The clinical presentation of hypopituitarism is often vague and nonspecific, leading to a further delay in diagnosis. Nonspecific symptoms include a feeling of general poor health, increased lethargy, feeling cool, chronic tiredness, reduced appetite, weight loss, and abdominal pain [2, 3]. Hypopituitarism can sometimes develops acutely, leading to a rapid onset of symptoms (excruciating headache, meningism, and cardiovascular collapse) necessitating admission and intensive care management, as is often seen in patients with tumor apoplexy.

The signs and symptoms of underlying diseases can sometimes follow hypopituitarism [3]. Symptoms attributed to the local effects of tumoral masses in the sellar region with suprasellar extension, such as headaches, rhinorrhea, and visual disturbances (typically bilateral hemianopsia, but can also occur as unilateral) frequently remain unrecognized by patients, mostly men, for a long period of time.

Deficits of anterior pituitary hormones may be secondary to hormone excess caused by functioning pituitary tumors, which produces a complex picture combining hormone excess and deficiencies, such as suppression of gonadotropins in hyperprolactinemia, growth hormone deficiency (GHD) caused by cortisol excess in Cushing’s syndrome [4] or growth hormone (GH) secreting macroadenoma that causes acromegaly and hypogonadism [5]. The presence of central Diabetes Insipidus (DI) usually indicates a non-pituitary lesion affecting the hypothalamus or pituitary stalk. Preoperatively, pituitary adenomas rarely cause DI.

The clinical presentation of male hypogonadism depends on the time of onset of androgen deficiency. In men with recent onset hypogonadism, the physical examination is usually normal, while diminished facial and body hair, gynecomastia, and small soft testes are features of longstanding hypogonadism [2]. The principal signs and symptoms of androgen deficiency in men are loss of libido, decreased sexual potency, loss of body hair (axillary and pubic), infertility, and low bone mineral density. The threshold testosterone level below which symptoms of androgen deficiency and adverse health outcomes occur and testosterone administration improves outcomes in the general population is currently not known [7].

Female adolescents have primary amenorrhea and lack of breast development, whereas in adult women, gonadotropin deficiency leads to reduced secretion of estradiol, resulting in infertility and oligo/amenorrhea. Low estrogen is also responsible for genital atrophy and decreased breast volume in chronic hypogonadism. There is a reduction of pubic and axillary hair, especially when concomitant dysfunction of the corticotroph axis is present.

At the prepubertal age, no obvious clinical signs or symptoms are present until the normal age of puberty onset (9–14 years in boys and 8–13 years in girls), when a lack of signs of normal pubertal development are then observed. It should be emphasized that micropenis with or without associated cryptorchidism is an important clinical clue that suggests congenital hypogonadotropic hypogonadism (where there is lack of the normal fetal secretion and postnatal surge of gonadotropins) rather than acquired hypogonadotropic hypogonadism [8].

The clinical picture of central hypothyroidism is very similar to primary hypothyroidism, but is often milder. Symptoms include cold intolerance, dry skin, decreased appetite with mild weight gain, and fatigue [9]. The presence of goiter usually indicates primary thyroid disease. In children, decreased growth velocity with impairment of neurological development is an important sign.

ACTH deficiency leads to decreased glucocorticoid levels. Mineralocorticoid secretion is preserved, since it is primarily modulated by the renin–angiotensin system. Hyperpigmentation is typical of primary adrenal disease and is absent in central disease. Symptoms of ACTH deficiency are largely nonspecific, including weakness, fatigue, anorexia, weight loss, arthralgia, postural hypotension, and tachycardia [10]. Hyponatremia, hypoglycemia, and eosinophilia may also occur. Ultimately, if left untreated, ACTH deficiency may lead to death due to vascular collapse, since cortisol is needed to maintain vascular tone. Mild ACTH deficiency may remain clinically unnoticed when cortisol production is sufficient for preventing symptoms in the absence of clinical stressors (e.g., infections). Hence, laboratorial evaluation is recommended in all patients at risk of ACTH deficiency.

