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U.S. Department of Agriculture: Agricultural Publications from USDA-ARS / UNL Faculty Research Service, Lincoln, Nebraska

1965

MECHANISMS CONTROLLING THE FORMATION AND PERSISTENCE OF THE

L. L. Anderson Iowa State University, Ames, [email protected]

R. M. Melampy Iowa State University, Ames

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Anderson, L. L. and Melampy, R. M., "MECHANISMS CONTROLLING THE FORMATION AND PERSISTENCE OF THE CORPUS LUTEUM" (1965). Publications from USDA-ARS / UNL Faculty. 738. https://digitalcommons.unl.edu/usdaarsfacpub/738

This Article is brought to you for free and open access by the U.S. Department of Agriculture: Agricultural Research Service, Lincoln, Nebraska at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Publications from USDA-ARS / UNL Faculty by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. MECHANISMS CONTROLLING THE FORMATION AND PERSISTENCE OF THE CORPUS LUTEUM 1

L. L. Anderson2 and R. M. Melampy Iowa State University, Ames

Mechanisms which control formation of (12); in the cow by McNutt (73, 74), Hammon~ corpora lutea during the , and (52), HCifliger (62) and Asdell et al. (l1); anci particularly factors affecting their persistence in the' mare by Harrison (56). The mature and regression in various reproductive stages, bovine corpus luteum may show a fluid-filled have been of considerable interest to physiolo­ cavity, whereas this gland is a solid structur'fIl gists concerned with developing methods for in the ewe, goat and sow. According to Harri~l control of the estrous cycle in domestic son (59), it has been observed in severa~ animals. Some recent reviews on control of species that cells invade th~ ovarian function are those by Chester Jones granulosa between day 1 and day 3 and tha~ and Ball (30), Anderson et al. (.2.) and Short vascularization of the gland occurs at abou~ (ill). the same time. Nearly every cell has ani endothelial covering by day 12. The reticulum found between luteal cells is produced by the Morphologic Aspects theca interna according to Solomons and Gatenby (126), but Corner (32, 33) stated that The mammalian has two principal it is probably laid down by endothelial cells. functions: the production and release of ova Corner (35) investigated the distribution of and the synthesis and secretion of hormones the theca interna cells in porcine corpora which regulate the reproductive tract and lutea and found these cells scattered among secondary . These hor­ the granulosa cells at day 18 of . It mones also influence mating behavior and was difficult, however, to' differentiate theca affect metabolism. Following , the interna cells after this time. wall of the ruptured follicle undergoes struc­ In the sow, Corner (31, 32) observed three tural and functional changes which transform principal types of luteal cells in the corpora it into a transient known as lutea of : (l) true lutein cells origi­ the corpus luteum. While the early develop­ nating from the granulosa; (2) cells witli ment of the corpus lateum appears to be quite smaller round or oval and more chromatic similar in many mammalian species, the nuclei which appear on the periphery of the functional life span varies according to whether gland and along the connective tissue septa the animal is nonpregnant, pseudopregnant, and (3) cells with a spindle shape and a cyto­ pregnant or lactating. In eutherian , plasm which stained dark brown or purple wiU it is generally accepted that the granulosa Mallory's stain. It was also noted that therE cells are transformed into luteal cells of the were transitional stages among the threE corpus lateum. The fate of theca interna cells types. is less clear and there appear to be species In evaluating the physiologic aspects of thE differences as to their subsequent functional formation and persistence of the corpus luteum significance in the corpus luteum. The litera­ it is desirable to consider briefly the mor· ture pertaining to the histogenesis of the phologic development and retrogression 0: corpus luteum has been reviewed by Marshall this gland. In the ewe, according to Warbrittol (79); Corner (31, 32); Hett (60); Pratt (103); (ill), the corpus luteum develops from botl Harrison (58, 59) and Brambell (23). According the granulosa and theca interna, but the lutea' to Amoroso and Finn (~) the original descrip­ cells of the mature gland appear to originat4 tion of the corpus luteum is usually credited entirely from the former. Three types 0 to Volcherus Coiter in 1573, but Harrison cells (embryonic, normal and regressing (58) has stated that Vesalius had observed it were noted and these represented three phasel in the ovary about 30 years earlier. in the life cycle of a single luteal cell derive. The developmental morphology of the corpus from the granulosa. The ovine corpus luteun luteum in the ewe has been described by reaches its maximum size at about the middl' Marshall (78), Grant (50), Quinlan and Mare of the cycle (Casida and McKenzie, 28). Th, (105), Casida and McKenzie (28) and War­ colo.r of the gland changes from blood red il britton (128); in the goat by Harrison (57); in an early corpus luteum through translucen the sow by Corner (31, 32, 34, 35)and Barker pink, opaque pink, cream and finally yellow.

1 Journal Paper No. J -4910 of the Iowa Agricultural and Home Economics Experiment Station, Ames, Iowa. Project Nc 1325. Supported by US PHS, National Institutes of Health (Grant HD 01168-05) and American Cyanamid Co., Princeton,N.: 2Lalor Foundation Fellow, 1964, at the Station de Recherches de Physiologie Anima1e, Centre National de Recherche Zoo techniques, J ouy-en-J osas, France.

