Book - The Hormones in Human Reproduction (1942) 7
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Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.
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Chapter VII. Endocrine Arithmetic
- "I often say that when you can measure what you are speaking about and express it in numbers you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind: it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science." - Lord Kelvin, in Popular Lectures and Addresses, lecture on Electrical Units of Measurement, 1883.
How much of a given hormone is found in the body at one time? How much is produced in a day? How much is found in the gland at one time ? What is the output of a single cell? These are questions to which we must have an answer if we want to understand the glands of internal secretion and use our knowledge for the benefit of mankind. Certainly every merchant must have this kind of information about his stock in trade, and the manufacturer about his materials and his product. The science of endocrinology is, however, a long way from any such basis for calculation. How can we measure the output of a factory (i.e. an endocrine gland) when we do not know exactly what raw materials it uses, how it makes the product, or what becomes of the product when it is used? In the case of most of these chemical factories we do not even know the capacity of the manufacturing plant. The insulin factory, for example, consists of many thousand bits of tissue, the pancreatic islets, irregular in size and shape, scattered through the pancreas. In the pituitary, although the gland is measurable as a whole, we do not know what particular cells are associated with the various hormones made in the gland, nor even indeed just how many hormones it produces. So it goes throughout this puzzling system of glands. We are dealing at present largely with unmeasurable organs and with incalculable processes. We are able only to appreciate some of the end results, not the fundamental steps. To measure and calculate what is going on within the glands and thus to understand the chemical reactions and strike the balance of input and outgo — that task lies ahead.
Rate of Secretion of the Corpus Luteum Hormone
It happens that of all the endocrine glands, the corpus luteum is the one with which we can go farthest at present toward calculating the answers to the questions with which this chapter opens. The amount of glandular tissue can be ascertained, for it occurs in discrete masses of more or less spherical form and is composed of cells which can be measured and even counted with a fair degree of accuracy. The chemical structure and molecular weight of the hormone are fully known, and the dose necessary to produce certain definite effects is known. With these data at hand, let us take pencil and paper and see how far we can get.
The following calculations are of course approximate, not precise. They represent a preliminary exploration in a brand new field of study. There are unavoidable flaws in our procedure. In our arithmetical operations, for instance, we shall have to combine figures obtained from observations on rabbits with others learned from swine, thus violating one of the primary-grade rules of arithmetic, picturesquely stated long ago by one of my teachers, "You can't add cows and horses." Some other uncertainties will appear as we go along. If our results come out anywhere between 50 per cent and 200 per cent of the true figures we shall be doing very well for a start. Physicians who have to decide on the dosage of ovarian hormones for their patients will be glad to have even that; and as for my lay readers, they may at least fmd this chapter amusing. At any rate, when I presented some of these calculations at the Cold Spring Harbor Symposium on Quantitative Biology in 1937, that earnest little assembly of research men surprised itself — and me — by being very much amused, partly perhaps because it really was funny to see a medical man so gaily slip the leash and wander down a strange pathway, and partly because of the incongruity between our simple experiments on rabbits and sows, and the final emergence into pure theory in terms of molecules by the billion. Toward the end of my discourse, however, the hearers settled down and discussed the calculation quite seriously. Our chairman, in fact, sat up all the next night figuring on a furtiier stage of the investigation, and in the morning, weary but still enthusiastic, brought me several more pages of arithmetic. What follows here is the substance of that presentation, revised in consideration of some facts contributed in discussion by members of the symposium, and corrected also in the light of subsequent knowledge.
1. How much progesterone is produced daily by a given amount of corpus luteum tissue? We begin by considering the fundamental property of the corpus luteum, namely, to produce progestational proliferation of the lining of the uterus (Chapter V, page 107 and Plate XVII, B), This has been studied chiefly in the rabbit, in which species it shows up with especial clearness. In a rabbit there are, of course, several corpora lutea at a time. By cutting down their number by surgical operation on the ovaries under anesthesia, it is possible to ascertain the minimum number of corpora lutea necessary to produce full progestational proliferation as in figure D of Plate XVIII.
(a) A young Frenchman, Joublot, the first to try such an experiment (1927), found that two corpora lutea were sufficient, but one was insufficient. I tried it also, and found that one corpus was sufficient, but half a corpus insufficient. Lucien Brouha, then in Belgium (1934), found one or two corpora lutea necessary. In our calculations we shall take the average of these three results and start with the assumption that in the rabbit one corpus luteum produces just sufficient progesterone to cause typical effects upon the lining of the uterus.
