Hypertrophy: Definition, Causes, Mechanism, Types, Consequences and Cellular Adaptation to Stress

It is an increase in the size of individual cells.

Hypertrophy, by definition, is an adaptive increase in the mass of a cell, tissue, or organ that does not result from cell proliferation .

Hypertrophy is a term used to describe one of the ways that cells, those little units that do important work in our bodies, adapt to environmental changes.

Environmental changes can be things like hormonal stimulation, inflammation, or an increased workload.

Examples include muscles that are enlarged due to weight training or thickening of the heart wall due to hypertension (and increased work required by the heart).

Although it is found less frequently in toxicological pathology than atrophy or other signs of adaptation, hypertrophy, however, can occasionally have significant consequences for the general well-being of the individual.

Hypertrophy is one of the ways that cells grow to adapt to changes in their environment, and it can have both favorable and unfavorable consequences. Healthy cells keep us alive and fit.

For our cells to stay healthy, the environment they live in must be healthy, and the work they are expected to do must be kept within normal limits.

If there is a significant change in the environment, the cells will try to adapt to the situation so that they can continue working.

One of the methods cells use to adapt is through the process of hypertrophy.

If a cell increases in size beyond what is normal for that cell, then we can say that the cell has undergone the process of hypertrophy.

Whenever you look hyper in a word, think of the words “excessive” or “overhead,” this in conjunction with troph, which refers to stimulation of nutrition, hormones, or other growth factors, thus hypertrophy is refers to a cell that has grown larger than normal.

It is the result of an increase in the synthesis of structural constituents of cells, not simply an accumulation of water or storage products such as glycogen or lipids.

Cells have small organelles within them that are the internal machinery of the cell.

As the cell grows in size, some of these organelles will increase in number to support the activities of a larger cell.

For example, mitochondria , the cellular power generators, will increase in number to provide enough energy for the larger cell.

The endoplasmic reticulum will increase to support the cell’s manufacturing processes, and the proteins in the plasma membrane will increase in number as the cell hypertrophies.

When a sufficient number of cells noticeably increase in size, a gross increase in tissue or organ mass can occur.

Hyperplasia can also contribute to an increase in tissue or organ mass.

In certain tissues, hypertrophy and hyperplasia can often occur simultaneously.

Hypertrophy is commonly associated with an increase in the functional capacity of a tissue.

For example, hypertrophy of heart muscle cells often results in increased cardiac output.

In this example, the cells increase in size due to an increased number of sarcomeres, which form the contractile units of the cell.

In another example, the liver can undergo hepatocyte hypertrophy.

One form of hepatocellular hypertrophy is attributable to an increase in the smooth endoplasmic reticulum with a concomitant increase in xenobiotic metabolizing enzymes.

These types of hypertrophy are generally reversible when the causative stimulus is removed.

The ability of cells to increase structural and functional capacity appears to depend on increased gene expression.

Identifying changes in gene expression responsible for hypertrophy is an area of ​​considerable interest, as is the mechanism of altered gene expression.

In some cases, activation of specific receptors by drugs or toxins has been clearly associated with hypertrophy.


Classically, hypertrophy is a response to the increased metabolic demand for specialized function provided by the particular cell population.

An obvious example is the improved size of the adenohypophyseal cells that produce gonadotropin-releasing hormone at the onset of puberty.

At the ultrastructural and histological levels, hypertrophy appears as an increase in the volume of cytoplasm.

As a result of the increase in the number of cellular organelles, microfilaments, microtubules, and other specialized structures necessary to meet the increased metabolic demand of the cell.

Hypertrophy, if it is global (that is, it involves all or most of the organelles in a cell), can be difficult to quantify at the ultrastructural and histological level without specialized morphometric techniques, but it is nevertheless generally evident.

As with atrophy, weighing an organ and calculating organ-to-body weight ratios may be the only way to detect subtle forms of global hypertrophy.

Cell enlargement, however, can also occur with an increase in the number of a particular type of organelle.

Examples of this phenomenon are common in toxicological pathology.

Phospholipidosis is another common cause of toxic-related hypertrophy due to the accumulation of organelles.

Agents that can alter phospholipid metabolism promote the accumulation of lysosomes loaded with phospholipid-rich degradation products.

In histological preparations, retained lipid-soluble degradation products will often dissolve from cells during processing in organic solvent baths, leaving a finely vacuolated or “moth-eaten” cytoplasm suggestive of vacuolar changes associated with direct cell injury.

However, by transmission electron microscopy, the “vacuoles” are observed to contain laminated whorls of partially degraded membranes, called myelin spirals, since the processing conditions for transmission electron microscopy do not use organic solvents.

Cellular adaptation to stress

Cellular stress occurs when a cell is placed in an inhospitable environment or required to do something that it cannot normally do.

Cells under stress will adapt to the new situation or die.

Cells will also undergo changes if the amount of stress applied to them decreases or if the type of stress changes.

Cellular adaptation generally refers to reversible changes in the size, number, phenotype or appearance, metabolic activity or functions of cells in response to adverse environmental conditions or internal body stresses.

Basically, just as we react to something in our environment, cells also change to try to overcome the problem.

There are 4 important ways they do this:

  • Hypertrophy.
  • Hyperplasia
  • Atrophy.
  • Metaplasia.

In hypertrophy there is no increase in the number of cells, but rather in size.

This type of cellular adaptation to stress occurs in several different cells, and is generally combined with another type of cellular adaptation, hyperplasia.

Hyperplasia is a cellular response that involves an increase in the number of cells in response to a stimulus.

Both hyperplasia and hypertrophy occur as compensatory mechanisms for an increased workload on the organ or cell.

Those cells that are unable to divide respond to stress with an increased workload due to hypertrophy. An example of this is in myocytes, or cells of the heart muscle in the fibers of the myocardium.