64 Corner (34) noted in the sow that, during the have been reported by Weeth and Herman ek following ovulation, corpora lutea attain (ill) and Foley and Reece (48). The latter we diameter of 8 to 10 mm. Ii the animal is investigated the gross and microscopic a regnant, there is further growth until an of the bovine corpus luteum between p verage diameter of 10 to 11 mm. is reached. 25 and 45 days of gestation and stressed the ~istologicallY it has not been possible to variation in size, shape and staining qualities distinguish between glands of the cycle and of the individual luteal cells. It was demon­ those of early pregnance. At approximately strated that the luteal tissue was more com­ day 16 of the cycle, a change occurs in the pact and that the cells were larger and more appearance of the corpus luteum in non­ rounding in shape, with the cytoplasm being pregnant animals. By day 18 the diameter more lightly stained between days 25 and 30. decreases to 6 mm., and the color changes Moss et al. (95, 96) have reported studies from pink of active capillary circulation to dealing with the histochemistry of the bovine whitish of scar tis sue, indicating retrogres­ reproducti ve tract, including the corpus sive changes in the nature offibrous involution. luteum. These investigators noted that the Eventually all that remains of the site of an cyclic corpus luteum contained large amounts , and subsequently a corpus of alkaline phosphatase until about the thir­ luteum (either of a cycle or pregnancy), is a teenth day of the cycle. This enzyme was very small mass of scar tissue, a . low or, except for capillary endothelium, McNutt (73, 74) studied the cyclic bovine absent in later stages of the cycle. Both corpus luteum as well as the corpus luteum theca and granulosa luteal cells contain phos­ of pregnancy and concluded that the luteal phatase activity up to mid-cycle; it is first cells arise from both the granulosa and theca lost from the granulosa cells and later from interna, but he added that many luteal cells the theca cells. The corpus luteum of cycling exhibited intermediate characteristics and that cows differs markedly from the corpus luteum the origin of these cells could not be stated of pregnancy with regard to the presence of with certainty. The newly formed corpus phosphatase. The presence of phosphatase in luteum may be identified on the fifth day when the former and not in the latter would suggest it protrudes above the level of the ovary. The that phosphatase is not concerned in the young corpus luteum measures about 6 to secretory activity of the corpus luteum but, 8 mm. in diameter. By 8 days it has increased rather, may be concerned in the initial stages to 18 to 20 mm., and when it is mature it of growth and development of this . measures 20 to 25 mm. The cyclic corpus The luteal cells of bovine corpora lutea luteum begins to regress about day 16 follow­ between 16 and 33 days of gestation have ing estrus. There is, however, no marked been classified into five types on the basis of reduction in size until the organ is 18 to 20 their cytological characteristics by Foley days old. and Greenstein (47). Type I cells represent Melampy and Gay (83) made a study of the "immature" luteal cells and Type II are weight of both the ovary and its corpus luteum mature cells which have reached their max­ of pregnancy in the cow. The estimated age imum size and development. Type III cells of the corpus luteum was based on the crown­ are believed to be in the initial stage of rump length of the . In the 298 cows regression which continues through Type IV examined, 90 percent of the , including and terminates with Type V cells. Between the corpus luteum of pregnancy, weighed 16 and 33 days of gestation, there is an between 6 and 13 gm. Luteal weights ranged increase in the number and the size of the from 3.0 to 6.5 gm. and were approximately Type II cells with a corresponding reduction one-half of the total ovarian weight. No re­ in the Type I. These investigators concluded lationship was observed between the weight of that the cytological changes in the bovine the ovary or the corpus luteum and the stage corpus luteum during early pregnancy coincide of pregnancy in the cow. The mean luteal with advancing gestation and are related to the weights in grams were as follows: Angus 4.8, reproductive performance of the individual Hereford 4.7, Shorthorn 5.2 and Holstein 5.4. animal. The mean weights for each breed were not significantly different. According to Asdell C!_2) the corpus luteum Physiologic Aspects becomes slightly larger during pregnancy than it is in the cycle, and the greatest size is Stimulation of ovulable follicles in with attained at about 4 months, after which time (LH) causes the formation the size and weight remain about constant. of corpora lutea, and the maintenance of Retrogressive changes begin a little before these structures in a functional capacity is parturition. According to Boyd (£1) the time of thought to be due to pituitary luteotropin, which its disappearance is from 30 to 90 days after is apparently identical with (Astwood, calving, but occasionally it disappears earlier 18; Evans et a1., 44, 45). Evidence for a than 30 days. pituitary luteotropin in the is particularly Results of histological and histochemical in­ well demonstrated by maintenance of corpora vestigations of the bovine corpus luteum have lutea, but not follicles, for several months

