What hormones from the anterior pituitary target the gonads?

The anterior pituitary secretes seven hormones that regulate several physiological processes, including stress, growth, and reproduction.

Learning Objectives

• Identify the location and the hormones produced by the anterior pituitary

Key Points

• A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland.
• The anterior pituitary regulates several physiological processes, including stress, growth, reproduction, and lactation.
• The anterior pituitary gland secretes 7 hormones: follicle -stimulating hormone, luteinizing horomone, adrenocorticotropic horomone, thyroid -stimulating horomone, prolactin, endorphins, and growth hormone.

Key Terms

• anterior pituitary gland: A major organ of the endocrine system that regulates several physiological processes including stress, growth, reproduction, and lactation.

A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis) is the glandular, anterior lobe of the pituitary gland. The anterior pituitary regulates several physiological processes including stress, growth, reproduction, and lactation.

Its regulatory functions are achieved through the secretion of various peptide hormones that act on target organs including the adrenal gland, liver, bone, thyroid gland, and gonads. The anterior pituitary itself is regulated by the hypothalamus and by negative feedback from these target organs.

Anatomy of the Anterior Pituitary Gland

The fleshy, glandular anterior pituitary is distinct from the neural composition of the posterior pituitary. The anterior pituitary is composed of multiple parts:

• Pars distalis: This is the distal part that comprises the majority of the anterior pituitary; it is where most pituitary hormone production occurs.
• Pars tuberalis: This is the tubular part that forms a sheath that extends up from the pars distalis and wraps around the pituitary stalk. Its function is poorly understood.
• Pars intermedia: This is the intermediate part that sits between the pars distalis and the posterior pituitary and is often very small in humans.

Major Hormones Secreted by the Anterior Pituitary Gland

• Adrenocorticotropic hormone (ACTH), is a polypeptide whose target is the adrenal gland. The effects of ACTH are upon secretion of glucocorticoid, mineralocorticoids, and sex corticoids.
• Beta-endorphin is a polypeptide that effects the opioid receptor, whose effects include the inhibition of the perception of pain.
• Thyroid-stimulating hormone is a glycoprotein hormone that affects the thyroid gland and the secretion of thyroid hormones.
• Follicle-stimulating hormone is a glycoprotein hormone that targets the gonads and effects the growth of the reproductive system.
• Luteinizing hormone is a glycoprotein hormone that targets the gonads to effect sex-hormone production.
• Growth hormone is a polypeptide hormone that targets the liver and adipose tissue and promotes growth through lipid and carbohydrate metabolism.
• Prolactin is a polypeptide hormone whose target is the ovaries and mammary glands. Prolactin influences the secretion of estrogen/progesterone and milk production.

Regulation

Hormone secretion from the anterior pituitary gland is regulated by hormones secreted by the hypothalamus. Neuroendocrine neurons in the hypothalamus project axons to the median eminence, at the base of the brain. At this site, these neurons can release substances into the small blood vessels that travel directly to the anterior pituitary gland (the hypothalamo-hypophysial portal vessels).

The anterior pituitary: The anterior pituitary, in yellow, is linked to the hypothalamus by a portal system. The hypothalamus releases signaling molecules that incite the anterior pituitary to produce hormones.

Development

The anterior pituitary, also known as adenohypophysis, is a classic endocrine gland in that it is composed of secretory cells of epithelial origin supported by connective tissue rich in blood and lymphatic capillaries. The anterior pituitary is derived from the ectoderm, more specifically from the Rathke’s pouch, part of the developing hard palate in the fetus. The Rathke’s pouch eventually loses its connection with the pharynx, giving rise to the anterior pituitary. The pouch becomes committed to organ development several days prior to the expression of markers of individual cell types within the mature anterior pituitary gland. Between the time of organ commitment and maturation, a series of cell type-specific differentiation and proliferative events occur.

