The pituitary gland produces and secretes various hormones that play a vital role in regulating endocrine function within the body. The pituitary gland consists of 2 lobes: an anterior and a posterior lobe. Hormones produced by the anterior lobe of the pituitary gland include growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropin (ACTH), and prolactin. Hormones stored and released from the posterior pituitary are antidiuretic hormone (ADH) or vasopressin and oxytocin. ADH and oxytocin are produced by neurosecretory cells in the hypothalamus. Trophic hormones produced by the hypothalamus stimulate the production of different anterior pituitary hormones, which in turn stimulate the production of hormones at the level of the target organ. Negative feedback by hormones produced by the target organ and tissue inhibits further production of the related pituitary hormones. Readers are directed to the Statpearls article on hypopituitarism for further details regarding pituitary hormone regulation.
Hyperpituitarism is defined as an excessive secretion or production of 1 or more of the hormones produced by the pituitary gland. In this article, we present an overview of the diagnosis and management of secretory tumors of the pituitary gland.
Prolactin-secreting pituitary tumors are known as prolactinomas. They are the most frequent secretory tumors of the pituitary gland accounting for at least 40% of all pituitary tumors. These are reported more commonly in women. Other causes of increased prolactin, apart from pituitary adenomas, include craniopharyngioma and other sellar or para sellar masses, infiltration of the hypothalamus, and head trauma. Mild elevations in prolactin may also be seen in patients with hypothyroidism, polycystic ovarian disease, and secondary to the use of certain medications such as antipsychotic agents, opioid analgesics, antidepressants, among others. Physiological causes of increased prolactin levels include stimulation of the nipple and sexual intercourse.
Excessive production of GH leads to acromegaly and gigantism. The incidence of acromegaly is 5 cases per million per year, and the prevalence is 60 cases per million. Over 95% of patients with acromegaly have a GH secreting pituitary adenoma derived from the somatotroph cell line. In less than 5% of cases, acromegaly is a result of excessive GH releasing hormone (GHRH) secretion from a hypothalamic or a neuroendocrine tumor. The ectopic production of GH is extremely rare.
Excessive ACTH production leads to the presence of hypercortisolism (Cushing syndrome). The incidence of Cushing syndrome is 2 to 3 cases per million. Pituitary adenomas (Cushing disease) accounts for greater than 80% of ACTH dependent hypercortisolism, and 10% to 20% are secondary to the ectopic production of ACTH. Cushing disease is more common in females than in males with a ratio of 3:1.4.
Pituitary adenomas that produce TSH (TSHoma) represent less than 1% of functioning pituitary adenomas, with the Swedish National Registry reporting an incidence rate of 0.15 cases per million inhabitants per year. Co-secretion of GH and prolactin is common.
The presence of a pituitary adenoma with pancreatic endocrine tumors and the parathyroid tumor is associated with multiple endocrine neoplasia (MEN) type 1 syndromes.
The incidence of hyperpituitarism is usually reported with a specific condition associated with the particular pituitary hormone excess. The incidence of each related pituitary hormone excess is indicated under the etiology section of this article.
The hypothalamic dysregulation may play a role in promoting tumor growth; however, intrinsic pituicyte genetic dysfunction plays a more significant role in tumorigenesis. As the pituitary gland is responsible for producing various hormones, the pathophysiology also varies significantly.
Cushing disease: Corticotropinomas occurs in people of all ages. They have a female preponderance. It refers to a pituitary adenoma that produces an adrenocorticotropic hormone (ACTH) in excess, which then leads to excess cortisol secretion. These adenomas are comparatively smaller than others. In adults, there is an absence of diurnal variation of plasma cortisol and ACTH; however, in children, these tumors present with weight gain and growth failure.
Gigantism: Somatotropinomas are adenomas of growth hormone-producing pituicytes, which may cause gigantism when in childhood, open epiphysial plates allow for excessive longitudinal growth. Aryl hydrocarbon receptor-interacting protein mutations have been found to be associated with early-onset gigantism.
Prolactinoma: This is the most common pituitary adenoma found in childhood. Prolactinomas take their origin from acidophilic cells that are derived from the same lineage as the thyrotropes and somatotropes. This is the reason why prolactinomas may also secrete growth hormone and TSH.