65 following autotransplantation of the pituitary pituitary transplantation was combined with to the kidney (Everett, 46). Intact rats with treatment, occurred, a pituitary homotransplanted beneath the kid­ but when pituitary transplantation was com­ ney capsule show a -like pro­ bined with treatment luteolysis longation of the diestrum in progress at the usually did not result. Maintenance of pro­ time of transplantation, with a tendency for lactin secretion in the rat may depend upon subsequent cycles to be prolonged (Quilligan progesterone and the failure of prolactin and Rothchild, 104). The stimulus of mating secretion may result from the depressive is necessary for pseudopregnancy in the spon­ effect of LH upon progesterone secretion taneously ovulating rat and . Pseudo­ (Rothchild, 113). Thus, prolactin secretion pregnancy follows ovulation with or without and absence of LH appear necessary for per­ mating in induced ovulators, such as the sistence of the rat corpus luteum, and this and ferret. Corpora lutea capable of will occur for prolonged periods when the secreting progesterone form during non-fertile pituitary is free of inhibitory affects of the cycles in spontaneously ovulating domestic CNS on prolactin secretion. animals, such as the cow, sow, and ewe. In 1961, Nalbandov proposed that the dis­ Prolactin alone is unable to provide luteo­ charge of a pituitary luteotropin (defined as tropic effects in the rabbit (Hilliard et a1., an unidentified substance or possibly LH) 61; Kilpatrick et al., 68, ~; Rennie et al., over a relatively short time (no longer than 107); guinea (Aldred et al., 1; Rowlands, 2 to 3 days in guinea and pigs) is suf­ 115); sow (Duncan et al., 43; Sammelwitz and ficient to maintain corpora lutea for their Nalbandov, 117); ewe (Denamur and Mauleon, normal life span during the estrous cycle. 40; Moore and Nalbandov, 21); cow (Smith Furthermore, no further release of pituitary et al., 125) or (Bradbury et al., 22; luteotropin occurs unless the female becomes Holmstrom and Jones, 63). .. pregnant, and, in this case, intrauterine events Rothchild (110) reported that is of implantation cause a secondary release of maintained in -treated hypophysectom­ the pituitary luteotropin which may then be ized rats bearing pituitary autotransplants; continuous throughout the gestation. These thus, luteotropin (LTH) secretion does not hypotheses were based on the assumption depend on stimulation from the central nervous that the luteolytic effect of exogenous pro­ system (CNS). It was proposed that a CNS gesterone is not due to a direct action on influence inhibits LTH secretion and that progesterone of the formed corpora lutea and another CNS influence stimulates FSH and that sufficient levels of exogenous proges­ LH secretion; therefore, progesterone could terone block secretion of a pituitary luteo­ maintain LTH secretion through its ability to tropic substance. Sammelwitz et al. (ill) suppress the CNS inhibition over LTH. A demonstrated that high doses of progesterone decrease in progesterone secretion allows injected into pregnant pigs from the time of the CNS inhibitor to increase its activity, ovulation until days 10 to 13 of gestation did thereby resulting in decreased LTH secretion. not prevent formation of corpora lutea, As a result, progesterone secretion is re­ whereas progesterone injections begun on duced to a lower level leading to complete days 12 to 16 of pregnancy resulted in com­ cessation of both LTH and progesterone se­ plete and rapid destruction of the formed cretion and consequently to the regression of corpora lutea. Recently, Brinkley et al. (25) the corpus luteum. Progesterone injected into reported that exogenous progesterone begin­ rats throughout the entire pregnancy or ning 1 or 2 days before ovulation, the day of pseudopregnancy does not alter luteal function ovulation, or 1 day after ovulation could not (Sammelwitz et al., 116). The same lack of prevent the formation and maintenance of effect of treatment with progesterone on the corpora lutea during the normal duration of size of the corpora lutea was observed in the of the cycle. Corpora lutea hypophysectomized rats with autotransplanted in these ~rogesterone-treated gilts were pituitaries. These findings demonstrate that normal as mdicated by chemical determination progesterone does not inhibit the secretion of progesterone content of the tissue at of pituitary luteotropin in the rat (Rothchild, slaughter. From these observations in the !.!.!). Increased levels of progesterone may pig (Brinkley et al., 25), it was concluded that prolong the life of corpora lutea in the rat the pituitary luteotropin needed for corpus by m a i n t a i n in g secretion of a pituitary luteum maintenance is released either before luteotropin (prolactin, LTH) (de Jongh and or simultaneously with the release of LH and Wolthuis, 66; Rothchild, ill). Furthermore, that this hormone is not required beyond the the effect of in this species initial "impetus" for formation of functional may be due to a deficiency or diminished corpora lutea. Du Mesnil du Buisson and secretion of LH, thus decreasing the luteolytic Leglise @l!) found that corpora lutea formed effectiveness of the . Estrogen in pigs hypophysectomized only a few hours treatment alone or combined with progester­ after the first signs of estrus. Also, corpora one, depressed LH secretion in the rat, but lutea were morphologically normal, contained progesterone treatment alone did not depress normal concentrations of progesterone, but secretion of LH (Rothchild, ill). When were generally smaller at days 13 and 14 66 of the cycle when hypophysectorn.ies were 16th day of the cycle and observed cycle perforrn.ed during early luteal