Signs such as increased body fat and waist-hip ratio, reduction in lean body mass, low muscle strength and endurance are some of the findings seen in GHD patients [11]. An evidently short stature for appropriate age or reduced height velocity over the course of few years and neurological deficits that may point to intracranial lesions (anosmia or visual deficits) are findings that require exclusion of GHD as the underlying cause, while neonatal signs include prolonged jaundice, microcephaly and hypoglycemia [3].

A detailed physical examination and patient history are key initial steps in the diagnostic workup, in order to assess the present signs and symptoms that may point to GHD. Basic laboratory findings may reveal a reduced GFR, dyslipidemia and impaired glucose levels [1] [11]. Endocranial MRI is a pivotal imaging procedure, as it may point to a lesion responsible for suppressed GH production, such as a tumor or other infiltrative diseases [3]. Evaluation for other pituitary hormone deficiencies (TSH, FH, LH, ACTH) should be performed as well, since individuals that have 3 or more pituitary hormone deficiencies can be almost definitely diagnosed with GHD without the use of GH stimulation test, an invasive and time-consuming, but also dangerous procedure because of potentially severe side effects [5]. Although GH stimulation (also known as insulin tolerance test, or ITT ) is considered to be the gold standard for the diagnosis, it is contraindicated in patients who report a history of seizures or ischemic heart disease [1] [3]. Additionally, false-positive values may be obtained in morbidly obese patients. For this reason,an introduction of alternative diagnostic methods, such as GH-releasing peptide-2 (GHRP-2) test into regular practice is becoming more common, since they are safe and more convenient [1]. Measurement of IGF-1 has also been recommended in GHD patients and values below normal are highly indicative of the diagnosis, but some patients may present with IGF-1 levels within physiological limits, in which case other tests need to be used for confirmation [1].

Substitution with GH is the cornerstone of treatment in all patients, but the optimal dose depends on age, gender, percentage of adipose tissue and additional drug use, which may present a challenge for the physician [1]. Recombinant human GH (rhGH) has become available in recent years and is recommended in a treatment of various diseases that disrupt the pituitary gland and GH concentrations [6]. It must be stated that the dose should never be titrated according to body weight and all of the mentioned factors should be taken into consideration [1]. In general, a dose of approximately 0.1 mg/day in the evening should be given when initiating treatment through subcutaneous injections and a gradual increase in dosing is recommended based on the individual response and laboratory values [1]. In women who receive estrogen, a higher GH dose is required, especially if estrogen is taken orally, as it interferes with GH and hepatic IGF-1 [1]. The appropriate dosage may be monitored through regular evaluation of serum IGF-1, and IGF-1 should be in the upper half of the physiological range throughout therapy [1]. rhGH is rather safe to use, as side effects are very rarely encountered [1] [12], most common being arthralgia and edema as a result of water retention by GH [1]. Hyperglycemia, hypertension, and dyslipidemia have also been reported as adverse effects, but more importantly, a growing number of papers are investigating a potential link between increased incidence of cancer in patients who receive GH, although no solid conclusions have been made so far [6]. Because of the fact that GHD necessitates life-long therapy, certain authors suggest that a quality-of-life questionnaire should be implemented in regular practice, for the purposes of long-term monitoring and design of optimal care [7]. Because of the beneficial effects on the cardiovascular, skeletal and endocrine system, treatment with rhGH is advised even after maximal height and plateau of body growth is reached, but its cost-effectiveness has questioned this type of treatment [4] [6].

When compared to the general population, mortality rates of AO-GHD have shown to be higher, primarily because of cardiovascular and other complications that develop in these patients, but the exact pathophysiological mechanisms that lead to increased mortality rates are not entirely clear [1]. Inappropriate replacement of pituitary hormones other than GH may be one of the reasons, while a presence of concomitant risks and adverse events that occur may also be involved [1]. It is important to mention that almost 50% of children with this condition are left undiagnosed [4], which is why high clinical suspicion toward GHD should be present when evaluating short stature and changes in growth and body composition.

