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Prorenin as a reproductive hormone. New form of the renin system
Prorenin as a Reproductive Hormone New Form of the Renin System
JEAN E. SEALEY, D.Sc. NICOLA GLORIOSO, M.D. New York, New York JOSEPH Norfolk,
ITSKOVITZ,
M.D.
Virginia
JOHN H. LARAGH,
M.D.
New York, New York
From the Cardiovascular Center, New York Hospital-Cornell University Medical College, New York, New York, and the Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia. This work was supported by National Heart, Lung, and Blood Institute Grant HL-18323SCR from the National Institutes of Health. Dr. ltskovitz was on leave from the Department of Obstetrics and Gynecoogy, Rambam Medical Center, Haifa, Israel, at the time of this study. Requests for reprints should be addressed to Dr. Jean E. Sealey, Cardiovascular Center, New York Hospital, 525 East 68th Street, New York, New York 10021. Manuscript submitted September 3, 1986, and accepted September 18, 1986.
Prorenin, the biosynthetic precursor of renin, is synthesized by the kidneys. Herein is reviewed recent evidence that the ovaries also secrete prorenin. It was found that prorenin is present in mature human ovarian follicular fluid in extremely high concentrations and that plasma prorenin levels increase transiently in blood during the menstrual cycle at the time of ovulation. No change in plasma active renin levels occurs at this time. Plasma prorenin level also increases lo-fold in pregnant women very soon after conception. The ovaries are apparently the source of this rise, since plasma prorenin levels did not increase in a pregnant woman with ovarian failure who received a donor egg. All of these changes in plasma prorenin levels appear to be caused by gonadotropic hormones. These results suggest a role for ovarian prorenin in human reproductive function. They may have relevance to studies of female infertility, birth control, and toxemia of pregnancy. They also suggest that a renin system exists that is regulated by changes in prorenin. Renin is classically considered to be an enzyme that is synthesized by the kidneys and secreted into the circulation where it cleaves angiotensin I from angiotensinogen. Angiotensin I has no known physiologic effect but is converted to the octapeptide angiotensin II by converting enzyme, a dipeptidase that is ubiquitous but that is present in very high concentrations in the lung. Angiotensin II is the active hormone of the reninangiotensin system, causing primarily arteriolar vasoconstriction and increased adrenal aldosterone biosynthesis [I]. Over the last 10 years or so, another component of the reninangiotensin system has received considerable attention, that is prorenin [2-41. This enzymatically inactive biosynthetic precursor of renin [5-71 is synthesized in the kidney and also in the placenta [8-IO]. Other tissue sources of prorenin are likely, since it continues to circulate in chronically nephrectomized male and female subjects, although active renin is absent from the circulation [ 11,121. Renin has been identified biochemitally and by immunohistochemical techniques in several extrarenal tissues [ 13- 151. However, no major source of prorenin has been identified in conjunction with the active enzyme in these tissues. Thus, the extrarenal sources of plasma prorenin have remained an enigma. Prorenin normally circulates in plasma of men and women in concentrations close to IO times those of active renin. It usually falls by about 90 percent following bilateral nephrectomy [ 161, suggesting that the kidneys are its major source. Nonetheless, the major form of renin found in kidney extracts is the mature active enzyme, and, in general, plasma prorenin changes in concert with plasma active renin [2], In the placenta, the
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major form detected is prorenin [8-l 0] and there is little evidence that, in humans at least, active renin is secreted from the placenta. Not much is known about placental prorenin. It is synthesized by the chorionic cells [9,17] and seems to be secreted into amniotic fluid, since it is found there in high concentrations [8]. The function of placental prorenin has not been described. A lo-fold rise in maternal plasma prorenin levels occurs early in pregnancy [ 18-201, and these elevated levels are maintained throughout gestation. It has generally been assumed that the source of this rise in prorenin level is the placenta. We began to question that view [ill when we observed that the increase in plasma prorenin level OCCUrrE!d very soon after conception and fell rather slowly after delivery. Thus, plasma prorenin reaches its maximal levels within four weeks following conception, and its fall after parturition is much slower than that of the other placental hormone, human chorionic gonadotropin, despite having a much shorter half-life [2 11. These observations prompted us to investigate whether changes in prorenin occurred during normal menstrual cycles [22], since it seemed possible that the rise in prorenin level during gestation may have been initiated during the previous menstrual cycle. We found that prorenin levels change predictably in blood during the menstrual cycle. They were quite stable during the two weeks of the follicular phase of the cycle, during which time one egg is normally selected for maturation. Prorenin levels then increased about twofold at midcycle at the time of the luteinizing hormone surge. This change in prorenin level was not associated with any change in active plasma renin level. Although plasma prorenin level was also above baseline during the mid-luteal phase of the cycle, it was lower than that measured at mid-cycle, and active renin level was often elevated too. The rise in active renin level at this time is presumed to be the result of the diuretic effect of progesterone [23]. Since the mid-cycle increase in