Thyrotropinoma: These adenomas secrete TSH mainly; however, they may also secrete excess prolactin, growth hormone, and alpha subunit. They are usually large and aggressive.
Presentation of patients with hyperpituitarism will depend on the hormone or hormones that are produced in excess, the presence of a mass pituitary lesion, and associated features of hypopituitarism. Local effects of a pituitary tumor such as visual field disturbances and headache may be present in the presence of a mass lesion. Pituitary tumors can be microadenomas less than 10 mm or macroadenomas greater than 10 mm. Macroadenomas usually cause hypopituitarism.
Excessive production of prolactin may occur in isolation or can occur with increased production of other hormones such as GH. Clinical features include infertility and galactorrhoea and secondary amenorrhea in females, loss of libido, and impotence in males. In males, the tumors are usually macroadenomas presenting with features of extension beyond the pituitary.
Excessive Production of Growth Hormone
Excessive production of GH in adults results in the condition known as acromegaly. Features include:
In children, before the fusion of epiphyseal plates in long bones (for example femur and tibia), excessive GH production results in gigantism.
Excessive production of TSH causes secondary hyperthyroidism. Clinical features are those of thyroid hormone excess and include weight loss, heat intolerance, anxiety, menstrual disturbances, and palpitations. Diffuse goiter may also be present. Hyperthyroid symptoms with TSHomas are often mild to moderate.
Excessive production of ACTH by the pituitary results in Cushing disease. Clinical features include central obesity, skeletal muscle wasting, the presence of buffalo hump, striae, excessive bruising, menstrual abnormalities, increased blood pressure, glucose intolerance, as well as depression, and psychosis.
The initial tests should be directed at the suspected excess hormone. Additionally, the possible deficiencies of other pituitary hormones should also be considered, and relevant testing performed.
Basal levels of prolactin are useful with values of greater than 200 ng/mL associated with the presence of a prolactinoma. Prolactin levels generally correspond with the tumor size. Prolactin (PRL) may be increased due to other causes not related to the pituitary disease, as described above. MRI and basal PRL levels are sufficient for the diagnosis. Provocative tests are not indicated. If PRL levels are normal with clinical features, then it is possible that there is assay interference, the “hook effect,” and samples should be diluted to provide a reliable result since the excess antigen is causing a prozone effect. Rarely patients have an increase in PRL due to macroprolactinomas, which is a harmless condition and can be diagnosed by contacting the laboratory for precipitating the big PRL.
Growth Hormone (Acromegaly/Gigantism)
Random GH levels are usually not recommended due to the diurnal and pulsatile nature of secretion that occurs during a day. Dynamic function (suppression testing) forms the cornerstone of laboratory investigations of GH excess. The oral glucose suppression test involves an intake of 75 gm of glucose with measurement of GH levels at zero, 60, and 120 minutes. A GH level of less than 1 ug/L usually excludes the diagnosis of acromegaly. The presence of increased IGF1 levels accompanies excessive GH production. IGF1 measurement does not require the use of fasting sample or suppression testing as a random sample adequately reflects the influence of GH excess/deficiency. Thus it is recommended as the initial screening test for acromegaly. It is vital that the relevant age and sex-matched reference intervals be used when interpreting IGF1 results. As the liver, under the action of GH, produces IGF1, significant liver disease may result in decreased IGF1 production. Other conditions affecting IGF1 results include renal failure, hypothyroidism, poorly controlled diabetes mellitus, and severe malnutrition. Around 30% of patients with acromegaly can have increased prolactin levels.
Adrenocorticotropic Hormone (Cushing Disease)
The laboratory investigations of Cushing syndrome include confirmation of excessive corticosteroid production followed by identification of ACTH dependent/independent production and determination of the site of ACTH production (whether ectopic production is present).
Tests for Confirmation of Hypercortisolism
Determination of ACTH Dependence/Independence
The CRH stimulation test may be accompanied by bilateral inferior petrosal sinus sampling (BIPSS) to confirm the presence of a pituitary lesion, causing Cushing syndrome. During this invasive procedure, the inferior petrosal sinuses into which the pituitary venous blood drains are catheterized by a radiologist. ACTH is measured at baseline and following stimulation with 100 micrograms of CRH from both IPS and peripheral veins. Measurement of prolactin is also performed to confirm the catheter is in the correct position. A ratio of IPS to peripheral ACTH of 2:1 before CRH stimulation and 3:1 after stimulation indicates the pituitary cause of ACTH production consistent with Cushing Disease. This modality has also been used to assist in the lateralization of the pituitary lesion.
