It appears that 75% of the pituitary needs to be damaged to result in hypopituitarism. Clinical features of hypopituitarism may be subtle and ill-defined or severe with the acute presentation. Conditions such as Sheehan syndrome/pituitary apoplexy, pituitary infection, hypophysitis, and traumatic brain injury present with acute findings. [8][9][10]

Presenting signs and symptoms may be linked to that of a deficiency of the pituitary hormone, mass effects in the presence of pituitary tumors, and/or features of the causative disease.

Patients with hormonal deficiencies present with the following:

• ACTH deficiency - Adrenal insufficiency
• TSH deficiency - Hypothyroidism
• Gonadotropin deficiency - Hypogonadism
• GH deficiency - difficult to thrive and short stature in children. Adults are usually asymptomatic; however, they may feel fatigued and weak.
• ADH deficiency - Polydipsia and polyuria

Mass effects include visual field defects known as bitemporal hemianopsia. Visual field defects may also occur unilaterally. Patients may also present with headaches, secondary to the mass lesions. See table 2  below. It summarises the clinical features of pituitary hormone deficiencies.

Physical examination may not reveal any significant findings as the presentation is usually subtle. Variable features may be present owing to the involvement of different target hormones, such as:

• Hypothyroidism - small and soft thyroid gland, dry and coarse skin, thinning of hair and alopecia, delayed tendon reflexes, cold skin with loss of sweating, and non-pitting type edema
• Adrenal insufficiency - buccal hyperpigmentation and postural hypotension in cases of Addison disease
• Hypogonadism -  small and atrophied testes in men. Loss of axillary and pubic hair in women.
• Neurological and ophthalmic involvement - loss of visual acuity, extraocular paresis, and bitemporal hemianopsia
• GH excess - in functioning adenomas may result in features consistent with acromegaly.

The presence of a secretory pituitary tumor may result in features of hormone excess for the particular hormone produced by a tumor while other pituitary hormones may be deficient.[11][12][13][14]

Investigations

Laboratory Investigations: Initial testing involves baseline levels of pituitary hormones and hormones produced by target glands. Due to the variation of hormone levels related to the time of day, season, and pulsatile secretion of certain pituitary hormones, baseline levels may not be helpful. In this instance, dynamic function testing may be performed to confirm biochemical deficiency or excess of a particular pituitary hormone. In dynamic function testing, for the investigation of a hormone deficiency, a stimulatory agent that would normally increase secretion of the hormone is given to the patient and blood levels are measured before and after the administration of the agent. After the administration of this stimulant, measurements are taken at defined intervals to determine if there has been an adequate response to stimulation. See Table 3. Lab findings for pituitary hormone deficiency (per specific hormone).

Insulin Tolerance Test: This is the best provocative test that is used to assess the presence of the deficiency of both GH and cortisol. Following an overnight fast, baseline samples are obtained for cortisol, GH, and glucose. An insulin dose of 0.1 U/kg or 0.05 U/kg is administered intravenously (IV). Further samples for analysis of the hormones measured in the baseline samples are then taken at several other time points after administration. It should not be performed in those with cardiac disease or epilepsy. The plasma glucose should fall to 40 mg/dl within 30 to 45 minutes or by 50% of baseline. The test is terminated by giving IV dextrose and assessing the patient's status for at least 90 minutes. A normal/adequate response is indicated by cortisol of more than 20 ug/dL and GH of more than 5 ng/mL to 10 ng/mL.

Modern Combined Test: The patient is given growth hormone-releasing hormone (GHRH), cortisol releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), and thyroid releasing hormone (TRH) as the provocative stimuli and GH, TSH, ACTH, cortisol, LH, and FSH are measured at baseline and at specified time intervals after that. Doses of each stimulating hormone are as follows

• GHRH (1.0 ug/kg)
• CRH (1.0 ug/Kg)
• GnRH (100 ug)
• TRH (200 ug).

However, this testing is rarely required.

Radiological Investigations: Imaging studies of the pituitary using magnetic resonance imaging (MRI) with gadolinium enhancement are used to visualize the pituitary, in particular, to detect the presence of a mass lesion. Visual field defects need to be assessed if a pituitary mass is the cause of hypopituitarism.

