On a molecular quest for eternal youth

ROIDED IS a new word that I have learnt. As may be guessed, it is American slang and refers to the practice of having taken steroid drugs ("steroided"), particularly the male hormone testosterone. Men who want to build their bodies in a short cut route take this hormone with the hope that their muscles will grow huge, their abdomens will become rock-hard, and overall they will look like a He Man or Hercules. Articles in the April 24 issue of Time magazine give an alarming picture of this unhealthy obsession and practice of some American men and boys; and if this is so in America, can India lag behind?

As may be guessed, this desire is stoked and fueled by commercial interests who want to promote their products through inducements and scientific-sounding announcements in the media. Until now, one had to administer the hormone as pills, shots or patches. But now comes a preparation of this steroid in a gel form, seductively named "Androgel" (andro meaning man), which is as easy to apply as cold cream or Vaseline. True, it is available not OTC (over the counter) but only with a doctor's prescription, but that is a minor inconvenience which can be suffered through.

Testosterone is a steroid molecule that is synthesized naturally in the body, and is the hormone that is responsible for " many things male". Its synthesis is particularly switched on in the growing male human body at puberty, and it is responsible for the transition of the boy into manhood. This is evidenced by spurts in hair growth (particularly on the face, chest, underarms and the genital area), deepening of voice, growth of lean muscle mass, increase in bone density, reproductive capability and so on. Its level in the body stays relatively high until the age of 30 or so, after which it tapers off to a steady value until late in life.

Many men cling to the belief that more "testo" means more "manly" and it is this notion that leads them to administer themselves with this hormone. Short doses of this hormone are known to result in increase of body build, stamina, a burst of energy, and the ability to tolerate pain and fatigue for short periods of time. It is for this reason that some athletes administer themselves doses of testo. Sports officials rightly debar these athletes from the competition for seeking unfair advantage through the use of such anabolic (body-building) drugs. But there are some basketball and baseball players who prime themselves regularly with set doses of testo and attempt to build themselves into super-sportsmen. The famous baseball player Mark McGwire admits to using Androgel.

The levels of sex hormones in a human body are naturally kept at regulated levels, and unduly high (or low) levels can lead to complications and side effects. These may range from acne to liver cancer. There is thus the real danger that "roiding" can lead to health risks. However, there are people, particularly the elderly, beyond the age of 55 or 60, who want to look, feel and act younger. Since the hormone levels have reduced in their bodies, some of them look for "natural" and acceptable ways of increasing them, and thus attempt to "reverse ageing", as it were. What they would like best is a natural and acceptable way of increasing the levels of hormones in the body when necessary. After all, for post-menopausal women, where osteoporosis or bone thinning and weakening is a major risk, doctors have been suggesting the so- called hormone replacement therapy (or HRT), which seems to be by and large accepted by many women. Are there special foods, "organic preparations", lotions or potions, herbs or plant extracts, or other naturally occurring substances that can be taken which would keep one younger and stronger longer?

This of course is the billion-dollar question that is being addressed by a variety of groups. Leading the pack are the "health food" people, a new tribe of commercial interest that is raking in profits by promoting and selling a spectrum of herb and plant extracts, oriental and native American traditional health products, as well as metabolic intermediates. Some of these are well known and accepted to be beneficial, while others need to be validated and verified. Companies such as General Nutrition Center (GNC) have their shops in every major shopping mall across America, selling not only traditional health aids such as ginseng, sarsaparilla, herbal tea and the like but also synthetic formulations based on what has been understood (or thought to be useful) from biochemical pathways in the body. Thus it is that vitamin E, folic acid and antioxidants share the shelf with St. Johns Wort (taken to counter depression and anxiety) and Ginkgo Biloba (neuroprotector and blood flow enhancer). All these formulations are sold as health aids and are thus not required to be cleared by the Food and Drug Administration (FDA) of the US government, as drugs are required to.

The latest to join this list of health promoting substances are two biochemical intermediates, the steroid molecules with the complicated names of Dehydroepiandrosterone or DHEA and its sulfate form DHEAS. DHEA also goes by the name of prasterone. Both DHEA and DHEAS have been dubbed as "mother hormones" and are sold with great fanfare as "fountain of youth" and "miracle pill", with scientific sounding assertions such as "antidote for ageing", "life extension molecules" and so on. Verily the modern equivalent of what traditional Indian medicine called as "kaya kalpa".

Biochemists have known for some time that prasterone is the major steroid molecule in the blood of humans. It is produced in the adrenal glands of both men and women, and is the parent molecule out of which many other steroids,including the "male hormone" testosterone and the "woman hormone" estradiol, are derived, in an age-dependent and sex- dependent manner. DHEAS itself is produced in the body from cholesterol through enzyme- catalyzed reactions, and exists both as the sulfate and in a form in which the sulfate is lost, namely as DHEA or prasterone. The level of DHEAS increases in the body, particularly at puberty and reaches a maximum around 15- 19 years in women and 20- 24 years in men, after which there is a steady decline with age. Generally males have 40per cent more DHEA and DHEAS in their bodies than women of the same age do. It is out of DHEA(S) that testosterone is made in the human body and this, in turn, produces the truly male hormones androsterone and its cousin that we shall simply call as ADG, as well as the female hormones such as estradiol. The relative levels of testo and ADG to that of estradiol vary distinctly between men and women; in men the ratio is tilted largely towards the former two steroids while in females the opposite is true.