plasma prorenin level was not associated with any change in active renin level, the kidney seemed an unlikely source of secretion. Since the rise occurred almost precisely at the time of ovulation, we considered the possibility that the ovary might be the source. When an egg matures at mid-menstrual cycle, a follicle develops around it that is filled with a fluid containing all but the higher-molecular-weight substances found in plasma. This fluid also contains high concentrations of various substances synthesized by the ovary, such as estrogen and progesterone. Human ovarian follicular fluid is readily available from women undergoing in vitro fertilization. We found that it contained very high concentrations of prorenin, more than 10 times higher than in the concurrently collected plasma [24]. Only 1 percent of the renin in ovarian follicular fluid was in the active form. From these data, it seemed likely that the mid-cycle change in plasma prorenin level is due to secretion of
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prorenin from the ovary, and that prorenin is produced by the mature ovarian follicle. We have been unable to detect any biochemical difference between prorenin from ovarian follicular fluid and prorenin from kidney or plasma [24]. The pH optima of trypsin-activated prorenin from plasma and follicular fluid are identical and the same as that of active renal renin. Antibodies against active kidney renin bind to ovarian prorenin as do highly specific antibodies prepared against the carboxyterminal portion of the prosegment of prorenin
P41.
Subsequent studies reinforced the idea that the ovaries secrete prorenin. We found that ovarian vein blood collected at mid-cycle from a baboon ovary with one mature follicle contained close to double the concentration of prorenin of that found in a peripheral vein [25]. The contralateral ovary did not have a mature follicle and did not show an arteriovenous increment in prorenin level. Following the sampling procedure, the baboon underwent bilateral ovariectomy, and peripheral venous prorenin level fell by 50 percent in 30 minutes [25]. On the ottier hand, the ovaries do not appear to secrete prorenin during the follicular phase of the cycle. Thus, we have found that the prorenin concentration in the follicular fluid from immature follicles of baboons is similar to the concurrent plasma level (unpublished observation). Also, the average plasma prorenin level of normal subjects during the follicular phase of the menstrual cycle is quite similar to that found in women over age 50 [24]. Other studies suggest not only that the ovary is a source of plasma prorenin but that the gonadotropic hormones luteinizing hormone and human chorionic gonadotropin stimulate ovarian prorenin production or secretion. When we investigated the relationship of the change in plasma prorenin level at mid-cycle to the luteinizing hormone surge, we found that the rise in luteinizing hormone level preceded the rise in prorenin level by about eight hours, and the peak of prorenin occurred about eight hours after the peak of luteinizing hormone [26]. The peak of prorenin was sustained for about 36 hours. Another study documented that human chorionic gonadotropin can stimulate prorenin. Infertile women and women undergoing in vitro fertilization are given folliclestimulating hormone or follicle-stimulating hormone and luteinizing hormone during the follicular phase of the menstrual cycle. This usually results in more than one egg being selected for maturation, with multiple follicles being formed. Since such women often do not have a spontaneous luteinizing hormone surge, they are routinely given human chorionic gonadotropin to induce ovulation. We found that they consistently have a marked increase in plasma prorenin level about 24 hours after administration of human chorionic gonadotropin [27,28]. The rise is sustained for several days, i.e., longer than the usual rise in prorenin level that occurs after an endogenous luteiniz-
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ing hormone surge. This prolonged response is consistent with the longer half-life of human chorionic gonadotropin compared with luteinizing hormone. Other studies suggest that human chorionic gonadotropin stimulates ovarian prorenin secretion. As just noted, prorenin levels are very high in the blood of pregnant women, about 10 times normal [l&20]. We found a weak but significant relationship between plasma prorenin and plasma beta human chorionic gonadotropin during the first trimester of pregnancy [2 I]. In more recent studies of women undergoing in vitro fertilization, we were able to define more precisely the time course of the changes in prorenin that occur following conception. We also obtained indirect evidence that this rise is also due to the secretion of ovarian prorenin. Thus, as just described, we found that plasma prorenin levels rose after human chorionic gonadotropin was administered to induce ovulation. They reached a peak four to six days after human chorionic gonadotropin and then fell back, close to baseline, by about 10 days after human chorionic gonadotropin [28-301. At that time, beta human chorionic gonadotropin was undetectable in the blood. In those women who conceived, prorenin levels began to rise again on days 12 to 16 after human chorionic gonadotropin (days 8 to 12 after embryo transfer) at precisely the time when endogenous human chorionic gonadotropin was detected again in the blood [29,30]. In the one normal pregnancy that we were able to monitor closely during the initial days following conception, we found a similar pattern [29]. Prorenin level increased transiently at the time of the lutenizing hormone surge, and then began to rise again sometime between day 5 and day 12 after the luteinizing hormone peak. Plasma beta human chorionic gonadotropin level was less than 5 mlU/ml on day 