Childhood growth hormone deficiency, a diagnosis in evolution: The intersection of growth hormone history and ethics.

In 1958 the first recorded case of a patient treated with human growth hormone for growth hormone deficiency was published. Since that time, the source and availability of human growth hormone have changed. With the increased availability of growth hormone, there has been an uptrend in the level below which childhood growth hormone deficiency is diagnosed based on provocative GH stimulation testing. This increase is despite better specificity of growth hormone assays in addition to a lack of supportive evidence regarding appropriate normal values. With these trends the diagnosis of childhood growth hormone deficiency is evolving, and clinicians should be aware that this may have potential ethical implications.

Live Longer Better: The Historical Roots of Human Growth Hormone as Anti-Aging Medicine.

In recent years, historians have turned their attention to the emergence of anti-aging medicine, suggesting that this interest group coalesced in the wake of widespread availability of recombinant human growth hormone (HGH) after 1985. We take a longer view of modern anti-aging medicine, unearthing a nexus of scientific, medical, and cultural factors that developed over several decades in the twentieth century to produce circumstances conducive to the emergence of this medical sub-specialty established on the premise of the anti-aging effects of HGH. Specifically, we locate these roots in earlier hormone replacement therapies and in the so-called life extension movement. We reveal the continual tension between, on the one hand, champions of a mainstream medical specialty and a field of biomedical research that aimed to improve health for the aged and, on the other hand, advocates who campaigned for medical endeavors to preserve midlife health in perpetuity, and even to extend the human lifespan. We also demonstrate that the two groups shared a belief in science to solve - or at least to ameliorate - the problems of aging. This commitment to science has been the hallmark of twentieth and twenty-first century prescriptions for living life longer and better.

The History of Growth Hormone Treatment for GHD in Japan.

In Japan, treatment of growth hormone deficiency with pituitary-extracted human growth hormone (phGH) was covered by health insurance for the first time in 1975. However, because of the shortage of phGH, the Foundation for Growth Science (FGS) was founded in 1977 to control the use of the product by its registration system and to collect pituitary glands in Japan. In 1986, recombinant human growth hormone was first approved. Since then, the FGS has been involved in the harmonization of growth hormone measurement, assessment for treatment eligibility according to the diagnostic criteria by the research group of the Ministry of Health and Welfare, and database generation and its utilization.

Growth hormone treatment in Japan: past, present, and future.

Growth hormone (GH) treatment was approved for growth hormone deficiency (GHD) in Japan in 1975. Since then, GH treatment has been approved for treating five other diseases with short stature. However, available data on adult height after long-term GH treatment is limited to patients with GHD and Turner syndrome. Although adult height of patients with GHD has improved with early diagnosis and early initiation of treatment, the adult height after long-term GH treatment is still not so satisfactory because the therapeutic dose used in Japan is smaller than that used in US and Europe. With early diagnosis, early high-dose treatment, and low-dose estrogen replacement therapy, both adult height and quality of life (QOL) of the patients with Turner syndrome have been improved.

History of growth hormone therapy.

The first human to receive GH therapy was in 1956; it was of bovine origin and was given for 3 wk for metabolic balance studies revealing no effects. By 1958, three separate laboratories utilizing different extraction methods retrieved hGH from human pituitaries, purified it and used for clinical investigation. By 1959 presumed GHD patients were being given native hGH collected and extracted by various methods. Since 1 mg of hGH was needed to treat one patient per day, >360 human pituitaries were needed per patient per year. Thus, the availability of hGH was limited and was awarded on the basis of clinical research protocols approved by the National Pituitary Agency (NPA) established in 1961. hGH was dispensed and injected on a milligram weight basis with varied concentrations between batches from 0.5 units/mg to 2.0 units/mg of hGH. By 1977 a centralized laboratory was established to extract all human pituitaries in the US, this markedly improved the yield of hGH obtained and most remarkably, hGH of this laboratory was never associated with Creutzfeld-Jacob disease (CJD) resulting from the injection of apparently prior- contaminated hGH produced years earlier. However, widespread rhGH use was not possible even if a pituitary from each autopsy performed in the US was collected, this would only permit therapy for about 4,000 patients. Thus, the mass production of rhGH required the identification of the gene structure of the hormone, methodology that began in 1976 to make insulin by recombinant technology. Serendipity was manifest in 1985 when patients who had received hGH years previously were reported to have died of CJD. This led to the discontinuation of the distribution and use of hGH, at a time when a synthetic rhGH became available for clinical use. The creation of a synthetic rhGH was accompanied by unlimited supplies of hGH for investigation and therapy. However, the appropriate use and the potential abuse of this hormone are to be dealt with. The illegitimate use of rhGH, unequivocally the abuse by athletes is, and should be, of primary concern to society and should be halted. The abuse of prescribing rhGH in an attempt to retard the aging process also should receive attention.

