What is the Impact of Accutane on Growth Hormone?

Introduction

Somatotropin, more commonly known as Growth Hormone (GH), plays a vital role in signalling cell growth and tissue regeneration throughout the body. This hormone is particularly critical during childhood and adolescence, driving physical development and growth. When GH is secreted excessively, it can lead to conditions like acromegaly, characterised by significant increases in stature and robust skeletal development. One of the most famous individuals associated with this condition is André the Giant, whose towering 7-foot frame was a result of excessive growth hormone production. Conversely, an underproduction of GH during childhood can result in significantly shorter stature. Without timely intervention, such as growth hormone therapy, this condition typically results in permanent stunted growth that persists throughout a person’s life.

The hand on the right shows the enlarged bone structure characteristic of Acromegaly, Philippe Chanson and Sylvie Salenave, CC BY 2.0 https://creativecommons.org/licenses/by/2.0, via Wikimedia Commons

Despite its dramatic effects, the gland responsible for its secretion is a tiny pea-sized region below the hypothalamus called the Pituitary gland. In other articles I’ve written about how Accutane treatment is associated with changes to pituitary function, and so it seems reasonable to posit that there may also be disturbances to Growth Hormone secretion too. In fact, the impact of Accutane on growth hormone is rather complex, as will become clear throughout this article.

The Difference Between IGF-1 and Growth Hormone

Growth Hormone, despite its name, isn’t primarily responsible for growth. Instead, GH is more like an initiator for the real cause of growth and development: Insulin-like Growth Factor-1 (IGF-1). When GH is secreted from the pituitary gland it travels through the blood stream to the liver, where it’s converted to IGF-1 which then travels to periphery tissues to exert effects on cell division and tissue growth. [1] Some people can be affected by a genetic condition where their body doesn’t synthesise IGF-1 in response to Growth Hormone, called Laron Syndrome. [2] Laron Syndrome proves unequivocally that IGF-1 is the mediator of growth and development, and not Growth Hormone itself. Individuals with Laron Syndrome display significantly short stature, facial abnormalities and even underdeveloped genitals.

The impact of growth hormone (via IGF-1) on growth has even made it desirable as Performance Enhancing Drug (PED). Most Ant-Doping agencies, including WADA, have been testing for Growth Hormone since the early 2000s – and for good reason too. Nitrogen balance is one of the key indicators of whether muscle tissues is growing (anabolism) or breaking down (catabolism). A positive nitrogen balance indicates that protein accumulation is taking place, and skeletal muscle is in a growth state. IGF-1 dramatically induces a positive shift in nitrogen balance. [3] Studies on men and women treated with Growth Hormone not only find improvements to strength and muscle size, but also bone density. These effects are most profound in individuals already suffering from a deficiency in growth hormone. [4] In one study of GH-deficient women, Growth Hormone therapy increased lean body mass by 11%.

What’s the effect of Accutane on Growth Hormone?

Studies have found that Isotretinoin (Accutane) can significantly reduce both IGF-1 and IGF-1 binding proteins (IGFBPs) following three months of treatment. [5] Almost all of the IGF-1 is bound to the six IGF-1 binding proteins, which carry IGF-1 through the blood stream to peripheral tissues (like bone and muscle) and prevent it from being rapidly broken down. The most significant of these binding proteins is IGFBP-3, and it’s this isoform that’s suppressed by Accutane treatment. Interestingly however, whilst IGF-1 is suppressed, Growth Hormone remains unchanged. In another study of 105 patients treated with Accutane for three months, IGF-1 and IGFBP3 levels were also reduced with the strongest effects being seen at the highest doses (0.2-05 mg/kg/day). [6] At this highest dose, IGF-1 dropped from 415.8±93.3 to 337.2±100.7.

It’s possible that the effect of Accutane on IGF-1 is directly related to its anti-acne effect, as there’s research to show an association between elevated IGF-1 levels are more severe acne. [7] Androgens, the male-typical hormones like testosterone and DHT (dihydrotestosterone), are more commonly considered responsible for acne development. However, androgen signalling is also strongly influenced by IGF-1 levels. IGF-1 can stimulate the enzyme that converts testosterone into the much more potent androgen DHT called 5-alpha-reductase. [8] It’s plausible that Accutane could treat acne through mechanisms related to androgen signalling as a secondary effect of reduced IGF-1.

Cell proliferation and β -catenin

IGF-1 binds to IGF-1 receptors (IGFR) on the surface of cells to activate mitogenic signalling pathways including Akt. Akt phosphorylates GSK-3β, which is one of the constituents of the destruction complex which continually breaks down the growth signalling protein called β-catenin. By inhibiting GSK-3β, IGF-1 increases β-catenin signalling. Over previous articles I’ve highlighted the significance of β-catenin in understanding the broad range of effects of Accutane throughout the body, and in particular the many adverse effects.

β-catenin is central to the process of cell proliferation. During cell proliferation, tissues growth individual cells grow whilst dividing, and therefor maintain cells of a roughly constant size. Some cells have a short life span and must be replaced by continual cell proliferation such as blood cells and epithelial cells of the skin or digestive tract. Stem cells are the unique cells in the body that can self-replenish and can convert into specialised tissue cells through a process called differentiation. However high levels of retinoic acid can directly inhibit stem cell proliferation, interfering with growth and repair. Its possible that Accutane can dramatically reduce stem cell proliferation by reducing IGF-1 signalling, and its downstream effect on β-catenin.

Conclusion

In conclusion, Accutane exerts a suppressive effect on IGF-1 signalling – despite having little effect on Growth Hormone itself. However, Growth Hormone is simply the initiator for IGF-1 which is in turn responsible for tissue growth, stem cell proliferation and repair. Accutane’s ability to suppress IGF-1 and its binding proteins is potentially involved in its anti-acne effects given the crosstalk with androgen signalling pathways. The suppression of β-catenin signalling via reduced IGF-1 activity provides a plausible mechanism for some of Accutane’s adverse effects, particularly on stem cell function, and tissue growth and repair.