BSE, CJD and Pituitary Glands

by   W.R.Parry, M.D.

15 The Drive, Retford, UK DN22 6SD. 0044 1777 702340

(Editor: You will have to read most of the article in order to get to the crux of it.  However, this is worth the bother)

Index:

History


In 1929  it was reported that injections of ox pituitary gland into milking cows would increase the milk yield. (Gruber, F and Stricker P. Klin. Eschr. 1929. 8. 2322.) The finding was confirmed in 1937  by  Asimov and Krouze using  crude pituitary gland extracts.

  During the second world war attempts were made to increase British food production but, as there was insufficient pituitary tissue available to make a significant  contribution, in spite of obtaining glands from Brazil and the Argentine, the attempt was abandoned.

 Articles were appearing dealing with increased milk yield using extracts of bovine pituitaries in the immediate post war period (Brit. med.Bull 1947  Young F.G5(23)1104.)
In the same journal Margaret Robinson reported on the failure of pituitary hormone, obained from Glaxo labs., to increase milk production in women suffering from hypogalactia. (Brit.Med Bull 1947 (23)1106.)

 In 1956  growth hormones were isolated from the pituitary glands of  humans, cattle, sheep, fish, monkeys and rats and it was found that these hormones were almost species specific. Primate somatotrophin was effective in ruminants but not vice-versa.

 Li, CH and Papkoff H.,  1956  Science 124. 3235, 1293-4 published  Preparation and properties of GH from Human and Monkey pituitary glands. They showed that purified beef GH is ineffective in man, fish GH is effective in fish but not rats. Monkeys respond to somatotrophin from monkey pituitaries but not from cattle and both human and beef hormone are active in the rat. The work was done at Univ of California, Berkeley. The human pituitaries were supplied from Stockholm,  and monkey glands came from Eli Lilly Labs.

 Work on pituitary hormones continued and the work was of interest to the livestock industry..
Gemzell CA and Hejkenskjold 1956 Growth hormone content in human pituitaries Endocrinology  59. 681-687.

A comparison of two GH preparations. Beaton GH. 1956  Endocrinology 59, 356-9
Preparation of GH from pituitaries of man and monkey. (Raben MS 1957 Science 125. 883.)
The effect of GH on the yield and composition of cows milk. ( Hutton JB 1957 J. endocrinol 16. 115-125)

Hormones as aids to increased production - a review. 1957. Vet. Record 69. 537-541.
The influence of GH on growth in young cattle (Brumby PJ, 1959 N.Z.J agric Res. 2.683-689)
In addition other substances. such as thyroxine, were tried to increase productivity. In 1959 J.animal Sci 18 (1) 427-436 Struempler AW and Borroughs,W. reported a positive relationship between the stilboestrol administration and production of growth hormone in sheep and cattle The growth hormone used in their experiments was a gift from NIH, Bethesda, Maryland. It had been known for many years that stilboestrol promotes growth in immature cattle and sheep by stimulating the pituitary gland.  Clegg and Cole in 1954 had noted the action of stilboestrol on the growth response of ruminants. J.animal Sci 13. 108

 It was therefore well known that the administration of various hormones would result in an increased milk yield and lean meat ratio and this use of hormones has gone on to this day - albeit using synthetic GH nowadays. It seems that various substances block the oestrogen receptors and there is a corresponding excess production of GH. GH has a relatively short half life (20 mins) and is produced in pulses. It stimulates the production of insulin like growth factor (IGF-1 ) which has a half life of 20 hours.

 By 1961 workers at the National Inst. for Research in Dairying, at Shinfield, Reading, had noted that human growth hormone had considerable lactogenic activity for mammals - in this case the rabbit.(Chadwick A et al., Lancet 1961 29th July. 241-3.)

 In 1979 the Lancet (Aug 18th p337-9), published an editorial on the transmission of CJD , saying that the agent had been adopted to primates and smaller laboratory animals and emphasizing the necessity for rigorous precautions in the PM room. Howie had classed CJD as comparable in infectivity to hepatitis B. Gajdusek,DC  et al. had already  pointed out the dangers in 1977 in N.Eng.Med 297.1253-8

  In 1981 there was a report on the use of bovine pituitary hormone to increase milk  yield and also to increase the ratio of muscle to fat in lean beef. (Peel CJ etal J.Nutrition 111. 1662-1671)
 Farmers had, by now, been using growth stimulants for years. Some of the substances used were capable of producing harmful effects in humans who consumed their product and, as a result, certain drugs were forbidden to be used. Prosecutions and fines followed in magistrates courts and articles, on the subject, appeared in Veterinary Records.

 Dec 22nd 1984 - Peter Stent, a dairy farmer, contacted a Petersfield vet - David Bee - about a sick cow at Pitsham Farm in West Sussex. The beast died 2 months later. Stent lost a further 9 cows and the last one was taken to the local ministry lab - the head was then sent to Central Vet Lab in Weybridge. BSE was diagnosed histologically in September 1985.

