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Pituitary Disorders
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Functioning Pituitary Adenomas – Current Treatment Options and Emerging Medical Therapies

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Published Online: May 5th 2019 European Endocrinology. 2019:15(1):30–40 DOI: https://doi.org/10.17925/EE.2019.15.1.30
Authors: Elena V Varlamov, Shirley McCartney, Maria Fleseriu
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Abstract
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Abstract:
Overview

Pituitary adenomas are benign tumours comprising approximately 16% of all primary cranial neoplasms. Functioning pituitary adenomas (prolactinomas, somatotroph, corticotroph, thyrotroph and rarely gonadotroph adenomas) cause complex clinical syndromes and require prompt treatment to reduce associated morbidity and mortality. Treatment approaches include transsphenoidal surgery, medical therapy and radiation. Medical therapy is the primary therapy for prolactinomas, and surgery by a skilled neurosurgeon is the first-line approach for other functioning pituitary adenomas. A multimodal treatment is frequently necessary to achieve biochemical and clinical control, especially, when surgery is not curative or when medical therapy fails. Several emerging, novel, medical treatments for acromegaly, Cushing’s disease and prolactinomas are in phase II and III clinical trials and may become effective additions to the current drug armamentarium. The availability of various management options will allow an individualised treatment approach based on the unique tumour type, clinical situation and patient preference.

Keywords

Pituitary adenoma, prolactinoma, acromegaly, Cushing’s disease, TSH-secreting adenoma, gonadotroph adenoma, transsphenoidal surgery, radiation, medical therapy

Article:

Pituitary adenomas are benign tumours that arise from the adenohypophysis. They are the second most frequent intracranial tumour type after meningiomas, and account for 16.2% of all primary cranial neoplasms.1 Though likely an underestimate, the incidence of pituitary adenomas is approximately four per 100,000 persons per year,2,3 and incidence increases with age.4 Prolactinomas and non-functioning pituitary adenomas are the most common pituitary adenoma types, followed by somatotroph, corticotroph and thyrotroph adenomas. Almost all gonadotroph adenomas are clinically non-functioning, and less than 1% are hormonally active.4,5 Functioning pituitary adenomas carry significant morbidity and increased mortality due to resultant clinical syndromes, concurrent hypopituitarism as well as tumour mass effect.6–8 Prompt and effective treatment is crucial to disease control and a reduction in associated health risks.9–11 In this review, treatment options for different types of functioning pituitary adenomas are presented, with a focus on current and emerging medical therapies.

 

Pituitary adenoma therapy

Therapy for pituitary adenomas includes transsphenoidal surgery, medical treatment and/or radiation therapy.

 

Surgery

Transsphenoidal surgery is the first-line therapy for most cases of functioning pituitary adenomas (except prolactinomas), as surgery can achieve rapid and sustained biochemical remission, along with decompression of the optic chiasm. However, surgery carries the risk of new pituitary deficiencies (3.6–19.4%), transient or permanent diabetes insipidus (4.3–17.7% and 0.3–7.3% respectively), hyponatremia (4.3–21%) and other surgical complications such as cerebrospinal fluid (CSF) leak (2.6–7%), haemorrhage (1.1–2.9%), infection (1.1–3.8%), carotid artery injury (0.1–1.1%) and vision loss (0.6–1.8%).12–14 In a meta-analysis, hypopituitarism was more common after transsphenoidal surgery for Cushing’s disease (25%) than acromegaly, prolactinoma or non-functioning pituitary adenomas (approximately 7–12%), and is thought to be related to prolonged glucocorticoid replacement and a more aggressive surgical technique used for corticotroph adenomas.15 Rates of surgical success and complications vary, with more favourable outcomes achieved with experienced surgeons and in high-volume centres.13,16 Microscopic and endoscopic techniques appear equally effective, with a similar complication rate.12,14

 

Medical

Medical therapy is generally used as adjunct therapy after a failed transsphenoidal surgery in Cushing’s disease and acromegaly, when surgery cannot be performed, or for recurrent disease. Often medical therapy becomes a long-term treatment option that requires monitoring for biochemical control and side effects. Pituitary-directed medications (somatostatin receptor ligands [SRLs] and dopamine agonists) exert antisecretory and antiproliferative effects on pituitary tumours; prolactinomas typically respond to dopamine agonists with considerable tumour regression, while in acromegaly and Cushing’s disease, tumour response to SRLs varies significantly. End-organ targeted therapy, such as inhibitors of adrenal steroidogenesis or receptor blockers, e.g. glucocorticoid or growth hormone receptor antagonists, can provide effective biochemical and/or clinical disease control (Table 1).

 

Radiation

Due to slow onset of response (up to several years) and development of new pituitary deficiencies, radiation therapy is considered a third-line therapy option following unsuccessful transsphenoidal surgery and failed medical treatment, or in cases of tumour recurrence.10,11 Conventional and stereotactic fractionated radiation is delivered in multiple small doses over 5–6 weeks, while stereotactic radiosurgery is performed in a single-session, high-dose treatment. Conventional and stereotactic radiosurgery therapy have similar effectiveness, although stereotactic radiosurgery may result in quicker normalisation of hypersecreted hormones.17–19 Stereotactic radiosurgery is more convenient for a patient; however, it carries a higher risk of damage to the optic apparatus in tumours located very close to the optic chiasm.18–20 Secondary brain tumours develop in 1.1–2.4% of patients after conventional therapy with relative risk ranging from no increased risk to 10.5 compared to the general population, and several studies have shown no increased risk compared to nonirradiated patients.21,22 Conventional radiotherapy may pose a slightly higher risk of stroke, especially in acromegaly,23 and it has been associated with neurocognitive impairment, specifically in verbal memory and executive function, regardless of tumour type.24

 

Prolactinomas

Prolactinomas are the most common functioning pituitary tumours (66%), with a female:male ratio of 10:1.2,25 The majority are microadenomas (80%) and men more commonly present with macroadenomas.2,26 Giant prolactinomas represent 1–5% of all prolactinomas.27

 

Medical

Dopamine agonists, the mainstay of medical therapy, are very effective at normalising prolactin levels and reducing pituitary adenoma size; resulting in a rapid, often within days, visual improvement and gradual restoration of hypogonadism and fertility.28,29 Cabergoline and bromocriptine are dopamine agonists available in the United States. Another dopamine agonist, quinagolide, is used in some European countries. Cabergoline is recommended over bromocriptine due to higher potency and effectiveness when compared with bromocriptine.28 Cabergoline normalises prolactin in 83% versus bromocriptine in 59% of women with hyperprolactinaemic amenorrhea.30 A meta-analysis of six observational studies and three randomised trials showed superiority of cabergoline at reducing prolactin levels and associated symptoms of hypogonadism in women.31 The effect on tumour volume reduction has not been assessed in randomised controlled trials. However, data extracted from two separate studies suggest greater efficacy of cabergoline on tumour volume reduction, 96% versus 64% with bromocriptine.32–34 This difference in efficacy is thought to be related to cabergoline having a stronger affinity for dopamine D2 receptors and a longer duration of action.28

 

Resistance, defined as inability to achieve normoprolactinaemia or 50% reduction in tumour volume with standard doses of dopamine agonist, occurs in 25% of patients treated with bromocriptine and 10% treated with cabergoline.28,35 It is estimated that up to 80% of those resistant to bromocriptine can achieve normal prolactin levels with cabergoline.28 The mechanism of resistance is also poorly understood, but may be due to decreased number of D2 receptors, presence of different receptor isoforms or downstream signalling changes in resistant prolactinomas.28,36,37 Cabergoline dose may be increased, typically (1–2 mg/week) to a maximal tolerable dose, though this is rarely reported to overcome resistance.28

 

Common side effects of dopamine agonists are nausea, dizziness and headache, with nausea being more pronounced in patients treated with bromocriptine. Additionally, there is growing evidence of an association of dopamine agonist use with impulse control disorders such as pathologic gambling and hypersexuality.38 Although the prevalence of these disorders in patients with prolactinomas is still unknown, one study reported that the risk of developing an impulse control disorder was 9.9 times higher in males treated with dopamine agonists compared to those with non-functioning adenomas.38,39 A very rare but serious complication is CSF leak in giant prolactinomas eroding the sellar floor, which typically requires urgent neurosurgical intervention.40 Although standard cabergoline doses are not associated with increased risk of valvular heart disease, doses >2 mg/week and high cumulative doses may still carry some risk, and monitoring with echocardiograms has been recommended by some groups.41–45 Few studies have reported association of bromocriptine with non-clinically significant valve fibrosis,46,47 and larger studies have reported no association.43

 

Investigation of emerging medical therapies is underway (Table 2). Lapatinib is a tyrosine-kinase inhibitor of epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase (ErbB2 or human epidermal growth factor receptor 2 [HER2]), which shows promise as a treatment for resistant prolactinomas. Lapatinib has been demonstrated to decrease prolactin levels by 60% and 40% in transgenic mice with pituitary expression of EGFR and HER2, respectively; prolactin remained unaltered in control mice.48 In two human subjects, addition of lapatinib to cabergoline after prolonged treatment with high dose cabergoline allowed for 22% tumour volume reduction and almost normalisation of prolactin at 6 months in one case, and suppression of tumour growth with 42% prolactin reduction in the other case.49,50 Side effects were mild alopecia, rash, diarrhoea and anorexia. Lapatinib is currently being evaluated in the phase II trial, Targeted Therapy with Lapatinib in Patients with Recurrent Pituitary Tumors Resistant to Standard Therapy (ClinicalTrials.gov Identifier; NCT00939523).

