T H E PONDERAL GROWTH O F T H E OVARIES AND UTERUS I N T H E FETAL DOG HOMER B. LATIMER Departments of Anatomy, University of Eansas and University of Hissouri FOUR FIGURES The size of the fetal ovaries and uterus, in man and in animals has not received as much attention as has been devoted to the study of the weights of these organs in postnatal life. The size, physiology and effects of the various hormones upon the organs of the adult female reproductive system have recently received much attention with less study devoted to " the ponderal growth in the prepuberal period. There are more quantitative data on the prenatal ovaries than the uterus, but the reverse is true for these adult organs. Jackson ('09) has studied the prenatal growth of the human ovaries and testes but he gives no data for the growth of the uterus. Felix ('12) and Bach ( '26) list measurements of length and breadth of the human ovaries and also linear measurements of the uterus for the fetal and early postnatal period. Prenatal weights are available for the ovaries of cattle (Bascam, '23)' for the horse (Cole et al., '33), the cat (Latimer, '39) and the postnatal growth in the albino rat (Donaldson, '24 and Eayrs and Ireland, '49). Data on the prenatal growth in weight of the human uterus have not been found in the literature and the only known data on the prenatal growth in weight of the uterus is for the cat (Latimer, '39). Quantitative data on the size of the human postnatal uterus have been published by Reynolds ( '51)' Weisman ( '51) and Poulos et al. ( '53). Allen ( '28) has reported linear nicasurements of the uterus in the monkey; Markee and Hinsey ('35) for the cat uterus and Donaldson ('24) has 731 732 HOMER B. LATIMER studied the postnatal growth in weight of ovaries and uterus in the albino rat. Rodgers and Taylor ('55) report postnatal changes in ovaries and uterus in the guinea pig. These are but a few of the many studies on growth and variability in size of the adult uterus. So far as is known, no previous study has been made on the prenatal or postnatal growth of the female reproductive system of the dog. MATERIALS A N D METHODS There have been many attempts t o show whether any of the hormones and other substances pass the placental barrier and in what way, if any, they affect fetal growth. The studies of Reynolds ( '46), Jost ('54) and Heggestad ('55) are but three of the many studies which have discussed the relative importance of (maternal and fetal hormones upon the developing conceptus. However effective the placental barrier may be, abnormal conditions within the maternal uterus usually result in the abortion of the conceptus, and since all of these fetuses were carried in the maternal uterus until the mother dogs were sacrificed, we may assume at least a certain degree of normalcy in these fetal dogs and in their organs. The growth of the testes in the male fetuses of this colleclection of fetal and newborn dogs has been described in an earlier report (Latimer, '55) and the description of the 211 specimens together with the methods of collecting, preserving and studying the data have been fully described (Latimer and Corder, '48 and Latimer, '50). Four specimens were too small to permit sex determination in gross examination and these gonads were included with the testes in the earlier report, thus leaving 99 females, of which 12 were newborn puppies. All of the specimens were preserved in 10% formalin for at least three months prior t o dissection and weighing. The ovaries and uteri, like the other organs, were weighed in weighing bottles on an analytical balance sensitive to 0.1 mg. All weights of the ovaries include both left and right ovaries. PRENATAL GROWTH OVARIES AND UTERUS 733 The weight of each uterus includes the vagina, the small corpus uteri with its cornua and the uterine tubes. All mesenteries were removed as completely as possible. The empirical formulae from which all of the curves, except the horizontal percentage lines, were drawn, were found by the method of least squares, as described in the earlier report (Latimer and Corder, '48). Growth of the ovaries The weights in milligrams of the ovaries, plotted on body weight in grams are shown in figure 1. The single circles represent the ovaries of the fetal dogs and the double circles, the