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 »  Abstract
 » Prolactinomas
 » Acromegaly
 » TSH-Secreting Tumors
 » Conclusion
 »  References
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Table of Contents    
REVIEW ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 7  |  Page : 20-27

Current Status of Diagnosis and Management of Functioning Pituitary Tumors: Part II


Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India

Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Nikhil M Bhagwat
Department of Endocrinology, Topiwala National Medical College and BYL Nair Charitable Hospital, Dr. A L Nair Road, Mumbai - 400 008, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.287672

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 » Abstract 


Functioning pituitary tumors contribute to significant morbidity and mortality. Proper diagnostic approach and management is essential for optimal outcomes. Prolactinomas, the commonest of these, are the only tumors which can be managed medically. Acromegaly, apart from acral enlargement, can have multiple comorbidities like diabetes, hypertension, and obstructive sleep apnea. The primary treatment is surgical and it can be supplemented by radiotherapy and medications such as somatostatin analogs, growth hormone receptor blockers, or cabergoline. Thyrotropin-secreting tumors are rare and present with hyperthyroidism. Optimal preoperative management followed by surgical resection often leads to cure.


Keywords: Acromegaly, functioning pituitary tumors, perioperative management, prolactinoma, thyrotropin tumor
Key Message: Patients with functioning pituitary tumors may have a plethora of presentations, and for this reason, may present to a neurosurgeon or an endocrinologist, among others. Excess hormone secretion needs to be recognized early and managed optimally. Medical therapy is the first line of therapy for prolactinomas, whereas somatotrophs and thyrotropin-secreting tumors require surgery. Perioperative management requires close coordination between both teams. Postoperative evaluation and hormone replacement should be done simultaneously while keeping a watch for complications arising out of surgery or radiotherapy.


How to cite this article:
Gada JV, Sanamandra P, Barasara SA, Chauhan YV, Bhagwat NM. Current Status of Diagnosis and Management of Functioning Pituitary Tumors: Part II. Neurol India 2020;68, Suppl S1:20-7

How to cite this URL:
Gada JV, Sanamandra P, Barasara SA, Chauhan YV, Bhagwat NM. Current Status of Diagnosis and Management of Functioning Pituitary Tumors: Part II. Neurol India [serial online] 2020 [cited 2020 Oct 31];68, Suppl S1:20-7. Available from: https://www.neurologyindia.com/text.asp?2020/68/7/20/287672




Pituitary tumors are slow-growing benign tumors arising from the anterior pituitary. The anterior pituitary has five cell lines, namely, corticotropes, somatotrophs, thyrotropes, gonadotrophs, and lactotrophs.[1] A tumor arising from any of these cell types causes a distinct clinical syndrome and is called a functional pituitary tumor. Correct approach in diagnosis and treatment may reduce morbidity and mortality caused by the clinical syndrome. In this second part of the review on functioning pituitary tumors, we discuss the presentation and management of growth hormone (GH), prolactin, and thyrotropin-secreting tumors.

Initial workup

A complete pituitary profile should include a thyroid profile, 8 am cortisol (fasting), adrenocorticopic hormone (ACTH), IGF-1, Growth Hormone, Prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and a and total testosterone in males, whereas a detailed menstrual history in females would give a clue to hypogonadism.[2],[3]

Perimetry is indicated in patients with visual complaints or those with macroadenomas (>1 cm) that extend to the chiasm.[2]

Imaging-Pituitary tumors are best diagnosed by dedicated high-resolution magnetic resonance imaging (MRI) of the hypothalamic-pituitary area in coronal and sagittal planes before and after gadolinium administration with a slice thickness <3 mm and dynamic sequences to obtain preferably cuts of 1 mm.[3],[4]