5 and 328 mlU/ml on day 12, whereas plasma prorenin level was 39 and 107 rig/ml per hour, respectively. That the rise in prorenin level during gestation is of ovarian and not of fetal origin is suggested by the observation that no such changes in prorenin occurred in a woman with ovarian failure who conceived after receiving a fertilized donor egg [29,30]. It is likely that the ovary secretes prorenin throughout pregnancy, as prorenin levels remain high throughout gestation and fall quite slowly after delivery, taking many days to return to baseline levels [2 11. Prorenin secretion by the corpus luteum may be quite sensitive to human chorionic gonadotropin, since maximal plasma levels of prorenin occur long before human chorionic gonadotropin has reached maximum levels [21]. This sensitivity to human chorionic gonadotropin may change as gestation proceeds, since plasma prorenin levels tend to fall after about the 12th week of gestation, as human chorionic gonadotropin falls from its maximal levels. Administration of human chorionic gonadotropin following hyperstimulation during the follicular phase of the menstrual cycle results in much higher plasma prorenin
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levels than occur normally during a spontaneous luteinizing hormone surge. In fact, the levels observed in some patients are among the highest we have ever seen, being similar to those found in renin-secreting tumors [31]. In analyzing the data from patients undergoing in vitro fet-tilization, we observed that the height of the plasma prorenin response to human chorionic gonadotropin was directly related to the number of follicles detected at the time of aspiration [28]. Since the concentration of prorenin in each follicle from hyperstimulated women was not higher than we found in ovarian follicular fluid from a woman who had a spontaneous luteinizing hormone surge (a patient of Dr. Andrew Silverman, New York), the results suggest that hyperstimulation and exogenous human chorionic gonadotropin administration do not result in abnormally high prorenin concentration in individual follicles, but that the high plasma prorenin levels are the result of the presence of multiple follicles. In pregnant patients undergoing in vitro fertilization, it is likely that many corpora lutea are formed from the multiple mature follicles. This may result in abnormally high prorenin levels as evidenced by the fact that the highest prorenin level we have seen in pregnancy (650 rig/ml per hour; 20-fold baseline) occurred in a patient undergoing in vitro fertilization who had 14 follicles and conceived with twins [29]. Although the previously cited results suggest that gonadotropins (luteinizing hormone or human chorionic gonadotropin) stimulate prorenin secretion, estrogens, or their precursors or metabolites, may play a role in the process. In each of the hyperstimulated women we have studied, we have observed a small increase in prorenin level before human chorionic gonadotropin administration [30] when plasma estradiol was at maximal levels. Hyperstimulation results in the presence of many follicles, which may be at different stages of development. In normal cycles, the resultant high concentration of estrogen causes a luteinizing hormone surge. Since a spontaneous luteinizing hormone surge does not usually occur in hyperstimulated women, it is possible to examine what happens in them when large follicles are’ present that have not been exposed to high concentrations of gonadotropin. What we observed was a significant, close to twofold rise in prorenin level on the day of human chorionic gonadotropin administration, before the hormone was given. The rise occurred whether the patients had been previously hyperstimulated with follicle-stimulating hormone alone or follicle-stimulating hormonelluteinizing hormone. Also, when we compared the magnitude of the increase in plasma prorenin level in response to exogenous human chorionic gonadotropin administration with the plasma estradiol levels, the relationship was highly significant (unpublished observations). Similarly, the rise in prorenin level following conception was highly related to the plasma estradiol level. Nonetheless, estradiol does not appear to be the complete answer to the question of
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what initiates ovarian prorenin biosynthesis, since plasma estradiol levels are also high during the mid-luteal phase of the menstrual cycle but plasma prorenin levels are not consistently elevated [22] and prorenin levels are not high in women receiving oral contraceptive therapy. Clearly, further studies are required to dissect these interrelationships. Altogether, the data suggest that during the follicular phase of the menstrual cycle, the ovary does not normally synthesize prorenin. It is unclear at precisely what time prorenin begins to be synthesized by the ovary (presumably by the maturing follicle) but it seems to be either just before or at the time of the luteinizing hormone surge. High concentrations of gonadotropins clearly augment prorenin biosynthesis at thjs time, and seem to be responsible for the ovulatory rise in plasma prorenin levels. We do not know if any prorenin is synthesized by the corpus luteum in nonconception, normal menstrual cycles. The corpus luteum does seem able to respond to gonadotropins, since the ovary apparently secretes prorenin as soon as human chorionic gonadotropin levels rise following conception and throughout gestation. Whether the ovaries are the sole source of the pregnancy-related rise in prorenin levels throughout gestation remains to be established. Whenever the plasma prorenin level is elevated, the plasma estradiol level is always high; further stud/es are required to determine whether high estrogen levels or related steroids are required for ovarian prorenin biosynthesis to occur. WHY
PRORENIN?
