Endocrine Development

The endocrine system is a system that functions in hormone synthesis and secretion. It consists of hormone producing endocrine cells organized as independent organs (e.g. the pituitary, thyroid, and adrenal glands), or as groups of endocrine cells within organs (e.g. the islets of the pancreas, Leydig cells of the testis, and granulosa cells of the ovary) or as solitary cells scattered diffusely within organs (e.g. enteroendocrine cells of the stomach and intestines, and neuroendocrine “Kulchitsky” cells of the trachea and the bronchial tree). In this chapter, the development of the major (independent) endocrine glands will be discussed; developments of groups of endocrine cells and solitary endocrine cells are discussed along with the developments of the organs where they reside.

Fig. 15.1.  The illustration shows the location of endocrine glands and endocrine cells within the human body.

Development of the Pituitary Gland

The pituitary gland, also known as the hypophysis cerebri, is often referred to as the master endocrine gland because regulates the activity of a number of other endocrine glands, such as the thyroid, adrenal glands, and the gonads. It is located on the floor of the cranium within a bony depression known as the sella turcica. It is structurally and functionally connected the brain. The pituitary has two main anatomical parts called the anterior pituitary and the posterior pituitary; histologically too it has two parts known as the adenohypophysis and the neurohypophysis. The anterior pituitary is essentially made of adenohypophysis and the posterior pituitary is neurohypophysis in essence. The anterior pituitary produces 6 major polypeptide hormones namely, the adrenocorticotrophic hormone (ACTH), the growth hormone (GH), the thyroid stimulating hormone (TSH), the follicle stimulating hormone (FSH), and the luteinizing hormone (LH). The posterior pituitary on the other hand produces two main hormones, which are oxytocin (OT) and antidiuretic hormone (ADH), also known as vasopressin.

Fig. 15. 2. The illustration shows the component parts of the adrenal the pituitary gland.

Embryologically, the pituitary gland has a dual origin; it has two different primordia, but it is of ectodermal origin. At the beginning of the 5^th week of embryonic development, one of the primordia called Rathke’s pouch develops from the ectoderm of the stomodeum, whereas the other primordium which known as the infundibulum, develops as an evagination of the neural ectoderm of the floor of the 2^nd ventricle of the brain (the diencephalon). In the 6^th week of embryonic development, the infundibulum grows towards Rathke’s pouch and ultimately comes in contact with it. The infundibulum rests on the posterior aspect of Rathke’s pouch, foreshadowing the formation of the posterior lobe of the pituitary gland. The posterior lobe of the pituitary remains connected to the diencephalon throughout life, whereas Rathke’s pouch detaches itself from the stomodeum (oral cavity) and form the anterior glandular lobe of the pituitary gland.

Fig. 15.3. The illustration on the left shows Rathke’s pouch as an outpocketing of the roof of the stomodeum (primitive oral cavity) and the infundibulum as an out pocketing of the floor of the diencephalon. The illustration on the right shows enlargement of both primordia to the extent that the infundibulum comes to lie on the posterior aspect of Rathke’s pouch.

Development of the neurohypophysis takes place as part of the development of the brain, beginning with the differentiation of neuroblast in the floor of the diencephalon in the region of the future hypothalamus into secretory neurons that synthesize oxytocin and vasopressin. These neurons aggregate into groups forming the hypothalamic supraoptic nucleus and the paraventricular nucleus. The axons of these secretory neurons elongate and project downwards towards Rathke’s pouch. These axonal projection are the primary components of the three parts of the neurohypophysis, the median eminence, the infundibular stalk (pituitary stalk) and the infundibular process (pars nervosa). The axons terminate in nerve endings that store are release both hormones, oxytocin and vasopressin, which are synthesized in the cell bodies of the secretory neuron. Hormone storage causes distention of the nerve endings that are visible under the microscope and known as Herring bodies. Thus, the neurohypophysis remains connected to hypothalamus throughout life by these axonal projections.

The hypothalamic supraoptic and paraventricular nuclei develop in the floor of the diencephalon in the vicinity of the optic chiasma. They made of large secretory nerve cell bodies with axons carrying secretory vesicles passing along axonal projection directed towards the pars nervosa. These axon projects contribute to the formation of the hypothalamic-physeal  tract.