phases of the lengths of 19, 78, 25, 60 and 18 days respec­ cycle. These results tend to support the con­ ti vely. Corpora lutea were rn.aintained until tention that a pituitary luteotropin secreted slaughter at 34 days post- estrurn. in 19 of 20 during the initial phases of the estrous cycle gilts injected daily with 7.5 or 15 rn.g. of may be sufficient for the forrn.ation and rn.ainte­ or -1 7 fJ per day beginning nance of the corpora lutea of that cycle. In on day 11 of the cycle (Gardner et a1., 49). progestin-treated nonpregnant gilts with fol­ Bowerrn.an et a1. (20) have investigated the licular growth induced by pregnant rn.are quantities of urinary estrogen rn.etabolites serum (PMS) treatment, a single injection of from gilts during the estrous cycle and preg­ an ovulatory-dose of hurn.an chorionic ganado­ nancy and exarn.ined the pos sibility of a uterine tropin (HCG) was sufficient to cause ovulation influence on the rn.etabolisrn. of estrogen by and forrn.ation of norrn.al corpora lutea, as corn.paring urinary rn.etabolites frorn. intact indicated by progesterone content (Brinkley and hysterectorn.ized and frorn. ovariectorn.ized et al., 24). However, daily injections of HCG and ovariectorn.ized-hysterectorn.ized gil t s inProgestin-blocked pregnant pigs will sup­ following adrn.inistration of exogenous hor­ port rn.orphologically norrn.al corpora lutea mones. Quantities of estrone were low in for as long as 16 days, but the luteal tissue urine at several stages from hysterectorn.ized is not physiologically norrn.al as shown by anirn.als in corn.parison to cycling and pregnant reduced progesterone concentrations. Thus, anirn.als. Rorn.bauts and du Mesnil du Buisson HCG apparently is without luteotropic action (109) recently reported that urinary excretion in the pregnant anirn.al. It was concluded that o!estrone rern.ained low in sows following corpora lutea of pregnancy, unlike those hysterectorn.y on day 70 of gestation. Results corpora lutea of the estrous cycle, are sup­ frorn. experirn.ents with ovariectorn.ized and ported by a continuous or sustained' release of ovariectorn.ized-hysterectorn.ized anirn.als did a luteotropic substance. not show any marked influence of the Using prepubertal larn.bs, Denarn.ur and or progesterone- stirn.ulated uterus on the Mauleon (40) found both that 1 to 3 ovulations manner in which injected could be induced with injections of PMS and was elirn.inated in the urine (Bowerrn.an et al., chorionic and that corpora lutea 20). The total arn.ount of injected estradiol formed were rn.orphologically and histologi­ benzoate recovered in the urine of these cally norma1. These corpora lutea rern.ained anirn.als as estrone ranged frorn. 39 to 60 functional until 12 days post-ovulation; the percent during a 4-day period. The estirn.ates onset of luteal regression occurred between for estradiol were consistently low and without the 12th and the 16th days, and regression rn.arked variation in any of the urine sarn.ples was corn.plete by the 20th day. Sirn.ilar develop­ studied. was not detected. These results ment, rn.aintenance and regression of corpora suggest that the uterus does not influence the lutea occurred in treated larn.bs hypophysec­ quantity or kind of estrogen rn.etabolites of tomized on the day of induced ovulation. gilt urine. Hypophysectorn.y or section of the pituitary Exogenous estrogen maintains corpora lute a stalk does not terrn.inate pregnancy in ewes in the hypophysectomized rabbit (l08), intact when these operations are perforrn.ed at various lamb (~ and sow (49,86) and has an apparent stages frorn. the 42nd to 90th days of gestation luteolytic action in the cow (51, 53, 72, 132). (Cowie et al., 36; Denarn.ur and Martinet, In the hypophysectorn.ized rat, exogenousestro­ 38). Gestation also continues whenovariectorn.y gen causes an increase in the number of ovarian precedes hypophysectorn.y at rn.id- gestation follicles and the amount of granulosa (101,102, (Denarn.ur and Martinet, 38). Ingoats, however, 130). Corpora lutea form in these rats follow­ hypophysectorn.y or pituitary stalk section is ing injections of PMS or HCG. According to followed by within a few days (Cowie Denamur and Mauleon (39), est r ad i 0 1 given et a1., 36). Luteal regression also occurs from the day of induced ovulation following hypophysectorn.y in pseudopregnant in lambs maintained rn.orphologically and ferrets, but stalk section of the pituitary is histologically normal corpora lutea for about compatible with full developrn.ent of corpora 50 days. Estrogen treatrn.ent did not rn.aintain lutea at least during the first rn. 0 nth of corpora lutea in larn.bs hypophysectorn.ized on pseudopregnancy (Donovan, 41). The isolated the day of induced ovulation; luteal regression pituitary in this species rn.ay store and se­ was complete within 20 days. Sirn.ilar results crete sorn.e luteotropin; however, the corpora have been obtained in the gilt by du Mesnil lutea eventually regress. It was further sug­ du Buisson (86). Estradiol benzoate, at doses gested that estrogen as well as a pituitary sufficient to rn.aintain corpora lutea for pro­ luteotropin rn.ay be required for luteal rn.ainte­ longed periods in the intact gilt, failed to nance in the ferret. rn.aintain corpora lutea following hypophysec­ Results of investigations have shown that torn.y. Daily injections of the estrogen were exogenous estrogen influences the luteal func­ initiated either 2 days before or 6 days after tion in various species (Arn.oroso and Finn, hypophysectorn.y in the early luteal phase of . ~). Kidder ~. (67) injected gilts with 3 mg. the cycle (days 6 or 8) and total luteal re­ on either the 6th, 11 th or gression occurred within 22 days after the