The changes in plasma prorenin that occur at the time of ovulation are not accompanied by any detectable change in circulating active renin 1221. Thus, ovarian prorenin seems to function in such a way that if active renin is formed, and is required for prorenin to have an effect, it does not enter the circulation in appreciable amounts. Active renin has been detected in ovarian follicular fluid, but its concentration is low (less than 1 percent) relative to the prorenin level [24,32]; angiotensins I and II have also been found in ovarian follicular fluid, in concentrations higher than the concurrent plasma level. However, this does not necessarily mean that either active renin or angiotensin I or II is normally present in these concentrations in vivo, since inadvertent activation of prorenin can occur in vitro [2], resulting in higher active renin levels than were present in vivo. Since renin substrate is present in follicular fluid, once active renin is formed, angiotensins could be generated in vitro. Renin is unusual amongst plasma proteases in that it circulates in the active form and has no endogenous inhibitors. Other plasma proteases such as those of the coagulation and fibrinolytic systems circulate as precursors of the active enzyme and are converted to the active
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form at a discrete site (such as the site of injury). Since the precursors of these other plasma proteases circulate in very high concentrations, a lot of active enzyme can be formed locally, but the effect of the enzyme is limited and localized by circulating inhibitors. The prorenin-renin system seems to work quite differently. Renin is synthesized and stored in high concentrations in the kidney. The active enzyme is secreted into the circulation where it acts continuously to form angiotensin I from plasma angiotensinogen. Prorenin is also apparently secreted by the kidney, but there is no good evidence that it is ever activated in the circulation. How then does ovarian prorenin function? If it is converted to active renin, how is its effect limited to a particular site? We have been unable to detect an inhibitor of renin in ovarian follicular fluid. One possibility is that prorenin has a receptor and that once bound to this receptor, the active site of renin is exposed. Prorenin appears to be very similar to the precursor of another aspartyl protease, pepsinogen. When pepsinogen is acidified, the prosegment of the molecule swings out of a cleft containing two separate parts of the active site, and the active site is formed [33]. Prorenin can be similarly activated by acidification and this activation can be reversed at a higher pH [34,35]. We hypothesize that bihding of prorenin to its receptor might accomplish the same effect, i.e., expose the active site of the enzyme. Angiotensinogen circulates in blood; it is present in ovarian follicular fluid and is reportedly also synthesized by the ovaries [36]. If the prorenin receptor were located near membrane-bound converting enzyme and the angiotensin II receptor, the activated prorenin could cleave angiotensin I from angiotensinogen; angiotensin I could in turn be converted to angiotensin II by the adjacent converting enzyme and then angiotensin II could bind to its receptor and have a local effect without appreciable amounts of it passing to other sites. There is some evidence that converting enzyme and the angiotensin receptor might be located together [37]. Clearly, other possibilities exist to explain how prorenin could have a physiologic effect, but any model that includes the formation of active renin runs the risk of unabated formation of active renin and resultant disruption of cardiovascular physiology. This makes attractive any hypothesis in which prorenin has an effect without the concurrent formation of active renin. OVARIAN
PRORENIN
FUNCTION
At this time, we can only speculate about the function of
ovarian prorenin. We do not know whether its putative action is confined to the ovary. If prorenin is a circulating hormone, an explanation would have to be made of how its effect could adjust to concurrent changes in secretion of prorenin from extraovarian sources. In this regard, the report [38] that circulating prorenin may not have the
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complete prosequence, as found in the kidney, is intriguing, since receptor binding could perhaps be altered by the presence of different portions of the prorenin segment. Since angiotensin II affects intracellular calcium and phospholipase activity, there are many potential roles for prorenin via angiotensin II action, ranging from an effect on pituitary luteinizing hormone release [ 151 to facilitation of egg extrusion [39] or alteration of ovarian steroid biosynthesis in a manner similar to the known action of angiotensin on adrenal cortical steroid biosynthesis [40]. The coming years should see exciting new research in this regard. Renin has been found in the male reproductive
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system [41,42], but it remains to be determined whether prorenin is synthesized in the testes in a manner analogous to that in the ovary. To date, the results in rodents suggest that active renin, not prorenin, is formed in the Leydig cells of the testes. Whatever the outcome, it seems likely that a new form and function of the reninangiotensin system exist that operate independently of changes in circulating active renin, and the effect of which is regulated by changes in prorenin. This new prorenin system seems to be involved in reproductive function. Future work to elucidate ovarian prorenin function may have clinical implications in the fields of birth control, infertility, a.nd toxemia of pregnancy.