ovaries of the newborn dogs. The formula for the line representing the increase in ovarian weight is: Ovaries W. = 0.2 (B.W.) - 0.426. This formula is valid from 6 to 440 gm of body weight. The average percentage deviation of the calculated from the observed values is 8.13%. Fig. 1 Weights of the two ovaries in milligrams plotted on body weight in grams. Each circle represents the weight of a pair of fetal ovaries and the double circles represent the newborn ovaries. The line rising uniformly throughout the period and surrounded by the individual cases represents the growth of the ovaries. The empirical formula from which this line was drawn is given in the text. The horizontal line represents the weights as percentages of body weight, with the percentage shown at the right. 734 HOMER B. LATIMER The lighter horizontal line represents the average of the weights of the ovaries as percentages of body weight, or 0.0186% throughout the entire fetal period. Both the straight regression line and this constant percentage line indicate that the ovaries follow very closely the increase in weight of the entire body in the fetal growth period. I I 100 I MG M 8 W- 40 0 - 0 OL ‘.i 0 01 50 90 110 130 150 170 190 210 000 1 I 230 250 270 MM Fig. 2 The weights of the two ovaries in milligrams plotted on body length in millimeters, with the symbols the same as i n the preceding figure. The horizontal line represents the two ovaries as percentages of body weight. The formulae from which these lines were drawn are given i n the text. Figure 2 shows these same weights of the ovaries in milligrams plotted on nose-anus length measured in millimeters in the heavier line with the individual weights as circles or double circles as in figure 1. The rate of increase in weight of the ovaries is more rapid in the larger fetuses as indicated by the steeper slope of the second line. These regression lines were drawn from the formulae : Ovaries W. = 0.27 (B.L.) - 22.85, from 90 t o 154 mm of body length, and Ovaries W. = 0.62 (B.L.) - 76.58 from 154 t o 250 mm of body length. The average percentage deviations for the above formulae are respectively, 8.31 and 7.08%. The lighter horizontal line without any cases, represents the weights of the ovaries as 0.0186% of body weight throughout the entire fetal growth period. These percentages were PRENATAL GROWTH OVARIES AND TJTERUS 735 about equally well distributed around the lines when plotted on either body weight or body length. They have a coefficient of variation of 26.65%, thus indicating a moderately wide scattering. It was stated in the earlier report (Latimer, '55) that the growth in body weight is not as rapid in the smaller fetuses as the increase in body length and this slower initial rate of increase in ovarian weight when plotted on body length in figure 2 together with the constant percentage of body weight is as expected. I n general the weights of the ovaries exhibit a rather constant percentage of body weight throughout the fetal period and they also have a uniform arithnietical relationship to body weight throughout the fetal growth period when plotted on body weight, while their increase in weight is slower at first and then more rapid toward the later part of the period when plotted on body length. Growth of the uterus The distribution of the weights of the uterus plotted on either body weight or body length is more variable than the weights of the ovaries similarly plotted and, due to their marked variability, the following curves and formulae merely indicate the trends of increase in weight of the uterus. I n figure 3 the weights of the uterus in milligrams are shown plotted on body weight in grams. The uteri of the smallest specimens, or those with a body weight under 40 gm, are not well represented by this curve, for all of this group are heavier than would be indicated by the curve were it continued from 40 gm back to 0.3 gm, the weight of the smallest specimen. These smaller uteri were difficult to remove accurately and a larger proportion of the uterine mesentery may have been included, or as will be suggested in the percentage curve in the following figure (fig. 4), they probably were actually relatively heavier in weight. 