(b) To produce the same effect with progesterone, giving one injection per day, requires about 0.2 milligrams daily. Dr. Pincus reports that by giving the hormone in two injections, the dail}' dose can be brought down to about 0.13 mg. Let us take this lower figure as the basis for subsequent calculations. It may help to visualize the quantities we are discussing if we remind ourselves again that an ordinary postage stamp weighs 60 milligrams.
From (a) and (b) we may conclude that one corpus luteum produces about 0.13 mg. of progesterone daily. Here we are making another assumption, namely that the progesterone we administer in oily solution is utilized by the rabbit as efficiently as she can utilize the progesterone she makes in her own ovaries. This is really not impossible, for only very small amounts of oil are used and they are slowly but completely absorbed. This point will be discussed again later when we attempt to calculate the rate of output of estrogenic hormone.
Our calculation can be checked roughly by considering another action of progesterone, namely the maintenance of pregnancy in the rabbit. This requires more of the hormone. Brouha found that to preserve pregnancy to the 8th day, the rabbit must have three or more corpora lutea (instead of merely the one corpus luteum required to produce typical changes in the uterus). If we want to maintain pregnancy with progesterone after removal of the ovaries, we must also increase the dose something like 3 times or more. Willard Allen found 0.5 to 1.0 mg. of progesterone daily to be the necessary dose. In this sort of experiment we find therefore that one corpus luteum provides the equivalent of 0.16 to 0.33 mg. of progesterone daily, a figure in crude agreement, at least, with that of 0.13 mg. arrived at previously.
The volume of tissue in a rabbit's corpus luteum is approximately 3.25 cubic millimeters. Dividing this into the daily output of 0.13 mg., we get the answer to question 1: One milligram of rahhifs corpus luteum produces about O.O4 milligram of progesterone daily,
2. How much progesterone is made daily in the ovaries of one rabbit? Although the number of eggs shed by a rabbit at one time, and hence the number of corpora lutea in one crop, varies from 1 to 18, the number occurring most frequently (modal number) is 8. Eight corpora lutea multiplied by 3.25 (the volume of one corpus luteum in cubic millimeters) and then by 0.04 (the output of progesterone, in milligrams, by one milligram of corpus luteum) gives the answer to question 2: The modal daily output of progesterone by the ovaries of one rabbit is about 1.04 milligrams^ and the range is from 0.13 mg. when only one corpus luteum is present, to 2.3 mg. with the maximum number of corpora lutea, namely 18.
3. How much progesterone is produced daily by the ovaries of a sow? This is important to know because the sow is the source of most of the natural progesterone that has been extracted and the only animal in which we know the amount that is present in the ovaries at any one time. The volume of one corpus luteum of the sow is approximately 625 cu. mm., the equivalent of 160 rabbit corpora lutea. Assuming that the corpora lutea of the two species are equally efficient, volume for volume, and therefore that the amount of progesterone produced in each is directly proportional to the amount of glandular tissue (an assumption for which at present there is no evidence) then 1 corpus luteum of the sow would produce 21 mg. of progesterone daily.
In a sow possessing the modal number of corpora lutea, which is 10 in that species, the total daily output of progesterone would be 210 mg. per day. The range would be from 21 mg. when one corpus luteum is present to 525 mg. with the maximum recorded number of corpora lutea in the sow, namely 25. This result seems improbably high, but since we have no present means of improving it, let us use it tentatively in answering the next question.
4. How does the daily output compare with the amount present in the ovaries at any one moment? All the corpora lutea in the ovaries of one sow, when the modal number is present, weigh about 5 grams. By direct extraction the yield of crude progestin is equivalent to 0.05 mg. of progesterone per gram of raw tissue. Therefore one sow having 10 corpora lutea has about 0.25 mg. progesterone in the ovaries at the moment of killing. If the total output per day, estimated in section 3 above as 210 mg., is anywhere near correct, this means that the amount present in the ovaries at any one moment is less than 2 minutes* supply. This is a very important fact, for it points to a very high rate of "turnover" of secretion in the gland. We must think of the corpus luteum as making the hormone quite rapidly, working up only a Httle at a time but putting it through very quickly.