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JEAN E. SEALEY, D.Sc. NICOLA GLORIOSO, M.D. New York, New York JOSEPH Norfolk,
ITSKOVITZ,
M.D.
Virginia
JOHN H. LARAGH,
M.D.
New York, New York
From the Cardiovascular Center, New York Hospital-Cornell University Medical College, New York, New York, and the Department of Obstetrics and Gynecology, Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia. This work was supported by National Heart, Lung, and Blood Institute Grant HL-18323SCR from the National Institutes of Health. Dr. ltskovitz was on leave from the Department of Obstetrics and Gynecoogy, Rambam Medical Center, Haifa, Israel, at the time of this study. Requests for reprints should be addressed to Dr. Jean E. Sealey, Cardiovascular Center, New York Hospital, 525 East 68th Street, New York, New York 10021. Manuscript submitted September 3, 1986, and accepted September 18, 1986.
Prorenin, the biosynthetic precursor of renin, is synthesized by the kidneys. Herein is reviewed recent evidence that the ovaries also secrete prorenin. It was found that prorenin is present in mature human ovarian follicular fluid in extremely high concentrations and that plasma prorenin levels increase transiently in blood during the menstrual cycle at the time of ovulation. No change in plasma active renin levels occurs at this time. Plasma prorenin level also increases lo-fold in pregnant women very soon after conception. The ovaries are apparently the source of this rise, since plasma prorenin levels did not increase in a pregnant woman with ovarian failure who received a donor egg. All of these changes in plasma prorenin levels appear to be caused by gonadotropic hormones. These results suggest a role for ovarian prorenin in human reproductive function. They may have relevance to studies of female infertility, birth control, and toxemia of pregnancy. They also suggest that a renin system exists that is regulated by changes in prorenin. Renin is classically considered to be an enzyme that is synthesized by the kidneys and secreted into the circulation where it cleaves angiotensin I from angiotensinogen. Angiotensin I has no known physiologic effect but is converted to the octapeptide angiotensin II by converting enzyme, a dipeptidase that is ubiquitous but that is present in very high concentrations in the lung. Angiotensin II is the active hormone of the reninangiotensin system, causing primarily arteriolar vasoconstriction and increased adrenal aldosterone biosynthesis [I]. Over the last 10 years or so, another component of the reninangiotensin system has received considerable attention, that is prorenin [2-41. This enzymatically inactive biosynthetic precursor of renin [5-71 is synthesized in the kidney and also in the placenta [8-IO]. Other tissue sources of prorenin are likely, since it continues to circulate in chronically nephrectomized male and female subjects, although active renin is absent from the circulation [ 11,121. Renin has been identified biochemitally and by immunohistochemical techniques in several extrarenal tissues [ 13- 151. However, no major source of prorenin has been identified in conjunction with the active enzyme in these tissues. Thus, the extrarenal sources of plasma prorenin have remained an enigma. Prorenin normally circulates in plasma of men and women in concentrations close to IO times those of active renin. It usually falls by about 90 percent following bilateral nephrectomy [ 161, suggesting that the kidneys are its major source. Nonetheless, the major form of renin found in kidney extracts is the mature active enzyme, and, in general, plasma prorenin changes in concert with plasma active renin [2], In the placenta, the
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major form detected is prorenin [8-l 0] and there is little evidence that, in humans at least, active renin is secreted from the placenta. Not much is known about placental prorenin. It is synthesized by the chorionic cells [9,17] and seems to be secreted into amniotic fluid, since it is found there in high concentrations [8]. The function of placental prorenin has not been described. A lo-fold rise in maternal plasma prorenin levels occurs early in pregnancy [ 18-201, and these elevated levels are maintained throughout gestation. It has generally been assumed that the source of this rise in prorenin level is the placenta. We began to question that view [ill when we observed that the increase in plasma prorenin level OCCUrrE!d very soon after conception and fell rather slowly after delivery. Thus, plasma prorenin reaches its maximal levels within four weeks following conception, and its fall after parturition is much slower than that of the other placental hormone, human chorionic gonadotropin, despite having a much shorter half-life [2 11. These observations prompted us to investigate whether changes in prorenin occurred during normal menstrual cycles [22], since it seemed possible that the rise in prorenin level during gestation may have been initiated during the previous menstrual cycle. We found that prorenin levels change predictably in blood during the menstrual cycle. They were quite stable during the two weeks of the follicular phase of the cycle, during which time one egg is normally selected for maturation. Prorenin levels then increased about twofold at midcycle at the time of the luteinizing hormone surge. This change in prorenin level was not associated with any change in active plasma renin level. Although plasma prorenin level was also above baseline during the mid-luteal phase of the cycle, it was lower than that measured at mid-cycle, and active renin level was often elevated too. The rise in active renin level at this time is presumed to be the result of the diuretic effect of progesterone [23]. Since the mid-cycle increase in plasma prorenin level was not associated with any change