 

Surgery

Transsphenoidal surgery is reserved for patients with resistant prolactinomas, those with intolerance or contraindications to medical therapy, as well as emergent situations such as apoplexy and CSF leak. Several studies have examined the outcomes of transsphenoidal surgery and reported variable remission rates; range 30–93%,51 with lower remission rates reported for invasive prolactinomas. Following transsphenoidal surgery, new pituitary deficiencies developed in 17.1% of patients in one study (7.0% anterior pituitary hypofunction), while improvement of existing deficiencies occurred in 14.6%.52 Although prolactinomas in men tend to be more aggressive, it has not been clearly demonstrated that men have poorer surgical outcomes.26,53 However, a recent study of prolactinomas in males who required surgery reported a high rate of residual tumour (92.6%) and frequent need for additional surgery and radiation.26 Preoperative dopamine-agonist therapy does not appear to significantly affect surgical cure.26,51,53 Following debulking surgery, medical therapy normalises prolactin levels in almost half of resistant adenomas, and with lower dopamine agonists doses.51 Recurrence of hyperprolactinaemia after initial remission following transsphenoidal surgery is common, reportedly varying between 5–58%; higher rates are reported in studies with longer follow up.51,52,54

Table 1: Current medical options for prolactinoma, acromegaly and Cushing’s disease

D = diarrhoea; D2 = dopamine receptor D2; GC = glucocorticoid; GH = growth hormone; ICU = intensive care unit;IM = intramuscular; IV = intravenous; LFT = liver function test; SRL = somatostatin receptor ligand; SSTR5 = somatostatin receptor 5; SC = subcutaneous; V = vomiting. QTC = electrocardiogram calculated duration of time from the start of the Q wave to the end of the T wave adjusted for a patient’s heart rate.

 Table 2: Emerging investigational drug medical therapies for pituitary adenomas

FSH = follicle stimulating hormone; LFT = liver function test; LH = luteinizing hormone; PO = per so (by mouth); SC = subcutaneously.

QTC = electrocardiogram calculated duration of time from the start of the Q wave to the end of the T wave adjusted for a patient’s heart rate.

Radiation

Radiation therapy is used for resistant and aggressive or malignant prolactinomas.55 Prolactin levels normalise in 26–52% of patients post radiation therapy, tumour growth is controlled in 89–92%55–57 and hypopituitarism occurs in one-third of patients.55 Some authors have reported that dopamine agonist use at the time of radiation may reduce remission rates, while others did not find this association.55,58,59 Therefore, there is no universal recommendation to withhold dopamine agonists prior to radiation.

Acromegaly

Growth hormone-producing adenomas represent approximately 9.0–13.2% of pituitary adenomas; 73.0% are macroadenomas,2,5,60 and giant adenomas constitute about 4.5%.27 Acromegaly affects males and females equally and is most commonly diagnosed during the fifth decade of life.61

Surgery

Transsphenoidal surgery is recommended as the first-line treatment due to rapid control of growth hormone levels. When performed by an experienced surgeon, remission is greater than 85% for microadenomas62,63 and 40–66% for macroadenomas.63,64 If biochemical remission is not achieved, patients require adjunctive medical therapy and/or radiation therapy. Even when the likelihood of cure is low, such as in the case of large or invasive adenomas, debulking surgery is still recommended as it provides better postoperative control by SRLs.65–8 Five-year recurrence after surgery is reported as 0.7–5.4% in various studies, and 10–15-year recurrence as 0.1–10%.64,69–71 Incidence of pituitary deficiencies after transsphenoidal surgery include 6.50% for adrenal insufficiency, 4.39% for central hypothyroidism, 6.70% for hypogonadism, 14.95% for growth hormone deficiency and 10.05% for transient and 2.42% for permanent diabetes insipidus, as assessed by a meta-analysis.72

Overall, surgery is more effective than primary medical therapy for treatment-naïve patients. A meta-analysis of prospective and retrospective studies demonstrated that surgically treated patients had higher remission rates than their medically treated counterparts (67% versus 45%, p=0.02).73

Finally, surgery can provide additional information about tumour granulation type and presence of somatostatin receptor (SSTR) on pathology. Densely granulated adenomas and SSTR2A-positive adenomas respond better to SRLs than sparsely granulated adenomas and SSTR2A-negative adenomas.74,75 This knowledge allows for an SRL response prediction, which serves to guide physicians in selecting individualised patient treatment plans (e.g. SRL monotherapy versus pegvisomant or early combination therapy).

Medical

Medical therapy may be used as primary therapy in poor candidates for surgery, in those who decline surgery or if surgery is unlikely to provide biochemical cure due to extent of the disease.10 Occasionally, medical therapy is used preoperatively in high-risk patients with a goal of reducing growth hormone levels and decreasing anaesthesia complications such as laryngeal oedema, high-output heart failure and uncontrolled hypertension.76,77 SRLs, growth hormone receptor antagonists (pegvisomant) and dopamine agonists are the three classes of medications currently used to treat acromegaly. They are used as a single agent or in combination.7,78

SRLs act on SSTR subtypes 2 and 5 located on somatotroph cells. First-generation SRLs (octreotide [OCT] long-acting release [LAR], lanreotide slow release and lanreotide autogel) seem to be equally effective in controlling growth hormone and insulin-like growth factor 1 (IGF-1) level in approximately 55% of patients (reported clinical studies range 17–70%).10,79,80 The wide range in reported efficacy can be explained by different clinical study methodology, selection bias, previous surgery or medical treatment, dose, duration of follow-up and other factors.79 Biochemical control can be maximised by escalating the dose of OCT-LAR (60 mg every 4 weeks)81 and lanreotide (180 mg every 4 weeks or 120 mg every 3 weeks) in treatment-responsive patients.82–84 First-generation SRLs are effective at shrinking the tumour in 30–66% of patients by 10–77%.85–87 Approximately one-third of patients experience 50% tumour volume reduction with primary medical therapy.86 Common side effects include gastrointestinal distress, gallstones and dysglycaemia.

Pasireotide is a multi-SRL with a high affinity for SSTR5 compared to other SRLs and has been demonstrated to have higher efficacy than OCT-LAR in a randomised controlled trial (31.3% versus 19.2%, respectively, p=0.007), while tumour volume reduction was similar, approximately 40%.88 Additionally, pasireotide can normalise biochemical control in 20% of patients resistant to first-generation SRLs;89 however, hyperglycaemia occurs in 57% of patients. Pasireotide-induced hyperglycaemia has been attributed to a reduction in insulin secretion, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels.90 Close monitoring in patients with impaired glucose tolerance and diabetes is required and treatment with metformin, dipeptidyl peptidase-4 (DPP-4) inhibitor or GLP-1 receptor agonist has been recommended for the management of hyperglycaemia.91

Pegvisomant is a highly selective growth hormone receptor antagonist that blocks growth hormone receptor to reduce IGF-1 production by the liver. Pegvisomant is used in patients who remained uncontrolled after transsphenoidal surgery or radiation therapy and sometimes as primary therapy if transsphenoidal surgery is not feasible or desired.10,92 In clinical trials, pegvisomant effectiveness was remarkable, with IGF-1 normalisation rates of up to 97% on maximal doses of 40 mg daily.93 However, long-term surveillance studies indicated that a real-world control rate was approximately 60%, likely reflecting lower standard doses used in everyday practice compared with clinical trials.10,82 Liver function tests are monitored and treatment should be discontinued if transaminases increase to greater than five-times the upper limit of normal (ULN). Despite a theoretical concern that lack of IGF-1 feedback may stimulate pituitary tumour growth, progression of tumour was noted only in 3% of patients.94 Although this may represent natural tumour progression independent of pegvisomant, serial magnetic resonance imaging (MRI) has been recommended.10

Dopamine agonists normalise IGF-1 and growth hormone in one-third of patients,95,96 and induce tumour volume reduction in up to 62%.95 Due to modest efficacy in acromegaly, cabergoline plays a role mostly as adjunctive therapy in cases with mildly elevated IGF-1.

