary ischemic apoplexy in a young woman using oral contraceptives: a case report.

Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy.

Pituitary apoplexy due to thyroxine therapy in a patient with congenital hypothyroidism.

A 24-year-old woman was admitted with general weakness, umbilical swelling, developmental delay, speech disorder, constipation, gait problem. Her findings were umbilical hernia, xerosis, dry hair, and short stature. After thyroxine treatment, she also had headache, vomiting, and palpitation, lack of appetite, and sleep disturbance. Pituitary magnetic resonance imaging revealed a heterogeneous mass at the central part of the gland on coronal section and it was interpreted as pituitary apoplexy. In the current case, the patient with congenital hypothyroidism (CH) developed pituitary apoplexy (PA) after thyroxine therapy. Therefore, it is suggested that the complaints were related to PA rather than adrenal insufficiency. Here we describe a case report evaluating PA in a patient with thyrotrophic pituitary adenoma due to CH. To the best of our knowledge, this is the first case in terms of PA associated with CH after thyroxine therapy in the literature.

Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice.

Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke's cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke's cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-ß (PDGFR-ß)-positive cells, which suggests that capillaries around Rathke's cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke's cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.

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

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.

Potential Association Between Anabolic Androgenic Steroid Abuse and Pituitary Apoplexy: A Case Report.

Introduction: Pituitary apoplexy (PA) is a rare, and potentially life-threatening condition, caused by hemorrhage or infarction into the pituitary gland with a rapid expansion of the contents of the sella turcica, associated with sudden intense headache, neurological and endocrinological deterioration. The identification of risk factors is crucial for prevention and optimal management. Herein we report a case of PA occurring 1 month after the initiation of anabolic androgenic steroid abuse for bodybuilding. Case Report: A 40-year-old male patient presents with abrupt onset headache associated with left partial third cranial nerve palsy. The MRI shows a sellar lesion involving left cavernous sinus with a heterogenous anterior aspect of the lesion with hemorrhagic zones in favor of PA. Endocrine work-up shows high testosterone level in patient who was using exogenous testosterone without a medical prescription for a month. Conclusion: We report a case of PA of a pituitary neuroendocrine tumor occurring shortly after AAS. The association between PA and AAS should be considered as a potential risk.

Asymptomatic pituitary apoplexy induced by corticotropin-releasing hormone in a 14 year-old girl with Cushing's disease.

OBJECTIVES: Pituitary apoplexy is a rare complication of Cushing's disease (CD), especially in the paediatric age and even more rarely it can occur following anterior pituitary stimulation tests. CASE PRESENTATION: We report a case of a 14-year-old girl who was admitted to our Hospital for evaluation of a possible Cushing's syndrome (CS). Her symptoms and initial laboratory tests were suggestive of CD. Magnetic resonance imaging (MRI) revealed a microadenoma of the pituitary gland. As part of her evaluation she was submitted to a corticotropin-releasing hormone (CRH) stimulation test. Two and a half months later the patient was re-evaluated and presented with both clinical improvement of CS, biochemical resolution of hypercortisolism and tumour size reduction in the MRI, also evidencing a haemorrhagic component favouring the diagnosis of pituitary apoplexy after CRH stimulation test. The patient denied any episodes of severe headache, nausea, vomiting or visual changes. CONCLUSIONS: To our knowledge, the authors report the first case of a pituitary apoplexy after a CRH stimulation test in the paediatric age.

Pituitary apoplexy induced by gonadotropin-releasing hormone (GnRH) agonist administration for treatment of prostate cancer: a systematic review.