Perioperative management

Perioperative steroid cover

Preoperative 8 am cortisol levels <3.6 μg/dL are suggestive of ACTH insufficiency and require perioperative steroid cover. Levels between 3.6 and 10 μg/dL require provocative testing with insulin tolerance test (ITT) or short synacthen test. However, synacthen is not freely available in India and ITT is seldom performed and, hence, these patients require stress cover. Patients with cortisol levels >10–15 μg/dL are usually ACTH sufficient. In this group of patients, if selective adenomectomy can be performed, many centers do not prefer perioperative steroid cover and reevaluate the hypothalamic-pituitary-adrenal (HPA) axis at day 1–3 postoperatively with 8 am cortisol levels. However, if selective adenomectomy is not possible, perioperative steroid cover is given. Perioperative steroid cover consists of 48 h of supraphysiological glucocorticoid therapy at tapering doses (50 mg q8h hydrocortisone on day 0, 25 mg q8h on day 1, and 25 mg at 8 am on day 2) with postoperative HPA axis evaluation at day 3–5. Postoperative cortisol levels <3.6 μg/dL require lifelong glucocorticoid replacement. Glucagon stimulation testing is required for levels between 3.6 and 9 μg/dL, levels between 9 and 16 μg/dL require only stress cover, and levels >16 μg/dL are usually cortisol sufficient.[5] In our center, a resource-limited setting, in order to reduce the morbidity and mortality, we prefer to give perioperative glucocorticoid cover to all patients undergoing pituitary surgery.

Diabetes insipidus and syndrome of inappropriate antidiuretic hormone

Electrolyte imbalances following pituitary surgery require close monitoring of fluid intake, urine output, serial serum and urine electrolytes, and osmolality.

Diabetes insipidus (DI) may occur in up to 25% of patients postoperatively. Patients typically complain of polydipsia and polyuria due to an inability to concentrate urine. DI is defined as urine output >3 L/day or 4 mL/kg/h with urine osmolality <300 mOsm/kg in the presence of a normal or elevated serum sodium. DI may be transient, permanent (if the stalk is damaged), or may show a triphasic response.[2],[6],[8]

DI can be managed acutely with either intravenous or subcutaneous desmopressin (0.5–2 μg q24h as required) or subcutaneous vasopressin (5–10 units, duration of action 2–8 h) and repeat dose once urine output increases.[8],[9] Chronic management includes DDAVP—oral (0.1/0.2 mg tablets) or intranasal (10 μg metered dose, to be used only after nasal mucosal healing). Start with lowest dose (0.05 mg) at bedtime and increase the dose and frequency (0.9 mg/day) to avoid polyuria and polydipsia.

Overtreatment increases the risk of hyponatremia.[8] Hence, the patients should be instructed only to drink to thirst and their DI medications be reassessed periodically. Adipsic or comatose patients are managed by balancing fluid intake and desmopressin, with close monitoring of biochemical parameters.[10]

Syndrome of inappropriate antidiuretic hormone (SIADH) can occur in up to 19% patients postoperatively.[11] Mild hyponatremia may be managed as outpatient with fluid restriction, but more severe (<125 mEq/L) requires aggressive inpatient management with fluid restriction, hypertonic saline, and vaptans.[8]

Management of postoperative hypopituitarism

Management of postoperative hypopituitarism is highlighted in [Table 1].[5],[7],[8],[12],[13],[14],[15]
Table 1: Management of Postoperative Hypopituitarism

Click here to view



 » Prolactinomas Top


Prolactinomas are pituitary tumors which arise from lactotrophs and account for ~40% of all pituitary tumors.[16] Majority of prolactinomas are microadenomas (<1 cm in diameter) and are 10 times more common in women as they are symptomatic. Macroadenomas (>1 cm in diameter) are common in men. Giant prolactinomas (>4 cm in diameter) are rare.[17],[18]

Premenopausal women commonly present with menstrual disturbances (oligomenorrhea/amenorrhea), galactorrhea, or infertility. Postmenopausal women and most men present with symptoms of mass effect.[19] Several affected men also manifest decreased libido, erectile dysfunction, oligospermia, infertility, and rarely gynecomastia and/or galactorrhea. Low bone mineral density may be observed in both men and women with hypogonadism due to prolactinoma.[3]