736 HOMER B. LATIMER The regression line in figure 3, representing the ponderal growth of the uterus from 36 to 400 gm of body weight, was drawn from the empirical formula: IJterns W. = 0.3 (B.W.) - 4.47. 120 MGM 100 80 60 40 20 0 Fig. 3 The weights of the uterus i n milligrams plotted on body weight in grams, with the symbols the same as in figure 1. The lighter line with no cases shown, represents the uteri as percentages of the body weight. Empirical formulae from which these lines were drawn are given i n the text. 0 01 OMM Fig. 4 The weight of the uterus plotted on body length, with the symbols the same a8 in figure 1. The lighter line represents the weights of the uterus as percentages of body weight. The empirical formulae used i n drawing these lines are given in the text. PRENATAL GROWTH OVARIES AND UTERUS 737 The average percentage deviation of the calculated from the observed values for this curve is 13.29% or slightly more than for any of the other curves in this report. The uterus of the adult normal rabbit mas one of the most variable organs (Latimer and Sawin, '55) with only two organs more variable, namely the ovaries and fat. I n the adult animal at least part of this variability in the weight of the uterus and ovary may be accounted for by their cyclic activity, which is not found in the fetus. The uterus weight as a percentage of the body weight is shown in the lighter line without any individual cases and increasing from about 0.021% to 0.032%. All of the percentage values were plotted on preliminary graphs and the lines and formulae found for these percentages as was done for the regression lines of growth in weight, but only the lines are shown here. This percentage curve was drawn from the formula : Uterus % of B.W. = 0.00003 (B.W.) + 0.0203. This formula is to be used only from 36 to 400gm of body weight. The average percentage deviation for this formula is 9.84%. The percentage weights of the uteri under 36gm-t of body weight are not included for they were the most variable group of these percentage weights. Above 36 gm of body weight the scatter of these percentage weights on the preliminary graphs was not as great as the scatter of the weights in grams. This lesser scatter of the percentage values is likewise true for the percentage weights of the ovary. Figure 4 shows the increase in weight in milligrams of the uteri plotted on body length in millimeters. From 80 to 140 mm of body length the uteri increase in weight but very little, with most of their ponderal increase occurring from 140 to 250mm of body length. The empirical formulae from which these curves were drawn are: Uterus W. = 0.095 (B.L.) - 2.97, from 79 t o 139 mm of body length, and Uterus W. = 0.97 (B.L.) - 124.38, from 139 to 250 m a of body length. The average percentage deviations for these formulae are, respectively, 6.01% and 13.25%. 738 HOMER B. LATIMER The lighter line decreasing from 80 to 114mm of body length and increasing from 114 to 250mm of body length, represents the weights of the uteri as percentages of body weight. These lines representing the changes in the weights of the uteri as percentages of body weight were drawn from the empirical formulae : vG Gterus of B.W. = 0.0767 -- 0.0005 (R.L.), f r o m 80 t o 114mm of body length, and Gttlrus 7' of B.W. = 0.00009 (B.L.) 0.0097, from 114 t o 250 mm of body length. + The average percentage deviations for these forlmulae are, respectively, 5.34 and 8.36%. This reduction in percentage weight of the uterus in the first part of this percentage curve, and the greater weight in milligrams of the uterus from 0.3 to 36 gm of body weight in figure 3, both seem to indicate that the uterus is relatively heavier in the very early fetus and then after this initial period it increases as an arithmetical function of both body weight and body length. I n general, the uterus, like the ovaries, increases as an arithmetical function of body weight and when plotted on body length both increase more rapidly in the later, than in the early fetal period. The ovaries show a constant average percentage of the body weight, but the uterus is relatively heavier, as a percentage of body weight, in the fetuses of shorter body length and after this initial period the percentage weights of the uterus increase when plotted on body weight or body length. DISCUSSION Very few data have been found in the literature on the prenatal