5. What is the daily output of the human corpus luteum? The volume of secretory tissue in the human corpus luteum is very difficult to measure, since the gland has a folded wall about a large cavity filled with connective tissue, like the monkey's corpus luteum shown in Plate IX, A. Estimates which I have made by two rough methods give 450 to 500 cu. mm. as the volume of secretory tissue in one corpus luteum. This is 150 times the volume of the rabbit's corpus luteum; and assuming once more that the human corpus luteum produces progesterone at the same rate as the rabbit's, volume for volume, then the daily output of the human corpus luteum may be estimated as about 20 milligrams per day.
This calculated result seems rather high when compared with a few estimates obtained in other ways. For example, Kaulfmann in 1935 reported producing a progestational endometrium in a human patient with 50 rabbit units in 15 days. These were presumably Clauberg units, of approximately 0.4 mg. each, making the dose about 1.3 mg. daily. Assuming that this is somewhere near the minimum effective dose, and allowing for a ratio of about 1 :4, as in the rabbit (section 1 above) between the minimum daily dose for progestational proliferation and the amount necessary to carry out the real task of the corpus luteum, namely maintenance of pregnancy, then the human corpus luteum would be expected to produce about 5 mg. daily. Wiesbader, Smith and Engle of Columbia University Medical School (1936) found that a certain effect of the removal of the human corpus luteum (bleeding from the uterus) cannot be prevented by substituting 0.5 mg. daily of progesterone by injection, but can be prevented by 5 mg. This suggests that 5 mg. is a quantity sufficient to produce one of the known effects of the corpus luteum, though not necessarily the full effects.
Another way of getting at this figure is through the fact that in human females, used-up progesterone leaves the body through the kidneys as sodium pregnanediol glycuronidate, as explained in Chapter V, page 120. Venning and Browne, who discovered this fact, found that if they administered a given quantity of progesterone, they could recover about half of it in the urine as the excretion product. When they collected all the pregnanediol excreted by a patient in a whole menstrual cycle, they found that the total recoverable amount was normally about 60 mg. This would mean about 120 mg. of progesterone actually produced. Since the corpus luteum is probably actively functional during about 10 days of each cycle, we arrive at an estimate of 12 mg. of progesterone produced daily. Another research group, Pratt and Stover of the Henry Ford Hospital, Detroit, obtained considerably smaller values, for their patients yielded only 2 to 3 mg. of pregnanediol daily, which we may consider to represent at the most 6 mg. of progesterone. It is known, however, that the chemical recovery of pregnanediol and estimations of corpus luteum activity based upon this method are subject to numerous errors not fully understood. It is perhaps all we should ask for, that the various estimates and calculations we have made and cited fall within limits as close as 5 and 20 milligrams per day (Appendix II, note 15).
Physicians who have used progesterone for disturbances of menstruation and for threatened abortion have seldom administered more than 2 mg. per day. If (as seems credible) beneficial results have been obtained with this and even smaller dosage, we must suppose that clinical benefit may require only the redressing of a slightly disordered balance. Our calculations make it clear, however, that larger doses, of the order of 5 mg. or more, will have to be given thorough trial before the medical possibilities of this hormone are fully understood.
6. What is the progesterone output of a single cell? Returning to the rabbit's corpus luteum, it is possible to calculate approximately the output of a single cell.
The averages of a number of measurements of the diameters of individual corpus luteum cells were 0.028 x 0.028 x 0.036 mm., giving for the cell a calculated volume of 0.000015 cu. mm. Dividing this into the volume of the whole corpus luteum we get 217,000, and making due allowance for space occupied by the blood vessels we arrive at an estimate of 180,000 endocrine cells in one corpus luteum of the rabbit.
Since 180,000 cells produce 0.13 mg. progesterone per day, the daily output of otie cell is about 0.0000007 mg.
The figure at first sight seems very small, but when the number of molecules is considered the resultant expression looks like the astronomer's rather than the biologist's quantities. We get the number of molecules made by a single cell, by the following calculation. We ascertain the molecular weight of progesterone by adding the atomic weights of the elements it is made of, namely 21 atoms of carbon, 30 of hydrogen, and 2 of oxygen. The sum is 314. This is the relative weight in comparison with the atomic weight of oxygen taken as 16. Applying Avogadro's law we know that 6 x 10^' molecules^ weigh 314 grams. Dividing the latter by the former figure, the actual weight of one molecule is 5.2 x 10"" gram. Dividing this weight into the weight of the daily output of one cell, we find that one cell produces about 1.3 x lO"-^ or 1,300,000,000,000 molecules, i.e. more than a thousand billion molecules of secretion produced in one day by one cell.