GHD may arise as a result of genetic, but also various acquired conditions [1] [2]:

• Transcription factor defects - mutations in PROP1, POUF-1 and HESX1, factors involved in gene transcription related to GH have shown to be an important cause of GHD [8].
• GH and growth hormone-releasing hormone receptor (GHRH) gene defects - Both autosomal dominant and recessive, but also X-linked modes of inheritance have been described in a literature [2] [3].
• Congenital structural abnormalities such as septooptic dysplasia, empty sella syndrome, encephalocele, and arachnoid cyst.
• Pituitary tumors - Adenoma, craniopharyngioma, glioma/astrocytoma, Rathke's cleft cyst, germinoma, or metastatic disease.
• Perinatal or postnatal trauma - Births in non-cephalic position (especially breech deliveries) have been one of the most common causes of trauma in newborns prior to the introduction of the cesarean section, but GHD due to early trauma is still being reported [2].
• Miscellaneous infiltrative diseases - Tuberculosis, sarcoidosis, and Langerhans cell histiocytosis.

In a small number of cases, the cause remains unknown, in which case the diagnosis of idiopathic GHD is made [1].

In the United Kingdom, GHD has an established incidence rate of 1 in 3,500-4,000 live births, with similar results obtained in the United States (1 in at least 3,480) [4] [9]. AO-GHD appears at an incidence rate between 1.42 and 1.9 per 100,000 individuals in Denmark, while prevalence rates in UK adults are around 1 in 3,000 [4]. Gender predilection toward males has been confirmed in several reports [9] [10].

Under physiological conditions, GH plays an essential role in maintaining normal body composition, primarily muscle mass, and percentage of adipose tissue [1]. Decreased glucose uptake and accelerated protein synthesis are induced in muscular tissue by GH, whereas cardiovascular effects include an increase in myocardial mass, cardiac output and increase in exercise capacity [4]. Because of GH deficiency, a significant decrease in lean body mass and total body water occurs, leading to an increase in fat content [1], while a low rate of bone mineralization leads to osteopenia and reduced bone mineral density [1]. An inability of the cardiovascular system to grow at desired rate occurs and is the reason why fatigue and the quality of life in general, is affected [4]. Apart from the apparent effects of GH on body composition, its role in an induction of inflammatory parameters (including CRP and IL-6) has been documented as well [1], leading to the assumption that GH also plays an important role in functioning of the immune system.

Unfortunately, it is not possible to prevent GHD, but an early diagnosis and identification of the underlying cause may significantly reduce the burden of the disease and provide a better quality of life.

Growth hormone deficiency (GHD) is a disorder that develops as a part of numerous conditions that involve the pituitary gland and cause insufficient production of growth hormone (GH) [1]. Genetic disorders involving GH and growth hormone-releasing hormone (GHRH) receptors, congenital abnormalities such as encephalocele, empty sella syndrome and septooptic dysplasia, endocranial tumors (adenoma, craniopharyngioma, or metastatic disease) and perinatal/postnatal trauma are some of the conditions that may interfere with production and activity of GH [1] [2]. Epidemiology studies show that the incidence rates of GHD vary between 1 in 4,000-10,000 live births and a significant predilection toward males is detected [3]. Under physiological conditions, GH is responsible for achieving adequate bone mass, lean body mass, and overall tissue growth, which is why the clinical presentation universally includes growth retardation and short stature [3]. Depending on the underlying cause, the onset of symptoms may be in childhood or in adulthood and the terms childhood-onset GHD (CO-GHD) and adult-onset GHD (AO-GHD) are frequently used in literature to distinguish the two forms [4]. Additional signs include increased obesity and neurological deficits that may suggest the underlying cause (bitemporal hemianopsia in the setting of a pituitary adenoma or anosmia due to a presence of a craniopharyngioma), but a thorough diagnostic evaluation is necessary to confirm GHD as a cause of symptoms. Dyslipidemia, impaired glucose metabolism and disturbances of other pituitary hormones, such as thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and follicular stimulating hormone (FSH) may be detected too, as studies have shown that GH abnormalities are present in almost 100% of cases when 3 or more pituitary hormones are disturbed [5]. Magnetic resonance imaging (MRI) of the endocranium is an important imaging procedure that may identify the lesion responsible for GHD, but to confirm the diagnosis, GH stimulation test should be performed [1]. Despite being the gold standard in these patients, it requires a rigorous preparation under close supervision, which is why GH-releasing peptide-2 (GHRP-2) test and measurements of insulin-growth factor 1 (IGF-1) are often done instead because they are safe and more easily performed [1] [3]. The mainstay of treatment is supplementation with recombinant human GH (rhGH) in a carefully designed regimen and life-long therapy may be recommended due to a prevention of adverse effects that may occur later in life (osteopenia, dyslipidemia, and other metabolic changes). The issue of cost-effectiveness, however, has emerged as an issue in clinical practice [6]. GHD has shown to affect the quality of life of many patients [7], making long-term care and evaluation mandatory in ensuring good patient outcomes.