Combination medical therapy

Pegvisomant can be used in combination with first-generation SRLs in patients who are uncontrolled on SRL alone. This may result in

IGF-1 normalisation in up to 95% of cases.97 A combination of pegvisomant and pasireotide may potentially allow for lower doses.

This has been examined in one study to date,98,99 where it was demonstrated that switching from first-generation SRLs to pasireotide allowed for a reduction in pegvisomant dose by half. Pegvisomant did not offset or prevent pasireotide-induced hyperglycaemia. Diarrhoea was a common side effect, but no elevation of transaminases was observed.

Dopamine agonists in combination with SRLs achieve normalised IGF-1 levels in approximately half of patients who are uncontrolled on SRLs alone.95 Cabergoline plus a low-dose pegvisomant combination is also a modestly effective option when liver enzyme elevation, diabetes or SRL-induced hyperglycaemia is a concern.100

Oestrogen is capable of lowering IGF-1 through inhibition of liver growth hormone receptor expression or through upregulation of suppressors of cytokine signalling-2, leading to decreased growth hormone signalling.101,102 Selective oestrogen receptor modulators bind to oestrogen receptors and exhibit oestrogen agonistic or antagonistic effects in different tissues. Raloxifene, tamoxifen and clomiphene have been studied as an add-on therapy in men and post-menopausal women with uncontrolled acromegaly.103–106 In one study, tamoxifen normalised IGF-1 in eight (47%) patients and decreased IGF-1 in 14 (82%) patients.104 A recent head-to-head open label study of raloxifene versus cabergoline add-on therapy to long-acting SRL showed similar lowering effect on IGF-1; IGF-1 normalised in 45.5% of patients with raloxifene and in 40.9% of patients with cabergoline.106 Adverse effects included flushing. A study of clomiphene in men has shown a decrease in IGF-1 by 41%, including normalisation of IGF-1 in 44% without reported side effects.105 Selective oestrogen receptor modulators are not part of standard acromegaly management and longer-term studies are needed to assess their safety and efficacy.106

Emerging medical therapy

Several new acromegaly treatment agents as well as a new SRL formulations are being tested in human clinical trials (Table 2). In a phase III clinical trial, oral OCT maintained biochemical control in 62% of patients who were switched from a long-acting SRL (from 89% controlled on SRL at baseline).107 There are two other ongoing phase III trials: Comparison of Oral Octreotide Capsules to Injectable Somatostatin Analogs in Acromegaly (MPOWERED; ClinicalTrials.gov Identifier: NCT02685709) and Efficacy and Safety of Octreotide Capsules (MYCAPSSA) in Acromegaly (OPTIMAL; ClinicalTrials.gov Identifier: NCT03252353).

An antisense oligonucleotide inhibitor of growth hormone receptors is a novel and promising therapy. A phase II study of ATL1103 demonstrated a 27.8% reduction of IGF-1 at week 14, with good tolerability but mild-to-moderate injection-site reaction occurring in 85%.108 A newer generation antisense oligonucleotide ISIS 766720, targeting hepatic expression of growth hormone receptor, is currently being investigated in a phase II trial (Safety, Tolerability, and Efficacy of IONIS-GHR-LRx in up to 42 Adult Patients with Acromegaly Being Treated with Long-acting Somatostatin Receptor Ligands; ClinicalTrials.gov Identifier: NCT03548415).

Another emerging therapeutic agent is an orally bioavailable nonpeptide SSTR2 biased agonist, CRN00808. CRN00808 is biased for SSTR2 activation (a process that causes reduction of growth hormone secretion) over receptor internalisation (which is a process that limits therapeutic activity of SSTR agonist). Preliminary phase I clinical trial data (Single and Multiple-Ascending Dose Study of CRN00808 in Healthy Volunteers; ClinicalTrials.gov Identifier: NCT03276858) show that a 2.5 mg once-daily dose lowers growth hormone-releasing hormone-induced growth hormone release by 73% in healthy volunteers.109 A phase II study evaluating CRN00808 in patients with acromegaly treated with SRLs is ongoing (A Study to Evaluate the Safety and Efficacy of CRN00808 for the Treatment of Acromegaly [ACROBAT EDGE]; ClinicalTrials.gov Identifier: NCT03789656).

Radiation

Radiation therapy is reserved for patients with persistent disease after surgery who failed medical therapy. However, remission onset is slow, taking many years and requiring medical therapy in the interim. Hormonal remission rates are 50–60% at 10–15 years with both stereotactic radiosurgery and conventional radiation, with stereotactic radiosurgery slightly more effective.23,110,111 Hypopituitarism develops in up to 50% of patients at 5 years.23,110 Some suggested that SRLs may prevent a full effect of radiation, but this has not been a consistent observation and may be due to the fact that in non-randomised studies, patients with more severe disease were more likely to continue SRL prior to treatment.20,112,113 Although not clearly recommended by current guidelines, some centres withhold SRLs for four to eight weeks prior to radiation therapy.20

Cushing’s disease

Adrenocorticotropic hormone (ACTH)-producing adenomas represent 4–6% of all adenomas, occurring more frequently in females (3:1 ratio).2,5 Only about a third are macroadenomas, while the majority are microadenomas, and approximately 12% of those are not detectable on MRI.5,114 Aggressive corticotroph adenomas are usually biochemically silent, and have an approximately 30% risk of recurrence.115

Surgery

Transsphenoidal surgery is the recommended treatment of choice for ACTH-producing adenomas. Remission rates range from 65–98%, with higher rates when a pituitary adenoma is identified on MRI and removed completely by an experienced and specialised surgeon.116,117 If a pituitary adenoma is not found during surgical exploration,

hemi-hypophysectomy/pan-hypophysectomy may be performed, with remission rates reported as 60–75%.116 However, more extensive transsphenoidal surgery carries greater risk of hypopituitarism. Postoperative pituitary deficiencies develop in 25% of patients with Cushing’s disease compared to approximately 7–13% in other pituitary adenomas.15 Transient diabetes insipidus is the most common postoperative pituitary dysfunction occurring in 4–48% of patients, while permanent diabetes insipidus has been reported in 3–46% of patients.15,118 Rates of postoperative thyrotropin and gonadotropin deficiency are 11–20% and 8–17% respectively.118–120 In one study, prevalence of growth hormone deficiency was 65% in patients who achieved long-term surgical remission.121

Failure of remission occurs when a pituitary adenoma is incompletely excised or missed on surgical exploration, if dural invasion is present, or if a pituitary adenoma is extra-pituitary.116,122,123 Repeat surgery is an option for those with persistent hypercortisolism; however, remission rates are lower, 57–71%.124,125 Given the possibility of delayed remission, the decision to repeat surgery should be postponed until persistent disease is biochemically confirmed. Hypercortisolism can recur in up to 35% of cases.116,126

Medical

Medical therapy is necessary for persistent or recurrent hypercortisolism after transsphenoidal surgery or if surgery is contraindicated or declined. Additionally, medical therapy can be used post-radiation therapy until radiation effect occurs. Current medical therapy is directed at three targets: ACTH production by a corticotroph tumour, steroidogenesis in the adrenal gland, and glucocorticoid receptors.

Pituitary-directed drugs include pasireotide and cabergoline. Pasireotide binds to SSTR5 receptor, which is predominantly expressed on corticotroph adenoma cells, and inhibits ACTH production. In a 12-month clinical trial of pasireotide in Cushing’s disease, subcutaneous pasireotide decreased urinary free cortisol (UFC) by approximately 50% and normalised levels in more than 20% of patients, mainly in those with mild-to-moderate cortisol hypersecretion. Tumour volume reduction was 43% on a maximum dose of 900 µg daily.127 A long-acting monthly intramuscular formulation, pasireotide LAR, is available and has a similar efficacy as the subcutaneous pasireotide.128 The most frequent side effect of both formulations is hyperglycaemia, occurring in more than half of patients. Gastrointestinal side effects such as nausea, diarrhoea and cholelithiasis are similar in frequency to other SRLs.127 Cabergoline acts via D2 receptors on cortocotroph tumours. It is mostly used as an add-on therapy. Short-term response with UFC normalisation is observed in 25–35% of patients,129–131 while long-term efficacy is lower, mainly due to treatment escape.129,132 The dose range is 1–7 mg/week, with a commonly used dose of 2–3.5 mg/week.