Since both the male and female steroid hormones are made from the common starting material DHEA(S), an idea that has been (rightly or wrongly) gaining ground is that it is safer and more acceptable to take DHEA as a health supplement and rejuvenator. This idea needs validation. The usual practice of controlled laboratory animal experiments will not work here, since the levels of DHEA(S) in animals, young or ageing, have not been described. In any event, the number of elderly men and women who are already taking DHEA, with the hope of reducing and even curing age- related diseases and debility, is already large and growing with time. Prasterone is thus thought to be not as much a drug against a given disease or dysfunction, but more as a tonic that helps improve the overall quality of life, help keep young, and as an antidote for ageing. A rigorous, controlled clinical trial involving human volunteers would be essential in order to test the efficacy of DHEA treatment, its safety and side effects, and related issues of socio-bio-medical nature.

It is with these in mind that a year-long study was conducted by Dr. Etienne-Emile Baulieu and colleagues in Paris, France. They selected 280 volunteers between the ages of 60 and 79, of which there were 70 men and 70 women in the 60-69 years of age bracket and an equal number of men and women in the 70-79 years bracket. These were chosen on the basis of prior health check-up which revealed them to be healthy of body and mind, with no symptoms related to ageing such as asthenia, memory complaints, hormone- dependent cancer or other conditions, dementia, pain, anxiety or other major depressive state. The study was conducted in a randomized, double blind fashion in which neither the doctors nor the volunteers knew who was given what treatment, so that no intrinsic bias creeps in. Half the volunteers were given a daily dose of two 25- milligram tablets of prasterone (DHEA), while the other half was given identical looking dummy tablets with no drug in it (called placebo in medical jargon). Each of them was monitored regularly for their psychological state, quality of life, sexual functions and libido, muscular strength, skin tone and texture, and also biochemically for the levels of DHEAS, testosterone, ADG and estradiol. The bone strength and its mineral density were tested using X- ray methods and the blood vessels by ultrasound. The results of the study, termed "The DHEAge Study", have just been published in the April 11 issue of PNAS, USA, and will also be available in the website www.dheage.com, which is under construction.

The Baulieu study recorded no potentially harmful accumulation of DHEAS or active steroids. In men, DHEA treatment led to an increase in testosterone and ADG levels, approaching those seen in young adult men. In women, the picture was slightly different in terms of the time taken, but even here the levels of DHEAS and ADG levels were raised to those seen in young women. Happily, no changes were seen in the levels of other hormones such as luteinizing hormone, thyroid hormones and so on. The skin tone improved, with less dryness and better hydration as well as oiliness. The skin colour improved somewhat, to a level that might be thought of as a trend towards rejuvenation. The bone mineralization parameters improved. With women, libido increased. The effect of DHEA on vasculature, namely blood vessels, was not significant, so that its use in hypertension or stroke is not clear. Overall, a number of biological indicators suggest that no harm arises from the daily dose of about 50 mg of DHEA for a year, and that this kind of replacement therapy reversed some effects associated with ageing, though it does not create "supermen" or "superwomen".

Just a month ahead of the Baulieu paper came a report in the journal Lipids from Dr. J. R. Williams of Temple University in Philadelphia, where he analyzed the effects of DHEA on cancer, obesity, the immune system and ageing. DHEA appears beneficial in these situations too, and the mechanisms seem to be multiple in nature. Some of these mechanisms have been highlighted and discussed by Williams, who also points out that some molecules that are related to DHEA, which are being tested for their effects on these mechanisms might offer themselves as candidates for clinically useful drugs based on the properties of DHEA. (For people who prefer natural foods for their nutrition and health, it needs to be said that as of today, there are no plant or other naturally occurring sources of DHEA; the wild yam contains a precursor molecule, but eating this does not lead to the production of DHEA in the human body, so that, as of now, we depend on the synthetic chemist).

Does this mean that we have found the miracle anti-ageing pill? Can we all start popping in DHEA and feel the flush of youth? Though the French study found largely beneficial trends and no side effects in these 280 volunteers, there are records of some side effects of DHEA. A whole website dedicated to DHEA, called http://dheanet, and another, more gushy one called www.naples.net., talk minimally about these. The GNC website, however, reports that DHEA can produce irritation, increased acne, facial hair, perspiration,oily skin, headache and sometimes more severe reactions in individuals. As in most other matters, do not rush to the nearest health food store for DHEA before you consult with your doctor!

D. Balasubramanian

L.V.Prasad Eye Institute

Hyderabad 500 034

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