The pituitary gland is an endocrine organ weighing about 0.6 g that sits in a bony space called the sella turcica. This is above the fleshy back part of the roof of the mouth. The optic nerves that connect the eyes to the brain pass close by it .
The pituitary gland is connected directly to the hypothalamus and provides a link between the brain and hormone producing endocrine glands of the organism. The hypothalamus releases hormones into small blood vessels connected to the pituitary gland, which cause the pituitary gland to produce and secrete its own hormones. The pituitary gland controls the level of many hormones made by the endocrine glands of the body .
The pituitary gland has two parts, the anterior pituitary and the posterior pituitary.
The anterior pituitary accounts for 80% of the total volume of the gland. Distinct cellular compartments within the pituitary gland secrete highly specific hormones in response to hypothalamic, intra pituitary, and peripheral hormonal signals ().
- Pituitary-thyroid axis (); TSH is the communicating hormone
- Pituitary-adrenocortical axis (), ACTH is the communicating hormone
- Pituitary-somatotrophic axis (; GH is the communicating hormone
- Pituitary-reproductive axis (); LH and FSH are the communicating hormones
- Prolactin causes milk production in the female breast. Prolactin is measured primarily in patients with disturbed reproductive function ().
The anterior pituitary communicates with its target organs via a mixture of continuous and intermittent signal exchange. Continuous signaling allows slowly varying control whereas intermittent signaling leads to pulsatile hormone secretion and permits large rapid adjustments. The control systems that mediate such homeostatic corrections operate in a species-, age-, and context-selective fashion .
The posterior pituitary is the smaller back part of the pituitary gland. The posterior lobe contains two hormones which are produced in the supraoptic and paraventricular nuclei of the hypothalamus and transported axonally via the pituitary stalk to be stored and released from the posterior lobe. The hormones released in the circulation are:
- Vasopressin (antidiuretic hormone, ADH) that causes the kidneys to keep water in the body ()
- Oxytocin that causes the uterus to contract in women during childbirth.
Pituitary adenomas are benign glandular tumors which do not metastasize. They stay in the sella turcica and sometimes grow into the bony walls of the sella turcica. Adenomas are divided into micro adenomas (diameter < 1 cm) and macro adenomas (diameter ≥ 1 cm). The adenomas are classified whether they secrete excess of hormones (functional adenomas) or no excess of hormones (non-functional adenomas).
Pituitary adenoma account for about 15% of primary intra cranial tumors. Benign monoclonal adenomas develop when specific types of pituitary cells proliferate and secrete their respective hormones in elevated concentration. The incidence of adenomas is 30–40 per million and year in the general population. Symptoms of patients suffering from pituitary adenomas are often misjudged. The endocrinologic laboratory workup includes the determination of hormones and the application of functional tests for the detection of pituitary hypo- or hyper function. In addition to the clinical features and hormone measurements imaging techniques, and visual field testing provide important diagnostic information. Any kind of pituitary adenoma can be clinically functioning or non- functioning. Approximately 40% of these tumors are endocrinologically inactive .
Non-functioning pituitary adenomas result in at least one pituitary deficiency due to either a mass effect from the compression of normal pituitary or functional abnormalities which may distort or compress the pituitary stalk. The clinical syndrome of complete or partial anterior pituitary insufficiency is determined on the basis of symptoms and laboratory findings confirming loss of partial functions with the resulting failure of corresponding target organs . In the case of a space-occupying lesion, the somatotrophic and gonadotrophic systems are affected first. Clinical symptoms are therefore menstrual abnormalities and amenorrhea in women, loss of libido and impotence in men. Secondary adrenocortical insufficiency and secondary hypothyroidism are late symptoms. In the case of a non-functioning pituitary adenoma, loss of a number of partial functions is much more common than isolated deficiencies of ACTH, GH, FSH and LH. If dysfunction is diagnosed in one axis, the other hormonal systems must also be investigated.
- Lactotroph adenomas (proactinomas) account for about 40% of functioning pituitary adenomas
- Somatotrophic adenomas secrete growth hormone and account for about 20% of pituitary adenomas
- Gonadotrophic adenomas produce LH and FSH and are very rare
- Thyrotrophic adenomas secrete TSH and are very rare
- Plurihormonal adenomas make more than one hormone
- Null cell adenomas do not make hormones (non-functional adenomas).
The clinical symptomatology of functional adenomas is due to excess hormone secretion (prolactinoma syndrome, acromegaly, Cushing’s disease, hyperthyroidism) or to a mass effect of the tumor (hypopituitarism, visual disturbance, cranial nerve palsies, headache). Non functioning adenomas do not release excess pituitary hormone.
Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or rarely released from the posterior lobe . The anterior lobe produces six hormones: growth hormone (GH), gonadotropins (FSH, LH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), and prolactin. The posterior pituitary lobe contains the hormones antidiuretic hormone (ADH) and oxytocin.
Hypopituitarism may be the result either of pituitary or hypothalamic dysfunction, the former interfering with the pituitary hormone secretion (secondary dysfunction) the latter with hypothalamic pituitary-releasing hormone secretion (tertiary dysfunction).
Hypopituitarism results from different etiologies:
- Pituitary and hypothalamic mass lesions or treatment of adenoma with pituitary surgery or radiotherapy
- Trauma and vascular injury
- Congenital etiology
The acuity of the damage to the hypothalamic-pituitary region and the resultant loss of hormones cause the clinical symptoms. Generally, the usual sequential pattern for hormonal deficiencies starts from the loss of GH, followed by the gonadotropins, then TSH and ACTH.
It is important to recognize the symptoms of hypophysitis an inflammation of the pituitary. The hypophysitis may be primary or secondary to sella or para sellar lesions, systemic diseases or drugs. Especially TSH and ACTH present deficits .
