Gigantism is more than just elevated HGH

Hiroki Yokota writes "The working hypothesis is that joint loading can lengthen long bone by activating cellular proliferation and differentiation in the growth plate.   However, joint loading can also affect cells in cortical bone and thicken cortex."  Now, lateral synovial joint loading activates stem cell differentiation into chondrocytes in adult chondrocytes by increasing hydrostatic pressure. I've shown in the past an increase in growth rate(cellular proliferation and differentiation) does not equal an increase in final growth mainly as a result of the factors that regulate chondrocyte senescence like telomere length.  However, Lateral Synovial Joint Loading works by activating new stem cells rather than relying on increasing proliferation of existing chondrocytes.  Joint loading can induce adaptation at only 30 microstrain which would seem to not be a great deal of weight but remember the microstrain is relative to the bone so we'd need a strain gauge to determine the relative strain of the weight given bone resistance.

Gigantism seems to get around these cellular senescence mechanisms.  You'd expect HGH to only affect growth rate(or an effect on chondrocyte hypertrophy) unless HGH had some sort of effect directly on the factors involved in cellular senescence.  If we understood why Gigantism causes such growth given all the limiting factors such as the number of Growth Hormone Receptors, we could better understand height growth. 

Endochondral gigantism: a newly recognized skeletal dysplasia with pre- and postnatal overgrowth and endocrine abnormalities 

"We report on a 3-year-old male, born at 34 weeks of gestation, with marked pre- and postnatal overgrowth, birth weight of 6,600 g, length of 61 cm, and head circumference of 38.5 cm. A striking phenotype was recorded at birth, which became more evident during the follow-up period. He had macrobrachycephaly, facial abnormalities, small thoracic cage, long trunk, deformed spine, rhizomelia, large hands and feets, absent subcutaneous fat, small umbilical hernia, inguinal hernias, and large joints with mild contractures. Hypoglycemic episodes and obstructive apnea complicated the neonatal period. During follow-up, overgrowth continued with a height of 146 cm (+11.65 SDS) and a weight of 39 kg (BMI 18.3 kg/m(2)) at 3.5 years. Endocrinological work-up disclosed extremely low levels of growth hormone, insulin-like growth factors, and insulin. What makes our patient unique is the association of marked prenatal overgrowth; unusual phenotype; skeletal dysplasia caused by accelerated endochondral ossification resulting in cartilage hyperplasia of the skull base and spine, and postnatal gigantism; and complete absence of subcutaneous fat. Other well-known overgrowth syndromes were excluded. We hypothesize that autocrine/paracrine growth factors could be the cause of excessive endochondral ossification. Alternately, activating mutations in transcription factors involved in both growth AND endocrine/metabolic homeostasis could be responsible for this unusual phenotype." 

There is always more to Gigantism than elevated HGH.  There is almost always some sort of tumor involved.   Scientists speculate that it is an enlargement of the pituatary gland which causes gigantism not just excess growth hormone.  An enlarged pituatary gland would affect endocrine and metabolic homeostasis.  

[Gigantism with low serum level of growth hormone: a case report] 

"Gigantism with low or normal basal concentrations of growth hormone (GH) is a rare condition, possibly due to abnormal GH secretory patterns, enhanced tissue sensitivity to GH, or the existence of an unidentified growth promoting factor. Here we report an 11 year-old female case of gigantism with a normal pituitary gland. Her height was 181 cm, body weight 77 kg, and bone age 11.1 years. Her basal serum GH levels were lower than 1 ng/ml. The levels of T3, T4, FT3, FT4, TSH, E2, LH, FSH, PRL, PTC and ACTH were normal. Serum GH response to insulin-induced hypoglycemia or arginine stimulation tests was blunted. In this case, non-pulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-1 and the existence of an unidentified growth promoting factor or biologically active anti-GH receptor antibodies may cause clinical gigantism." 

Enhanced tissue sensitivity to GH could indicate an increased number of Growth Hormone Receptors.  There's also a non-pulsatile secretion of HGH.  Maybe the rate of HGH secretion affects growing taller as well.  A change in HGH secretion pattern would affect homeostasis and could alter cellular pathways.  There are way more hormones that affect height growth than what they measured so there are other confounding variables involved.

Osteoarticular Changes in Acromegaly

"Acromegaly is caused by hypersecretion of growth hormone (GH) and consequently of insulin-like growth factor-I (IGF-1) due to pituitary tumor. Other causes, such as increased growth-hormone releasing hormone (GHRH) production, ectopic GHRH production, and ectopic GH secretion, are rare. The issue of osteoarticular manifestations is still very actual, due to development of complications in the majority of patients with acromegaly. Traditionally, acromegaly is considered as a cause of secondary osteoporosis. GH excess leads to increased bone turnover, defined by changes of bone markers."

"The effect rhGH on bone remodeling is biphasic: rhGH causes a maximal effect on bone resorption after 3 months and on bone formation after 6 month. The effect on bone formation is sustained for prolonged periods of time. The effect of rhGH on biochemical markers of bone turnover is dose dependent but not influenced by the modality of administration. RhGH causes an increase in urinary and serum calcium after 3–6 months, an effect caused by calcium mobilization from the skeleton, an increase in intestinal calcium absorption and in the renal reabsorption of calcium due to increased sensitivity to PTH. RhGH is antiphosphaturic and increases the intestinal absorption of phosphate which leads to increased levels of serum phosphate. RhGH may also normalize the circadian rhythm of PTH secretion. Receptors for IGF and GH have been demonstrated in osteoclasts, thus GH and IGF-1 may directly affect their function and activity. In addition, GH/IGF-1 axis indirectly affects bone resorption by stimulating the release of paracrine mediators that regulate the resorption of bone"

"Radiological changes in early phase [of acromegaly] are joint space widening and periarticular soft tissue hypertrophy."  Later stages of acromegaly are characterized by narrowing of joint spaces.