The median eminence develops posterior to the optic chiasm and constitutes a connecting interface between the hypothalamus and the rest of the pituitary gland. It is the site where the hypothalamic releasing hormones pass into the hypophyseal portal circulation. It differentiate into two layers, an inner layer and an inner layer. The inner layer contains axons of the secretory neurons of the supraoptic and paraventricular nuclei that contain oxytocin and vasopressin (ADH). The outer layer comprises axons and nerve endings that contain hypothalamic hormone-releasing hormones including gonadotrophin releasing hormone and thyroid-stimulating-hormone-releasing hormone. This outer layer also contains the capillary loops of the hypothalmo-phypophyseal portal system. These capillaries drain into veins that break up into capillaries within the pars distalis of the anterior pituitary passing hormone-releasing hormones to the endocrine cells of the pars distalis influencing the activities of these endocrine cells. A portal system is vascular system consisting of veins interposed between two sets of capillaries.

Fig. 15. 4. Illustration showing the axonal connections of the three parts of the neurohypophysis (median eminence, hypophyseal stalk, and the pars nervosa) to the supraoptic and paraventricular nuclei of the hypothalamus.

The hypophyseal stalk (pituitary stalk) connects the median eminence to the pars distal anteriorly and the pars nervosa posteriorly. It contains axons passing down from the hypothalamus to the pars nervosa as part of the hypothalamo-hypophyseal tract and also contains hypophyseal portal veins that carry the hypothalamic hormone-releasing hormones towards the pars distalis of the anterior lobe of the pituitary.

Pars nervosa is the largest part of the neurohypophysis and is the distal most; it constitutes the bulk of the posterior lobe of the pituitary gland. It is primarily made of axons traversing down from the hypothalamus in addition to nerve endings of these axons. The axons are unmyelinated axons and transport oxytocin and vasopressin to the nerve endings. Nerve endings engorged by these two hormones are known as Herring bodies. The two hormones are released from these nerve endings to adjacent blood capillaries to be carried by the blood stream to their target cells and organs. In addition, pars nervosa contains modified neuroglial cells known as pituicytes.

The pituitary adenohypophysis develops from Rathke’s pouch, which an outpocketing of the ectodermal roof of the primitive oral cavity (the stomodeum). Rathke’s pouch appears in the 3^rd week of embryonic development and grows upwards towards the developing brain vesicles. In the 4^th or 5^th week of embryonic development, Rathke’s pouch detaches from the roof of the oral cavity and come to lie in contact with the diencephalic infundibulum that will form the neurohypophysis.

Fig. 14.5.  The illustration on the left shows development of the adeno- and neurohypophysis, whereas the one right shows development of the pars distalis, pas tuberalis and the residual lumen from Rathke’s pouch.

The anterior wall of Rathke’s pouch proliferates greatly and forms the pars distalis. Its cells differentiate into endocrine cells that produce several polypeptide hormones that include FSH. LH. ACTSH, and TSH. The endocrine cells arrange themselves into cord and clusters associated with blood capillaries. The posterior wall of Rathke’s pouch does not enlarge greatly and give rise to the inconspicuous pars intermedia is often represented a thin layer of endocrine cells present between the anterior and posterior lobes of the pituitary but is usually considered as part of the anterior pituitary. It produces the melanocyte stimulating hormone that regulates the activity of skin melanocytes. It also produces small amounts of ACTH.

The pars tuberalis develops from the anterior wall of Rathke’s pouch. Cell proliferate and migrate upwards towards the hypophyseal stalk gradually surrounding it. The function of the pars tuberalis is not yet clearly understood but it is thought to be involved in the annual biological cycles (circannual rhythms). It also secretes small amounts of TSH.

The endocrine cells of the adenohypophysis are all derived from the ectoderm of the primitive oral cavity, whereas secretory neurons of the hypothalamus and pituicytes of the neurohypophysis are derived from the neural tube ectoderm of the diencephalon. The connective tissue elements of the pituitary gland are derived from the neural crest which in turn is ectodermal in origin.

Fig. 15.6. The illustration shows the various parts of the fully developed pituitary gland.

Developmental anomalies of the pituitary gland include a range of abnormalities such as hypoplasia of the anterior pituitary, ectopic posterior pituitary, anomalies of the pituitary stalk, and a sella empty of a gland. These anomalies may cause endocrinopathies, such as hypopituitarism. Hypoplasia of the anterior pituitary is the most common and results from failure of Rathke’s pouch to develop normally. Ectopic posterior pituitary result from abnormal growth the diencephalic diverticulum which results in the presence of the posterior pituitary in unusual locations. Empty sella results from faulty bone growth that compresses the developing pituitary gland that is flattened by compression of the walls of the sella turcica.

Fig. 15.7. The illustration shows the embryonic origin of the various parts of the pituitary gland.