Anterior Pituitary

Anterior pituitary among the six hormones that secreted by anterior pituitary we focus to disorder of growth hormone (GH) that has more known cardiovascular manifestation. GH is the most abundant hormone in the adult pituitary gland, and it plays an important role in maintaining the metabolic process.2 It is synthesized, stored, and secreted by somatotrope cells located predominantly in the anterior pituitary gland and comprises between 35% and 45% of pituitary cells.2 The cellular effects of human growth hormone (hGH) are exerted through two major pathways. The first is binding the hormone to specific hGH receptors on target cells that have been identified in the heart, skeletal muscle, fat, liver, and kidneys, as well as in many cells throughout fetal development. The second effect of hGH is done by stimulation of the synthesis of insulin-like growth factor type 1 (IGF-1). This protein is synthesized primarily in the liver, but other cell types can produce IGF-1 under the influence of hGH. IGH-1 acts as a second messenger and mediates most actions of hGH. The clinical activity of disease in patients with an excess of hGH (acromegaly) correlates better with serum levels of IGF-1 than with hGH levels.3 GH enhances lipolysis and fatty acid oxidation and increases clearance of low-density lipoprotein (LDL) by activating expression of hepatic LDL receptors.4,5 In GH deficiency (GHD), the atherogenic profile of lipoproteins increases and is reduced by GH therapy.6 Disorders related to GH are mainly separated into two categories, GH deficiency and GH excess (acromegaly).

Structure of the anterior pituitary

The anterior pituitary is composed of five different cell types, each of which secretes a different hormone (Table 4.1). The most abundant type of secretory cell in the anterior pituitary is the somatotroph. These cells account for around 50% of the secretory cells in the gland and are principally located in the anterior wings of the gland. Lactotrophs are located throughout the gland and represent between 10% and 30% of the secretory cells. These two cell types are described as acidophils because they stain with acidic dyes. The other cell types are basophils because they stain with basic dyes. There are three types of basophils, the most numerous being gonadotrophs which make up about 20% of the secretory cells in the gland, with corticotrophs 10% and thyrotrophs 5%. The basophils are mostly found in the medial section of the anterior pituitary. All the secretory cells of the anterior pituitary contain secretory granules and are histologically typical of peptide-secreting cells (see Ch. 1). There is another group of cells, called folliculostellate cells, in the anterior pituitary which make up around 10% of the gland volume and are distributed throughout the gland. These cells do not contain secretory granules and do not stain with either acid or basic dyes. Their function is not clear but it is possible that they are pituitary stem cells, capable of differentiating into one of the secretory cell types.

Cellular Composition of the Anterior Pituitary

The anterior pituitary is derived from oral ectoderm and has an appearance typical of an endocrine gland, with cells grouped in cords and follicles. Approximately 50% of the cells of the anterior pituitary are somatotrophs that produce growth hormone (GH) (Figure 2.3). These cells are primarily located in the lateral wings of the anterior lobe, but can also be scattered in the median wedge [24]. Prolactin (PRL)-secreting lactotrophs represent ∼15% of cells in the anterior pituitary and are randomly distributed throughout the lobe, but are most numerous in the posteromedial and posterolateral portions [24]. Corticotrophs express proopiomelanocortin (POMC), which is the precursor of adrenocorticotropin (ACTH), melanocortin hormone (MSH), lipotropic hormone (LPH) and endorphins. Corticotrophs comprise about 15% of anterior pituitary cells. They mostly cluster in the central mucoid wedge, but are also scattered in the lateral wings, and are the predominant cell type in the poorly developed human intermediate lobe. Gonadotroph cells produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and represent up to 10% of the human anterior pituitary cell population. In the rat, gonadotroph cell number varies with age, sex and hormonal status [25]. Gonadotrophs are scattered throughout the pars distalis and are the major constituent of the pars tuberalis [26]. Thyrotrophs are the least abundant cell type in the anterior pituitary, comprising ∼5% of the total cell population, and are mostly found in the anteromedial portion of the gland [24], but are also located in the pars tuberalis [26].

Many supporting and/or non-neuroendocrine cells are scattered throughout the anterior pituitary. These include follicular cells surrounding follicles [24,27], agranular folliculostellate cells with long branched cytoplasmic processes [28,29], incompletely differentiated null cells that do not secrete specific hormones [30] and mitochondria rich oncocytes [24].

Pituitary Fragments

Anterior pituitaries are each divided into 8 fragments, and 16 fragments/vial are incubated in 1 ml of modified Krebs–Ringer bicarbonate buffer. Vials are incubated for 1 hr at 37°C in a Dubnoff metabolic shaker in an atmosphere of 98% O2 and 5% CO2. The medium is replaced with fresh medium and vials are incubated for another hour, and then the medium is collected (basal values). Medium is replaced with fresh medium containing either saline (vehicle) or the drug or peptide under investigation, and the incubation is continued for the time desired (e.g., 1 hr).