Maintenance of proper body composition and adequate growth are the main functions of growth hormone (GH), which is synthesized in the hypophysis (also known as the pituitary gland) and numerous conditions may impair its activity in the body or its production. Growth hormone deficiency (GHD) is a clinical entity that is defined as markedly reduced activity of GH in the body, leading to growth retardation and symptoms such as accumulation of fat and reduction in muscle mass. Other findings include a reduced bone mass that may be a risk for fractures, as well as various neurological symptoms, depending on the underlying cause. Brain tumors, genetic diseases that affect GH receptors, trauma experienced in pregnancy or during delivery and various congenital defects may all be responsible for an insufficient synthesis of GH. It is estimated that 1 in 4,000-10,000 individuals develops GHD due to any cause and a significant predilection toward males is established. To make an initial diagnosis, it is essential to perform a thorough workup consisting of laboratory studies that may reveal changes in lipid levels, altered glucose concentrations and derangement of other pituitary hormones, together with imaging studies of the brain in the form of magnetic resonance imaging (MRI), which may point to the underlying cause. To confirm GHD, however, GH-stimulation test is considered to be the most reliable diagnostic method and consists of serial blood sampling in a matter of several hours after use of various drugs. But because it is contraindicated in patients suffering from seizures and heart disease and the fact that it may cause serious adverse effects, alternative and safer methods of evaluation are more frequently performed, including measurement of insulin-growth factor 1 (IGF-1) and GH-releasing peptide-2 (GHRP-2) test. Treatment principles rely on supplementation with recombinant human GH (rhGH) and the regimen depends on the patient's age, gender, a presence of comorbidities and current drug use. The beneficial effects of prolonged rhGH supplementation on the musculoskeletal and cardiovascular system have been brought into question by a very large cost of treatment, while certain studies are pointing to an increased risk of malignancy when using GH as a therapeutic measure. Because GHD may severely impact the overall quality of life of the patient, long-term monitoring, and care are necessary to provide optimal therapy.

1. Fukuda I, Hizuka N, Muraoka T, Ichihara A. Adult Growth Hormone Deficiency: Current Concepts. Neurol Med Chir (Tokyo). 2014;54(8):599-605.
2. Bierich JR. Aetiology and pathogenesis of growth hormone deficiency. Baillieres Clin Endocrinol Metab. 1992;6(3):491-511.
3. Stanley T. Diagnosis of Growth Hormone Deficiency in Childhood. Current Opinion in Endocrinology, Diabetes, and Obesity. 2012;19(1):47-52.
4. Ahmid M, Perry CG, Ahmed SF, Shaikh MG. Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement. Endocr Connect. 2016;5(3):R1-R11.
5. Hartman ML, Crowe BJ, Biller BM, et al. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?. J Clin Endocrinol Metab. 2002;87(2):477-485.
6. Hazem A, Elamin MB, Bancos I, et al. Body composition and quality of life in adults treated with GH therapy: a systematic review and meta-analysis. Eur J Endocrinol. 2012;166(1):13-20.
7. Rosilio M, Blum WF, Edwards DJ, et al. Long-term improvement of quality of life during growth hormone (GH) replacement therapy in adults with GH deficiency, as measured by questions on life satisfaction-hypopituitarism (QLS-H). J Clin Endocrinol Metab. 2004;89 (4):1684-1693.
8. Rainbow LA, Rees SA, Shaikh MG. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf). 2005;62(2):163-168.
9. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. The Journal of Pediatrics. 1994;125(1):29-35.
10. Stochholm K, Gravholt CH, Laursen T, Jorgensen JO, Laurberg P, Andersen M. Incidence of GH deficiency - a nationwide study. Eur J Endocrinol. 2006;155(1):61-71.
11. Cuneo RC, Salomon F, McGauley GA, Sönksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf). 1992;37(5):387-397.
12. Blethen SL, Allen DB, Graves D. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996;81(5):1704-1710.