Hypopituitarism

Etiology

Hypopituitarism can originate from 2 primary sources—pathology of the hypothalamus, which affects the production of tropic hormones that act on the pituitary, or direct pathology within the pituitary gland itself. The predominant cause of hypopituitarism is pituitary tumors, which account for 61% of cases. These tumors may cause overproduction of a single hormone, leading to a deficiency in other pituitary hormones. For instance, in acromegaly, an excess of GH coincides with hypopituitarism due to macroadenoma.

Most pituitary tumors are benign and can be either secretory or nonsecretory. In rare cases, secondary metastases from breast, colon, and prostate cancers can also impact the pituitary gland. Hypopituitarism can also be associated with hypothalamic and para-pituitary tumors, such as suprasellar meningiomas, gliomas, and craniopharyngiomas. In addition to tumors, various injuries to the pituitary gland, such as traumatic brain injury, iatrogenic injury during surgery, or cranial irradiation, may also cause hypopituitarism.[4]

Inflammatory conditions that affect the pituitary gland may also contribute to the development of hypopituitarism. Infectious agents associated with pituitary insufficiency include Mycobacterium tuberculosis and agents that don't belong to the genus Mycobacterium, such as histoplasmosis, syphilis, viruses, and protozoa.

Lymphocytic hypophysitis is a specific inflammatory condition often observed in the postpartum period. This condition responds well to steroid therapy and manifests as a mass lesion on magnetic resonance imaging (MRI) due to the infiltration of lymphocytes and plasma cells within the pituitary.

The latest immunotherapy category involving immune checkpoint inhibitors, including cytotoxic T-lymphocytes antigen-4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PDL-1), can cause hypophysitis. This condition is characterized by central adrenal insufficiency. On rare occasions, it may lead to central hypothyroidism or hypogonadism.[5] In most cases, hormonal alterations can persist even after discontinuing the medication, frequently resulting in permanent changes.[6][7][8][9]

Infiltrative diseases such as hemochromatosis, sarcoidosis, and histiocytosis have been associated with hypopituitarism development. In these conditions, abnormal deposition of substances or immune-related processes can cause damage and dysfunction of the pituitary gland, ultimately leading to hypopituitarism.

Hypopituitarism induced by traumatic brain injury is one of the more recently recognized mechanisms that can result in isolated or global pituitary deficits. Some studies indicate worse outcomes and minimal recovery in such cases. Although a timely diagnosis can be beneficial, it is not always straightforward, as symptoms can be nonspecific and may overlap with the effects of the underlying injury.[10][11]

Pituitary apoplexy is a medical emergency that arises from acute ischemic infarction or hemorrhage within the pituitary gland. Although pituitary apoplexy generally occurs in the presence of a pituitary adenoma, it may also happen in the normal pituitary gland. Sheehan syndrome occurs due to infarction of the hyperplastic pituitary gland following significant blood loss during postpartum hemorrhage. The pituitary gland's rich and intricate vascular supply sets it apart from other brain tumors and contributes to the heightened risk of bleeding within pituitary adenomas.[12]

Congenital absence of the pituitary gland is related to midline craniofacial defects. Genetic mutations in transcription factors, such as HESX1, PROP1, and Pit-1, can lead to congenital hypopituitarism.[13][14]

Empty Sella syndrome is a rare disorder characterized by the enlargement or malformation of the sella turcica, resulting in a herniation of the arachnoid membrane into the pituitary fossa. This displacement pushes the pituitary gland toward the floor of the fossa, potentially resulting in a more minor or absent pituitary gland. Empty Sella syndrome may be idiopathic or be secondary to factors such as treated pituitary tumors, head trauma, or a condition called pseudotumor cerebri, which is also known as idiopathic intracranial hypertension.

Kallmann syndrome is another rare genetic condition characterized by an inability to detect odor, also referred to as hyposmia or anosmia, and hypogonadotropic hypogonadism, marked by decreased FSH, LH, testosterone, or estradiol levels. This syndrome results from a mutation in the Kal1 gene, which is the most frequently observed genetic abnormality in males affected by this condition.

Epidemiology

Hypopituitarism is categorized as a rare disorder by the National Institute of Health (NIH), with limited data available on the incidence and prevalence of the condition. A study conducted by Regal et al in Northwestern Spain reported a prevalence of 45.5 cases per 100,000 population.[15][16]

History and Physical

Evidence suggests hypopituitarism develops when 75% of the pituitary gland is compromised. The clinical manifestations of hypopituitarism can vary from subtle and ill-defined to severe with an acute presentation. Conditions such as Sheehan syndrome, pituitary apoplexy, pituitary infection, hypophysitis, and traumatic brain injury present with acute findings.[17][18][19]

The presenting signs and symptoms of hypopituitarism may be attributed to various factors, including deficiencies in pituitary hormones, the mass effects associated with pituitary tumors, and characteristics of the underlying causative disease.