Development of the Thyroid Gland

The thyroid gland is the first of the endocrine glands to develop; it originates from the floor of the primitive pharynx during the 1/3^rd week of embryonic development. It is of endodermal origin and begins to form as a thickening of proliferating endodermal cells in the vicinity of the foramen cecum at the base of the tongue between the tuberculum impar and the copula. The proliferating cells evaginate from the floor of the primitive pharynx between the first and second pharyngeal pouches thus forming the thyroid diverticulum. It is recalled that several structures and organs develop from the primitive pharynx and the pharyngeal pouches; these include the tympanic cavity, the eustachian tube, the palatine tonsils, the parathyroid lands, the thymus, the pharynx, the larynx, the trachea and the lungs.

Fig. 15.8.  The illustration shows the primordium of thyroid gland originating as a ventral diverticulum of the primitive pharynx between the 1^st and 2^nd pharyngeal pouches.

The thyroid diverticulum, which is endodermal in origin, grows ventrally, solidifies, enlarges and then by the 7^th week of embryonic development, bifurcates into two lobes connected by a narrow bridge called the isthmus. The thyroid diverticulum remains connected to the site of origin at the foramen cecum by duct called the thyroglossal duct which regresses later in development and by the 10^th week of gestation the detaches from the pharynx and reaches its final destination to be situated in front of the 2^nd – 5^th tracheal rings.

The endodermal cells of the thyroid diverticulum differentiate into thyroid follicular endocrine cells that arrange themselves into solid cords that further differentiate in hollow spheres known as the thyroid follicle. The thyroid follicular cells synthesize and secrete the thyroid hormones T3 and T4 and store it as colloid within the follicular lumen. When need arises, the colloid is resorbed and T3 and T4 resealed into the surrounding capillaries. The parafollicular calcitonin-secreting cells of the thyroid gland are also endodermal cells but they develop from the ultimobranchial bodies that originate in the vicinity of the 5^th pharyngeal pouch. The ultimobranchial cells migrate and reside within the developing thyroid gland occupying the peripheries of the thyroid follicle.

The connective tissue element of the thyroid interstitium and thyroid capsule are derived the mesenchyme in the region. The pharyngeal mesoderm which surrounds the developing thyroid diverticulum differentiates into mesenchyme that yields loose connective tissue. The loose connective tissue divides the developing thyroid into lobules and along the surrounding thyroid capsule it provides structural support to the thyroid.

Fig. 15. 9.  The illustration shows the thyroid primordium originating as a diverticulum from the floor of the primitive pharynx between pharyngeal pouches 2 and 3, and the ultimobranchial body (source of theroid C-cells) from the 5^th pharyngeal pouch. Derivatives of the other pouches are also shown.

Developmental anomalies of the thyroid gland include hypoplasia, ectopy and athyreosis. They may cause hyperthyroidism or hypothyroidism. Hypoplasia results from retarded development of the thyroid primordium causing underdevelopment of the thyroid gland, ectopy is the presence of the thyroid gland in an unusual location and results from abnormal migration and descent of the thyroid diverticulum. Athyreosis is the total failure of the thyroid gland to develop. Another known congenital anomaly is the persistent thyroglossal duct.

Fig. 15.10.  The illustration shows the normal and congenital abnormal (ectopic) locations of the thyroid gland and thyroid tissue.

Development of the Parathyroid Glands

The parathyroid glands are four small pea-size endocrine glands present in the neck region associated with or embedded within the thyroid gland. They produce the parathyroid hormone (PTH) which regulates the blood calcium levels.

Fig. 15.11.  The illustration shows the two pairs of parathyroids, the superior pair and the inferior pair, and their relations to the thyroid gland.

The parathyroid glands are endodermal in origin, their primordia developing from the pharyngeal pouches, which are outpocketing of the cranial part of the foregut.  The primordia differentiate into the parathyroid endocrine chief and oxyphil cell. The connective tissue elements of the capsule and stroma are derived from the surrounding mesenchyme. The two pairs of parathyroid primordia develop in the 3^rd and 4^th pharyngeal pouches, a pair from each pouch. The parathyroid that develops from the 3^rd pouch is called parathyroid-III, whereas the one which develops from the 4^th pouch is referred to as parathyroid-IV. The pair that develops in the 3^rd pouch shares its origin with the primordia of the thymus. As the thymus descends down towards the thoracic cavity, it pulls parathyroid-III downwards thus brining parathyroid-III to lie inferior to parathyroid-IV. Hence parathyroid-IV is designated as the superior parathyroid and parathyroid-III as the inferior parathyroid.

Fig. 15. 12.  The illustrations show the development of the superior and inferior parathyroid from the pharyngeal pouches 3 and 4. The inferior parathyroid (parathyroid-III) develops from the 3^rd pharyngeal original above the superior parathyroid (parathyroid-IV) but is pulled downwards by the developing thymus to occupy a position below parathyroid-IV).