1 In dealing with very large numbers and very small decimal fractions it is convenient to avoid writing dozens of ciphers by using exponents. Thus 100 is 102 and .01 is 10-2. 600 is 6 x 102. The figure cited above, 6 X 1028, when written in full is 6 followed by 23 zeros, or six hundred thousand billion billions.
For comparison, it may be noted that in one cubic centimeter (about 1/3 of a thimbleful) of air there are about 10" molecules.
What has just been presented is to the best of my knowledge the first attempt to calculate the actual output of a single secretory cell in any organ. It is, of course, no more than a first approximation to the truth. Yet such conjectures as this, improved and extended beyond the present powers of science, are going to lead us some day to the innermost secrets of cellular life. Perhaps the reader begins to be confused by all this reckoning of enormous numbers of very small things. Perhaps, on the other hand, he has acquired an awesome sense of the complexity of the cells, each one of them an island universe, a frail microscopic enclosure within which arise whirling billions of molecules, themselves in turn complex frameworks of latticed atoms. Upon the correct behavior of these fantastic congeries of particles in the corpus luteum each one of us depended for life itself when we were embryos ; so did all our mammalian ancestors and so will our descendants forever.
Quantitative Aspects of the Receptor Organ
We can get a further glimpse of the workings of the corpus luteum by doing a little figuring about the receptor organ, that is to say the uterus, which receives the progesterone and is affected by it.
As we have seen (Chapter V) the corpus luteum acts upon the epithelial cells which cover the inner surface of the uterus and dip down to form the uterine glands. It is the growth and multiplication of these cells which constitute the progestational proliferation by which the early embryos are nourished and implanted.
From a count of the epithelial cells in sections of the uterus, I estimate that a rabbit's uterus contains (in the two horns) about 100,000,000 epithelial cells. This means that each of the 180,000 epithelial cells in a corpus luteum can affect about 500 epithelial cells. The corpus luteum cells are, however, about 25 to 50 times as large (in volume) as the epithelial cells, and therefore each of the former takes care of about 10 to 20 times its volume of the latter at the start of progestational proliferation. The disproportion is not quite so great if we calculate on the basis of the amount of corpus luteum tissue to maintain pregnancy, not merely to induce progestational proliferation. On this basis one corpus luteum cell controls at first about 3 to 5 times its volume of epithelial cells. By the time the effect is complete, the number of epithelial cells has increased a great deal, and thereafter the corpus luteum cell must maintain more of them. This means that small amounts of progesterone stir up a proportionately large effect in the uterus. That sort of trigger-like action ("You push the button, we do the rest") is characteristic of the internal secretions. It is necessary to suppose that some sort of chemical reaction between the hormone and something in the cells of the uterus starts a chain of secondary reactions which profoundly change the physiology of the uterine lining. We might have a better idea of what actually happens if we could know how much progesterone actually reaches each epithelial cell; but this cannot be calculated, because we do not know what proportion of the hormone is diverted to other receptors (the uterine muscle, the mammary gland cells, and possibly other tissues). If all of it went to the epithelial cells of the uterus, each such cell would receive daily about 1.3 x 10"* milligrams. This is almost 10^^ molecules. The actual share received must be considerably smaller.
The Rate of Secretion of Estrogenic Hormone
It is not possible at present to estimate the rate of secretion of estrogenic hormone with anything like the fullness and probability with which such an estimate could be made regarding the corpus luteum. As pointed out in Chapter III, the cells which produce the estrogenic hormone are probably scattered throughout the ovary in the walls of small and large follicles. The number and the total volume of these cells is obviously not subject to computation, and therefore the best we can do is to estimate the activity of the ovaries as a whole. I shall give here a summary of such an estimation which was published recently in more technical form elsewhere. As in the case of the corpus luteum, we get our answer by finding out how much of the hormone we need to administer in order to restore one or another of the functional effects of the ovaries after they have been removed.