The symptoms associated with hormonal deficiencies are listed below.[20]

• ACTH deficiency: ACTH deficiency results in adrenal insufficiency.
• TSH deficiency: TSH deficiency leads to hypothyroidism.
• Gonadotropin deficiency: Gonadotropin deficiency leads to hypogonadism.
• GH deficiency: GH deficiency in children can result in poor growth and short stature. Although this hormonal deficiency is typically asymptomatic in adults, some individuals may experience fatigue and weakness.
• ADH deficiency: ADH deficiency leads to diabetes insipidus, characterized by symptoms such as polydipsia and polyuria.

Visual field defects, such as bitemporal hemianopsia, are the most common manifestation of pituitary tumor mass effects, followed by unilateral defects. Patients may develop headaches as a secondary symptom caused by these mass lesions.

Physical examination of patients may not yield significant findings, as the presentation of hypopituitarism is typically subtle. However, variable features may be present due to the involvement of different target hormones, resulting in the following conditions:

• Hypothyroidism: Symptoms may include a small and soft thyroid gland, dry and coarse skin, hair thinning and alopecia, delayed tendon reflexes, cold skin with reduced sweating, and non-pitting type edema.
• Adrenal insufficiency: Common symptoms include fatigue and postural hypotension.
• Hypogonadism: In men, this condition can manifest as small and atrophied testes, whereas in women, it may lead to the loss of axillary and pubic hair.
• Neurological and ophthalmic involvement: This can result in a loss of visual acuity, extraocular paresis, and bitemporal hemianopsia.
• Diabetes insipidus: Symptoms include hypernatremia, polyuria, and diluted urine.

Evaluation

A secretory pituitary tumor can lead to an overproduction of the hormone specific to the tumor, causing symptoms related to excess hormone levels. Meanwhile, other pituitary hormones may become deficient.[21][22][23][24]

Investigations

Laboratory investigations: Initial testing involves assessing baseline levels of pituitary hormones and hormones produced by the target glands. Because hormone levels can fluctuate based on several factors, such as the time of day, season, and pulsatile secretion of certain pituitary hormones, assessing the baseline levels may not always provide useful information. In such cases, dynamic function testing can help confirm the presence of any biochemical deficiency or excess of a particular pituitary hormone.

Dynamic function testing involves the administration of a stimulatory agent that would typically trigger an increase in the secretion of the hormone in question. The patient's blood levels are measured before and after administering this stimulant. Measurements are taken at defined intervals to assess whether a proper response to the stimulation has occurred.[25]

Insulin tolerance test (ITT): ITT is considered the most reliable and historical standard provocative test for assessing deficiencies of both GH and ACTH levels in patients. Baseline measurements of cortisol, growth hormone, and glucose are obtained after an overnight fast for individuals undergoing ITT. Subsequently, an intravenous (IV) insulin dose of 0.1 or 0.05 U/kg is administered to patients, and hormone and glucose samples are collected at regular intervals. The plasma glucose level should ideally decrease to 40 mg/dL during the test within 30 to 45 minutes or 50% from the baseline level. The test is concluded by administering IV dextrose and monitoring the patient's condition for 90 minutes. Cortisol levels above 20 µg/dL and GH levels between 5 and 10 ng/mL demonstrate an adequate response. Notably, an ITT should not be performed in individuals with cardiac conditions or epilepsy. 

ACTH stimulation test: This test is an alternative to ITT when the latter poses a health risk due to severe hypoglycemia. This test assesses the function of the hypothalamic-pituitary-adrenal axis. Instead of insulin, synthetic ACTH is administered via IV or intramuscular (IM) route at either 1 or 250 mcg, which is the most commonly used dose. Cortisol levels are measured before administering ACTH to patients at 30-, 60-, and 90-minute intervals. A normal response is indicated when cortisol levels exceed 18 mcg/dL.[26]

Modern combined test: This test represents a comprehensive approach to hormone assessment. During this test, the patient receives GH-releasing hormone (GHRH), cortisol-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), and thyroid-releasing hormone (TRH) as provocative stimuli. The GH, TSH, ACTH, cortisol, LH, and FSH levels are measured at baseline and specified time intervals thereafter. The doses of each stimulating hormone are as follows: GHRH 1.0 µg/kg, CRH 1.0 µg/kg, GnRH 100 µg, and TRH 200 µg. However, it is noteworthy that this test rarely applies in clinical practice due to its infrequent necessity.