Management is dependent on the cause of hypopituitarism. Initial treatment is to address the underlying cause of hypopituitarism. Mass lesions may be removed surgically, and other medical conditions treated accordingly. Many patients may require hormone replacement therapy.

ACTH Deficit: Corticosteroid replacement should be initiated before the replacement of the thyroid hormone to avoid precipitating an adrenal crisis. Hydrocortisone at a dose of 10 mg to 20 mg in the morning and 5 mg to 10 mg in the evening. Prednisone may also be used.

Increased dosages of corticosteroids are given during periods of stress, surgery, and pregnancy.

TSH Deficit: Thyroid hormone (L-thyroxine) replacement, in particular for the elderly and those with cardiac disease. It is important to start with a low dose of 25 ug/daily and then up-titrate as required according to biochemical findings, and clinical signs and symptoms.

FSH/LH Deficit: In secondary hypogonadism, testosterone can be delivered by gel, patch, or intramuscular (IM) injections every two weeks with careful monitoring of prostate-specific antigen (PSA) and testosterone levels.

In women: estrogen/progesterone hormone replacement therapy via oral, intramuscular, or transdermal routes can be given.

If fertility is desired, then one starts with human chorionic gonadotropin (HCG) to augment testosterone levels and improve semen quality. If this is not successful after one year, consider human menopausal gonadotropin (HMG)/recombinant FSH concomitant therapy to further enhance fertility.

Growth hormone deficit: Unlike in children with short stature due to GH deficiency, the role of GH replacement in the treatment of adult GH deficiency has not been well established. In children, synthetic growth hormone replacement is used for this purpose such as somatotrophin. Replacement therapy is titrated against IGF1 levels. The goal of treatment is to ensure that adult height is obtained. Further evaluation is made post-puberty to determine whether GH replacement should continue into adulthood.

ADH deficit: Replacement of ADH with intranasal desmopressin (synthetic vasopressin) helps stabilize water balance and polyuria.

A diagnosis of hypopituitarism may be missed or delayed in complex situations where apparently normal pituitary hormone levels are misinterpreted in the context of suboptimal target organ hormone levels. However, adrenal insufficiency should be treated on the basis of clinical suspicion without waiting for the biochemical evidence.

Following are some differential diagnoses that may be considered while making a diagnosis of hypopituitarism:

1. Primary hypothyroidism
2. Kallman syndrome
3. Pituitary macroadenomas
4. Hyponatremia
5. Polyglandular autoimmune syndrome type-1
6. Polyglandular autoimmune syndrome type-2
7. Polyglandular autoimmune syndrome type-3

Patients who are stable on hormone replacement, usually have a good prognosis. Mortality increases in patients with acute decompensation who are in a critical state.

Morbidity is variable and depends on the type of hormone deficiency. The systemic effects of hypopituitarism are also variable depending on the extent of pituitary involvement.

Some clinical states that result from the acute decline in pituitary production may lead to increased mortality risk, such as deficiency of ACTH leading to adrenal crisis or TSH deficiency causing myxedema coma and death.[15]

Patient education should mainly focus on the need for lifelong hormone replacement therapy, increased glucocorticoid dose during times of stress, and rapid medical access as appropriate. Regular monitoring to prevent inadequate or excessive replacement is crucial.

Patients with hypopituitarism should carry some form of identification with them. This can be in the form of a bracelet to be worn on the wrist or neck.

For emergency purposes, patients may also need to carry a vial of hydrocortisone 100 mg and a syringe at home and while traveling.

The diagnosis and management of hypopituitarism are done with an interprofessional team that consists of a neurosurgeon, endocrinologist, pathologist, radiologist, primary care provider, nurse practitioner, and an ophthalmologist. Management is dependent on the cause of hypopituitarism. Initial treatment is to address the underlying cause of hypopituitarism. Mass lesions may be removed surgically, and other medical conditions treated accordingly. Many patients may require hormone replacement therapy. The outcome in most patients with hypopituitarism is good, but those who have a neurological deficit may continue to have partial deficits even after treatment. [1][16][17](Level V)