Endocrine System and Central Nervous System

Anterior pituitary dysfunction has been described in up to 20% of patients with LCH, usually associated with diabetes insipidus (DI). However, anterior pituitary function has not been systematically studied in adults; most information has been obtained from studies in children. Anterior pituitary deficiency in LCH is almost always associated with DI; only a few cases of pituitary hormone insufficiency without DI have been described in the literature. DI is by far the most common disease-related endocrine consequence and is found in up to 30% of all patients or in 40% of patients with multisystem disease and even in 94% of adults with other pituitary deficiencies. Although DI may predate the diagnosis, it usually develops at approximately 12 months of age, with a range that can extend to many years from diagnosis. Associated features are multisystem disease with skull vault defects and, notably, temporal bone or orbital lesions with intracranial tumor extension. Growth hormone deficiency (GHD) occurs in approximately 40% of affected children and in up to 50% of patients with DI, and it has been also related to histiocytic infiltration of the hypothalamus. GHD is frequently the first endocrine defect in addition to DI, with a median latency of approximately 1 year from diagnosis. Growth retardation, although previously described, is thought to be an infrequent presentation of LCH, but GHD should always be considered in children with LCH and DI. As adults with GHD may show an increase in well-being and a favorable metabolic profile in response to GH therapy, assessment of GHD may be an important part of the evaluation of adult patients with LCH.

There are only a few reports on gonadal function in patients with LCH, as most studies have been on prepubertal children. Although the early studies in adults with LCH and DI failed to demonstrate abnormalities of gonadotropin secretion, this sequela is the second most common pituitary deficiency presenting either with menstrual disturbances in women or with decreased libido in men. Similarly, thyroid hormone deficiency can be a major component of anterior pituitary dysfunction in patients with LCH and is almost always associated with panhypopituitarism. Adrenocorticotropic hormone (ACTH) deficiency presents mostly in the context of generalized pituitary involvement, although a few cases of isolated ACTH deficiency have also been described.

Imaging studies of patients with LCH and CNS involvement have shown that more than one type of lesion may be present in 87% of individual patients, including patients with DI. In addition, abnormalities of the hypothalamo–pituitary axis (HPA) were observed in 68% of patients with CNS lesions and in 81.5% of patients with DI [infundibular thickening, partial or complete empty sella with a lack of posterior pituitary bright spot on T1-weighted magnetic resonance imaging (MRI) sequences, or a pituitary mass lesion]. Morphological changes in the HPA are optimally demonstrated by MRI with administration of gadolinium-dimeglumine gadopentetate. A small pituitary or empty sella has also been described in cases of combined anterior and posterior pituitary insufficiency. However, anterior pituitary dysfunction may also occur in the absence of structural changes on imaging and has been attributed to microinjury leading to vascular impairment and scarring. Other possible mechanisms include cytokine modulation from adjacent osseous lesions or an autoimmune effect.

Efforts to identify predictors of late endocrine sequelae in children with LCH showed that dynamic endocrine pituitary testing was not a useful predictor. Neither the site of involvement nor the extent of the disease was associated with further endocrine deterioration. Therefore, it seems that only DI in association with markedly abnormal hypothalamo-pituitary imaging identifies patients with LCH at higher risk for anterior pituitary dysfunction. As DI is associated with multisystem disease and progression that may be greatly delayed, such patients should be under regular and prolonged follow-up to identify such dysfunction and provide adequate replacement.

DI with structural changes in the HPA often heralds the involvement of other parts of the brain with more global neurological or neuropsychological sequelae, depending on the location of the involvement. The signs and symptoms of nonendocrine hypothalamic involvement range from disturbances in social behavior, appetite and temperature regulation to abnormal sleeping patterns. Further abnormalities, such as disturbances in thermoregulation and adipsia, can make DI difficult to treat and complicate the overall management of these problematic cases. This is particularly significant when there is also memory impairment and problems with compliance. More serious problems from CNS involvement, though of rare incidence, include mass lesions in the brain parenchyma or choroid plexus (resulting in hydrocephalus), space-occupying masses from neighboring bone or meningeal lesions, and diffuse infiltration of the cerebellum, leading to ataxia and visual problems.

Thyroid gland involvement is rare, with only a few reported cases involving goiter and in some cases hypothyroidism. Pancreatic infiltration has also been reported but without apparent dysfunction.