67 previous estrus. Absence of luteal maintenance Microgram amounts of ovine LH in the in­ by estrogen in hypophysectomized lambs and cubation medium increased in vitro phos­ gilts may indicate an indirect action of this phorylase activity of luteal slices from preg­ hormone on the life span of the corpus luteum. nant cows (Marsh and Savard, 76). Luteinizing Results of recent experiments on the effect hormone not only maintained the high initial of injecting various pituitary hormones on level of phosphorylase activity but was capable luteal function generally have been negative of increasing this activity after it had reached in sheep and swine. Homogenates of fresh, relatively low levels. Prolactin, ACTH, whole pituitary glands from gilts at different peroxide-in-activated LH and adenosine 31, stages of the estrous cycle and gestation did 51 -monophosphate (31, 51 -AMP) were ineffec­ not alter the life span of corpora lutea in tive in stimulating phosphorylase activity, vivo or affect progesterone synthesis by swine whereas ovine FSH and ovine GH were stimu­ luteal tissue in vitro (Anderson et aI., 9; latory. The stimulating effects of the latter Duncan et al.;-4j'f.""Short et al. (122) found hormones were explained as due to LH con­ that pro.gesteronesecretion ofthe corpus lutem tamination. A corresponding increase in in was unaffected on the 9th and 15th day of the vitro progesterone synthesis and phosphor~ estrous cycle by injections of ovine prolactin, lase activity occurred in bovine luteal slices ovine LH, or chorionic gonadotropin. Further­ when measured in the same luteal tissue. more, ovine FSH, growth hormone (GH), ACTH, Marsh and Savard (77) reported that the addi­ thyrotropic hormone (TSH), PMS, fresh and tion of 3 1, 51 -AMP to incubating slices of acetone -dried ovine pituitaries or endometrical bovine corpus luteum increased the rate of extracts failed to alter the secretory activity progesterone synthesis without increasing the of the ovine corpus luteum, over a short phosphorylase activity of the tissue. The 2- period of time at the 9th day of the estrous to 3-fold stimulation by 3 1, 51 -AMP of the cycle (Short, 121; Short et al., 122). Denamur amount (mcg.) of progesterone synthesized and Maule'on (39) reported that bovine pro­ was accompanied by a similar increase in the lactin injected daily from the day of induced incorporation of acetate-I- C 14 into the . ovulation for 20 days did not maintain corpora Results of incubating active and involuting lutea in intact lambs (up to 2,400 I. U. pro­ bovine corpora lutea surgically removed at lactin per day) or in lambs hypophysectomized different stages of the estrous cycle were on the day of ovulation (1,200 I.U. prolactin reported by Armstrong et al. (12). Maximal per day). In hypophysectomized (Kil­ progesterone synthesis occurred from cows patrick et aI., 6S, 69; Rermie et al., 107) and 4 to 13 days post estrus, declined gradually in guinea pigs (Rowlands, 115) ovine prolactin until day IS and decreased to undetectable has failed to maintain corpora lutea. However, levels at day 19. Addition of LH to the incuba­ ovine LH was luteotropic in hypophysectomized tion medium increased progesterone synthesis rabbits (Kilpatrick et al., 6S, 69). through day IS, but was ineffective on corpora PMS, HCG or LH in the incubation medium lutea obtained from day 19 or later. Progester­ stimulates in vitro synthesis of progesterone one synthesis in corpora lutea obtained from of corpora lutea from the ewe (Legault­ day 19 or later was partially restored by addi­ Demare et al., 70); cow (Mason et aI., SI; tion of or of TPNpius glucose-6- Savard and Casey,- 119; Armstrong et al., 12; phosphate to the incubation medium. TPN Armstrong, .!l; Marsh and Savard, 76, 77); plus glucose-6-phosphate were only minimally rat (Armstrong et al., 13), but little stimu­ effective in stimulating progesterone synthesis lating effect on progesterone synthesis from in corpora lutea from early stages of the swine luteal tissue (Duncan et al., 43; Neill estrous cycle (Armstrong, !..!.). It as suggested et al., 100). Increase in synthesis of pro­ that possibly TPNH is not rate limiting in gesterone by bovine luteal slices was effected fresh luteal tissue but is rate limiting if by TPN and glucose-6-phosphate; DPN and tissue is deprived of or nutrient DPNH did not alter this process. LHincreased supply. Inactive corpora lutea were not de­ the incorporation of Cl~ acetate into proges­ ficient in stores of cholesterol but may be terone 3 to 5 times, whereas addition ofNADP deficient in the enzyme system necessary for and glucose-6-phosphate caused an S-to 15- conversion of this probable precursor in fold increase in progesterone production with progesterone synthesis. Simmons and Hansel no increase in the incorporation of C 14 into (124) investigated luteal progesterone from the steroid (Marsh et al., 75; Mason et al., heifers given different hormone treatments SI; Savard and Casey, 11S). The minimum and suggested the occurrence of a specific effective concentration of LH required for bovine luteotropin hormone which is not bovine increased synthesis of progesterone in vitro growth hormone, equine LH or ovine pro­ was 0.01 - 0.02 mcg./gm. of bovine luteal lactin. tissue (Mason and Savard, SO). Prolactin did Armstrong and Greep (14) observed a stimu­ not produce a stimulatory effect on in vitro latory effect of LH upon the uptake of glucose progesterone synthesis (Mason et al.,SI) and by slices of luteinized rat ovaries and two­ the stimulating effect of FSH was attributed thirds of the utilized glucose was converted to to small amounts of LH in the preparation lactic acid (Armstrong, !..Q.). Lactic acid for­ (Mason and Savard, §l). mation was stimulated by in vivo LH and in 6S proportion to its stimulation of glucose uptake. induce luteal regression. During pregnancy In these experiments FSH and prolactin did and following hysterectomy, this uterine in­ not stimulate glucose uptake except at levels hibition is absent in some species and as a which could be caused by LH contamination. result functional corpora lutea per sis t When the LH was given intravenously to rats (Nalbandov, personal communication). 4 hr. prior to autopsy, there was a significant Increasing attention has been given to the increase in the conversion of glucose to C02 role of the uterus in alteration of pituitary and lipid, as well as an overall increase in and function. Maintenance of the func­ the uptake of glucose by the luteal slices. tional corpus luteum during at least the initial However, when LH was added directly to the phases of gestation is well recognized in incubation medium there resultedanincreased s eve r a 1 species (Amoroso and Finn, .f). progesterone synthesis without affecting the Hysterectomy alters ovarian function which rate of glucose metabolism (Armstrong etal., results in persistence of the corpus luteum 13). Increased glycolysis appeared to be an in the (Butcher et aI., 27; Loeb, effect rather than a cause for the increased 71; Rowlands,114)iewe(DenamurandMauleon, synthesis of luteal progesterone. Armstrong 39; Moor and Rowson, 91; Wiltbank and Casida, (11) found that stimulation of glycolysis fol­ 131); sow (Anderson et al., ~ Anderson et' al., lowing LH was involved in the replenishment 7; du Mesnil du Buisson and Dauzier, 87; of stores of lipid precursors which have been Neill and Day, 99; Spies et al., 127) and cow depleted as a result of the stimulatory action (Anderson and Bowerman, 4; Anderson et al., of LH upon progesterone synthesis. It was ~; Armstrong and Hansel; 15; Wiltbank and proposed that LH possibly mobilizes lipid Casida, 131; Wiltbank et al., 133). The corpora stores for progesterone synthesis by the lutea following hysterectomy are maintained corpora lutea and these lipid stores are for a period approaching or exceeding the replenished both from cholesterol and long length of gestation in these species. However, chain free fatty acids brought to the tissue by that same operation has no apparent effect the plasma. on ovarian function in the ferret, , In the ewe, corpora lutea, induced by ovine monkey, woman or unmated rat, mouse and pituitary extract at different luteal phases of rabbit (Amoroso and Finn, .f.; Anderson et al., the estrous cycle, regress at the same time 5). Hysterectomy performed at different phases as the natural corpora lutea, even after the of the estrous cycle has been reported natural corpora lutea have been removed recently in the gilt (Anderson et aI., .1); (Inskeep et al., 65). It was concluded that the guinea pig (Rowlands, 114); ewe (Moor and life span of corpora lutea in this species is Rowson, 91) and at different stages of pseudo­ determined by a factor extrinsic to the gland pregnancy in the rat (Melampy et al., 82). itself. However, in the gilt, induced and Silbiger and Rothchild (123) suggest that natural corpora lutea of different ages on the hysterectomy in the rat results in decreased same ovary retain their luteal life spans of secretion of both FSH and LH and that a approximately one estrous cycle (Neill and decrease in the luteolytic effectiveness of Day, 99). Thus, an intrinsic mechanism de­ the pituitary is associated with the diminished termining the life of the corpus luteum pos­ secretion of LH. sibly at the time of luteal formation is likely In the gilt, removal of the uterus at estrus in this species. Both natural and induced or days 5, 10, 14 and in a majority at day 16, corpora lutea persist in hysterectomized resulted in formation and maintenance of gilts. corpora lutea. Estrus and ovulation occurred There appear to be species differences in within a few days when the uterus was removed the relationship between the level of ovarian at day 18. Although morphologic changes as­ and subsequent luteal function and the degree sociated with luteal regression occurred in of pituitary activity (Nalbandov, 97). For hysterectomized gilts during the interval be­ example, the events of ovulation, whether tween days 16 and 18, the presence of a induced or spontaneous, are sufficient to luteolytic or absence of luteotropic action cause the formation and maintenance of corpora may be initiated at an earlier stage of the lutea in the pig for a period oHime character­ cycle. Hysterectomy as late as day 15 of the istic of this species. In the ewe, however, the cycle prevented impending estrus and ovula­ physiologic events leading to the development tion in guinea pigs (Rowlands, 114) and, in of these glands do not appear adequate for ewes (Moor and Rowson, ..21), arrested the their maintenance without supplemental pitui­ involutionary changes in luteal cells, provided tary stimulation. It is possible, in species the corpus luteum was still functional at the producing functional corpora lutea, that time of the operation. In rats, hysterectomy luteolysis during the estrous cycle is initiated on days 5, 9 and 11 of pseudopregnancy as a result of an inhibitory humoral or resulted in prolongation of the life span of neurohumoral stimulus of uterine origin acting corpora lutea to approximately that of normal on the by way of the CNS. gestation, whereas luteal regression was This action could lead either to inhibition of initiated somewhat earlier when the uterus hypophysial luteotropin or alteration in gonado­ was removed at day 13 (Melampy et al., 82). tropic complex activity and would thereby Enucleation of the persisting corpora lutea