Currently available inhibitors of steroidogenesis are ketoconazole, metyrapone, mitotane and etomidate. Ketoconazole is an antifungal agent used off-label in the United States (licensed in Europe) for Cushing’s syndrome. Ketoconazole inhibits cytochrome P450 enzymes on multiple levels of steroidogenesis and at higher doses effectively lowers glucocorticoid and androgen synthesis.133 Studies report efficacy in 30–90% of patients. The largest retrospective study to date showed that 49% of patients with Cushing’s disease achieved normal UFC and 25% had at least 50% reduction in UFC; however, 15% experienced escape from control after 2 years of treatment.134–7 Severe ketoconazole-induced hepatotoxicity (black box warning in the United States) is rare; however, mild liver enzyme elevation is relatively common and therefore requires close monitoring.138 Gynecomastia and hypogonadism due to inhibition of androgen synthesis limits use in males.

Metyrapone can effectively lower cortisol in 43–76% of patients with Cushing’s syndrome without apparent escape.139 Blockade of 11-beta hydroxylase causes accumulation of mineralocorticoid and androgenic precursors resulting in hypertension, hypokalaemia, oedema, hirsutism and acne. Mild gastrointestinal symptoms are common. Mitotane plays a major role in the treatment of adrenal carcinoma due to its adrenolytic effect on tumour cells, but it is occasionally used in Cushing’s disease. Very potent, but with a slow onset of action, mitotane induces eucortisolaemia in 72–82% of patients11 and often leads to adrenal insufficiency, requiring hydrocortisone replacement. Side effects include gastrointestinal upset, lethargy and abnormal liver function. Etomidate is a parenteral anaesthetic, which at lower, sub-hypnotic doses, rapidly inhibits cortisol production and thus has been used in patients with severe Cushing’s syndrome in the acute setting as well as preoperatively to decrease the risk of hypercortisolaemia related complications.140

Mifepristone is a glucocorticoid receptor antagonist that has been shown to significantly improve clinical manifestations of Cushing’s syndrome, including glucose metabolism, hypertension and weight gain. Overall, a clinical response was observed in up to 87% of patients.141 However, its mechanism of action causes ACTH and cortisol levels to rise during treatment, and therefore, they cannot be used to guide management; caution is required for potential tumour enlargement, especially in the case of macroadenomas.142 When encountered, adrenal insufficiency due to glucocorticoid receptor blockade should be treated with high doses of dexamethasone. Additionally, unopposed mineralocorticoid activity of cortisol can cause hypertension, oedema and hypokalaemia. The latter can be ameliorated by use of the mineralocorticoid blocker spironolactone. Also, an antiprogestin effect may result in endometrial hyperplasia.143

Combination medical therapy

Combination therapy is increasingly used for those patients who have failed monotherapy or if side effects of a single agent do not permit a dose increase. Regimens such as pasireotide plus cabergoline, ketoconazole plus cabergoline, and ketoconazole plus metyrapone have been successfully utilised.144,145

Emerging medical therapy

Multiple new medical therapies are currently in development and are undergoing clinical testing (Table 2). New inhibitors of steroidogenesis include levoketoconazole, osilodrostat and ATR-101. Levoketoconazole is a more potent enantiomer of ketoconazole and was proposed to achieve similar effectiveness with smaller doses and less pronounced side effects than ketoconazole. In a phase III, open-label trial, 81% of patients had initial UFC normalisation at the end of the dose titration period (up to 21 weeks), but only 30% of patients had normal UFC levels during the maintenance phase without a dose increase.146 Nausea and headache were most common side effects and liver function test elevation of >3 ULN in 11% of patients is relatively similar to the ketoconazole data from retrospective and observational data, although the studies are not comparable.139 Levoketoconazole is currently being assessed in a phase III, double-blind, withdrawal and rescue/restoration study (A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome; ClinicalTrials.gov Identifier: NCT03277690).

Osilodrostat is an oral nonsteroidal corticosteroid biosynthesis inhibitor that inhibits 11 beta-hydroxylase with higher affinity than metyrapone and has a longer half-life.147 In an open label study, osilodrostat induced normalisation of UFC in 84% of patients at week 10 and 79% at week 22.148 Despite the increase in the precursor 11-deoxycorticosterone, hypokalaemia was mild and hypertension has not been observed. Hirsutism and acne occurred in one-third of women due to elevated testosterone. Two phase III studies are ongoing: Safety and Efficacy of LCI699 for the Treatment of Patients with Cushing’s Disease (ClinicalTrials.gov Identifier: NCT02180217) and Efficacy and Safety Evaluation of Osilodrostat in Cushing’s Disease (LINC-4) (ClinicalTrials.gov Identifier: NCT02697734).

ATR-101, is a selective acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1)1 inhibitor that reduces cholesterol ester formation from cholesterol, thereby decreasing the substrate supply for steroidogenesis in the adrenal glands. ATR-101 was shown to reduce cortisol level by 50% in animal studies and is currently being studied in a phase II, double-blind study in humans (A Study of ATR-101 for the Treatment of Endogenous Cushing’s Syndrome; ClinicalTrials.gov Identifier: NCT03053271).

Relacorilant (CORT125134) is a selective antiglucocorticoid receptor antagonist that has an advantage of avoiding the progesterone receptor inhibitory effects of mifepristone. A phase II trial is ongoing (Study to Evaluate CORT125134 in Patients with Cushing’s Syndrome,

ClinicalTrials.gov Identifier: NCT02804750). Preliminary results of the low-dose arm showed improvement in glucose control, blood pressure, marker of bone formation and, somewhat surprisingly, a relatively small increase in ACTH and cortisol.149

Pituitary-targeted therapies in phase II trials include roscovitine and gefitinib. Roscovitine is a cyclin-dependent kinase inhibitor that suppresses 2/cyclin E on corticotroph tumour cells causing inhibition of the ACTH precursor hormone, proopiomelanocortin (POMC), with a subsequent decrease of ACTH production, although with a minimal antiproliferative effect.150 It is currently studied in a dose of 400 mg orally twice daily for 4 days every week, for a total of 4 weeks in Cushing’s disease (Treatment of Cushing’s Disease with R-roscovitine; ClinicalTrials.gov Identifier: NCT02160730).

Roscovitine has also been assessed in phase I trials in patients with various malignant solid tumours; some showed stabilisation of growth.151,152 Side effects were dose dependent and included fatigue, skin rash, hyponatremia and hypokalaemia occurring at doses of 800 mg and higher.151 Gefitinib is an EGFR inhibitor approved for non-small cell lung cancer. EGF binds to EGFR on corticotroph tumour cells and promotes POMC and ACTH synthesis.152 Approximately half of corticotroph tumours harbour a somatic USP8 mutation which causes over-expression of EGFR.153 Gefitinib has been shown to inhibit ACTH production in USP8-mutated corticotroph tumours.76,152 A study of gefitinib 250 mg once daily for 4 weeks is ongoing (Targeted Therapy with Gefitinib in Patients with USP8-mutated Cushing’s Disease; ClinicalTrials.gov Identifier: NCT02484755). Common adverse events are rash, diarrhoea and elevation of liver enzymes.153 Interstitial lung disease of grade 3–4 occurs in 0.7% of patients (package insert).154 Other mutations harboured by corticotroph tumours (e.g. USP48 and BRAF) are being actively investigated, but are beyond the scope of this review.155

Retinoic acid decreases ACTH by suppressing pro-opiomelanocortin gene transcription and exerts an anti-tumour effect in corticotroph adenomas.156 In a small prospective study, retinoic acid at 80 mg daily for 6–12 months decreased UFC to 22–73% of baseline levels; however, some patients were non-responders.156 Another small study (16 patients) showed a normalisation of UFC in 25% of participants at study end.157 Emerging pituitary-targeted drug treatments not yet in clinical trials include heat shock protein inhibitors, histone deacetylase inhibitors, monoclonal ACTH antibodies and others.158,159

Radiation

Radiation therapy is used when pituitary surgery is unsuccessful, in invasive adenomas or in poor surgical candidates. All patients should receive medical treatment while awaiting radiation effects, which may take several years. Control of hypercortisolism is achieved in up to 83% of patients undergoing conventional radiation and 70% undergoing stereotactic radiosurgery.18,160 Time to remission with stereotactic radiosurgery appears to be shorter, 14.5 months versus 18.0–42.0 months with conventional radiation.161 Recurrence after initial control has been observed in 18% of patients after stereotactic radiosurgery, which confirms the need for lifelong monitoring.161