growth of the female reproductive system, and these are often fragmentary and not readily comparable with the present data. Jackson ('09) states that the percentage weights of the human ovaries from 2 to 10 months of prenatal age decrease from 0.112 to 0.022% of body weight while the fetal dog ovaries average 0.0186% of body weight throughout the entire fetal period. The human ovaries unlike the dog ovaries, are much smaller than the testes a t corresponding ages PRENATAL GROWTH OVARIES AND UTERUS 739 throughout fetal life, but like the cat ovaries (Latimer, '39) they decrease in percentage weight. The linear measurements of length and breadth of the right and left ovaries in the human fetus (Felix, '12) show much irregularity in growth and an increase of 5 fold in each measurement during the fetal period. Graper ('38) states that the human ovaries increase from 0.02 to 0.20gm from 6 to 9 fetal months of age. The growth in length and breadth of the ovaries in fetal cattle (Bascom, '23) shows the greatest irregularities in the smallest fetuses. The ovaries as well as the testes, in the fetal horse (Cole et al., '33) are unique in that their maximum weight occurs at approximately the middle of the fetal growth period. The ponderal growth of the ovaries in the fetal cat (Latimer, '39) is much like that in the fetal dog, for when plotted on body weight, both form straight lines increasing regularly throughout the period, and when plotted on body length, both sets of ovarian weights increase more rapidly in the late fetal period. The ovaries of the newborn cats are heavier and not well fitted by the regression line, while the ovaries of the newborn dogs are well distrihuted around the regression line. The weights of the ovaries as percentages of body weight, decrease in the early fetal period and then remain constant in the cat, while the dog ovaries maintain a constant average percentage throughout the entire period. All of these fetal ovaries show much variation in both linear and ponderal measurements and Wald and Scammon ( '32) in their 'study of the growth in weight of the testes and ovaries in human fetuses give regression lines for the growth of the testes but could find no reasonable trend in the weights of the ovaries, due to their variability. The variation in the size of the human uterus in postnatal life has been studied by Reynolds ('46 and '51), Weisman ('51), Poulos and Langstadt ('53) and others. The postnatal growth of the uterus has been reported by Donaldson ( '24) for the albino rat and for the cat by Markee and Hinsey ( '35). The only known data on the prenatal ponderal growth 740 HOMER B. LATIMER of the uterus is for the cat (Latimer, '39). The growth of the fetal cat uterus is represented by lines concave superiorly when plotted on body weight or on body length, while figure 3 shows that the weights of the fetal dog uterus increase as a constant arithmetical function of body weight throughout the fetal period, following an initial brief period of aceelerated but irregular growth. The uterus of both dog and cat, when plotted on body length show an accelerated growth rate in the later part of the fetal period, and a larger percentage of body weight in the older fetuses. There is an initial decrease in these percentages of the dog uteri when plotted on body length (fig. 4) which has been discussed. The weights of the newborn uteri in the cat are all much heavier than the fetal uteri, while the uteri of the newborn dogs are much more closely and unifonmly distributed around the regression line. I n both the dogs and cats the weights of the uteri are more variable than the weights of the ovaries. This variability in the uterus, as well as in the ovaries in the fetal period cannot be explained by the periodicity of the menstrual cycle. According to Felix (,la) and Gillman ('48) the testes begin t o grow and differentiate before the ovaries, while the growth of the ovaries is more uniform throughout the fetal period. To compare the fetal growth of these. organs in these dogs and cats, the weights of the testes, ovaries and uteri were computed f o r lOgm, 2Ogm and for each 20gm increase in body weight thereafter and these values combined in a table (not shown). At 10 and 20 gm of body weight the fetal dog ovaries were 78% of the weights of the