Anomalies of the parathyroid glands include ectopic parathyroids and DiGeorge syndrome. In cases of ectopic parathyroid glands are found in unusual locations, within the thymus for example. DiGeorge syndrome is a well-known anomaly which is often accompanied by dysplasia of the parathyroids; it is often accompanied by congenital heart defects, and cleft palate.

Fig. 15. 13.  Picture of a child with DiGeorge syndrome with distinct facial features such a cleft lip and a cleft palate. Patients with the syndrome often suffer hypocalcemia resulting parathyroid dysplasia.

Development of the Adrenal Glands

The adrenal glands, which are also called the suprarenal glands, are two in number, each is an independent small (about 5cm long) pyramidal-shaped endocrine gland located retroperitoneally superior to the kidney. Each is surrounded by a capsule and consists of an outer cortex and an inner medulla. The cortex produces steroid hormones is divided into three zone known as the zona glumerulosa, the zona fasciculata, and the reticularis: the glomerulosa being the innermost, the fasciculata the middle one, and the reticularis the innermost zone. The medulla occupies the core of the gland and produces epinephrine (adrenaline) and norepinephrine (noradrenaline). The adrenal gland has a rich blood supply provided by several arteries.

Fig. 15.14. The illustration shows the structure of the adrenal gland made up of inner medulla and an outer cortex surrounded by a fatty capsule.

Fig. 15.15. An H&E-stained section of the adrenal gland showing the fatty capsule, the medulla, and the cortical zones.

Embryologically, the adrenal gland has a dual origin, the adrenal medulla developing independent of the adrenal cortex. The adrenal medulla is of neural crest origin. The neural crest develops from the ectoderm concurrent with the development of the neural tube. Precursor adrenal medulla cells migrate from the neural crest and aggregate in the vicinity of the dorsal aorta, where they differentiate into chromaffin cells under the influence of growth and differentiation factors including BMP. The adrenal cortex on the other hand is of mesodermal in origin; it develops from the urogenital ridge of the intermediate mesoderm. In 5^th week of embryonic development, the urogenital ridge gives rise to the adrenogonadal primordium which differentiate into the somatic gonadal cells of the indifferent gonad and steroid secreting adrenocortical cells. The adrenocortical cells aggregate to form the adrenal primordium in the vicinity of the dorsal aorta. In the 7^th week of embryonic development migrate and settle within adrenal primordium as discrete groups scattered throughout the adrenal primordium until birth. They coalesce together after birth forming the adrenal medulla. The fetal adrenal gland is one of the largest fetal organs at term. It is primarily made of adrenal cortical cells, but the cells are not clearly arranged into zones

Fig. 15.16.  The illustration shows the dual origin of the adrenal gland, the cortical cells (yellow colour)  originating from the urogenital ridge and the medullary cells (black color) originating from the neural crest.

The most common of adrenal congenital anomalies include complete failure of development of the gland (adrenal agenesis, fusion of the two adrenals together (horseshoe adrenal), under development of the adrenal gland (adrenal hypoplasia) which causes adrenal insufficiency, and abnormal location of the adrenal gland (ectopic adrenal).

Development of Pancreatic Islets of Langerhans

The pancreas is a mixed exocrine and endocrine gland. Its exocrine part consists of secretory acini and ducts, synthesizes and secretes digestive enzymes into the duodenum, whereas its endocrine parts consist of ductless islets of Langerhans made of different types of endocrine cells that produce different types of hormones including insulin, glucagon and somatostatin.  

Fig. 15.17.  An H&E-stained section showing endocrine cells and capillaries of an islet.

The pancreas develops from two buds that arise from the dorsal and ventral aspects of the foregut in the region of the future duodenum; thus, it is endodermal in origin. The buds branch and rebranch and the branches intermingle with each forming a single structure. Most of the branches remain connected to foregut forming the exocrine pancreas. Some branches on the other hand detach and lose connection to the foregut differentiating into hormone-secreting endocrine cells. The endocrine cells aggregate into masses containing networks capillaries; these are the pancreatic islets or islets of Langerhans. Under the influence of several biomolecules such as PDX1, PAX4, EGF, and Isl1 the endocrine cells into alpha (α) cells, beta (β) cells, and delta (δ) cells. Alpha cells produce glucagon; beta cells produce insulin whereas delta cells produce somatostatin. A fourth type of endocrine cells present in the pancreatic islet's pancreatic peptide hormone; these cells are referred to as PP cells.

Fig. 15. 18. The illustration shows how pancreatic epithelial cells detach from the duct system and differentiate into endocrine cells to form islets of Langerhans.

Developmental anomalies of the pancreatic islets include agenesis of islets of Langerhans where there is total failure of the islets develop leading to severe diabetes, islet cell hyperplasia, and congenital hyperinsulinism that causes hypoglycemia.

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