The measurement of serum prolactin in a single sample is sufficient for the diagnosis of hyperprolactinemia. Moderate elevations in serum prolactin levels (up to 150 ng/mL) are seen in multiple physiologic and pathologic conditions or due to a wide variety of medications [Table 2] which should be excluded before considering pituitary imaging.
Table 2: Secondary causes of Hyperprolactinemia

Click here to view


An approach to hyperprolactinemia is shown in [Figure 1].[1],[20],[21],[22],[23],[24]
Figure 1: Approach to hyperprolactinemia[1],[20] *When a person does not have any symptoms of raised prolactin, consider ruling out the presence of macroprolactin. It is a big or big-big molecule of prolactin composed of complexes formed by an IgG with monomeric prolactin which is biologically inactive. Thus, assessment of macroprolactinemia by polyethylene glycol precipitation should be performed to confirm true monomeric hyperprolactinemia.[21],[22] †Sometimes, a very large tumor may present with mildly elevated prolactin levels. Here, the prolactin assay should be repeated with serial dilution of serum sample to eliminate the Hook Effect.[20],[23]

Click here to view


Pituitary imaging

Diagnosis of prolactinoma is made when there is sustained hyperprolactinemia with radiologic evidence of a pituitary tumor. A dynamic contrast-enhanced pituitary MRI should be performed to rule out a tumor.[20] However, one should remember that a normal MRI does not exclude the diagnosis of microprolactinoma and that ~10% normal population may harbor pituitary incidentaloma. Primary hypothyroidism is associated with elevated serum prolactin levels. The MRI in such patients may reveal a hyperplastic pituitary which is often misdiagnosed as a prolactinoma.

Management

The goals of treatment are to restore gonadal function by normalizing the serum prolactin levels, relieving mass effects, correcting other pituitary hormone deficiencies, and addressing bone health.

Dopamine agonists (DA) are the first line of management in the treatment of prolactinomas. Cabergoline is preferred over bromocriptine as it is more efficacious in lowering prolactin levels, shrinkage of tumor size, and restoring gonadal function. Medical management of prolactinomas is outlined in [Table 3].[25],[26],[27],[28],[29],[30]
Table 3: Medical Management of Prolactinomas

Click here to view


Other considerations

The fall in serum prolactin level typically occurs within the first 2–3 weeks, whereas a decrease in tumor size usually occurs by 6 weeks of treatment initiation.[31] Giant prolactinomas and patients with visual impairment at baseline can also be managed successfully with DAs.[32]

High-dose cabergoline use in Parkinson's disease patients is associated with valvular heart disease but not with the lower doses used in prolactinoma.[33],[34] Echocardiography may not be required as the risk for cardiac valvular regurgitation is low at the doses used.[20]

CSF rhinorrhea may occur after starting DA if tumors which invade the sellar floor or extend into the sphenoid sinus or ethmoidal sinus.[35]

Resistance to therapy is defined by a failure to achieve a normal prolactin level and a failure to achieve a 50% reduction in tumor size with maximal conventional doses of DA (≥15 mg/day of bromocriptine or 2 mg/week of cabergoline for at least 3 months).[36],[37],[38] Mechanism of resistance, although poorly understood, is due to decreased expression of D2 receptors.[37] 25% tumors may be resistant to bromocriptine, of which 80% may respond when switched to cabergoline.[29] 10% tumors may be resistant to cabergoline,[27] in which cases, increasing the doses up to 11–12 mg/week may help.[27]

Monitoring[20] includes periodic prolactin estimations and therapy is titrated to normalize prolactin levels and reverse the hypogonadism. MRI should be done at 1 year, or at 3 months in macroadenoma if they have a poor response to therapy or if new symptoms occur. Visual fields (in case of chiasmal involvement) and bone mineral density should be regularly monitored.

DA therapy may be tapered after at least 2 years of therapy in patients who maintain a normal prolactin concentration and have no remnant tumor on MRI.[20]

Surgical indications are:[39]

  1. Increasing tumor size or persistent chiasmal compression despite optimal medical therapy
  2. Pituitary apoplexy
  3. Intolerant or resistance to DA therapy
  4. In women seeking fertility, if DA-resistant microadenoma or a macroadenoma near chiasm (with prepregnancy debulking)
  5. Medically unresponsive cystic prolactinoma
  6. CSF leak during administration of DA
  7. Macroadenoma in a psychiatric patient with contraindication to DA.