testes. At 40gm of body weight the ovaries were 1.17 times the testes weight and thereafter the ratio increased steadily and uniformly until at 440grm of body weight the ovaries were 2.36 times the weight of the testes. Similar ratios for the cat gonads show that at 10, 20 and 40 gm of body weight the ovaries were respectively, 45, 63 and 86% of the weights of the testes. At 60 gm of body weight the ovaries were 1.01 times the weights of the testes and thereafter these ratios increase slowly but PRENATAL GROWTH OVARIES AND UTERUS 741 regularly until at 140 gm of body weight (newborn body weight for the cat) the ovaries were 1.26 times the testes weight. The early growth of the fetal testes, compared to that of the ovaries, seems to be confirmed in both the dog and cat, for in the smallest specimens the testes were heavier than the ovaries, but soon this ponderal relationship was reversed and at birth the ovaries were larger than the testes, with the greatest difference in the dogs. I n the adult cat as well as in the adult rabbit (Latimer and Sawin, '55) the testes are much heavier than the ovaries, the ratios being 9.2 and 8.6 times respectively. No ratios are known for the adult dog gonads. The uteri of the dogs under 40 gm of body weight were not well fitted by the formula (fig. 3) hence the comparison of the computed weights of the uterus begins at 40 grm of body weight, and for this body weight the uterus averages 99% of the weight of the ovaries. Then from 60 to 440 gm of body weight, the weight of the uterus exceeds the weight of the ovaries beginning at 1.17 times in the 6 0 g m specimens and increasing regularly to 1.48 times at 440gm of body weight. Thus in the larger fetal dogs there is not as much difference between the weights of the uterus and ovaries as there is between the weights of the ovaries and testes. I n the fetal cats, the uterus is 2.27 times the weight of the ovaries at 10 gm of body weight and 1.9 and 2.0 times at 20 and 40 gm of body weight respectively, and from 60 gm of body weight, and above, this ratio increases to its maximum of 5.13 times at 140gm of body weight. Thus in the newborn dogs there is a greater difference between the weights of the gonads and less difference between the ovaries and uterus than the sibmilar ratios reported for the newborn cat. Jackson ('09) reports a percentage of 0.080 for the testes in the 10th fetal month and 0.022% for the ovaries in the 7th fetal month of human gestation. Jackson quotes percentages from Vierordt of 0.026% of the body weight for both gonads in the human newborn. All of these percentages of 742 HOMER B. LATIMER the gonads in the human fetus and newborn are relatively heavier than the percentages of 0.0168 for the ovaries and 0.0097 for the testes in the full term dogs, or 0.016% for the ovaries and 0.013% for the testes of the full term cats. Both gonads in the fetal cats have their maximum percentages of body weight or 0.108%, at the beginning of the fetal period, thus resembling the changes in the percentages of the fetal dog testes. The ovaries of the dog have a uniform percentage weight throughout the entire fetal period. Throughout the fetal growth period the ovary, testis and uterus, like these organs in the adult cat (Latimer, '39) and rabbit (Latimer and Sawin, '55) are extremely variable. This variability in the adult organs may be attributed, in part, to their cyclic activity, which has not been shown to be a normal attribute of these fetal organs, hence we must conclude that the gonads and uteri are just inherently variable, due to some as yet unknown cause. SUMMART- The growth in weight of the ovaries in the fetal dog, plotted on body weight, may be represented by a single straight line, but these same data plotted on body length are best represented by two straight lines with the second, ~~'Iiich represents the larger specimens, rising more rapidly. The pairs of ovaries form an average of 0.0186% of the body weight throughout the entire period, and these percentages have a coefficient of variation of 26.6%. The weight of the uterus increases as an arithmetical function of body weight in fetuses above 4Og.m of body weight. These uterine weights plotted on body length, increase rather slowly up to 139 mm of body length and more rapidly thereafter. The weights of