 More cases of B.S.E. started to appear in 1986  although some might have been missed and been diagnosed previously as senile unsteadiness.

 There was another outbreak in Ashford in 1987. One assumes that the beasts went to the felmongers because not only time expired cows but also carcasses unfit for human consumption have some market value.

 In 1985 there was a report on the response of high producing dairy herds to long term treatment with bovine pituitary  hormone. Treatment was given for 188 days and it was found that  milk yield increased by 16%.(Bauman D.E. et al 1985 J dairy Sci 68.6. 1354-62)

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Hind sight:-

 In the late 1950's a letter was sent to all pathologists, working as morbid anatomists in the N.H.S., asking them to remove pituitary glands at necropsy and send them to the Biochemistry Laboratory at Cambridge for processing. The aim was to obtain human growth hormone for injection into children who had insufficient hormone and were, in consequence, dwarfs. The normal glands, which are the size of a large pea, were to be placed in glass bottles containing acetone as a preservative. 50 glands at a time were to be sent and the mortuary technician would be paid one shilling for each gland despatched. The scheme had the blessing of the Medical Research Council. The M.R.C. is a government agency for the promotion of medical and related biological research and few would care to challenge such a request. Dwarf children, whose bone growing ends had not fused, were given injections of the pituitary gland extract two or three times a week for a number of years. The injections worked and normal stature was attained. Pituitary derived GH was used in many countries. In Australia it was used from 1964 to 1985.

 Then, in 1985, tragedies started to occur. Some of the patients developed C.J.D. The incubation period is long,  in some cases 20 to 25 years, although in many cases of iatrogenic CJD, resulting from brain surgery, the incubation period is only two or three years.  C.J.D. is a rare naturally occurring notifiable disease and it became apparent that pituitary glands, processed in batches of 2,000  or more, possibly would  contain at least one gland which had come from a case of C.J.D. There are now many recorded deaths attributable to the hormone injections and it has been estimated that the risk of dying  from C.J.D., in cases treated with the natural hormone, is 1 in 200.
 

Pituitary hormones involved in the outbreak of BSE?

 The coincidence is striking. Pituitary gland injections in man and in cattle. B.S.E. and C.J.D. appearing at about the same time and now there are cases of C.J.D. which are slightly different from the naturally occurring cases, and blamed on eating beef. Could there have been a mix up? Were the somatotropin ampoules  from cattle pituitaries easily identifiable from ampoules of human somatotropin? Did cattle ever get human hormone injections,
either accidentally or intentionally? Did we give C.J.D. to cattle? Did cattle give B.S.E. to us?
The answer to all the questions is - yes, and the time sequences fit.
 
 

Further remarks:-

The Merck Index gives human growth hormone as a simple polypeptide chain of 191 amino acids with a molecular weight of 22,124 and an isoelectric point of 4.9. It has been marketed under many headings ( somatotrophin, CB311, Asellacrin, Bio-tropan, Crescorman, Grorm, Nanomon, Norditropin and Saizen), and issued free by the MRC as hGH.
The synthetic HGH produced in bacteria from recombinant DNA has a complete sequence of natural hormone amino acids plus an additional  N-terminal methionine. It is marketed as Methiconyl HGH, Somatrem, met HGH, Gentonorm, Genatropin, Maxomat, Protropin, Somatonorm and Umatrope.  Somatropin and Humatrope are identical to hGH but are tissue culture produced.

The national pituitary agency in the USA (NPA), was formed in 1960, and had similar programmes to the Canadian MRC, and the Australian MRC.
Commercial hGH began in 1968 with Calbiochem. Its source of pituitaries was not in the USA (- where was it?), but Calbiochem sold its interest to Hoechst-Roussel in 1977, having previously been granted FDA approval in 1976. ( ? check the FDA specification). Hoechst sold its interest to Serono who marketed hGH aggressively in the USA eventually getting 80% of market share. (Jour Pediatrics 131, 1, 2, S1-4.). Serono was joined in the market by KABI in 1979 who tried to collect pituitaries in competition with the NPA - producing anger and resistance. When the ill effects of hGH became apparent KabiVitrum withdrew its product early on but Nordisk initially thought their preparation was safe.
(Kabi Vitrum marketed hGH as Crescorman, which is possibly the same as the German Somacton).

The University of California is suing Genentech for $1.2 billion dollars because Professor Seeburg is said to have taken a sample of GH DNA from its laboratories and this helped Genentech to produce Protropin. Commercial firms  and dairy farming have many similarities
They have  finished products and need to make profits on them.

The use of growth stimulants still occurs. GHRH (growth hormone releasing hormone) is a single polypeptide of 108 amino acids. A synthetic polypeptide (Sermorelin), containing the first 29 amino acids, is nearly as potent as full length GHRH and is marketed by Serono as Geref
Rinquet H. et al.,  1994, J. Animal Sci., 72. (10). 2709-17 reports on the long term effects of human growth hormone-releasing hormone in dairy heifers in Canada.