69 in hysterectomized gilts (Anderson et al.,..2.) removed. Recent investigations in the ewe and heifers (Anderson and Bowerman, .1) is by Moor and Rowson (91) showed that one-half followed within a few days by estrus, ovulation of the cycles were extended beyond 20 days and maintenance of the newly formed corpora when one uterine horn was removed, whereas lutea. one-fourth of the cycles were extended when Secretion of a hypophysial luteotropin for only the distal half of one horn was removed. maintenance of corpora lutea for prolonged Uterine and endometrial autotransplants in the periods in the hysterectomized ewe and gilt guinea pig (Butcher et aI., 26) and uterine is evident by luteal regression following hypo­ autotransplants in the pig (Anderson et al., 1; physectomy in these animals. Denamur and du Mesnil du Buisson and Rombauts, 89) Mauleon (39) found that corpora lutea were results in continuation of estrous cycles and, in the proces s of regres sion or completely in rats, (Melampy et aI., 82) reduces the regressed 20 days after hysterectomizing duration of pseudopregnancY:- A functional and hypophysectomizing ewes on the day of , as evaluated histologically, ap­ ovulation. Furthermore, luteal reg res sion was pears to be necessary for luteal regression complete within 20 days in ewes hypophy­ in these species. sectomized 20 days after hysterectomy. Unilateral regression of corpora lutea has Du Mesnil du Buisson and Leglise (88) re­ been observed on the side of the uterine ported that luteal regression began within fragment in partially hysterectomized gilts 5 days and was complete by 10 to 11 days (du Mesnil du Buisson, 85). In gilts mated in gilts previously hysterectomized during after one uterine horn was severed from the the early luteal phase (days 4 to 8) and hypo­ uterine body, early failure of pregnancy oc­ physectomized 22 days after the beginning of curred in the in t act horn (du Mesnil estrus. Similar results were obtained when du Buisson, 84). Gestation continued in these gilts were hypophysectomized 29, 46, 97 and animals if the non-gravid horn was removed 99 days after hysterectomy (du Mesnil by day 14, but pregnancy was terminated du Buisson, 86). Complete luteal regression when unilateral hysterectomy was postponed also occurred within 20 days when hypo­ until after day 16 (du Mesnil du Buisson, 84). physectomies were performed at estrus and Unilateral luteal regression occurred on The followed by in the early luteal side of the non-gravid horn in gilts that phase of the cycle (du Mesnil du Buisson, 86). became pregnant with either a whole or Maintenance of corpora lutea in the anterior half or quarter of a sterile horn hysterectomized ewe and gilt is not possible present (Rathmacher and Anderson, 106). in the absence of the pituitary. Persistence Normal pregnancy and maintenance of corpora of corpora lutea following hypophysectomy in lutea on both ovaries occurred in unilaterally previously hysterectomized guinea pigs indi­ hysterectomized animals. It is apparent that cates that removal of the uterus does not the non-gravid horn is responsible for the affect luteal function by secretion of a pituitary termination of pregnancy through a luteolytic luteotropin this species (Rowlands, 115). In action which it initiates. The physiologic experiments of Deanesly and Perry (37), both basis of this action is unknown, but it is progesterone and reserpine caused regression possible that ovarian-uterine vascular rela­ of corpora lutea in hysterectomized guinea tionships may be involved in the initiation of pigs. They concluded that in the guinea pig this luteolysis. the corpora lutea of hysterectomy do not The duration of anestrum was prolonged function independently of the pituitary. more than 100 days in 6 of 8 intact gilts Short (ill) has proposed a system of dual injected with an optimum total of 35 mg. of control of the life span of the corpus luteum estradiol benzoate over a 7-day period be­ for the ewe by a pituitary luteotropin and a ginning on days 7, 9 or 12 of the cycle uterine luteolysin. In this scheme, a pituitary (du Mesnil du Buisson, 86). Estrogen treat­ "on" mechanism would stimulate and maintain ment beginning at day 14 had no effect on the the corpus luteum life span but perhaps not length of the estrous cycle. Corpora lutea were its secretory activity by a single release of a maintained in both ovaries in estrogen-treated pituitary luteotropin at the time of ovulation. unilaterally pregnant gilts with one empty However, the luteotropin may be released into uterine horn at 30, 55 or 90 to 103 days of the circulation continuously. A uterine "off" gestation. Therefore, estradiol benzoate sup­ mechanism would determine the length of the presses luteolytic action, not only during the estrous cycle by providing a luteolysin. Of estrous cycle, but also in unilaterally pregnant the two mechanisms, the uterine luteolysin gilts in which the non-gravid uterine horn would have the overriding effect. would otherwise effect a unilateral regression Subtotal hysterectomy in the guinea pig of corpora lutea on the side of the non-gra vid (Butcher et al., 27); gilt (Anderson et al., horn. Du Mesnil du Buisson and Rombauts 6); heifer (Anderson et al., 8) and ewe (Moor (90) found that gestation continued in a ma­ and Rowson, 91) results in luteal regression jority of gilts in which all of the uterus was and continuation of estrous cycles. However, removed except one and its corre­ the duration of the estrous cycle in these sponding portion of uterine horn on the 12th species is affected by the proportion of uterus day of pregnancy. When a certain number of