The remission rate after TSS in prolactinoma patients is variable (30%–93%). Restarting DAs in resistant prolactinomas after debulking surgery normalizes prolactin levels in half the patients and with lower doses.[40]

Resistant (failure of medical and/or surgical therapy) or malignant prolactinomas may be subjected to radiotherapy, although it may take up to 20 years for maximal effect with a response rate ranging from 26%–31.4% depending upon modality of radiotherapy.[36],[41]

Temozolomide therapy may be considered for malignant prolactinomas.[20]


 » Acromegaly Top


Acromegaly is caused by proliferation of somatotrophs resulting in hypersecretion of GH.[42] It has an incidence of ~10 per million population, and the prevalence of 28–137 per million.

Etiology

The most common cause is GH secreting pituitary tumor (98%). Macroadenomas are common. Ectopic secretion of growth hormone-releasing hormone (GHRH) [hypothalamic or peripheral tumor] or GH and genetic causes (X-linked acrogigantism, MEN-1 syndrome, Carney Complex,  McCune-Albright syndrome More Details, and AIP mutation) are rare causes.[42]

Clinical features

Acromegaly has insidious onset and is a slowly progressive disease. GH/IGF-1 hypersecretion characteristic clinical features of acromegaly include acral and soft tissue enlargement leading to large hands, large fleshy nose, coarsening of facial features, musculoskeletal manifestations, hyperhidrosis, and deepening of the voice. These, however, are the presenting features in only ~20% of patients.[43] The common (>80%) presentations include headache, impaired vision due to optic chiasm compression, or other symptoms related to mass effect. Obstructive sleep apnea and metabolic disturbances (diabetes mellitus) are common in acromegaly patients. Acromegalics have an increased risk of colonic polyp.[44],[45]

Associated cardiac conditions include hypertension, left ventricular dysfunction, valvular regurgitation, and asymmetric septal hypertrophy. The overall mortality rate is higher in acromegaly patients with a standardized mortality ratio of ~1.72. Deaths attributed to acromegaly are mainly due to cardiovascular, respiratory, and cerebrovascular diseases.

Diagnosis

Serum IGF-1 level is the initial screening method of choice. Hepatic and renal failure, malnutrition, severe infection, poorly controlled diabetes mellitus, and hypothyroidism can result in falsely low levels. The diagnosis is confirmed by unsuppressed nadir GH (GH >1 ng/mL; standard assay, GH >0.4 ng/mL; sensitive assay) level after 75 g OGTT with documented hyperglycemia.[46]

MRI is to be done for tumor localization and to assess the parasellar extent.[46] Approximately, 77% of acromegaly patients harbor a macroadenoma,[47] but contrast-enhanced pituitary MRI with two-millimeter slices is recommended to diagnose microadenomas.[46] Densely granulated somatostatinomas appear hypointense while sparsely granulated tumors appear hyperintense on T2W-images.[48]

Preoperatively assessment of prolactin (stalk compression or cosecretion), other pituitary hormones, perimetry, blood glucose, echocardiography, sleep study for OSA, colonoscopy should be done to screen for comorbidities.

Treatment

Preoperative medical therapy

Routine use of preoperative medical therapy is not indicated but may be considered in patient with increased pharyngeal thickness (can cause difficult intubation), sleep apnea, high output cardiac failure, and uncontrolled diabetes and hypertension.[46],[49],[50]

Surgery

Transsphenoidal surgery is the first line of treatment for a pituitary tumor. The cure rate is 73% for microadenomas and 61% for macroadenomas. Small tumor volume, lower Knosp score, lower preoperative GH and IGF-1 level, and experience of surgeon are favorable factors for the remission.[46],[51] Surgical debulking should be considered in patient with parasellar disease to improve subsequent response to medical therapy.[46],[51]

