At the cellular level growth can occur either through proliferation (hyperplasia) or through an increase in cell size (hypertrophy). In practice, cell size is restricted by limits in the distance of diffusion, so most growth occurs by an increase in cell number (proliferation).
Proper growth is a function of adequate nutrition and appropriate endocrine regulation. The natural measure of growth that occurs during childhood is the height attained, or stature. Stature is a function of growth by the long bones in the body, thus we will focus on understanding the endocrine regulation of bone growth.
During development, the long bones form by a process that is known as endochondral ossification, which literally means “bone formation within cartilage”. First, mesenchymal cells condense and then differentiate as chondrocytes to form a cartilage model of the bone (the blue figure at left). Mesenchymal cells are the developmental precursors of connective tissue cells.
The cartilage model is replaced by bone following a particular pattern. The first part of the model to turn into bone (become ossified) is the shaft of the bone. The chondrocytes enlarge and change, and blood vessels penetrate into the tissue, carrying bone precursor cells (osteoblasts) that secrete bone matrix, eventually replacing the cartilage with bone. Ossification of the shaft spreads outwards towards the epiphyses (ends of bone). Secondary ossification centers eventually appear in the epiphyses. The ultimate result is that all of the cartilage is replaced by bone except for a small region of cartilage at each end, the epiphyseal growth plate.
Postnatal growth of the long bones occurs through the stimulation of chondrocyte proliferation at the epiphyseal growth plates. The size of the epiphyseal growth plate remains the same as long as cartilage proliferation keeps pace with the rate of ossification.
Statural growth will occur as long as the epiphyseal growth plates persist. The gonadal steroids (estrogen, testosterone) cause closure of the epiphyseal growth plates in late adolescence. The cartilage becomes entirely replaced with bone, and statural growth ceases.
The key endocrine regulator of postnatal growth is growth hormone (GH), which is secreted by cells in the adenohypophysis. The main way that GH stimulates growth at the epiphyseal plate is indirect. GH stimulates production of insulin-like growth factor-1 (IGF-1), and it is IGF-1 that directly stimulates chondrocyte cell division and bone growth. IGF-1 can be considered to act as both a hormone and a paracrine. Some of the IGF-1 is produced by the liver, and travels to the growth plate via the circulation, while some of the IGF-1 is produced locally by chondrocytes in the growth plate.
Typical of a hormone secreted by the adenohypophysis, GH secretion is regulated by hormones that are secreted by parvocellular cells in the hypothalamus. A special feature is that there is both a stimulatory hormone, growth hormone releasing hormone (GHRH) and an inhibitory hormone, somatostatin. As well, IGF-1 has negative feedback effects that limit GH secretion.
There are also several other hormones that are regulators of growth. Thyroid hormone is important for growth because it promotes growth hormone synthesis. Gonadal steroids (estrogen and testosterone), whose secretion increases at puberty, initially promote growth by increasing GH secretion, and then subsequently cause growth to end by causing the closure of the epiphyseal growth plates. Cortisol, which is released in response to stress, causes an inhibition of growth.
Short stature can be caused by a defect in GH secretion (growth hormone deficiency), but it may also be caused by a defect in the growth hormone receptor (growth hormone resistance). Growth hormone resistance is also called Laron syndrome. Growth hormone deficiency is treated with GH replacement; Laron syndrome is treated with IGF-1 replacement.
Hypersecretion of GH by a pituitary tumor causes different disorders according to when during life the hypersecretion begins. Rarely, GH hypersecretion begins before closure of the epiphyseal plates. This disorder, known as gigantism, causes excessive growth of the long bones and abnormally tall stature. GH hypersecretion that starts after adulthood is called acromegaly. Acromegaly has an insidious onset due to the fact that GH-secreting tumors are slow growing. High levels of GH and IGF-1 cause excessive growth of soft tissues and appositional growth in certain bones, particularly the jaw and skull, leading to disfiguring facial changes. Because of its metabolic effects, GH hypersecretion causes insulin resistance and lipid disorders. Abnormal growth of the heart leads to heart disease, while abnormal growth in the joints causes arthritis. To see an interesting image showing the physical effects of acromegaly, open this article in the New England Journal of Medicine and look at Figure 1a. (Off-campus access: open LINK TO PROXY SERVER. Next, type in this URL: http://www.nejm.org/doi/full/10.1056/NEJM200408193510825)
Acromegaly can be treated by surgery to remove the tumor. If surgery is not feasible, or is not completely effective, another treatment option is the use of a somatostatin agonist, such as octreotide.