Bilateral adrenalectomy

Bilateral adrenalectomy is reserved as a third-line treatment option for patients with uncontrolled hypercortisolism despite pituitary surgery, appropriate medical therapy and/or pituitary radiation. It can be life-saving in patients with severe and prolonged Cushing’s syndrome who require rapid and permanent control of hypercortisolism.162,163 Lastly, it may be selected earlier in patients desiring fertility options in whom pituitary irradiation or surgery is likely to result in irreversible hypogonadism. Rarely, hypercortisolism may persist or recur due to remnant adrenal tissue. Corticotroph tumour progression (Nelson’s syndrome) occurs in 0–47% of patients post bilateral adrenalectomy,164,165 and some data suggest that prior pituitary radiation may reduce the risk.166,167 It is important to periodically monitor ACTH and pituitary MRI. Mortality in the first year seems to be high post bilateral adrenalectomy.164

Thyroid stimulating hormone-secreting adenomas

Thyroid stimulating hormone (TSH)-secreting adenomas are rare, 0.5–3.0% of all pituitary adenomas, with equal male–female distribution, and are mostly macroadenomas at diagnosis.168 Surgical resection is the first-line treatment, with remission rates of 55–83%.169,170 Complete surgical removal is often impossible due to the fibrotic nature of these tumours and parasellar extension/invasion, necessitating adjunct medical therapy and/or radiation.168 Pre-treatment with antithyroid drugs, beta-blockers and SRLs is necessary in some cases to control severe hyperthyroidism to reduce the risk of perioperative thyroid storm.169,171 In a series of 68 operated patients (67% macroadenomas), six patients (9%) developed new hypopituitarism; hypogonadism in two, hypoadrenalism in two, both hypoadrenalism and hypogonadism in one, and panhypopituitarism in one patient.169 A smaller series of 13 patients reported postoperative hypopituitarism in five patients (38%); hypoadrenalism in three, hypothyroidism in one, growth hormone deficiency in two and hypogonadism in one patient.172 Radiation for persistent disease controls hyperthyroidism in 20–50% and produces tumour volume reduction in 26% of patients, and hypopituitarism occurs in approximately one-third of patients.169

Octreotide and lanreotide reduce TSH and normalise thyroid hormone levels in more than 80% patients.169,173 In a study of pre-operative OCT-LAR for a median of 33.5 days, T4 normalisation occurred in 84% of patients.172 Another study of mixed patient population (post pituitary surgery with or without additional radiation or medical therapy and those who were treatment-naïve) showed that lanreotide was effective at normalising thyroid hormone levels in 81% of patients.174 Resistance and escape from therapy are uncommon. As marked suppression of thyroid function can occur, patients should be monitored for hypothyroidism. SRLs induce tumour shrinkage in 39–61% of patients.171,174 Although TSH-secreting tumours express D2 receptors, dopamine agonists are less effective, with favourable results observed mostly in mixed prolactin/TSH-secreting adenomas.168,175

Gonadotroph adenomas

Functioning gonadotroph adenomas are very rare and treatment algorithms are limited to case reports and small case series. Adenomectomy is, however, the principal treatment approach; it restores gonadal function in men and women, and leads to the resolution of ovarian and testicular enlargement caused by hyperstimulation by gonadotroph adenoma.176 Radiation has been used as adjunct therapy after surgery, as well as for recurrent adenomas.177–180 Dopamine agonists, SRLs, gonadotropin-releasing hormone agonists and antagonists have been tried both as primary therapy and after transsphenoidal surgery, and in the majority of cases showed no benefit for clinical symptoms or tumour shrinkage.176

Aggressive pituitary adenomas

Aggressive pituitary adenomas are those that exhibit clinically significant growth despite appropriate medical, surgical and radiation therapy.181 They are often characterised by an elevated Ki68 index (≥3–10%), high p53 immunoreactivity and increased number of mitoses; however, these criteria have not been validated as strong prognostic markers of aggressiveness. Debulking surgery or near-total resection is recommended, especially for tumours with mass-effect on optic chiasm. Radiation therapy following surgery should be considered in patients without contraindication to radiation therapy, as it can provide a durable control of tumour growth. Medical therapy usually includes the use of temozolomide, an alkylating agent, alone or in combination with standard medical therapy for functioning pituitary adenomas (dopamine agonist, SRLs).182,183 Temozolomide is typically administered in cycles of 5 days every 28 days, with a maximum number of cycles of 9–12. Response rate (tumour shrinkage) differs by tumour type and is estimated from a small case series to be 44% in prolactinomas, 56% in corticotroph tumours, 38% in somatotroph tumours and only 22% in non-functioning tumours.182 Absent or low expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that interferes with temozolomide action, has been correlated with better response to temozolomide by some, but not all, authors.184,185 Temozolomide is usually well tolerated; however, myelosuppression can occur.185

Conclusion

Management of functioning pituitary adenomas often requires multiple treatment modalities to achieve rapid and durable remission and thus improve morbidity, mortality and quality of life. Treatment should be tailored individually based on the tumour type, availability of each therapeutic option and patient preference. Emerging medical therapies are being developed and may present future suitable options for patients with uncontrolled disease or intolerance to other medications.⬛

Article Information:
Disclosure

Maria Fleseriu has been a principal investigator for studies with research grants to Oregon Health & Science University from Chiasma, Ionis, Millendo, Novartis, Pfizer and Strongbridge, and has been an occasional scientific consultant to Chiasma, Ionis, Ipsen, Novartis, Pfizer and Strongbridge. Elena V Varlamov and Shirley McCartney have nothing to declare in relation to this article.

Compliance With Ethics

This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review

Authorship

All named authors meet the criteria of the International Committee of Medical Journal Editors for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

Correspondence

Maria Fleseriu, Oregon Health & Science University, CH8N, 3303 SW Bond Ave, Portland, Oregon, 97239, USA. E: fleseriu@ohsu.edu

Support

No funding was received for the publication of this article.