OBJECTIVE: We aimed to review of literature on the clinical presentation, management and outcomes of pituitary apoplexy following gonadotrophic release hormone (GnRH) agonist administration for the treatment of prostate cancer. METHODS: We used PRISMA guidelines for our systematic review and included all English language original articles on pituitary apoplexy following GnRH agonist administration among prostate cancer patients from Jan 1, 1995 to Dec 31, 2020. Data on patient demographics, prostate cancer type, Gleason score at diagnosis, history of pituitary adenoma, clinical presentation, GnRH agonist, interval to pituitary apoplexy, laboratory evaluation at admission, radiologic findings, treatment of pituitary apoplexy, time to surgery if performed, pathology findings, and clinical/hormonal outcomes were collected and analyzed. RESULTS: Twenty-one patients with pituitary apoplexy met our inclusion criteria. The mean age of patients was 70 (60-83) years. Leuprolide was the most common used GnRH agonist, used in 61.9% of patients. Median duration to symptom onset was 5 h (few minutes to 6 months). Headache was reported by all patients followed by ophthalmoplegia (85.7%) and nausea/vomiting (71.4%). Three patients had blindness at presentation. Only 8 cases reported complete anterior pituitary hormone evaluation on presentation and the most common endocrine abnormality was FSH elevation. Tumor size was described only in 15 cases and the mean tumor size was 26.26 mm (18-48 mm). Suprasellar extension was the most common imaging finding seen in 7 patients. 71.4% of patients underwent pituitary surgery, while 23.8% were managed conservatively. Interval between symptoms onset to pituitary surgery was 7 days (1-90 days). Gonadotroph adenoma was most common histopathologic finding. Clinical resolution was comparable, while endocrine outcomes were variable among patients with conservative vs surgical management. CONCLUSION: Although the use of GnRH agonists is relatively safe, it can rarely lead to pituitary apoplexy especially in patients with pre-existing pituitary adenoma. Physicians should be aware of this complication as it can be life threatening. A multidisciplinary team approach is recommended in treating individuals with pituitary apoplexy.

An unsuspected complication with immune checkpoint blockade: a case report.

BACKGROUND: Immunotherapy treatment with immune-checkpoint blockade has become a new paradigm in cancer treatment. Despite its efficacy, it has also given rise to a new class of adverse events, immune-related adverse events, which may affect any organ, including the thyroid and the pituitary. CASE PRESENTATION: We present a case of a 77-year-old Caucasian man with metastatic renal cell carcinoma on immunotherapy treatment who was admitted to our hospital with a severe persistent headache of sudden onset. He had been on corticosteroid therapy for 10 days for suspected immune-related thyroiditis. The patient had tachycardia and mild diarrhea, and his thyroid function tests were compatible with subclinical hyperthyroidism with a suppressed thyroid-stimulating hormone level of 0.01 µIU/ml (0.4-4.5), a raised free T4 level of 2.17 ng/dl (0.7-1.9), and a free T3 level of 4.66 pg/ml (2.27-5). Computed tomography and magnetic resonance imaging revealed an enlargement of the pituitary gland compatible with macroadenoma. In the face of a probable immune-related hypophysitis, high-dose corticosteroid treatment was started. A posterior hormonal evaluation revealed secondary hypothyroidism with a suppressed thyroid-stimulating hormone level of 0.11 µIU/ml (0.4-4.5) and low thyroid hormones, a normal free T4 level of 1.02 ng/dl (0.7-1.9), and a low free T3 level of 1.53 pg/ml (2.27-5). These new findings suggested central hypothyroidism possibly due to pituitary apoplexy as a complication of the macroadenoma. Therefore, levothyroxine substitution was started along with the previously started corticosteroid therapy. The patient's headache and asthenia gradually resolved, and after a few days, he was released from the hospital with levothyroxine substitution and corticosteroid tapering. CONCLUSIONS: This case emphasizes the importance of the differential diagnosis when dealing with patients on immune checkpoint inhibitors because other non-immune-related events may present. Our patient was finally diagnosed with immune-related hyperthyroidism and a concurrent pituitary macroadenoma. This case also highlights the importance of a prompt start of corticosteroid therapy once immune-related adverse events such as hypophysitis are suspected, because otherwise the outcome would be fatal.

Pituitary Apoplexy in Long-Term Cabergoline User During Thrombocytopenia Due to Chemotherapy for Chronic Myelocytic Leukemia.

BACKGROUND: Pituitary apoplexy (PA) is a life-threatening syndrome. The usage of a dopamine agonist, such as bromocriptine or cabergoline, is considered a predisposing factor for PA, which commonly occurs 1.5 years within commencement. CASE DESCRIPTION: A 64-year-old female with a >15-year history of cabergoline therapy for pituitary prolactinoma was referred to our department of neurosurgery after complaining of headache, blurred vision, diplopia, and ptosis for 3 days during hospital admission for chemotherapy of chronic myelocytic leukemia. Computed tomography and magnetic resonance imaging revealed findings indicative of PA. As the patient was experiencing thrombocytopenia related to chemotherapy, blood transfusion was preceded, and after a platelet count of 15.0 × 104/µL was confirmed, transnasal neuroendoscopic surgery was performed 5 days from the onset of symptoms. The majority of the prolactinoma was removed, and the prolactinoma in the cavernous sinus was intentionally left. The postoperative course was generally good. The ptosis and diplopia improved, and the blurred vision resolved. CONCLUSIONS: PA related to dopamine agonist therapy can occur in cases of elevated bleeding tendency, even in long-term users, suggesting that attention should be paid in the administration of a dopamine agonist in the patient experiencing thrombocytopenia. Surgical intervention should be performed after the preoperative platelet number and adequate response to transfusion are confirmed, and the aggressive removal of prolactinoma in the cavernous sinus should be avoided to reduce the risk of hemorrhagic complications.