Radiological investigations: Imaging studies of the pituitary involve using MRI with gadolinium enhancement, which is the preferred method for visualizing the pituitary, primarily to detect the presence of a mass lesion. Visual field defects must be assessed if a pituitary mass is suspected to be the underlying cause of hypopituitarism.

Treatment / Management

The primary objective and management strategies for hypopituitarism are customized to address the condition's underlying cause. Surgical removal of mass lesions is critical, and concurrent medical conditions also require appropriate treatment. Many patients may require hormone replacement therapy to restore hormonal balance and alleviate associated symptoms.[27]

ACTH deficit

Corticosteroid replacement should be initiated before the thyroid hormone replacement to prevent the risk of precipitating an adrenal crisis. Hydrocortisone is typically recommended at 10 to 20 mg in the morning and 5 to 10 mg in the afternoon. Some endocrinologists advocate for 3 daily doses in symptomatic patients to imitate the physiological hormonal secretion. However, the last dose, whether the second or third, should not be administered to patients at night to prevent insomnia. Occasionally, patients respond well to once-daily dosing, which can be considered individually.[28] Prednisone may also be used once daily. Increased dosages of corticosteroids are required during stressful situations, surgery, or pregnancy.(B3)

TSH deficit

Individuals at an advanced age or those with cardiac disease require the thyroid hormone, also called L-thyroxine, replacement therapy. Treatment initiation generally involves a low dose of 25 µg/d of L-thyroxine, followed by gradual adjustments based on biochemical results and clinical indicators. As TSH is no longer a reliable marker, peripheral hormone levels of free or total thyroxine (T4) should be assessed.

FSH/LH deficit

In men, testosterone replacement can be delivered through various methods, including gels, patches, oral medications, or IM injections. Prostate-specific antigen and hemoglobin levels should be closely monitored in this group.[29]

In women, estrogen and progesterone hormone replacement therapy can be administered IM, orally, or transdermally. Hormone levels should be carefully monitored and normalized across all axes in this group, not just for the reproductive system, especially when fertility is desired.[30](A1)

For men seeking fertility, human chorionic gonadotropin (HCG) can augment testosterone levels and improve semen quality. If this approach is unsuccessful after one year, adding concomitant therapy with human menopausal gonadotropin (HMG) and recombinant FSH could further enhance fertility. Specialty fertility clinics are dedicated to further evaluating and managing these patients.[31](B3)

GH deficit

In contrast to the well-defined role of synthetic GH replacement therapy in treating GH deficiency–related short stature in children, the role of GH replacement therapy for adults with GH deficiency has not been firmly established. In pediatric cases, synthetic GH treatments, such as somatotropin, are utilized, and the therapy is adjusted according to insulin-like growth factor 1 (IGF-1) levels. The objective of the treatment is to attain the individual's complete adult stature. Further evaluation is conducted after puberty to determine whether GH replacement therapy should continue until the individual reaches adulthood.

ADH deficit

ADH replacement with intranasal or oral desmopressin, a synthetic analog of vasopressin, aids in stabilizing the water balance and addressing polyuria in patients. Maintaining sodium levels within the normal range is essential. Monitoring urine-specific gravity and osmolality helps validate the effectiveness of ADH replacement and ensures appropriate water regulation. These measurements are crucial indicators to confirm the efficacy of the treatment regimen.

Differential Diagnosis

In complex situations, a diagnosis of hypopituitarism may be overlooked or delayed, especially when normal pituitary hormone levels are misinterpreted within the context of suboptimal target organ hormone levels. However, clinical treatment should be initiated in cases of suspected adrenal insufficiency without waiting for definitive biochemical evidence.

The differential diagnoses that may be considered when assessing for hypopituitarism in patients include primary hypothyroidism, Kallmann syndrome, pituitary macroadenomas, hyponatremia, and autoimmune polyglandular syndrome types 1, 2, and 3.[32]

Prognosis

Patients in stable condition and can adhere to hormone replacement therapy typically have a favorable prognosis. Mortality rates increase in patients experiencing acute decompensation and critical states. The extent of morbidity varies and is contingent on the hormone deficiency type.

The systemic effects of hypopituitarism vary depending on the extent of pituitary involvement. Certain clinical states that result from the acute decline in pituitary production may increase the mortality risk. For instance, ACTH deficiency can lead to an adrenal crisis, whereas TSH deficiency may cause myxedema coma, potentially resulting in death.[33]

Complications

Other hormonal deficiencies that often accompany hypopituitarism can contribute to developing secondary diseases. For instance, a human GH (HGH) deficiency is associated with obesity, elevated cholesterol levels, and metabolic syndrome. Likewise, estradiol deficiency can potentially lead to osteoporosis.[34]