How much estrogen is required daily by the monkey? As described in Chapter VI, removal of the ovaries of the Rhesus monkey causes menstruation-like bleeding from the uterus due to removal of the source of estrogenic hormone. If we take out the ovaries and then administer estrogenic hormone, we can try various doses and discover how much we have to give to prevent bleeding. This amount will represent the replacement of the hormone formerly produced by the ovaries when they were present. In my notebooks there are records of twelve experiments of this kind which are suitable for our present consideration. In each of them the animals received 125 international units of estrone daily, beginning the day the ovaries were removed. Of these, 4 bled from the uterus beginning on various days from the 3d to the 14th after the operation, in spite of the treatment with estrone. Seven did not bleed at all during the 15 days of the experiment. One, which received a larger dose of estrone, namely 500 international units, showed a few red blood cells from time to time, beginning on the 3d day, but no external bleeding. The experiment shows that 125 international units of estrone will substitute in many cases, but not in all, for the natural product of the animal's own ovaries, as tested by the prevention of postcastration bleeding. A somewhat larger dose would obviously be required to prevent such bleeding in every case.
A variation of this experiment is to give castrated female monkeys large doses of estrogenic hormone and then drop the dosage until bleeding sets in. A number of such experiments were reported by S. Zuckerman of Oxford, England, in 1936. This investigator found that whenever he reduced the daily dose from several hundred or several thousand international units to any amount below 200 international units, estrindeprivation bleeding occurred thereafter. With more than 200 international units daily no bleeding occurred.
These observations suggest that the output of estrogenic hormone from the normal ovaries, which is of course sufficient to prevent estrin-deprivation bleeding, may be about 150 or 200 international units.
A third means of estimating the probable amount of estrogenic hormone produced by the monkey is provided by the fact that the so-called sex skin (the red swollen areas of the rump and thighs) is under the control of the hormone. Removal of the ovaries leads to shrinkage and pallor of the sex skin, whereas administration of an estrogen in sufficient amount will within a few days restore the color of this region. One of my animals, a young adult, had its ovaries removed at a time when its sex skin was in exceedingly florid condition. The whole area over the rump, the back of the thighs, and the ventral side of the base of the tail was swollen, thrown into distinct ridges and deep red in color. After the operation, but on the same day, the color and swelling were slightly reduced, owing no doubt to the stress of the operation. One hundred twenty-five international units of estrone was given daily beginning on the day of operation. A slight but definite decrease in the color of the sex skin took place during the next 10 days. The swelling of this region diminished also, although not to the same extent as the color, and on the 10th day, in spite of the administration of estrone, external vaginal bleeding began.
From the facts that the condition of the sex skin retrogressed very slowly and external bleeding did not begin until the 10th day, that is to say later than if the animal had been given no estrogen at all, it seems that the dose of 125 international units daily was almost but not quite sufficient to maintain the animal in the same condition as before removal of the ovaries. We may estimate therefore that 150 or 200 international units would have been required to substitute completely for the ovaries.
Another method of arriving at the desired information depends upon the fact that effective action of progesterone upon the endometrium to produce the progestational ("premenstrual") condition in castrated female monkeys requires that an estrogenic hormone be administered in conjunction with the hormone of the corpus luteum. Engle of Columbia University (1937) stated that a satisfactory combination for the castrated Rhesus monkey is 30 AUen-Doisy rat units of estrone (this is approximately 150 international units) daily with 0.5 Corner- Allen unit of progesterone (approximately 0.5 milligram). Hisaw and Greep (1938) gave a similar figure, i.e. about 150 international units of estrogen with 0.5 mg. of progesterone. These experiments are subject to the difficulty that they involve varying the dosage of two hormones simultaneously. The animals used by Hisaw and Greep were, moreover, relatively young, and the progestational changes involved were not as elaborate as the natural progestational state. The result fits however those obtained above in giving 150 international units of estrone as somewhat less than an adequate substitute for what the animal's own ovaries produce.
Probable daily output of estrogenic hormone by the monkey. By all these means of estimation we arrive at the result that the probable daily output of estrogenic hormone by the young adult Rhesus monkey is equivalent to somewhat more than 150 international units and may be set tentatively at the equivalent of 200 international units of estrone. This is a minimum figure; the true amount may be greater, but can hardly be smaller.