In summary, adult patients with LCH presenting with DI are at high risk for anterior pituitary hormonal deficiency and hypothalamic involvement, especially when accompanied by abnormal HPA imaging. Endocrine abnormalities should be actively sought in patients with LCH, as their recognition and management play important roles in the treatment of this difficult condition.

Cellular Composition of the Anterior Pituitary

The anterior pituitary is derived from oral ectoderm and, typical of an endocrine gland, has cells grouped in cords and follicles. Approximately 50% of the cells are somatotrophs that produce GH (Fig. 2.3). These cells are primarily located in the lateral wings of the anterior lobe, but can also be scattered in the median wedge [26]. Prolactin (PRL)-secreting lactotrophs represent ~15% of cells in the anterior pituitary, and are randomly distributed throughout the lobe, but are most numerous in the posteromedial and posterolateral portions [26]. Corticotrophs express proopiomelanocortin (POMC), which is the precursor of adrenocorticotropic hormone (ACTH), melanocortin hormone (MSH), lipotropic hormone, and endorphins. Corticotrophs comprise about 15–20% of anterior pituitary cells. They mostly cluster in the central mucoid wedge in the center of the gland, but are also scattered in the lateral wings, and are the predominant cell type in the poorly developed human intermediate lobe. Gonadotroph cells produce LH and FSH and represent up to 10% of the human anterior pituitary cell population. (In the rat, gonadotroph cell number varies with age, sex, and hormonal status [27].) Gonadotrophs are scattered throughout the pars distalis and are the major constituent of the pars tuberalis [28]. Thyrotrophs are the least abundant cell type in the anterior pituitary, comprising approximately 5% of the total cell population, and are mostly found in the anteromedial portion of the gland [26], but are also found in the pars tuberalis [28].

Supporting and/or non-neuroendocrine cells are scattered throughout the anterior pituitary, including follicular cells surrounding follicles [26,29], agranular folliculostellate cells with long-branched cytoplasmic processes [30,31], incompletely differentiated null cells that do not secrete specific hormones [32], and mitochondria-rich oncocytes [26].

Abstract

Anterior pituitary failure is caused by several etiologic factors. Mass lesions and their treatment, genetic mutations, infiltrative and infectious disease, and traumatic brain injury are but a few of the causes of hypopituitarism. Patients with hypopituitarism have an increased mortality rate. The clinical manifestations of hypopituitarism vary widely and depend upon the underlying etiology, the number and type of pituitary hormones affected, and the age of onset of the deficiency. The diagnosis of pituitary failure depends upon the measurement of anterior pituitary hormones and their target hormones in serum, coupled with a patient’s history and clinical findings that suggest the insufficiency. Dynamic testing is often required for a full evaluation of pituitary function. The treatment of pituitary insufficiency usually entails replacement of target hormones, but can include replacement of pituitary hormones or hypothalamic hormones, depending upon the clinical situation and the desired outcome.

1 Pituitary gland

Anterior pituitary release of β-EP (as well as ACTH and β-LPH) is under the influence of corticotropin releasing factor (CRF), a recently discovered hypothalamic peptide which contains 41 amino acids (Vale et al., 1981). The release of CRF may be inhibited by central norepinephrine inputs and stimulated by central serotoninergic influences (Fig. 4.1). The feedback circuitry for regulation of anterior pituitary ACTH (and, concomitantly, β-EP and β-LPH) is dependent upon ACTH stimulation of the release of glucocorticoids from the adrenal cortex. Two negative feedback loops have been defined: short-loop feedback, whereby glucocorticoids act directly at the pituitary gland to decrease ACTH, and long-loop feedback at brain centers that inhibit hypothalamic release of CRF.

Recently, Pettibone and Mueller (1981) defined another system that may have important regulatory effects upon release by the anterior pituitary of proopiomelanocortin products. These investigators reported in vitro and in vivo studies revealing that the α-agonist clonidine acts at the pituitary as a potent stimulus for the release of β-EP immunoreactive substances. From their work and the work of others (Reisine et al., 1983), it is speculated that blood borne norepinephrine or epinephrine, activated by autonomic responses, may act in concert with CRF to stimulate the release of these anterior pituitary hormones (Fig. 4.1).