Received

18 October 2018

References

 
  1. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19 Suppl. 5:1–88.
  2. Daly AF, Rixhon M, Adam C, et al. High prevalence of pituitary adenomas: A cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab. 2006;91:4769–75.
  3. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: A community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010;72:377–82.
  4. Aflorei ED, Korbonits M. Epidemiology and etiopathogenesis of pituitary adenomas. J Neurooncol. 2014;117:379–94.
  5. Tjornstrand A, Gunnarsson K, Evert M, et al. The incidence rate of pituitary adenomas in western Sweden for the period 2001-2011. Eur J Endocrinol. 2014;171:519–26.
  6. Jasim S, Alahdab F, Ahmed AT, et al. Mortality in adults with hypopituitarism: A systematic review and meta-analysis. Endocrine. 2017;56:33–42.
  7. Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119:3189–3202.
  8. Dekkers OM, Horvath-Puho E, Jorgensen JO, et al. Multisystem morbidity and mortality in Cushing’s syndrome: A cohort study. J Clin Endocrinol Metab. 2013;98:2277–84.
  9. Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:3888–3921.
  10. Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933–51.
  11. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:2807–31.
  12. Agam MS, Wedemeyer MA, Wrobel B, et al. Complications associated with microscopic and endoscopic transsphenoidal pituitary surgery: Experience of 1153 consecutive cases treated at a single tertiary care pituitary center. J Neurosurg. 2018:1–8.
  13. Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: Results of a national survey, review of the literature, and personal experience. Neurosurgery. 1997;40:225–36.
  14. Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: A systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84:843–9.
  15. Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: A structured review and meta-analysis. Pituitary. 2012;15:71–83.
  16. Barker FG 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumors in the United States, 1996-2000: Mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab. 2003;88:4709–19.
  17. Mitsumori M, Shrieve DC, Alexander E 3rd, et al. Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys. 1998;42:573–80.
  18. Sheehan JP, Xu Z, Salvetti DJ, et al. Results of gamma knife surgery for Cushing’s disease. J Neurosurg. 2013;119:1486–92.
  19. Lee CC, Vance ML, Xu Z, et al. Stereotactic radiosurgery for acromegaly. J Clin Endocrinol Metab. 2014;99:1273–81.
  20. Ding D, Mehta GU, Patibandla MR, et al. Stereotactic radiosurgery for acromegaly: An international multicenter retrospective cohort study. Neurosurgery. 2019;84:717–25.
  21. Minniti G, Traish D, Ashley S, et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: Update after an additional 10 years. J Clin Endocrinol Metab. 2005;90:800–4.
  22. van Varsseveld NC, van Bunderen CC, Ubachs DH, et al. Cerebrovascular events, secondary intracranial tumors, and mortality after radiotherapy for nonfunctioning pituitary adenomas: A subanalysis from the Dutch National Registry of Growth Hormone Treatment in Adults. J Clin Endocrinol Metab. 2015;100:1104–12.
  23. Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary. 2017;20:154–68.
  24. Lecumberri B, Estrada J, Garcia-Uria J, et al. Neurocognitive long-term impact of two-field conventional radiotherapy in adult patients with operated pituitary adenomas. Pituitary. 2015;18:782–95.
  25. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006;27:485–534.
  26. Liu W, Zahr RS, McCartney S, et al. Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: A retrospective single center study. Pituitary. 2018; 21:454–62.
  27. Shimon I, Jallad RS, Fleseriu M, et al. Giant GH-secreting pituitary adenomas: management of rare and aggressive pituitary tumors. Eur J Endocrinol. 2015;172:707–713.
  28. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:273–88.
  29. Moster ML, Savino PJ, Schatz NJ, et al. Visual function in prolactinoma patients treated with bromocriptine. Ophthalmology. 1985;92:1332–41.
  30. Webster J, Piscitelli G, Polli A, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med. 1994;331:904–9.
  31. Wang AT, Mullan RJ, Lane MA, et al. Treatment of hyperprolactinemia: A systematic review and meta-analysis. Syst Rev. 2012;1:33.
  32. Colao A, Di Sarno A, Landi ML, et al. Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: A prospective study in 110 patients. J Clin Endocrinol Metab. 2000;85:2247–52.
  33. Molitch ME, Elton RL, Blackwell RE, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: Results of a prospective multicenter study. J Clin Endocrinol Metab. 1985;60:698–705.
  34. Molitch ME. Management of medically refractory prolactinoma. J Neurooncol. 2014;117:421–8.
  35. Berinder K, Stackenas I, Akre O, et al. Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up. Clin Endocrinol (Oxf). 2005;63:450–5.
  36. Kukstas LA, Domec C, Bascles L, et al. Different expression of the two dopaminergic D2 receptors, D2415 and D2444, in two types of lactotroph each characterised by their response to dopamine, and modification of expression by sex steroids. Endocrinology. 1991;129:1101–3.
  37. Pellegrini I, Rasolonjanahary R, Gunz G, et al. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab. 1989;69:500–9.
  38. Noronha S, Stokes V, Karavitaki N, Grossman A. Treating prolactinomas with dopamine agonists: Always worth the gamble? Endocrine. 2016;51:205–10.
  39. Bancos I, Nannenga MR, Bostwick JM, et al. Impulse control disorders in patients with dopamine agonist-treated prolactinomas and nonfunctioning pituitary adenomas: A case-control study. Clin Endocrinol (Oxf). 2014;80:863–8.
  40. Chapin W, Yedinak C, Delashaw J, Fleseriu M. Cabergoline-induced cerebral spinal fluid leak in a patient with a large prolactinoma and MEN1. Endocrinologist. 2010;20:198–202.
  41. Vallette S, Serri K, Rivera J, et al. Long-term cabergoline therapy is not associated with valvular heart disease in patients with prolactinomas. Pituitary. 2009;12:153–7.
  42. Wakil A, Rigby AS, Clark AL, et al. Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease. Eur J Endocrinol. 2008;159:R11–14.
  43. Drake WM, Stiles CE, Howlett TA, et al. A cross-sectional study of the prevalence of cardiac valvular abnormalities in hyperprolactinemic patients treated with ergot-derived dopamine agonists. J Clin Endocrinol Metab. 2014;99:90–6.
  44. Caputo C, Prior D, Inder WJ. The third case of cabergoline-associated valvulopathy: The value of routine cardiovascular examination for screening. J Endocr Soc. 2018;2:965–9.
  45. Gamble D, Fairley R, Harvey R, et al. Screening for valve disease in patients with hyperprolactinaemia disorders prescribed cabergoline: A service evaluation and literature review. Ther Adv Drug Saf. 2017;8:215–29.
  46. Elenkova A, Shabani R, Kalinov K, Zacharieva S. Increased prevalence of subclinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment. Eur J Endocrinol. 2012;167:17–25.
  47. Boguszewski CL, dos Santos CM, Sakamoto KS, et al. A comparison of cabergoline and bromocriptine on the risk of valvular heart disease in patients with prolactinomas. Pituitary. 2012;15:44–9.
  48. Liu X, Kano M, Araki T, et al. ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. Endocrinology. 2015;156:71–9.
  49. Ben-Shlomo A, Cooper O. Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: From bench to bedside. Curr Opin Endocrinol Diabetes Obes. 2017;24:301–5.
  50. Cooper O, Mamelak A, Bannykh S, et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine. 2014;46:318–27.
  51. Primeau V, Raftopoulos C, Maiter D. Outcomes of transsphenoidal surgery in prolactinomas: improvement of hormonal control in dopamine agonist-resistant patients. Eur J Endocrinol. 2012;166:779–86.
  52. Kreutzer J, Buslei R, Wallaschofski H, et al. Operative treatment of prolactinomas: Indications and results in a current consecutive series of 212 patients. Eur J Endocrinol. 2008;158:11–18.
  53. Qu X, Wang M, Wang G, et al. Surgical outcomes and prognostic factors of transsphenoidal surgery for prolactinoma in men: A single-center experience with 87 consecutive cases. Eur J Endocrinol. 2011;164:499–504.
  54. Serri O, Rasio E, Beauregard H, et al. Recurrence of hyperprolactinemia after selective transsphenoidal adenomectomy in women with prolactinoma. N Engl J Med. 1983;309:280–3.
  55. Cohen-Inbar O, Xu Z, Schlesinger D, et al. Gamma knife radiosurgery for medically and surgically refractory prolactinomas: Long-term results. Pituitary. 2015;18:820–30.
  56. Pan L, Zhang N, Wang EM, et al. Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg. 2000;93 Suppl. 3:10–13.
  57. Pouratian N, Sheehan J, Jagannathan J, et al. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery. 2006;59:255–66.
  58. Jezkova J, Hana V, Krsek M, et al. Use of the Leksell gamma knife in the treatment of prolactinoma patients. Clin Endocrinol (Oxf). 2009;70:732–41.
  59. Sheplan Olsen LJ, Robles Irizarry L, Chao ST, et al. Radiotherapy for prolactin-secreting pituitary tumors. Pituitary. 2012;15:135–45.
  60. Mestron A, Webb SM, Astorga R, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol. 2004;151:439–46.
  61. Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N. Epidemiology of acromegaly: Review of population studies. Pituitary. 2017;20:4–9.
  62. Jane JA Jr, Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. 2011;96:2732–40.
  63. Starke RM, Raper DMS, Payne SC, et al. Endoscopic vs microsurgical transsphenoidal surgery for acromegaly: Outcomes in a concurrent series of patients using modern criteria for remission. J Clin Endocrinol Metab. 2013;98:3190–8.