This estimate is based necessarily on the assumption that an ovarian hormone injected once daily in oil solution is utilized by the body as efficiently as hormone produced in the animal's own ovaries. There is at present no way of ascertaining how nearly this is true, but in any case, the slow absorption of an oily solution must afford a fairly good imitation of natural processes, and we may recall that my estimate of the rate of secretion of progesterone, which involved the same assumption, turned out to be near the truth, when checked by the recovery of the excretion product, pregnanediol.
Administration of estrogenic hormone in pellets. In recent years many experimental workers have been administering estrogenic hormones by compressing them into small hard pellets which are buried under the skin. This method has the advantage that the hormone is absorbed continuously from the surface of the pellet, whereas when given by injection the rate of absorption fluctuates, being high just after an injection and lower as more and more of the injected dose is absorbed. For this reason a given effect is obtained from a smaller daily dose when absorbed from a pellet than when injected. Pellets will probably be used in human cases in which long continued action is required, not only because of the continuous absorption, but also because insertion of the pellet, which can be done through a hollow needle, avoids repeated hypodermic punctures.
It becomes important for our present calculations to kjiow just how much more effective this method is, dose for dose, than injections, because our estimate of the daily need for estrogenic hormone is based on comparison with injected doses. At first sight the results obtained by pellets seem to be achieved by very small doses indeed, and it is generally taken for granted that the method is much more effective than injection. Very little, however, is known about the exact comparison by actual experiment. Carl G. Hartman has reported, for instance, that the sex skin of a Rhesus monkey was kept red and swollen for 4 months with a single 3-milligram pellet of estrone. This seems small, but assuming that the pellet was entirely used up, this gives a daily dose of 0.025 mg. or 250 international units (3 mg. divided by 120 days). Hartman's monkey thus actually received a larger daily dose than is called for on the basis of our estimate, namely 200 international units.
Deanesly and Parkes of London, who introduced the pellet method, cite an experiment with one of the male hormones which indicates that the dose by pellet is about one-half that by injection. I have heard of experiments with another male hormone in which the ratio was 2 to 3. If any such proportion as these is true of estrone, then our calculated daily output of estrogen by the monkey is roughly one-third to one-half too large.
But here again we are guessing. What evidence is there that absorption from a pellet is really comparable to the natural absorption of the animal's own hormone from the ovarian cells? Nobody knows the answer to this. It might even be true that the pellets yield their substance to the blood stream more easily than do the cells of endocrine glands, in which the hormone is made and stored within the cellular substance. The big molecules of the hormone have to make their way through the outer layers of the cell, not merely drop off the surface of a pellet.
In short, it would be premature to let the pellet method outweigh, in these very crude calculations, the results from injections, about which at present wc know very much more; and therefore I propose to maintain for the present the estimate arrived at above, namely that a female Rhesus monkey produces from her two ovaries estrogenic hormone equivalent to about 200 international units of estrone daily.
If this were actually estrone, the daily output would weigh 0.02 milligram.
Application of these calculations to the human female. Can we apply this estimate to the human female? A woman weighs on the average 15 times as much as a monkey. Two hundred international units x 15 gives 3,000 international units as the daily output of the woman's ovaries. Various medical observations which have been published might be analyzed to give us some sort of check on the estimate. My friend, W. M. Allen, for example, informs me that in his treatment of women whose ovaries had been removed previously he could induce menstruation-like bleeding with estrogenic hormone equivalent to about 4,200 international units of estrone daily. This figure, which is the most pertinent I can find, is roughly 50 per cent higher than my calculation from the monkey experiments, but we have no way of telling how closely this amount compares with that needed by a normal woman. Perhaps what Allen was trying to do required more, perhaps less, than the normal output.
Unfortunately we cannot get help in this problem by measuring the estrogen discharged in the urine, because we do not know just what relationship exists between the hormone which is at work in the body and that which is excreted. The number of milligrams of estriol and similar substances recovered from the urine does not tell us how much of the ovarian hormone was made and used in the body (Appendix II, note 16).
This chapter has contained, after all, a good deal of valiant shooting in the dark. Our conclusions and estimates are sure to be better in time to come. Meanwhile the reader will perceive that after the excitement and drama of the pioneer phase of research on the ovarian hormones, we are in for a lot of tedious, unspectacular measurement and computation, until the reactions of these substances in the body are quantitatively known as well as the chemist knows the reactions in his flasks. Then, as Lord Kelvin said, we shall really understand our subject.
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