- Pituitary apoplexy, Sheehan’s syndrome and traumatic brain injury that may result in hypophysitis from compression of hormone secreting cells or the stalk compression causing hypogonadism, growth hormone deficiency or central diabetes insipidus.
- Late complication of radio therapy. Somatotroph cells seem to be the most vulnerable to damage followed by gonadotroph, thyrotroph and corticotroph cells.
- Immune checkpoint inhibitors (ICI). The ICIs are monoclonal antibodies used in the management of solid and hematological malignancies. The antibodies target immune checkpoints such as cytotoxic T-cell antigen 4 (CTLA-4; CD28) and cause a T-cell activation resulting in anti-tumor immunity, reversing immune escape and promoting tumor cell death. Immune-mediated adverse events of ICIs are inflammation of endocrine glands, mostly represented by hypophysitis.
Acute hypopituitarism is associated with a high risk of mortality, usually secondary to loss of ACTH and subsequent hypoadrenalism. Sudden onset of acute headache, usually retro orbital in nature, should alert clinicians to the possibility of acute pituitary damage . Neuroophthalmic signs and diabetes insipidus also can be signs of acute pituitary damage
The clinical presentation of chronic hypopituitarism is usually non-specific. The signs and symptoms depend on the extent of the hormonal loss.
Progression from isolated GH deficiency (IGHD) to combined pituitary hormone deficiency in children depends on the etiology. Children with IGHD display a significant risk of developing additional pituitary deficiencies. This risk ranks between 5.5% in childhood-onset idiopathic IGHD and 35% in adult-onset organic IGHD. The type and age at occurrence of additional pituitary deficits are highly variable and they cannot be easily predicted on the etiology, severity and age at onset of IGHD. All patients diagnosed with IGHD need a careful and indefinite follow-up for additional hormone deficiencies.
Hyperprolactinemia seen with non-functioning pituitary adenoma, from compression of gonadotroph cells or from stalk compression- induced hyperprolactinemia results from the inability of dopamine to be delivered to lactotroph cells and hence of its inhibitory control.
Macro adenomas, micro adenomas and craniopharyngiomas account for the most pituitary mass lesions. Macro adenomas (≥ 1 cm) are commonly associated with deficiencies in anterior pituitary hormones. Micro adenomas (< 1 cm) are found to 27% of biopsies in the general population and are rarely associated with hypopituitarism. Craniopharyngiomas account for para sellar tumors and one third occur in patients below 18 years.
Hypopituitarism is the common consequences of pituitary surgery and radiotherapy
Traumatic brain injury is associated with hypopituitarism in 21 to 54% of cases . In a study following dynamic pituitary hormones change after traumatic brain injury patients with decreased FSH, testosterone, GH, FT3, and FT4 were at high risk for poor neurological outcome.
Sheehan’s syndrome is the result of pituitary infarction that occurs after severe postpartum hemorrhage
- Pituitary apoplexy results from infarction or hemorrhage into the pituitary
- Infiltrative disorders involving the hypothalamic- pituitary axis, and in particular the pituitary stalk causing hypopituitarism are sarcoidosis, tuberculosis, histiocytosis X, and hemochromatosis
- Immunologic disorders. Immune-mediated diffuse infiltration of the anterior pituitary with lymphocytes and plasma cells cause lymphocytic hypophysitis and hypopituitarism. In most cases lymphocytic hypophysitis is evident in pregnancy or post partum. Clinical symptoms are headache and visual failure.
Naturally occurring mutations have demonstrated a role of several factors in the etiology of pituitary hormone deficiency . The development of the pituitary gland depends on the expression of transcription factors and signalling molecules. Genetic mutations in these factors can lead to congenital hypopituitarism that can present with non-specific symptoms in neonates, but in some instances the full expression of hypopituitarism evolves over time, with the last deficiency presenting in adolescence or young adulthood .
- A complex phenotype including anterior pituitary hormone deficiencies in association with extra-pituitary abnormalities or malformations such as pituitary stalk interruption syndrome or midline defects. The transcription factors involved in these phenotypes are early expressed in regions that determine the formation of forebrain and related midline structures such as hypothalamus and pituitary. Mutations of these genes are therefore characterized by marked phenotypic heterogeneity.
- Pure endocrine phenotype including anterior pituitary hormone deficiencies, normal hypothalamo-pituitary morphology (regardless of the size of the pituitary gland) and no extra-pituitary malformation. These phenotypes are due to mutations of late reacting pituitary specific transcription factors. The most frequently published defect is the gene mutation of Prop1.
Laboratory hypopituitary diagnosis is based on hormone measurements and functional testing. Refer to:
The normal reaction of various pituitary hormones in each of 5 healthy male and female individuals is shown in:
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AD, autosomal dominant; AR, autosomal recessive
Clinical and laboratory findings
Figure 33.1-1 Regulation of anterior pituitary hormone secretion by hypothalamic peptides and control of target organs. GHRH, growth hormone releasing hormone; CRH, corticotropin releasing hormone; TRH, thyrotropin releasing hormone; GnRH, gonadotropin releasing hormone; ACTH, adrenocorticotropin; GH, growth hormone; IGF-1, insulin-like growth factor 1; PR, prolactin; FSH, follicle stimulating hormone; TSH, thyroid stimulating hormone; T4, thyroxine.
Figure 33.3-1 Pituitary stimulation test using 4 releasing hormones in male healthy individuals. Endocrine reaction after simultaneous injection. PRL, prolactin; GH, human growth hormone. Resting period from 8:00–10:00 a.m.; administration of the releasing hormones at 10:00 a.m.