  64. Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol. 2005;152:379–87.
  65. Karavitaki N, Turner HE, Adams CB, et al. Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide. Clin Endocrinol (Oxf). 2008;68:970–5.
  66. Petrossians P, Borges-Martins L, Espinoza C, et al. Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur J Endocrinol. 2005;152:61–6.
  67. Fahlbusch R, Kleinberg D, Biller B, et al. Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly. Pituitary. 2017;20:668–75.
  68. Gheorghiu ML, Galoiu S, Vintila M, et al. Beneficial effect of dose escalation and surgical debulking in patients with acromegaly treated with somatostatin analogs in a Romanian tertiary care center. Hormones (Athens). 2016;15:224–34.
  69. Fernandez Mateos C, Garcia-Uria M, Morante TL, Garcia-Uria J. Acromegaly: Surgical results in 548 patients. Pituitary. 2017;20:522–8.
  70. Freda PU, Wardlaw SL, Post KD. Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg. 1998;89:353–8.
  71. Swearingen B, Barker FG 2nd, Katznelson L, et al. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998;83:3419–26.
  72. Carvalho P, Lau E, Carvalho D. Surgery induced hypopituitarism in acromegalic patients: A systematic review and meta-analysis of the results. Pituitary. 2015;18:844–60.
  73. Abu Dabrh AM, Mohammed K, Asi N, et al. Surgical interventions and medical treatments in treatment-naive patients with acromegaly: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99:4003–14.
  74. Brzana J, Yedinak CG, Gultekin SH, et al. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: A large single center experience. Pituitary. 2012;16:490–8.
  75. Fougner SL, Casar-Borota O, Heck A, et al. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol (Oxf). 2011;76:96–102.
  76. Fleseriu M, Hoffman AR, Katznelson L, AACE Neuroendocrine and Pituitary Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Management of acromegaly patients: What is the role of pre-operative medical therapy? Endocr Pract. 2015;21:668–73.
  77. Gadelha MR, Kasuki L, Lim DS, Fleseriu M. Systemic complications of acromegaly and the impact of the current treatment landscape: An update. Endocr Rev. 2019;40:268–332.
  78. Fleseriu M. Advances in the pharmacotherapy of patients with acromegaly. Discov med. 2014;17:329–38.
  79. Carmichael JD, Bonert VS, Nuno M, et al. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: A meta-analysis. J Clin Endocrinol Metab. 2014;99:1825–33.
  80. Cozzi R, Montini M, Attanasio R, et al. Primary treatment of acromegaly with octreotide LAR: A long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J Clin Endocrinol Metab. 2006;91:1397–1403.
  81. Giustina A, Bonadonna S, Bugari G, et al. High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: A randomised controlled trial. Eur J Endocrinol. 2009;161:331–8.
  82. Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14:552–61.
  83. Fleseriu M. Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: A literature review. Pituitary. 2011;14:184–93.
  84. Giustina A, Mazziotti G, Cannavo S, et al. High-dose and high-frequency lanreotide autogel in acromegaly: A randomized, multicenter study. J Clin Endocrinol Metab. 2017;102:2454–64.
  85. Giustina A, Mazziotti G, Torri V, et al. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PloS one. 2012;7:e36411.
  86. Melmed S, Sternberg R, Cook D, et al. A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab. 2005;90:4405–10.
  87. Mazziotti G, Giustina A. Effects of lanreotide SR and autogel on tumor mass in patients with acromegaly: A systematic review. Pituitary. 2010;13:60–7.
  88. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: A head-to-head superiority study. J Clin Endocrinol Metab. 2014;99:791–9.
  89. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): A randomised, phase III trial. Lancet Diabetes Endocrinol. 2014;2:875–84.
  90. Henry RR, Ciaraldi TP, Armstrong D, et al. Hyperglycemia associated with pasireotide: Results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98:3446–53.
  91. Samson SL. Management of hyperglycemia in patients with acromegaly treated with pasireotide LAR. Drugs. 2016;76:1235–43.
  92. Tritos NA, Chanson P, Jimenez C, et al. Effectiveness of first-line pegvisomant monotherapy in acromegaly: An ACROSTUDY analysis. Eur J Endocrinol. 2017;176:213–20.
  93. van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358:1754–9.
  94. van der Lely AJ, Biller BM, Brue T, et al. Long-term safety of pegvisomant in patients with acromegaly: Comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012;97:1589–97.
  95. Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: A meta-analysis. J Clin Endocrinol Metab. 2011;96:1327–35.
  96. Sherlock M, Fernandez-Rodriguez E, Alonso AA, et al. Medical therapy in patients with acromegaly: Predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues. J Clin Endocrinol Metab. 2009;94:1255–63.
  97. van der Lely AJ, Bernabeu I, Cap J, et al. Coadministration of lanreotide autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone. Eur J Endocrinol. 2011;164:325–33.
  98. Muhammad A, Coopmans EC, Delhanty P, et al. Efficacy and safety of switching to pasireotide in acromegaly patients controlled with pegvisomant and somatostatin analogues: PAPE extension study. Eur J Endocrinol. 2018;179:269–77.
  99. Muhammad A, van der Lely AJ, Delhanty PJD, et al. Efficacy and safety of switching to pasireotide in patients with acromegaly controlled with pegvisomant and first-generation somatostatin analogues (PAPE study). J Clin Endocrinol Metab. 2018;103:586–95.
  100. Higham CE, Atkinson AB, Aylwin S, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: A prospective clinical trial. J Clin Endocrinol Metab. 2012;97:1187–93.
  101. Domene HM, Marin G, Sztein J, et al. Estradiol inhibits growth hormone receptor gene expression in rabbit liver. Mol Cell Endocrinol. 1994;103:81–7.
  102. Leong GM, Moverare S, Brce J, et al. Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro. Endocrinology. 2004;145:5525–31.
  103. Attanasio R, Barausse M, Cozzi R. Raloxifene lowers IGF-I levels in acromegalic women. Eur J Endocrinol. 2003;148:443–8.
  104. Balili I, Barkan A. Tamoxifen as a therapeutic agent in acromegaly. Pituitary. 2014;17:500–4.
  105. Duarte FH, Jallad RS, Bronstein MD. Clomiphene citrate for treatment of acromegaly not controlled by conventional therapies. J Clin Endocrinol Metab. 2015;100:1863–9.
  106. Imani M, Khamseh ME, Asadi P, et al. Comparison of cabergoline versus raloxifene add-on therapy to long-acting somatostatin analogue in patients with inadequately controlled acromegaly: A randomized open label clinical trial. Endocr prac. 2018;24:542–7.
  107. Melmed S, Popovic V, Bidlingmaier M, et al. Safety and efficacy of oral octreotide in acromegaly: Results of a multicenter phase III trial. J Clin Endocrinol Metab. 2015;100:1699–1708.
  108. Trainer PJ, Newell-Price JDC, Ayuk J, et al. A randomised, open-label, parallel group phase II study of antisense oligonucleotide therapy in acromegaly. Eur J Endocrinol. 2018;179:97–108.
  109. Madan A, Zhu YF, Markison S, et al. Phase I clinical trial of CRN00808, an orally bioavailable sst2-selective, nonpeptide somatostatin biased agonist for the treatment of acromegaly: Safety, pharmacokinetics, and inhibition of GHRH-induced GH secretion. 2018. Abstr ORO6-3. Available at: www.endocrine.org/meetings/endo-annual-meetings/abstract-details?ID=46822 (8 October 2018).
  110. Abu Dabrh AM, Asi N, Farah WH, et al. Radiotherapy versus radiosurgery in treating patients with acromegaly: A systematic review and meta-analysis. Endocr prac. 2015;21:943–56.
  111. Minniti G, Jaffrain-Rea ML, Osti M, et al. The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin Endocrinol (Oxf). 2005;62:210–16.
  112. Castinetti F, Taieb D, Kuhn JM, et al. Outcome of gamma knife radiosurgery in 82 patients with acromegaly: Correlation with initial hypersecretion. J Clin Endocrinol Metab. 2005;90:4483–8.
  113. Landolt AM, Haller D, Lomax N, et al. Octreotide may act as a radioprotective agent in acromegaly. J Clin Endocrinol Metab. 2000;85:1287–9.
  114. Kasaliwal R1, Sankhe SS, Lila AR, et al. Volume interpolated 3D-spoiled gradient echo sequence is better than dynamic contrast spinecho sequence for MRI detection of corticotropin secreting pituitary microadenomas. Clin Endocrinol (Oxf). 2013;78:825–30.
  115. Langlois F, Lim DST, Yedinak CG, et al. Predictors of silent corticotroph adenoma recurrence: A large retrospective single center study and systematic literature review. Pituitary. 2018;21:32–40.
  116. Dallapiazza RF, Oldfield EH, Jane JA Jr. Surgical management of Cushing’s disease. Pituitary. 2015;18:211–16.
  117. Hofmann BM, Hlavac M, Martinez R, et al. Long-term results after microsurgery for Cushing disease: Experience with 426 primary operations over 35 years. J Neurosurg. 2008;108:9–18.
  118. Atkinson AB, Kennedy A, Wiggam MI, et al. Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol (Oxf). 2005;63:549–59.
  119. Hassan-Smith ZK, Sherlock M, Reulen RC, et al. Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab. 2012;97:1194–201.
  120. Post FA, Soule SG, De Villiers JC, Levitt NS. Pituitary function after selective adenomectomy for Cushing’s disease. Br J Neurosurg. 1995;9:41–6.
  121. Pecori Giraldi F, Andrioli M, De Marinis L, et al. Significant GH deficiency after long-term cure by surgery in adult patients with Cushing’s disease. Eur J Endocrinol. 2007;156:233–9.
  122. Zaidi HA, Penn DL, Cote DJ, Laws ER Jr. Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease. J Clin Neurosci. 2018;53:153–9.
