Human Growth Hormone: A History

The Fascinating Journey of Human Growth Hormone: From Ancient Giants to Modern Medicine

This article delves into the captivating history of human growth hormone (hGH), drawing upon the comprehensive research detailed in “Human Growth and Growth Hormone: From Antiquity to the Recombinant Age to the Future” by Graber, Reiter, and Rogol. From ancient tales of towering giants to the groundbreaking scientific discoveries of the 20th century, this exploration will illuminate the remarkable path leading to the revolutionary medical applications of hGH we witness today.

Overgrowth: Giants Through the Ages

Since antiquity, humans have been captivated by extremes in human size. Tales of giants like Goliath, who faced the young David in the biblical narrative, highlight our enduring fascination with exceptional growth. Goliath, according to the Old Testament, suffered from gigantism, likely caused by a pituitary tumor. This tumor, growing beyond the confines of the sella turcica, would have pressed upon the optic chiasm, potentially explaining Goliath’s tunnel vision – a symptom of bitemporal hemianopia.

This ancient tale raises fascinating questions about the underlying causes of gigantism. Could Goliath’s immense stature have been influenced by genetic factors, similar to the Irish Giants studied by Marta Korbonits and her team in the 21st century? These researchers identified a specific genetic mutation in the aryl hydrocarbon-interacting protein gene (AIP) within families of Irish giants, suggesting a hereditary component to their remarkable height.

Beyond biblical narratives, artistic representations like Goya’s colossal figure in “The Colossus” further demonstrate our intrigue with excessive growth. While the painting’s true meaning remains open to interpretation, it undeniably captures the awe-inspiring presence of a giant.

The Scientific Pursuit of Growth’s Secrets

The scientific quest to unravel the mysteries of human growth began in earnest in the early 20th century. Pioneering researchers like Aschner, using a bold buccal approach, removed the pituitary glands of puppies, revealing the profound impact of this tiny gland on growth. Their experiments demonstrated that removing the pituitary, or even just its anterior lobe, resulted in severely stunted growth. These findings laid the groundwork for decades of research focused on isolating the growth-promoting agent within the anterior pituitary.

By the 1930s, the link between pituitary tumors and acromegaly was firmly established. But the isolation of a specific growth-promoting substance remained elusive. Early attempts focused on replacing the various hormonal deficits resulting from hypophysectomy, with the assumption that normal growth would be restored through the synergistic action of multiple hormones. However, this approach relied on crude mixtures of hormones, limiting the ability to draw definitive conclusions.

A breakthrough came in 1938 when Evans and his team developed a precipitation procedure for isolating growth hormone. This method, though still yielding a product with contaminating hormones, represented a significant step forward. Frankel-Conrat and colleagues further refined the purification process, resulting in a more homogenous product with decreased contaminants.

Simultaneously, the development of bioassays for growth hormone proved crucial in isolating and characterizing this elusive factor. Early assays focused on measuring body weight gain in rats. Later, a more sensitive assay utilizing the epiphyseal growth plate of immature rats was developed, greatly accelerating the purification of animal and subsequently, human growth hormone.

Species Specificity: A Roadblock to Animal-Derived hGH

While animal-derived insulin revolutionized diabetes care, the same could not be said for growth hormone. Knobil and colleagues, through their research with Rhesus monkeys, revealed a critical difference: animal growth hormones were ineffective in primates. Unlike insulin, hGH exhibited species specificity, meaning only primate growth hormone could stimulate growth in primates.

This species specificity sparked the “active core” hypothesis, suggesting that despite structural variations, different growth hormones possessed a core amino acid sequence responsible for their biological activity. It was theorized that if these cores could be identified and synthesized, they might offer a solution to the species specificity challenge. However, the complex structure of hGH, with its two disulfide bonds, made identifying and synthesizing a contiguous core a formidable task.

Despite extensive research with fragments of human and animal growth hormone, no preparation unequivocally demonstrated reproducible activity in humans. The dream of readily synthesized, biologically active growth hormone seemed distant.

