We think of the estrogens – estradiol and estrone – as being quintessentially female hormones, and so they are. They are the hormones of breasts, periods, pregnancy and menopause. But men produce estrogens as well, and in large quantities; it is the stuff from which testosterone is made. Not all male estrogen is converted, and what remains appears to be critical in stopping the growth of bones. Two other men have been found in recent years – one in Japan, the other in New York – who cannot produce estrogens at all for want of an enzyme. They too were in their twenties and still growing fast. Conversely, children who produce an excess of estrogen tend to go through puberty very early. They grow fast but stop soon and remain short all their lives.
But there must be more to stopping growth than estrogen. Testicular estrogen may instruct adolescent bones to fuse their growth plates and so cease growing, but men without estrogen or its receptor do not grow at a rate of nearly an inch per year for their entire lives. The eunuchs who guarded Ottoman harems, regulated the affairs of the Celestial Empire and bestrode the stage of La Scala may have been imposing figures, but they were not nine feet tall. This is probably because after adolescence, bloodstream levels of IGF-1 decline, causing a general slowdown in rates of cell division throughout the body. That it does so is probably just as well.
ON BEING THE RIGHT SIZE
Growth hormone and IGF are extremely powerful growth-promoting molecules. Vital if a child is to grow to the size that it should, they must also be continually kept in check. If they are not, growth spins out of control, and the result is growth without growth’s checks and balances, or, as it more commonly known, cancer.
Among the body’s devices that curb IGF-1’s propensity to make cells proliferate is a protein called PTEN. Infants who are born with a single defective copy of the PTEN gene show, initially, little sign that anything is wrong with them; they have, at worst, slightly larger skulls than normal. The problems come later when, as inevitably happens, the second copy of the gene mutates in a few cells of the growing child. In these cells, and their descendants, a want of PTEN protein causes cell division to spin out of control; the result is an exotic array of tumors in the mucosal lining of the mouth, lower colon, breast, ovaries and thyroid and, oddly enough, hair follicles.
These cancers are often fatal. But inheriting a defective copy of PTEN can have far more devastating consequences than this. Should the second mutation happen to occur in the first cells of the embryo (instead of in late childhood), a large fraction, perhaps even a half, of the infant’s body will be completely devoid of PTEN. The afflicted fraction of the body becomes, in effect, a single, enormous and inexorably spreading tumor.
The condition is known as Proteus syndrome, named for the most versatile of Greek gods. ‘Some have the gift to change and change again in many forms,/Like Proteus, creature of the encircling sea/Who sometimes seemed a lad, sometimes a lion/Sometimes a snake men feared to touch, sometimes/A charging boar, or else a sharp-horned bull,’ wrote Ovid, who elsewhere calls the sea-god ‘ambiguous’. The syndrome is very rare, known from no more than sixty people worldwide. Children with Proteus syndrome appear normal at birth, but their faces and limbs become increasingly distorted with age as chaotic outgrowths of bone and soft connective tissue expand over their bodies, often just on one side. They have large tracts of creased and crenulated skin, particularly on the soles of their feet, and they usually die before the age of five. In some, the cerebral hemispheres of their brains grow lopsided and they die of neural seizures; others cannot breathe because of overgrown ribs; yet others die when one of the many odd tumors to which they are prone becomes malignant. It is now believed that James Merrick, the so-called ‘Elephant Man’ who died in 1890 at the age of twenty-eight, had Proteus. If he did, then in one sense he was lucky to have lived for as long as he did.
The intimate relationship between growth and cancer is shown by dogs. A Great Dane puppy has far more IGF circulating in its bloodstream than a Chihuahua puppy does, and grows nearly eight times faster to ten times the size. It pays a cost for doing so. Great Danes, Newfoundlands, St Bernards and many other giant breeds of dogs have a risk factor of osteosarcoma or bone cancer eighty times greater than do smaller breeds. The cancer nearly always begins in one leg, and usually only amputation will prevent its spread.
Osteosarcoma is also one of the most common cancers in children. As in dogs, it usually begins in the leg bones, and then during the pubertal growth spurt when the cells of the growth plate are dividing most vigorously. In the Hunterian Museum, not too far from Charles Byrne’s skeleton, is a display cabinet containing a desiccated ribcage and larynx taken from a young man who died of advanced osteosarcoma. These macabre specimens have the added horror of being covered in hard, grey nodules resembling lumps of coal. They are secondary tumors, clumps of bone-producing cells that had metastasised from the primary leg tumor – which Hunter had attempted to cure by radical amputation. In children, as in dogs, size is a risk factor for osteosarcoma. More than 50 per cent of cases are found in children who are in the seventy-fifth centile for height at any given age.
Big dogs and tall children may be more susceptible to cancers simply because they have more cells than smaller dogs and shorter children. More likely, however, it is probably not large size per se that is dangerous, but rather the high levels of growth hormone and IGF that big dogs and children tend to have. Pituitary tumors, of the sort that the giant Charles Byrne must have had as a child, occasionally appear in adults as well. As in Byrne’s case, they produce vast amounts of growth hormone, but this doesn’t cause an increase in height, since the long-bone growth plates have fused. Instead, only the bones of the jaws, hands and feet grow, a condition known as ‘acromegaly’. Often the first sign that an adult has a pituitary tumor is the need for ever-larger shoes. A pituitary tumor is a moderately dangerous and unpleasant thing in itself. But it also has a nasty indirect effect, causing elevated rates of colon, breast and blood cancers (leukaemias). These cancers are not caused by metastasis of the pituitary tumor, which is benign, but rather by something it does: namely, stimulate the entire growth-hormone-IGF system.
Why this should cause high levels of cancer is not exactly clear, but one idea is that IGF stops sick cells from dying. Cells that are stricken with a potentially carcinogenic mutation often suicide. IGF overrides this altruistic impulse and so acromegalics, big dogs and tall children are relatively prone to cancers. It is as well to be clear about the magnitude of these risks. Of all the spectres that might assail a parent, childhood cancer is the least substantial. Osteosarcoma, though a pernicious and aggressive disease, is very rare: it afflicts only 1 in 300,000 children. The parents of tall teenagers should not worry; the owners of large dogs should.