  123. Dickerman RD, Oldfield EH. Basis of persistent and recurrent Cushing disease: An analysis of findings at repeated pituitary surgery. J Neurosurg. 2002;97:1343–9.
  124. Benveniste RJ, King WA, Walsh J, et al. Repeated transsphenoidal surgery to treat recurrent or residual pituitary adenoma. J Neurosurg. 2005;102:1004–12.
  125. Ram Z, Nieman LK, Cutler GB Jr, et al. Early repeat surgery for persistent Cushing’s disease. J Neurosurg. 1994;80:37–45.
  126. Fleseriu M, Hamrahian AH, Hoffman AR, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Diagnosis of recurrence in Cushing disease. Endocr prac. 2016;22:1436–48.
  127. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase III study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366:914–24.
  128. Lacroix A, Gu F, Gallardo W, et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: A 12 month clinical trial. Lancet Diabetes Endocrinol. 2018;6:17–26.
  129. Godbout A, Manavela M, Danilowicz K, et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 2010;163:709–16.
  130. Pivonello R, De Martino MC, Cappabianca P, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009;94:223–30.
  131. Vilar L, Naves LA, Azevedo MF, et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary. 2010;13:123–9.
  132. Ferriere A, Cortet C, Chanson P, et al. Cabergoline for Cushing’s disease: A large retrospective multicenter study. Eur J Endocrinol. 2017;176:305–14.
  133. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: A focus on novel therapies. Pituitary. 2016;19:643–53.
  134. Sonino N, Boscaro M, Paoletta A, et al. Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf). 1991;35:347–52.
  135. Castinetti F, Morange I, Jaquet P, et al. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing’s disease. Eur J Endocrinol. 2008;158:91–9.
  136. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015;36:385–486. Epub 2015 Jun 11.
  137. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: Is it worth a try? J Clin Endocrinol Metab. 2014;99:1623–30.
  138. Young J, Bertherat J, Vantyghem MC, et al. Hepatic safety of ketoconazole in Cushing’s syndrome: Results of a Compassionate Use Programme in France. Eur J Endocrinol. 2018;178:447–58.
  139. Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating Cushing’s syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100:4146–54.
  140. Alexandraki KI, Grossman AB. Therapeutic strategies for the treatment of severe Cushing’s syndrome. Drugs. 2016;76:447–58.
  141. Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012;97:2039–49.
  142. Fleseriu M, Findling JW, Koch CA, et al. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing’s disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014;99:3718–27.
  143. Fleseriu M, Molitch ME, Gross C, et al. A new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone. Endocr prac. 2013;19:313–26.
  144. Cuevas-Ramos D, Lim DST, Fleseriu M. Update on medical treatment for Cushing’s disease. Clin Diabetes Endocrinol. 2016;2:16.
  145. Feelders RA, de Bruin C, Pereira AM, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med. 2010;362:1846–8.
  146. Fleseriu M, Pivonello R, Elenkova A, et al. Safety and Efficacy of Levoketoconazole in Cushing Syndrome: Initial Results from the Phase III SONICS Study. Presented at: 18th Congress of the European Neuroendocrine Association, Wroclaw, Poland, 17–20 October 2018.
  147. Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: Results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014;99:1375–83.
  148. Fleseriu M, Pivonello R, Young J, et al. Osilodrostat, a potent oral 11beta-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing’s disease. Pituitary. 2016;19:138–48.
  149. Moraitis AG, Agrawal N, Bancos I, et al. Open-label phase II study to assess safety and efficacy of relacorilant (CORT125134), a selective cortisol modulator, in the treatment of eEndogenous hypercortisolism. 2018. Available at: www.corcept.com/pdf/Moraitis-Andreas-G-AACE-poster.pdf (8 October 2018).
  150. Liu NA, Araki T, Cuevas-Ramos D, et al. Cyclin E-mediated human proopiomelanocortin regulation as a therapeutic target for Cushing disease. J Clin Endocrinol Metab. 2015;100:2557–64.
  151. Benson C, White J, De Bono J, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007;96:29–37.
  152. Fukuoka H, Cooper O, Ben-Shlomo A, et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest. 2011;121:4712–21.
  153. Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M. Pathogenesis of Cushing disease: An update on the genetics of corticotropinomas. Endocr prac. 2018;24:907–14.
  154. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.
  155. Chen J, Jian X, Deng S, et al. Identification of recurrent USP48 and BRAF mutations in Cushing’s disease. Nat Commun. 2018;9:3171.
  156. Pecori Giraldi F, Ambrogio AG, Andrioli M, et al. Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab. 2012;97:3577–83.
  157. Vilar L, Albuquerque JL, Lyra R, et al. The role of isotretinoin therapy for Cushing’s disease: Results of a prospective study. Int J Endocrinol. 2016;2016:8173182.
  158. Langlois F, Chu J, Fleseriu M. Pituitary-directed therapies for Cushing’s disease. Front Endocrinol (Lausanne). 2018;9:164.
  159. Lu J, Chatain GP, Bugarini A, et al. Histone deacetylase inhibitor SAHA is a promising treatment of Cushing disease. J Clin Endocrinol Metab. 2017;102:2825–35.
  160. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med. 1997;336:172–7.
  161. Mehta GU, Ding D, Patibandla MR, et al. Stereotactic radiosurgery for Cushing disease: Results of an international, multicenter study. J Clin Endocrinol Metab. 2017;102:4284–91.
  162. Reincke M, Ritzel K, Osswald A, et al. A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol. 2015;173:M23–32.
  163. Tritos NA, Biller BM. Cushing’s disease. Handb Clin Neurol. 2014;124:221–34.
  164. Ritzel K, Beuschlein F, Mickisch A, et al. Clinical review: Outcome of bilateral adrenalectomy in Cushing’s syndrome: A systematic review. J Clin Endocrinol Metab. 2013;98:3939–48.
  165. Assie G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: A reappraisal of Nelson’s syndrome. J Clin Endocrinol Metab. 2007;92:172–9.
  166. Mehta GU, Sheehan JP, Vance ML. Effect of stereotactic radiosurgery before bilateral adrenalectomy for Cushing’s disease on the incidence of Nelson’s syndrome. J Neurosurg. 2013;119:1493–7.
  167. Nagesser SK, van Seters AP, Kievit J, et al. Long-term results of total adrenalectomy for Cushing’s disease. World J Surg. 2000;24:108–13.
  168. Beck-Peccoz P, Lania A, Beckers A, et al. 2013 European Thyroid Association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013;2:76–82.
  169. Malchiodi E, Profka E, Ferrante E, et al. Thyrotropin-secreting pituitary adenomas: Outcome of pituitary surgery and irradiation. J Clin Endocrinol Metab. 2014;99:2069–76.
  170. Yamada S, Fukuhara N, Horiguchi K, et al. Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: A single-center study of 90 cases. J Neurosurg. 2014;121:1462–73.
  171. Fukuhara N, Horiguchi K, Nishioka H, et al. Short-term preoperative octreotide treatment for TSH-secreting pituitary adenoma. Endocr J. 2015;62:21–7.
  172. Gatto F, Grasso LF, Nazzari E, et al. Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: Might somatostatin analogs have a role as first-line therapy? Pituitary. 2015;18:583–91.
  173. Kuhn JM, Arlot S, Lefebvre H, et al. Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide. J Clin Endocrinol Metab. 2000;85:1487–91.
  174. Socin HV, Chanson P, Delemer B, et al. The changing spectrum of TSH-secreting pituitary adenomas: Diagnosis and management in 43 patients. Eur J Endocrinol. 2003;148:433–42.
  175. Mulinda JR, Hasinski S, Rose LI. Successful therapy for a mixed thyrotropin-and prolactin-secreting pituitary macroadenoma with cabergoline. Endocr prac. 1999;5:76–9.
  176. Ntali G, Capatina C, Grossman A, Karavitaki N. Clinical review: Functioning gonadotroph adenomas. J Clin Endocrinol Metab. 2014;99:4423–33.
  177. Christin-Maitre S, Rongieres-Bertrand C, Kottler ML, et al. A spontaneous and severe hyperstimulation of the ovaries revealing a gonadotroph adenoma. J Clin Endocrinol Metab. 1998;83:3450–3.
  178. Tashiro H, Katabuchi H, Ohtake H, et al. An immunohistochemical and ultrastructural study of a follicle-stimulating hormone-secreting gonadotroph adenoma occurring in a 10-year-old girl. Med Electron Microsc. 2000;33:25–31.
  179. Karapanou O, Tzanela M, Tamouridis N, Tsagarakis S. Gonadotroph pituitary macroadenoma inducing ovarian hyperstimulation syndrome: Successful response to octreotide therapy. Hormones (Athens). 2012;11:199–202.
  180. Djerassi A, Coutifaris C, West VA, et al. Gonadotroph adenoma in a premenopausal woman secreting follicle-stimulating hormone and causing ovarian hyperstimulation. J Clin Endocrinol Metab. 1995;80:591–4.
  181. Raverot G, Burman P, McCormack A, et al. European Society of Endocrinology Clinical Practice guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178:G1–24.
  182. Ji Y, Vogel RI, Lou E. Temozolomide treatment of pituitary carcinomas and atypical adenomas: Systematic review of case reports. Neurooncol Pract. 2016;3:188–95.
  183. Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: A French multicenter experience. J Clin Endocrinol Metab. 2010;95:4592–9.
  184. Halevy C, Whitelaw BC. How effective is temozolomide for treating pituitary tumours and when should it be used? Pituitary. 2017;20:261–6.
  185. Losa M, Bogazzi F, Cannavo S, et al. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. J Neurooncol. 2016;126:519–25.

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