Growth hormone: the expansion of available products and indications.

Growth hormone is a widely used hormone. This article describes its historical use, current indications and studies for possible future uses.

Growth hormone: historical notes.

A brief review of important contributions to our present knowledge of growth hormone is given. In 1887 it had been noted that a pituitary tumor was present in most patients with acromegaly. Even at the beginning of the 20. Century relationship between growth disorders and the pituitary was contested. From 1908 pituitary surgery became established treatment in GH hypersecretion. In 1922 it was demonstrated that injection of pituitary extract to animals caused excessive growth and soon after the opposite: removal of the pituitary caused growth retardation. A huge number of studies on the effects of GH were subsequently reported as were trials with GH treatment. They were impeded by failure to recognize the impact of species specificity of GH. After this issue was clarified in 1957, treatment with human growth hormone proved effective. In 1985 it was realized that Creutzfeldt-Jakob's disease might be transmitted through human growth hormone. At this time recombinant GH had become available. In 1971 the structure of human GH was established. In the same period both GH releasing and inhibiting hormones were identified and an analogue of somatostatin had evolved into the first effective pharmacological treatment for acromegaly.

The not-so-good old days: working with pituitary growth hormone in North America, 1956 to 1985.

Before 1985 the use of growth hormone (GH) was governed by a philosophy of scarcity and conservation of resources. Between 1956 and 1959 human pituitary GH was shown to be effective. The competition for gland collection and extraction that followed benefited only certain patients with motivated parents and only a few investigators. To maximize gland collection, the distribution of GH for clinical investigation, and the number of patients who could be treated, the National Institutes of Health and the College of American Pathologists formed the National Pituitary Agency (NPA). In Canada a similar program was developed by the Canadian Medical Research Council. For more than 20 years the NPA supervised most of the GH treatment in the United States. Commercial pituitary GH entered the U.S. market in 1976, and competition soon appeared. Patients treated through the NPA were subjects in clinical studies for part of the first year of treatment, after which the limited availability of GH dictated treatment for only part of the year and caps on final heights. By 1984 treatment was year round and the height caps largely unenforced. In the last year of its distribution NPA GH was used in 2450 patients in the United States and commercial pituitary GH was used in 600 to 800; slightly more than 300 patients were being treated in Canada. And then, in 1985, came Creutzfeldt-Jacob disease. While the not-so-good old days are gone and need not be lamented, there remains virtue in a conservative therapeutic philosophy. If anything can be learned from the use of pituitary GH in children, it is a healthy respect for the law of unintended consequences.

Pioneering recombinant growth hormone manufacturing: pounds produced per mile of height.

The first efforts to produce recombinant human growth hormone (GH) for clinical use were begun by scientists at Genentech, Inc., almost a generation ago, late in 1979. The very small market for GH that was predicted at the time led to this manufacturing effort being done as a demonstration project. Among the early issues was whether the Escherichia coli host cell could be routinely produced in a stable manner and be inactivated after the GH production run (as required by Federal guidelines) without the GH being permanently denatured. A 10 L E. coli process was developed, and phase I testing began in early 1981. The approval of this recombinant GH product by the FDA in 1985 paved the way for many improvements and a sustained production effort in the next decade. The more than 1990 fermentation runs have produced tons of E. coli and more than 130 pounds of GH for both clinical research and the treatment of severely short children.

A history of growth hormone.

After the debacle of Brown-Séquard testicular extracts, hormone replacement therapy proper began in 1891 with the use of sheep thyroid extract to treat myxoedema. The second success in the field was "bovine' insulin to treat human diabetes in 1992. In contrast, the first successful use of growth hormone in a human pituitary dwarf did not come until 1958. Growth hormone preparations of reasonable purity had been made in the 1920s and were shown to be effective in rats and dogs, but the need for primate growth hormone in primates was not recognised until the late 1940s.