70 were removed with or without the of the corpus 1uteum of that cycle. Luteinizing corresponding portion of the hormone is required for the processes of around the 40th or 80th day of gestation, follicular maturation and ovulation as indicated pregnancy continued in most animals in which by experimental induction of ovulation and by some embryos with corresponding uterine depletion of pituitary gonadotropin content horns were removed, whereas very few gilts prior to ovulation. The necessity for a remained pregnant when only some embryos luteotropin, whether this is luteinizing hormone were removed. The portion of empty uterine or an unidentified pituitary luteotropin, is not horn apparently had a negative influence on clearly established for the initial development maintenance of pregnancy after the first 40 of the corpus 1uteum during the estrous cycle. days, but uterine 1uteo1ytic activity of the Maintenance of the corpus 1uteum in the empty horn was not evident on the correspond­ pregnant or hysterectomized animal is de­ ing ovary at this time. pendent upon an apparent continuous require­ Surgical removal of embryos during the ment of pituitary gonadotropin with luteo­ first 12 days in the ewe resulted in subse­ tropic action. quent normal estrous behavior, whereas re­ The role of the uterus in altering the life moval of embryos on the 13th and 14th days of the corpus 1uteum in the cow, sow and ewe after estrus resulted in a marked extension is evident by extension of the luteal life span of the 1utea11ife span (Moor and Rowson, 21). during pregnancy and following hysterectomy, Furthermore, transfer of 12 or 13 day em­ and, in the case of the sow, 1uteo1ytic action bryos to the uterus of non-pregnant recipient of a non-gravid portion of the uterus in ewes on the 12th day of their cycle resulted in partially hysterectomized or unilaterally preg­ normal . Embryonic loss fre­ nant animals. The physiologic basis of uni­ quently occurred when 13 day embryos were lateral regression of corpora 1utea is transferred to day 13 recipient ewes. It was unknown. It is possible that ovarian-uterine suggested that the life span of the corpus vascular relationships may be involved in 1uteum in this species was not irrevocably the initiation of this 1uteo1ysis. In subtotally determined until after the 12th day of the hysterectomized animals, estrous cycles oc­ estrous cycle. cur, however, the duration of the cycle is al­ Estrous cycles are altered by uterine dis­ tered by the proportion of uterus removed. tention in_ the rat (Se1ye, 120); guinea pig Estrous cycles occur following autotrans­ (Donovan and Traczyk, 42; Moore, 92); cow plantation of the uterus in the guinea pig and (Armstrong and Hansel, 15; Chatterjee and sow and in rats the duration of pseudopreg­ Luktuke, 29; Hansel, 54; Hansel and Wagner, nancy is reduced. A functional endometrium 55; Yamauchi and Nakahara, 134) and ewe appears necessary for luteal regression in (Inskeep et a1., 64; Moore andNa1bandov, these species. It may be that in the cycling 93; Na1bandov et a1., 98) but not in the pig female the uterus maintains a positive in­ (Anderson, 1). Uterine innervation in these hibition of pituitary luteotropin secretion and species can play a role in changing ovarian during pregnancy or following hysterectomy, function, possibly by affecting central nervous this inhibition is lacking; hence, the persist­ system activity and thereby pituitary hormone ence of corpora 1utea. secretion or possibly by a more direct action on the ovary. However, mechanisms by which uterine distention modifies the cycle may be Literature Cited unrelated to those mechanisms affecting the physiological processes in the for mat ion, (1) Aldred, J. P., Samme1witz, P. H. and maintenance and regression of the corpus Na1bandov, A. V. 1uteum during the normal estrous cycle or 1961. Mechanism of Formation of during pregnancy. Corpora Lutea in Guinea- Pigs. Jour. Reprod. Fertil. 2: 394. (2) Amoroso, E. C. and Finn, C. A. Summary 1962. The Ovary. Academic Press, London. p. 451. Follicular growth and maturation are de­ (3) Anderson, L. L. pendent upon pituitary ; ovulation 1962. Effect of Uterine Distention on is followed by further proliferation of granu­ the Estrous Cycle of the Gilt. losa and theca cells which form the corpus Jour. Anim. Sci. 21: 597. 1uteum. In the ewe and sow the ovary is (4) Anderson, L. L. and Bowerman, A. M. capable of ovulation when the pituitary is re­ 1963. Utero-Ovarian Function in Oxy­ moved at or just prior to ovulation, the corpus tocin- Treated Heifers. Jour. 1uteum which develops subsequently is main­ Anim. Sci. 22: 1136. (Abstr.). tained . for the approximate duration of the (5) Anderson, L. L., Bowerman, A. M., and estrous cycle. It has been proposed that Melampy, R. M. perhaps a pituitary luteotropin, if required, 1963a. Advances in Neuroendocrin­ is secreted for a brief period at the time of ology. Univ. Ill. Pre s s, ovulation and is sufficient for the development Urbana. p. 345.