Apoplexy accompanying pituitary adenoma as a complication of preoperative anterior pituitary function tests.

Pituitary apoplexy occurs as a very rare complication of the pituitary function test. We have experienced two cases of pituitary apoplexy following anterior pituitary function tests for preoperative assessment: a triple bolus test and a TRH test. To elucidate such a rare complication, we outline our two cases and review 28 cases from the literature. The clinical characteristics, etiology, pathophysiology, and diagnostic and therapeutic implications are also discussed. The combined data suggest that pituitary function tests have the potential to precipitate pituitary apoplexy, and its manifestations range from a clinically benign event to a catastrophic presentation with permanent neurological deficits or even death, although most patients may fortunately have a good outcome. We suggest that the pituitary function test should not be done as a routine test, and when such a test is planned, the patient should be observed with caution for any symptomatic changes for at least 2 hours following the test for appropriate treatment. Further, MRI, especially enhanced studies, may provide an earlier diagnosis of the pituitary apoplexy since CT scan images often fail to demonstrate either density changes or obvious enlargement of the pituitary adenoma at the acute stage.

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

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.

Pituitary apoplexy after leuprolide.

Clinically unsuspected pituitary adenomas are common among adults on autopsy and MRI survey. Acute pituitary hemorrhage is far more rare. We report a case of a 61-year-old male patient with locally advanced prostate cancer who presented with an acute picture of pituitary apoplexy after his first dose of leuprolide. He developed headache and neck pain within a few hours of treatment followed by nausea, vomiting, ptosis and diplopia. Pituitary apoplexy is a potentially life threatening medical emergency. Although the pathophysiology is poorly defined, various conditions and treatments have been reported to trigger apoplexy. Apoplexy has been reported in response to pituitary stimulation by GnRH or GnRH-agonists. Initial stimulatory effects of gonadotropin releasing hormone (GnRH) analogue may induce apoplexy in patients with asymptomatic gonadotroph adenomas.

Pituitary Apoplexy After Initial Leuprolide Injection.

BACKGROUND: Pituitary apoplexy is a rare complication of the initial administration of leuprolide acetate. CASE DESCRIPTION: We present the case of a 63-year-old man who experienced headache, blurred vision, and loss of consciousness after initial leuprolide treatment for prostate carcinoma. Neuroimaging showed pituitary hemorrhage. CONCLUSIONS: Clinicians should be aware of this rare but known complication of leuprolide injection so that prompt diagnosis and treatment initiation are performed in patients with leuprolide-associated pituitary apoplexy.

Pituitary apoplexy following gonadotropin-releasing hormone agonist administration with gonadotropin-secreting pituitary adenoma.

Gonadotropin-releasing hormone (GnRH) agonists are widely used in hormone therapy for prostate cancer. We report a patient with pituitary apoplexy following this therapy as a rare complication and review the related literature. A 62-year-old man presented with elevated prostate specific antigen. Transrectal ultrasound guided biopsy of the prostate gland revealed adenocarcinoma. Whole-body (18)F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed FDG-uptake in the pituitary region. MRI also demonstrated a pituitary tumor, diagnosed as an incidental non-functioning adenoma. The patient received his first dose of GnRH agonist (leuprolide 11.25mg) against prostate cancer. He complained of a severe headache 10 minutes after leuprolide administration and suffered from right third nerve palsy in the next 48 hours. MRI demonstrated a high intensity area on T1-weighted images, diagnosed as pituitary apoplexy. The patient underwent transsphenoidal surgery. Pathology revealed predominantly necrotic tissue and a gonadotropin secreting pituitary adenoma. Overall, 15 patients, including ours, have been reported with pituitary apoplexy after GnRH agonists with pathologic gonadotropin secreting adenoma. Fourteen of 15 patients were male. Pituitary apoplexy developed within 4 hours after administration of the agents in 8/15 patients. The combined data suggest that GnRH agonists have the potential to precipitate pituitary apoplexy in men with gonadotropin secreting adenoma. Therefore, prior to GnRH agonist therapy for prostate cancer, a known pituitary adenoma should be treated. Otherwise, the patients should be cautiously observed for any symptomatic change following drug administration.