in active renin level, the kidney seemed an unlikely source of secretion. Since the rise occurred almost precisely at the time of ovulation, we considered the possibility that the ovary might be the source. When an egg matures at mid-menstrual cycle, a follicle develops around it that is filled with a fluid containing all but the higher-molecular-weight substances found in plasma. This fluid also contains high concentrations of various substances synthesized by the ovary, such as estrogen and progesterone. Human ovarian follicular fluid is readily available from women undergoing in vitro fertilization. We found that it contained very high concentrations of prorenin, more than 10 times higher than in the concurrently collected plasma [24]. Only 1 percent of the renin in ovarian follicular fluid was in the active form. From these data, it seemed likely that the mid-cycle change in plasma prorenin level is due to secretion of
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prorenin from the ovary, and that prorenin is produced by the mature ovarian follicle. We have been unable to detect any biochemical difference between prorenin from ovarian follicular fluid and prorenin from kidney or plasma [24]. The pH optima of trypsin-activated prorenin from plasma and follicular fluid are identical and the same as that of active renal renin. Antibodies against active kidney renin bind to ovarian prorenin as do highly specific antibodies prepared against the carboxyterminal portion of the prosegment of prorenin
P41.
Subsequent studies reinforced the idea that the ovaries secrete prorenin. We found that ovarian vein blood collected at mid-cycle from a baboon ovary with one mature follicle contained close to double the concentration of prorenin of that found in a peripheral vein [25]. The contralateral ovary did not have a mature follicle and did not show an arteriovenous increment in prorenin level. Following the sampling procedure, the baboon underwent bilateral ovariectomy, and peripheral venous prorenin level fell by 50 percent in 30 minutes [25]. On the ottier hand, the ovaries do not appear to secrete prorenin during the follicular phase of the cycle. Thus, we have found that the prorenin concentration in the follicular fluid from immature follicles of baboons is similar to the concurrent plasma level (unpublished observation). Also, the average plasma prorenin level of normal subjects during the follicular phase of the menstrual cycle is quite similar to that found in women over age 50 [24]. Other studies suggest not only that the ovary is a source of plasma prorenin but that the gonadotropic hormones luteinizing hormone and human chorionic gonadotropin stimulate ovarian prorenin production or secretion. When we investigated the relationship of the change in plasma prorenin level at mid-cycle to the luteinizing hormone surge, we found that the rise in luteinizing hormone level preceded the rise in prorenin level by about eight hours, and the peak of prorenin occurred about eight hours after the peak of luteinizing hormone [26]. The peak of prorenin was sustained for about 36 hours. Another study documented that human chorionic gonadotropin can stimulate prorenin. Infertile women and women undergoing in vitro fertilization are given folliclestimulating hormone or follicle-stimulating hormone and luteinizing hormone during the follicular phase of the menstrual cycle. This usually results in more than one egg being selected for maturation, with multiple follicles being formed. Since such women often do not have a spontaneous luteinizing hormone surge, they are routinely given human chorionic gonadotropin to induce ovulation. We found that they consistently have a marked increase in plasma prorenin level about 24 hours after administration of human chorionic gonadotropin [27,28]. The rise is sustained for several days, i.e., longer than the usual rise in prorenin level that occurs after an endogenous luteiniz-
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ing hormone surge. This prolonged response is consistent with the longer half-life of human chorionic gonadotropin compared with luteinizing hormone. Other studies suggest that human chorionic gonadotropin stimulates ovarian prorenin secretion. As just noted, prorenin levels are very high in the blood of pregnant women, about 10 times normal [l&20]. We found a weak but significant relationship between plasma prorenin and plasma beta human chorionic gonadotropin during the first trimester of pregnancy [2 I]. In more recent studies of women undergoing in vitro fertilization, we were able to define more precisely the time course of the changes in prorenin that occur following conception. We also obtained indirect evidence that this rise is also due to the secretion of ovarian prorenin. Thus, as just described, we found that plasma prorenin levels rose after human chorionic gonadotropin was administered to induce ovulation. They reached a peak four to six days after human chorionic gonadotropin and then fell back, close to baseline, by about 10 days after human chorionic gonadotropin [28-301. At that time, beta human chorionic gonadotropin was undetectable in the blood. In those women who conceived, prorenin levels began to rise again on days 12 to 16 after human chorionic gonadotropin (days 8 to 12 after embryo transfer) at precisely the time when endogenous human chorionic gonadotropin was detected again in the blood [29,30]. In the one normal pregnancy that we were able to monitor closely during the initial days following conception, we found a similar pattern [29]. Prorenin level increased transiently at the time of the lutenizing hormone surge, and then began to rise again sometime between day 5 and day 12 after the luteinizing hormone peak. Plasma beta human chorionic gonadotropin level was less than 5 mlU/ml on day 5 and 328 mlU/ml on day 