Criteria for cure

Random GH may be assessed immediately post surgery. Normal IGF-1, random GH level less than 1 ng/mL, or nadir GH <1 ng/mL standard assay (<0.4 ng/mL-ultrasensitive assay) after OGTT, done at 12-week post surgery, are defined as cure. Same GH and IGF-1 assay should be used throughout the management.[52] MRI pituitary should be done 12 weeks after surgery.[49]

Management of persistent disease

Resurgery may be considered when there is an accessible intrasellar component.[53]

Medical Therapy: Medical options for acromegaly are shown in [Table 4] Anticonvulsants: opiates, benzodiazepines.[54],[55],[56],[57],[58],[59],[60],[61],[62]
Table 4: Medical Management of Acromegaly.

Click here to view


Indication:[49]

  • When surgery is not possible or is refused
  • Uncured status after surgery
  • Used as a bridge therapy while awaiting the response to radiation therapy.


Combination therapy

When response is partial after high dose of somatostatin receptor ligands (SRL), the addition of pegvisomant results in normalization of IGF-1 in 95% but transient transaminase elevation occurs in 27% patients.[63] Cabergoline combined with SRL normalized IGF-1 levels in 42%–60% patients.[62]

Radiotherapy

Radiotherapy is considered as an adjuvant therapy in persistent disease or in those who cannot afford medical therapy. Therapeutic effect of stereotactic radiation therapy may take years (mean 3.17 year) and remission rate is 59% at 10 years.[64]

Management of comorbidities

Longitudinal monitoring and treatment of comorbidities like diabetes, hypertension, cardiovascular disease, obstructive sleep apnea, and osteoarthritis should be done. Colonoscopy for colonic polyp screening should be done. These comorbidities may be debilitating in spite of remission.


 » TSH-Secreting Tumors Top


Thyrotropin-secreting tumors (TSH-omas) are a rare cause of hyperthyroidism and comprise 1%–3% of all pituitary tumors.[65],[66]

These patients have a goiter and present with mild symptoms of thyrotoxicosis.[67] These tumors may be large, invasive, and fibrous at the time of resection.[66],[68]

When to suspect?

Inappropriately normal or elevated TSH with elevated serum T4/free T4 levels in a hyperthyroid patient.[69] Most TSH-secreting tumors only secrete TSH; however, cosecretion of prolactin or GH may occur.

Differential diagnosis

Patients with resistance to thyroid hormone, an autosomal dominant inherited disorder, also present with the same thyroid profile and 20% may show a tumor on MRI.[70],[71]

Management

Somatostatin analogs (SSA) with antithyroid drugs (ATD) (carbimazole or methimazole) along with propranolol should be administered in order to restore euthyroidism before surgery to avoid the risk of thyroid storm.[65],[72] Long-term ATD therapy or thyroid ablation without SSAs should be avoided because of concerns of pituitary tumor growth.

Transsphenoidal surgery is the mainstay of therapy. Majority of patients with a microadenoma and 60% with macroadenoma achieve complete cure.[65]

If not cured, medical management, radiotherapy, or repeat surgery may be considered.

Postoperative adjunctive medical therapy with SSA and/or radiation therapy may be useful if there is persistent central hyperthyroidism, especially for nonresectable TSH-omas.[73]

Long-acting SSAs (Octreotide LAR 20 mg 4 weekly) reduce TSH and restore euthyroidism in 90% patients, reduce goiter size in 30% patients, reduce tumor size in 40% patients, and visual improvement occurs in 70% patients.[65],[67],[73]

Criteria for cure

Remission of hyperthyroidism, disappearance of neurological symptoms, negative imaging, and normalization of thyroid function tests including the molar ratio criteria for cure. Undetectable TSH levels 1 week after surgery indicate complete adenomectomy.[74]


 » Conclusion Top


The management of functional pituitary tumors is a team approach. There has to be a dialog between the endocrinologist and neurosurgeon for proper management and optimizing outcomes.[75],[76],[77],[78]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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