Therefore, the heart responds primarily with hypertrophy to increased workload.

Other examples are adult skeletal muscles and neurons.

Physiological and pathological hypertrophy

Hypertrophy and hyperplasia, while it can be physiological to help the body, can also be disease-related or pathological, and is a very important indicator of disease.

Physiological hypertrophy

Physiological hypertrophy is caused by an increase in workload, increased functional demand, or stimulation by hormones and growth factors.

But, the most frequent stimulus for hypertrophy is an increase in workload.

An example of workload-induced hypertrophy would be muscle dilation in bodybuilders as the muscles are forced to tolerate new loads.

An example of hormone-induced hypertrophy is in the endometrium and myometrium of the uterus, as the upregulation of estrogen during the follicular stage of the menstrual cycle stimulates an increase in muscle proteins in the endometrial stroma and the great layer of muscle. myometrial smoothness and therefore the size of the muscle.

pathological hypertrophy

Pathological hypertrophy occurs in the heart muscles when there is an increase in end-diastolic volume, or the amount of blood that must be pumped out of the heart due to contraction that occurs due to defective valves or hypertension.

Similarly, if one kidney has a problem, then the opposite kidney increases in size to function more effectively to compensate for the opposite kidney (note that the kidney cells are also hyperplasia).

Mechanism of hypertrophy

Hypertrophy arises as a result of an increase in the proliferation of cellular proteins.

Increased cellular proteins in cardiac myocytes in particular can occur due to various stimuli, such as mechanical stretch receptors that detect increased workload, increased growth factors, and the presence of agonists.

There are 3 basic steps in the synthesis of these cellular proteins:

  • The integrated action of mechanical receptors, agonists, and growth factors that activates signal transduction pathways.
  • These signal transduction pathways produce various transcription factors.
  • These transcription factors in turn cause the increase in muscle protein synthesis and therefore hypertrophy.

It should also be noted that hypertrophy is, in fact, also mediated by the conversion of the adult form of contractile proteins, to the larger neonatal form of the same proteins.

The hypertrophied organ has no new cells, only larger cells.

This increase in cell size is due to the synthesis of more structural components and not due to cell swelling.

Cells capable of division can respond to stress by experiencing both hyperplasia and hypertrophy, whereas in non-adherent cells, such as myocardial fibers, hypertrophy occurs.

Nuclei in hypertrophied cells may have a higher DNA content than in normal cells, probably because the cells stop in the cell cycle without undergoing mitosis.

Hypertrophy is caused by an increase in functional demand or by specific hormonal stimulation.

Types of hypertrophy

Muscular hypertrophy

Striated muscle cells in the heart and skeletal muscles are capable of tremendous hypertrophy, perhaps because they cannot adequately adapt to the increased metabolic demands of mitotic division and the production of more cells to share the work.

The most common stimulus for muscle hypertrophy is increased workload.

Thus, the developed muscles of bodybuilders who use an “iron pump” are the result of the increase in the size of the fibers of the muscles in response to a greater demand.

The workload after hypertrophy is shared by a greater mass of cellular components, each muscle fiber shares the excess work and, in this way, muscle injuries are avoided.

The enlarging muscle cell reaches a new equilibrium, allowing cell function at a higher level of activity.

The higher number of microfilaments per cell allows an increase in workload with a level of metabolic activity per unit cell volume not different from that supported by the normal cell.

The stimulus for hypertrophy in the heart is usually chronic hemodynamic overload, which is the result of diseases such as hypertension or defective valves.

Faced with this stress, a synthesis of more proteins and filaments occurs, reaching a balance between the capacity of the cell and the demand that exists for its functioning.

After birth, ventricular expression of the gene is down-regulated.

Some genes that are expressed only during early development are re-expressed in hypertrophic cells, and the products of these genes are involved in the cellular response to stress.

Cardiac hypertrophy, however, is associated with reinduction of gene expression.

Genes that are induced during hypertrophy include those that encode transcription factors, vasoactive agents, mechanical triggers, such as stretch, and trophic triggers, such as polypeptide growth factors.

Although the traditional view of cardiac and skeletal muscle is that these tissues are incapable of proliferation, their enlargement is entirely the result of hypertrophy.

Recent data suggest that even these cell types are capable of limited proliferation as well as repopulation of precursors.

This view emphasizes the concept, that hyperplasia and hypertrophy often occur concomitantly during the responses of tissues and organs to increased stress and cell loss.

Hypertrophy of the endometrial mucosa in pregnancy

The massive physiological growth of the uterus during pregnancy is a good example of the hormone-induced increase in the size of an organ that results from hypertrophy and hyperplasia.

Cell hypertrophy is stimulated by estrogenic hormones that act on the estrogen receptors in smooth muscle, eventually resulting in increased smooth muscle protein synthesis and an increase in cell size.

Similarly, prolactin and estrogen cause breast hypertrophy during lactation.

These are examples of physiological hypertrophy induced by hormonal stimulation.

Cell size is regulated by nutrients and environmental signals and involves several signal transduction pathways that are being unraveled.


While the consequences of hypertrophy can be benign in the short term and simply reflect a physiological response to an increased demand on a tissue for its specialized function.

There are situations in which the increased mass of organelles exceeds physiological limits and induces dysfunction of hypertrophied tissue.

Examples of “pathologic” hypertrophy in response to a toxic stimulus abound in toxicologic pathology.

For example, the tremendous hypertrophy of the smooth endoplasmic reticulum in the hepatocytes of individuals treated for long periods with phenobarbital or other anticonvulsant drugs.

This can lead in severe cases to the loss of other functions of the hepatocytes such as urea production (manifested as hyperammonemia) and bile excretion (manifested as icterus).