Thyroid Stimulating Hormone
Secondary hyperthyroidism presents with increased or unsuppressed TSH levels and elevated thyroid hormone (free and total T4 and T3) levels. This picture is also seen in the presence of laboratory interference and thyroid hormone resistance, both of which are more commonly encountered than TSH producing pituitary tumors. Since glycoprotein hormones have alpha and beta subunits, tumors can produce an excess of alpha subunits in TSHoma.
Thyroid releasing hormone (TRH), if available, can be used in a stimulation test to verify if the TSH is of pituitary origin. Following the administration of TRH, TSH is measured. Patients with a TSH producing tumor have an impaired response.
FSH, LH, estradiol, and testosterone levels may be useful in ascertaining the deficiency of these hormones secondary to a pituitary tumor. Rarely elevated FSH and LH may be associated with a gonadotropin cell adenoma.
Pituitary imaging studies using unenhanced or gadolinium-enhanced MRI are preferred to CT scans for visualization of pituitary adenomas. Often pituitary adenomas are discovered incidentally when imaging studies have been done for other reasons.
Adenomas are slow to take up gadolinium as opposed to the normal pituitary tissue; therefore, they tend to appear as hypoenhancing lesions.
Management of hyperpituitarism will depend on the cause and the hormone or hormones affected.
It includes the use of somatostatin analogs and competitive receptor antagonists. For prolactinomas, medical therapy is the usual choice and consists of dopamine agonists such as bromocriptine and cabergoline.
Prolactinomas are the only pituitary adenomas in which long-term pharmacological therapy is satisfactory. Unless there is an acute threat, medical management should always be preferred to surgical intervention in such cases. Dopamine agonists suppress prolactin effectively and decrease serum prolactin levels. They also reduce galactorrhea and recover the gonadal function. Dopamine agonists have also been found to cause tumor shrinkage. This class of drugs includes bromocriptine and cabergoline.
In cases of Cushing disease, medical management has only an adjunctive role as the cornerstone of management is surgical intervention. The drugs used in this regard are adrenal enzyme inhibitors, such as metyrapone, aminoglutethimide, and ketoconazole.
Somatostatin analogs have been effectively used in patients with GH excess. Octreotide reduces circulating levels of growth hormone and IGF-1. Long-acting octreotide and lanreotide suppress GH and IGF-1 consistently as they act for a longer time.
Resection of the pituitary gland and its tumors is technically challenging because of the anatomical location. Minimally invasive procedures are increasingly utilized. These include trans-sphenoidal surgery for acromegaly, prolactinoma-macroadenoma, and Cushing syndrome with an adenoma. However, as many patients with pituitary tumors often present late with large tumors, complete resection is often not possible. 
Conventional radiotherapy may be used to reduce tumor size; however, pituitary damage and resultant hypopituitarism may occur.
Differential diagnoses of hyperpituitarism depend on the type of hormone involved. The differentials to be considered in hyperprolactinemia include:
In cases of raised cortisol the differential diagnoses include:
The differential diagnoses of growth hormone excess include:
The prognosis for hyperpituitarism secondary to pituitary tumors is very good in children. Medical therapy or transsphenoidal surgery are treatments of choice with good clinical outcomes.
Endocrinologists play a crucial role in the management of pituitary adenomas. Their role is not confined to medical management rather their role is in the preoperative, perioperative and postoperative period as well.
The expertise of the neurosurgeon is imperative for the better outcome of the surgery. Genetic counseling should be done in order to guide genetic testing.
The management of hyperpituitarism is best done with an interprofessional team, including the endocrine nurses. To improve patient outcomes in patients with hyperpituitarism, it should never be assumed that there is excess secretion of only one hormone. While the initial tests should be directed at the suspected excess hormone, possible deficiencies of other pituitary hormones should also be considered, and relevant testing performed. Leaving untreated hormonal excess is associated with high morbidity.
The outcomes of patients with hyperpituitarism depend on the size of the lesion, presence of any neurological deficit, response to treatment, comorbidity, and patient age. Most patients with microadenoma have good outcomes.
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