Beyond Growth: The Somatomedin Hypothesis and IGF-1

The discovery of insulin’s role in glucose metabolism inspired researchers to investigate similar hormonal mechanisms for growth. Yalow and Berson’s groundbreaking immunoassay for insulin paved the way for similar assays for growth hormone, allowing for the diagnosis of growth hormone deficiency and overproduction.

The work of Salmon and Daughaday in the 1950s further illuminated the intricate workings of hGH. They demonstrated that the growth-promoting effects of hGH relied on the production of a growth hormone-dependent factor. This factor, initially termed “sulfation factor” due to its ability to stimulate sulfate uptake in rat cartilage, was eventually isolated and identified as insulin-like growth factor-I (IGF-I).

This discovery transformed our understanding of hGH’s action, shifting from a purely endocrine model to one incorporating paracrine/autocrine activity. The original somatomedin hypothesis evolved to acknowledge the individual functions of both GH and IGF-I, recognizing their complex interplay in regulating growth.

The Dawn of Human Growth Hormone Therapy

The purification of human growth hormone in the late 1940s, followed by the confirmation of its distinct identity from prolactin, marked a pivotal moment in medical history. hGH could now be used to treat children with growth hormone deficiency. Raben, a pioneer in hGH research, documented the first case of an adolescent treated with hGH in 1958. This patient, initially just over 4 feet tall with no signs of sexual development, achieved a near-normal adult height after two and a half years of hGH therapy.

Further research solidified hGH’s impact on growth and metabolism. Studies involving hypopituitary children demonstrated its ability to promote linear growth, nitrogen retention, mineral retention, and even influence glucose metabolism.

However, a major challenge arose: the limited supply of hGH extracted from human pituitary glands. Competition for these glands intensified, prompting the establishment of the National Pituitary Agency (NPA) in the US in 1963. The NPA, under the leadership of Dr. Robert Blizzard, coordinated the collection, extraction, and distribution of hGH for both research and treatment. This program, later renamed the National Hormone and Pituitary Program (NHPP), ensured equitable access to this precious resource for children with growth hormone deficiency.

Despite its success, the NPA era was marked by limited supply and the looming threat of Creutzfeldt-Jakob disease (CJD). The dependence on cadaveric hGH carried an inherent risk of transmitting this fatal prion disease. This reality underscored the urgent need for a safer and more readily available source of hGH.

The Recombinant DNA Revolution: A New Era for hGH

Just as the limitations of cadaveric hGH became glaringly apparent, a scientific revolution was brewing. In 1972, the first study demonstrating the power of recombinant DNA technology was published. Within a decade, researchers had successfully inserted the hGH gene into the genome of E. coli bacteria, enabling the production of biologically active rhGH.

This breakthrough marked the beginning of a new era for hGH therapy. The promise of unlimited quantities of safe, synthetic hGH opened up a world of possibilities for treating not only growth hormone deficiency but also a wide range of other conditions affecting growth and development.

Tragically, the first cases of CJD linked to cadaveric hGH emerged in 1985, just as rhGH was becoming a reality. The heartbreaking stories of young adults succumbing to this devastating disease underscored the urgency of transitioning to a safer alternative. The rapid development and approval of rhGH proved to be a lifesaver, ensuring that treatment for growth hormone deficiency could continue.

Expanding Horizons: FDA-Approved Uses of rhGH

The advent of rhGH ushered in a new era of clinical research, allowing for larger, more robust studies to evaluate its effectiveness in a variety of conditions. Since the first approval of rhGH for growth hormone deficiency in 1985, the FDA has approved its use for seven additional pediatric indications:

Chronic Renal Insufficiency (1993): Children with CRI often experience growth faltering. Research demonstrated that rhGH could effectively stimulate growth in this population, leading to its FDA approval for this indication.
Turner Syndrome (1996): This genetic condition, characterized by short stature and other developmental abnormalities, was one of the first conditions to be considered for hGH therapy. Numerous studies confirmed the growth-promoting effects of rhGH in girls with Turner syndrome, paving the way for its approval.
Prader-Willi Syndrome (2000): Children with PWS often exhibit short stature, increased truncal fat, and low IGF-I levels. rhGH was found to not only improve growth but also reduce fat mass and potentially enhance cognition in these individuals.
Small for Gestational Age Without Catch-Up to Normal Stature (2001): Children born SGA who fail to catch up in growth can benefit from rhGH therapy. Studies demonstrated that rhGH could promote linear growth and improve body composition in this population.
Idiopathic Short Stature (2003): This indication has sparked considerable debate, raising ethical considerations about the medicalization of short stature. Nevertheless, research consistently showed that rhGH could increase height in children with ISS, leading to its controversial approval.
Short Stature Homeobox-Containing Gene Deficiency Haploinsufficiency (2006): This specific genetic cause of short stature was identified in the early 2000s. Children with SHOX deficiency were found to respond well to rhGH, resulting in its rapid FDA approval.
Noonan Syndrome (2007): This genetic disorder, characterized by short stature and various physical features, was another target for rhGH therapy. Despite concerns about potential cardiac complications, studies demonstrated the safety and efficacy of rhGH in children with Noonan syndrome.

Beyond FDA Approval: Exploring rhGH’s Potential

While the FDA has approved rhGH for a limited number of indications, researchers have investigated its potential in a wide range of other conditions, including:

Cystic Fibrosis: Although children with CF may benefit from improved nutrition and specialized therapies, rhGH has shown mixed results in accelerating linear growth and augmenting lean body mass. Further research is needed to determine its role in this population.
X-Linked Hypophosphatemia: This rare skeletal dysplasia features disproportionate short stature and renal phosphate wasting. Studies suggest that rhGH may improve linear growth in children with XLH, but more research is needed to establish its long-term benefits and potential impact on body disproportion.
Achondroplasia: This common skeletal dysplasia results in significant short stature. Japan is currently the only country to approve rhGH for achondroplasia, citing its ability to increase height velocity in the short term. However, its long-term impact on adult height and body proportions remains unclear.

These ongoing investigations demonstrate the continued exploration of rhGH’s potential in addressing various growth-related challenges.

The Future of hGH Therapy: Long-Acting Analogues and Beyond

One of the persistent challenges of hGH therapy has been the need for daily injections, potentially impacting adherence and treatment outcomes. This hurdle has spurred the development of long-acting GH (LAGH) preparations, offering the promise of less frequent dosing. Several LAGH formulations are currently available or in development, each with unique pharmacokinetic and pharmacodynamic properties:

Depot preparations: These involve encapsulating rhGH in biodegradable microspheres, allowing for sustained release. However, early versions faced challenges with inconsistent release profiles and local injection site reactions.
PEGylated preparations: Attaching polyethylene glycol (PEG) molecules to rhGH extends its circulatory half-life. However, some preparations have encountered issues with injection site reactions and PEG accumulation in the brain.
Prodrug preparations: These involve chemically modifying rhGH to create an inactive prodrug that is slowly converted to active rhGH in the body. This approach offers controlled release and potentially fewer side effects.
Non-covalent albumin binding GH: Modifying rhGH to enhance its binding to albumin prolongs its half-life. This approach has shown promising results in clinical trials, demonstrating growth responses comparable to daily rhGH.
GH fusion proteins: Fusing rhGH to other proteins, such as the Fc-domain of immunoglobulin or parts of human chorionic gonadotropin, can extend its half-life and improve its pharmacokinetic profile.

The development of LAGH represents a significant advancement in hGH therapy, potentially enhancing patient adherence and treatment outcomes. However, ongoing research is crucial to optimize dosing, monitoring strategies, and assess long-term safety and efficacy.

Concluding Thoughts: Reflecting on a Remarkable Journey

The story of human growth hormone is a testament to human curiosity and scientific ingenuity. From ancient tales of giants to the intricate workings of the GH-IGF-I axis, our understanding of growth has evolved dramatically over time. The development of rhGH has revolutionized the treatment of growth hormone deficiency and expanded our ability to address a range of growth-related challenges.

As we look to the future, the development of LAGH and the continued exploration of hGH’s potential in other conditions offer hope for even more effective and convenient therapies.

We’ve come a long way since the days of Goliath and General Tom Thumb. The journey of hGH, driven by scientific inquiry and a desire to improve lives, underscores the remarkable progress we’ve made in understanding and influencing human growth. What new discoveries and innovations lie ahead? The future of hGH therapy is filled with exciting possibilities.