12, whereas plasma prorenin level was 39 and 107 rig/ml per hour, respectively. That the rise in prorenin level during gestation is of ovarian and not of fetal origin is suggested by the observation that no such changes in prorenin occurred in a woman with ovarian failure who conceived after receiving a fertilized donor egg [29,30]. It is likely that the ovary secretes prorenin throughout pregnancy, as prorenin levels remain high throughout gestation and fall quite slowly after delivery, taking many days to return to baseline levels [2 11. Prorenin secretion by the corpus luteum may be quite sensitive to human chorionic gonadotropin, since maximal plasma levels of prorenin occur long before human chorionic gonadotropin has reached maximum levels [21]. This sensitivity to human chorionic gonadotropin may change as gestation proceeds, since plasma prorenin levels tend to fall after about the 12th week of gestation, as human chorionic gonadotropin falls from its maximal levels. Administration of human chorionic gonadotropin following hyperstimulation during the follicular phase of the menstrual cycle results in much higher plasma prorenin
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levels than occur normally during a spontaneous luteinizing hormone surge. In fact, the levels observed in some patients are among the highest we have ever seen, being similar to those found in renin-secreting tumors [31]. In analyzing the data from patients undergoing in vitro fet-tilization, we observed that the height of the plasma prorenin response to human chorionic gonadotropin was directly related to the number of follicles detected at the time of aspiration [28]. Since the concentration of prorenin in each follicle from hyperstimulated women was not higher than we found in ovarian follicular fluid from a woman who had a spontaneous luteinizing hormone surge (a patient of Dr. Andrew Silverman, New York), the results suggest that hyperstimulation and exogenous human chorionic gonadotropin administration do not result in abnormally high prorenin concentration in individual follicles, but that the high plasma prorenin levels are the result of the presence of multiple follicles. In pregnant patients undergoing in vitro fertilization, it is likely that many corpora lutea are formed from the multiple mature follicles. This may result in abnormally high prorenin levels as evidenced by the fact that the highest prorenin level we have seen in pregnancy (650 rig/ml per hour; 20-fold baseline) occurred in a patient undergoing in vitro fertilization who had 14 follicles and conceived with twins [29]. Although the previously cited results suggest that gonadotropins (luteinizing hormone or human chorionic gonadotropin) stimulate prorenin secretion, estrogens, or their precursors or metabolites, may play a role in the process. In each of the hyperstimulated women we have studied, we have observed a small increase in prorenin level before human chorionic gonadotropin administration [30] when plasma estradiol was at maximal levels. Hyperstimulation results in the presence of many follicles, which may be at different stages of development. In normal cycles, the resultant high concentration of estrogen causes a luteinizing hormone surge. Since a spontaneous luteinizing hormone surge does not usually occur in hyperstimulated women, it is possible to examine what happens in them when large follicles are’ present that have not been exposed to high concentrations of gonadotropin. What we observed was a significant, close to twofold rise in prorenin level on the day of human chorionic gonadotropin administration, before the hormone was given. The rise occurred whether the patients had been previously hyperstimulated with follicle-stimulating hormone alone or follicle-stimulating hormonelluteinizing hormone. Also, when we compared the magnitude of the increase in plasma prorenin level in response to exogenous human chorionic gonadotropin administration with the plasma estradiol levels, the relationship was highly significant (unpublished observations). Similarly, the rise in prorenin level following conception was highly related to the plasma estradiol level. Nonetheless, estradiol does not appear to be the complete answer to the question of
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what initiates ovarian prorenin biosynthesis, since plasma estradiol levels are also high during the mid-luteal phase of the menstrual cycle but plasma prorenin levels are not consistently elevated [22] and prorenin levels are not high in women receiving oral contraceptive therapy. Clearly, further studies are required to dissect these interrelationships. Altogether, the data suggest that during the follicular phase of the menstrual cycle, the ovary does not normally synthesize prorenin. It is unclear at precisely what time prorenin begins to be synthesized by the ovary (presumably by the maturing follicle) but it seems to be either just before or at the time of the luteinizing hormone surge. High concentrations of gonadotropins clearly augment prorenin biosynthesis at thjs time, and seem to be responsible for the ovulatory rise in plasma prorenin levels. We do not know if any prorenin is synthesized by the corpus luteum in nonconception, normal menstrual cycles. The corpus luteum does seem able to respond to gonadotropins, since the ovary apparently secretes prorenin as soon as human chorionic gonadotropin levels rise following conception and throughout gestation. Whether the ovaries are the sole source of the pregnancy-related rise in prorenin levels throughout gestation remains to be established. Whenever the plasma prorenin level is elevated, the plasma estradiol level is always high; further stud/es are required to determine whether high estrogen levels or related steroids are required for ovarian prorenin biosynthesis to occur. WHY
PRORENIN?