ADH deficiency results in polyuria (urine volume >3 L/day in adults) and polydipsia. If the thirst mechanism is not present, as is the case in some patients with hypothalamic lesions, then lack of polydipsia leads to a high risk of life-threatening dehydration and hypernatremia [11].

Provocative GH testing has several caveats. They are not physiological, since the secretagogues used do not reflect normal GH secretion; the cutoff level of normal is arbitrary and the tests are age dependent. Furthermore, the tests rely upon GH assays of variable accuracy and are all uncomfortable, cumbersome, and risky for the patient [12, 17]. Therefore, there is currently no gold standard provocative GH test for GHD in children. As a result, subnormal responses to two secretagogues are necessary for diagnosis, with the exception of patients presenting with a central nervous system disorder, multiple pituitary hormone defects, or a known genetic defect. In these cases, one test is sufficient to establish the diagnosis [18].

These stimulation tests are performed after an overnight fasting. After the pharmacologic stimulus, serum samples are collected at intervals designed to capture the peak GH level. A “normal” response is defined by a serum GH concentration of greater than 7–10 mcg/L, although the ideal threshold may vary with the assay used. Of note, all patients should be euthyroid and should not be under supraphysiological doses of glucocorticoids before any testing is performed (Tables 8.3 and 8.4).

Clonidine, an α-2 adrenergic receptor agonist, promotes GH release, mainly through GHRH secretion. It is a stronger stimulant for growth hormone release, and therefore false negative results can follow. On the other hand, children presenting with a GH subnormal response to such stimulus rarely secrete normal GH in response to any other stimuli [19]. The test commonly causes hypotension and drowsiness that may last for hours and promote late hypoglycemia.

Insulin-induced hypoglycemia is a potent stimulant of GH release and, therefore, the Insulin Tolerance Test (ITT) is among the most specific tests for GHD. However, safety concerns have prevented the widespread use of this test. The proposed mechanism by which hypoglycemia promotes GH secretion is through the suppression of somatostatin tone and stimulation of α-adrenergic receptors [20]. This test requires constant supervision by a clinician and is contraindicated in children less than 2 years of age.

Administration of glucagon promotes GH secretion through a poorly understood mechanism, with the activation of central noradrenergic pathways as a plausible hypothesis [21]. Glucagon presents mild and transient side effects, such as nausea, vomiting, and sweating, and therefore is a very good choice for infants and young children who are more susceptible to the risks of insulin-induced hypoglycemia.

ITT is considered the most validated test currently available and is the diagnostic test of choice for GHD in adults. However, it is contraindicated in patients with seizure disorders or ischemic heart disease and requires monitoring, even in healthy adults. Adequate hypoglycemia (<2.2 mmol/L) is not always achieved, and therefore, larger doses of insulin up to 0.3 U/kg may be necessary in obese patients and those with fasting blood glucose above 5.5 mmol/L [23]. An assay cutoff of 5.1 μg/L is recommended for diagnosis [22].

A GHRH and arginine test (GHRH-Arg test) is a very potent and reproducible test. Arginine potentiates the response to GHRH presumably through the inhibition of hypothalamic somatostatin secretion [24]. This combined test is not affected by gender or age and shows few side effects with no hypoglycemia. On the other hand, the assay cutoff for GHD diagnosis depends on the body mass index (BMI) [25]. In addition, GHRH directly stimulates the pituitary, and patients with GHD of hypothalamic origin, mainly after radiotherapy, could present a falsely normal GH response [26].

Administration of glucagon allows for the assessment of GH and ACTH-cortisol reserves, and has few side effects with minimal contraindications. It is a good choice when other tests are unavailable or contraindicated. In adults, an assay cutoff between 2.5 and 3.0 μg/L is recommended for GHD diagnosis [22].