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74 (77) Marsh, J. M., and Sav~rd, K. de la ge station de la T ruie et 1964b. The Effect ~f 3', 5' -AMP on maintien des corps jaunes. Progesterone Synthesis. Fed. Ann. BioI. Anim. B i 0 c h. Proc. 23: 462. Biophys. 3: 445. (78) Marshall, F. H. A. (91) Moor, R. M., and Rowson, L. E. A. 1903. The Oestrous Cycle and the For­ 1964. Influence of the Embryo and mation of the Corpus Luteum in Ute rus on Lute al Function in the Sheep. Phil. Trans. Roy. the Sheep. Nature. 201: 522. Soc. London, Ser. B. 196: 47. (92) Moore, W. W. (79) MarslhaU, F. H. A. 1961. Effect of Uterine Distention on 191\0. The Physiology of Reproduction the Estrous Cycle of the (lst ed.). Longmans, Green Guinea Pig. Physiologist. 4: and Co., London. 76. (Abstr.). (80) Mai;ollr, N. R., and Savard, K. (93) Moore, W. W., and Nalbandov, A. V. H}64. Specificity of GonadotropinStim­ 1953. Neurogenic Effects of Uterine ulation of Progesterone Syn­ Distention OIl the Estrous thesis in B 0 vi n e Corpus Cycle of the Ewe. 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