The release of intermediate-lobe β-EP is not directly regulated by hormonal feedback systems (Fig. 4.2). Instead, evidence indicates that tuberoinfundibular dopamine pathways project from the arcuate nucleus to exert an inhibitory influence on intermediate-lobe β-EP release (Holaday and Loh, 1981). Dopamine antagonists such as haloperidol increase the release of β-EP, whereas dopamine agonists block the stress-induced release of β-EP. It has also been suggested that serotonin as well as α-and β-adrenergic agonists can have a stimulatory action on intermediate lobe neuropeptide release (Fig. 4.2) (Pettibone and Mueller, 1982).

Negative feedback systems are believed to predominate in the regulation of most neuroendocrine systems, with the possible exception of the prepubertal surges of luteinizing hormone and follicle stimulating hormone. As such, feedback inhibition allows for the release of neuroendocrine substances to be regulated by both an ‘on’ and ‘off’ switch. In contrast, positive feedback systems result in an ‘open loop’ (i.e., two ‘on’ switches without an ‘off’ switch). Activation of these systems would result in perpetual increases in hormonal release. However, it is possible that positive feedback systems have a physiological role in amplifying the sudden surge of endogenous opioid activity when activated by stressors (Holaday and Loh, 1981). The neuroendocrine regulation of β-EP release potentially allows for at least three such systems (Holaday and Loh, 1981). As one example, since β-EP inhibits tuberoinfundibular dopaminergic activity (Gudelsky and Porter, 1979), and since this dopamine pathway inhibits intermediate lobe β-EP (Przewlocki et al., 1978), circulating β-EP may enhance its own release through disinhibition of the intermediate lobe (Holaday and Loh, 1981). What would turn such a system off? I have speculated that part of the biological significance of opiate tolerance mechanisms would provide for the 'off switch in such a situation (Holaday and Loh, 1981).

At present, mechanisms mediating the posterior pituitary release of dynorphin and enkephalin are poorly understood. It appears that dynorphin and vasopressin share common regulatory mechanisms; dehydration depresses pituitary content of both of these peptides, and they are presumably released into the circulation. In opposition to the effects of adrenal glucocorticoid feedback upon anterior pituitary pro-opiomelanocortin-derived opioid substances, dynorphin and Leu-enkephalin content in the posterior pituitary (along with vasopressin) decreases with adrenalectomy and increases following corticosteroid injections (Hollt et al., 1981).

The similarities in vasopressin and dynorphin responses following pharmacological and physiological manipulations suggested two possibilities: either these substances originate from a common precursor, or dynorphin may be a component of the neurophysins. However, three observations indicate that these possibilities are unlikely. The observation that Brattleboro rats (which lack vasopressin) had ‘normal’ anatomical patterns of dynorphin distribution (Watson and Akil, 1982) as well as ‘normal’ dynorphin responses to the above mentioned pharmacological and physiological manipulations (Herz et al., 1982) favors the hypothesis that these neuropeptides are separately synthesized. In addition, on a molar basis, dynorphin concentrations are at least 1,000 fold less than vasopressin levels in these tissues (Cox et al., 1982).

Hormonal Assessment of Pituitary Function

Anterior pituitary function should be evaluated in patients with known or suspected pathology of the hypothalamus or the pituitary sella, and in patients complaining of symptoms related to the different pituitary hormonal axes. Patients with symptoms and signs of hypogonadism, decreased libido, anemia, weakness, tiredness, gynecomastia, galactorrhea, weight gain, hyponatremia, hypoglycemia, central hypothyroidism, muscle weakness, and other symptoms reflecting one or more hormone deficiencies should be screened for pituitary failure. Comprehensive evaluation of pituitary function/reserve includes GH (measured during dynamic stimulation tests), IGF-1, TSH together with T3 and T4, serum cortisol (morning and during stimulation), testosterone, estradiol, LH and FSH, and serum PRL. Normal test results usually exclude pituitary hormone deficiency. Importantly, patients with hypopituitarism secondary to pituitary masses commonly present with mild hyperprolactinemia due to continuous pressure on the pituitary stalk.

In cases of mild to moderate polyuria and polydipsia suspected for central (pituitary) diabetes insipidus, a dehydration test is commonly performed to confirm the diagnosis and to differentiate from nephrogenic diabetes insipidus or from excess water intake. During the test, serum and urine osmolality as well as urine volume are measured, and the response to administration of parenteral ADH or desmopressin (ADH analog) is assessed.