In the transition period (i.e., after the cessation of linear growth and completion of puberty), the majority of GHD patients must be retested. Those patients with conditions causing multiple pituitary hormone deficiencies (MPHD) (i.e., three or more pituitary hormone deficits), can continue on GH therapy, but require determination of an adequate dose. Other patients without MPHD but who present with known mutations or irreversible structural hypothalamic-pituitary lesions/damage should be screened for serum IGF-I levels after terminating therapy for at least 1 month. IGF-I levels below −2 SD are sufficient for GH therapy reinstitution. If the IGF-I level is within the normal range, then one provocative testing is mandatory for GH therapy in case of a subnormal response.

In the remaining patients, mostly with idiopathic causes, a serum IGF-I test and one provocative test must be performed, and in case of discordant results, a second provocative test is necessary for the diagnosis of persistent GHD [22, 27].

It is unclear whether different assay cutoffs should be adopted during this transitional period, as opposed to GHD assay cutoffs in adults. Some studies suggest that the assay cutoffs in these cases should be higher than for older adults, with levels of 6.1 μg/L and 19.0 μg/L for the ITT and GHRH-arg, respectively [28, 29].

In men, low or inappropriately normal levels of gonadotropins combined with low levels of serum testosterone are indicative of secondary hypogonadism. Semen analysis is indicated when considering fertility and may demonstrate a reduced sperm count or possibly azoospermia.

In younger women, oligo/amenorrhoea with low serum estradiol levels and low or inappropriately normal FSH and LH concentrations is consistent with secondary hypogonadism. In postmenopausal women, the absence of the normal rise of FSH and LH levels is sufficient for establishing a diagnosis.

In secondary hypogonadism, serum prolactin should always be measured to exclude hyperprolactinemia, which might occur for several reasons, such as prolactinomas, sellar and parasellar masses causing pituitary stalk compression, and use of drugs with antidopaminergic activity.

In adults, there is no usefulness in performing the gonadotropin-releasing hormone (GnRH) provocative test because it does not provide any additional information [5].

Evaluation of the thyrotrophic axis is based on the measurement of basal serum TSH and thyroid hormone levels. Central hypothyroidism is diagnosed when serum TSH levels are low or inappropriately normal coupled with low levels of serum free T4. Occasionally, TSH levels may be slightly elevated but usually remain lower than 10 mIU/mL. In these patients, the elevation of serum TSH is associated with decreased bioactivity due to increased sialylation [30]. In patients with concomitant GH and TSH deficiencies, serum-free T4 may be normal (usually at the lower tertile), decreasing only after GH replacement [31, 32]. More recently, it has been proposed that echocardiography can be useful in the evaluation of patients with hypothalamic-pituitary disease and free T4 levels within reference range, as some of these patients present signs of tissue hypothyroidism, a condition that could be named “subclinical central hypothyroidism” [33].

The TRH stimulation test has been performed in the past to diagnose central hypothyroidism [34]. However, this test is not currently recommended due to a lack of accuracy [35].

Cortisol secretion follows a circadian cycle, being highest in the early morning and lowest at midnight. Hence, a basal serum cortisol measurement may not reflect disturbances of the hypothalamus-pituitary-adrenal (HPA) axis. In addition, alterations in the levels of cortisol-binding globulin (CBG), which is frequently seen in clinical practice (e.g., higher levels of CBG, and consequently serum total cortisol, during oral estrogen treatment as a contraceptive) may also mask the diagnosis of central hypoadrenalism. Therefore, early morning serum cortisol (between 07:00 and 09:00) may be measured as a first step in the evaluation [10]. Stimulation tests are frequently required for corticotropic assessment. The most commonly used stimuli in clinical practice are insulin-induced hypoglycemia, Metyrapone, synthetic ACTH (ACTH_1-24), and CRH (Tables 8.3 and 8.4).

Hypoglycemia is a potent activator of the HPA axis, and the ITT is usually regarded as the “gold standard” for diagnosis (see more details in “GH stimulation testing”).