the uterus as percentages of body weight, and plotted on body weight, increase rather slowly but uniformly. However, when these same percentages are plotted on body length, the percentages decrease from 80 to 114mm of body length and increase thereafter. PRENATAL GROWTH OVARIES AND UTERUS 743 Empirical formulae are given whereby the weights or percentage weights of the ovaries or uteri may be estimated from either body weight or body length. In the smallest fetuses, the ovaries weigh less than the testes, but from 40 to 440 gm of body weight, the ovaries are heavier, attaining a ratio in the full term fetuses of 2.36 times the weight of the testes. The uterus is practically the same weight as the ovaries in the 40 gm fetuses! but it grows more rapidly and becomes 1.46 times the weight of the ovaries in the late fetal stages. Both the ovaries and uteri are exceedingly variable in weight in these fetal dogs. LITERATURE CITED ALLEN,EDGAR 1928 Further experiments with an ovarian hormone in the ovariectomized adult monkey, Macacus rhesus, especially the degenerative phase of the experimental menstrual cycle. Am. J. Anat., 42: 4 6 7 4 8 7 . BACH, F. 1926 Wachstum der Geschlechts-Organe. Tab. Biol., :'5 708. BASCOM, K. F. 1923 The interstitial cells of the gonads of cattle with especiaE reference t o their embryonic development and significance. Am. J. Anat., 31: 223-259. COLE,H. H., G. H. HART,W. R. LYONSAND H. 12. CATCHPOLE 1933 The development and hormonal content of fetal horse gonads. Anat. Rec., 56: 275-293. DONALDSON, H. H. 1924 The rat. The Wistar Press, Philadelphia. 469 pp. EAYRS,J. F., AND K. F. TRELAND 1949 The effect of total darkness on thc growth of the newborn albino rat. J. Endocrinology, 6: 386-397. FELIX,W. 1912 The development of the urogenital organs. Chap. 19, pp. 752-979. Manual of IIuman Embryolog?, F. Keibel and F. P. Mall., Lippincott Go., Philadelphia. GILLMAX,J. 1948 The development of the gonads in man, with a consideration of the role of fetal endocrines and the histogenesis of ovarian tumors. Carnegie Inst. Wash., Contrib. to Embryol., 3%: 81-131. GRAPER,L. 1938 Weibliche Kindliche Geschlechtsorgane. Handbuch der Anat. des Kindes. 2, 1 Lieferung: 78-113, Munchen, J . F. Bergman. HEGGESTAD, C. B. 1955 Retardation of ponderal growth in hypophysectomized fetal rats and its prevention by means of an injected growth hormone. Anat. Rec., 111: 3 9 9 4 0 0 . JACKSON, C. M. 1909 On the prmatal growth of the human body and the relative growth of the various organs and parts. Am. J. Anat., 9: 119-165. JOST, A. 1954 Hormonal factors in the development of the fetus. Cold Spring Harbor Symposia on Quant. Biol., 19: 167-181. 744 HOMEB B. LATIMER LATINER,H. B. 1939 The prenatal growth of the cat. V I I I . The weights of the kidneys, bladder, gonads and uterus, with weights of the adult organs. Growth, 3 : 89-108. 1950 Variation in the number and in the weights of the fetuscs in each litter in a series of puppies. Growth, 14: 107-110. 1955 The prenatal growth of the testes in the dog. Growth, 19: 207-213. LATINER,H. B., AND R. L. CORDER1948 The growth of the digestive system i n the fetal dog. Growth, 1%:285-309. H. B., AND P. B. SAWIN 1955 Morphogenetic studies of the rabbit. LATIMER, X I I . Organ size i n relation t o body wcights in adults of small sized race X. Anat. Bee., 123: 81-102. MARKEE, J. E., AND J. C. HINSEY 1935 Studies on uterine growth. 11. A local factor in the pregnant uterus in the cat. Anat. Rec., 61: 311-319. POULOS, P. P., AND J. R. LANGSTADT1953 The rolume of the uterus during labor and its correlation with birth weight. 1. A method for the prediction of birth weight. Am. J. Obst. and Gynec., 6 5 : 233-244. REYNOLDS, S. R. M. 1946 The relation of hydrostatic conditions in the uterus to the size and shape of the conceptus during pregnancy: a concept of uterine accomodations. Anat. Rec., 95: 283-296. 1951 Determinants of uterine growth and activity. Physiol. Revs., 31: 244-273. ROGERS, J. B., AND R. C. TAYLOR 1955 Age changes in the uterus and ovary of the guinea pig. Anat. Rec., 2 2 1 : 448. WALD, H., AND R. E. SCAYMON1932 Prenatal growth of human testes and ovaries. Proc. SOC.Exp. Biol. and Med., 29: 416-420. WEISMAN,A. I. 1951 The volumetric capacity of the human nulliparous uterus. Am. J. Obst. and Gynec., 6 2 : 202-204.