The changes in plasma prorenin that occur at the time of ovulation are not accompanied by any detectable change in circulating active renin 1221. Thus, ovarian prorenin seems to function in such a way that if active renin is formed, and is required for prorenin to have an effect, it does not enter the circulation in appreciable amounts. Active renin has been detected in ovarian follicular fluid, but its concentration is low (less than 1 percent) relative to the prorenin level [24,32]; angiotensins I and II have also been found in ovarian follicular fluid, in concentrations higher than the concurrent plasma level. However, this does not necessarily mean that either active renin or angiotensin I or II is normally present in these concentrations in vivo, since inadvertent activation of prorenin can occur in vitro [2], resulting in higher active renin levels than were present in vivo. Since renin substrate is present in follicular fluid, once active renin is formed, angiotensins could be generated in vitro. Renin is unusual amongst plasma proteases in that it circulates in the active form and has no endogenous inhibitors. Other plasma proteases such as those of the coagulation and fibrinolytic systems circulate as precursors of the active enzyme and are converted to the active
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form at a discrete site (such as the site of injury). Since the precursors of these other plasma proteases circulate in very high concentrations, a lot of active enzyme can be formed locally, but the effect of the enzyme is limited and localized by circulating inhibitors. The prorenin-renin system seems to work quite differently. Renin is synthesized and stored in high concentrations in the kidney. The active enzyme is secreted into the circulation where it acts continuously to form angiotensin I from plasma angiotensinogen. Prorenin is also apparently secreted by the kidney, but there is no good evidence that it is ever activated in the circulation. How then does ovarian prorenin function? If it is converted to active renin, how is its effect limited to a particular site? We have been unable to detect an inhibitor of renin in ovarian follicular fluid. One possibility is that prorenin has a receptor and that once bound to this receptor, the active site of renin is exposed. Prorenin appears to be very similar to the precursor of another aspartyl protease, pepsinogen. When pepsinogen is acidified, the prosegment of the molecule swings out of a cleft containing two separate parts of the active site, and the active site is formed [33]. Prorenin can be similarly activated by acidification and this activation can be reversed at a higher pH [34,35]. We hypothesize that bihding of prorenin to its receptor might accomplish the same effect, i.e., expose the active site of the enzyme. Angiotensinogen circulates in blood; it is present in ovarian follicular fluid and is reportedly also synthesized by the ovaries [36]. If the prorenin receptor were located near membrane-bound converting enzyme and the angiotensin II receptor, the activated prorenin could cleave angiotensin I from angiotensinogen; angiotensin I could in turn be converted to angiotensin II by the adjacent converting enzyme and then angiotensin II could bind to its receptor and have a local effect without appreciable amounts of it passing to other sites. There is some evidence that converting enzyme and the angiotensin receptor might be located together [37]. Clearly, other possibilities exist to explain how prorenin could have a physiologic effect, but any model that includes the formation of active renin runs the risk of unabated formation of active renin and resultant disruption of cardiovascular physiology. This makes attractive any hypothesis in which prorenin has an effect without the concurrent formation of active renin. OVARIAN
PRORENIN
FUNCTION
At this time, we can only speculate about the function of
ovarian prorenin. We do not know whether its putative action is confined to the ovary. If prorenin is a circulating hormone, an explanation would have to be made of how its effect could adjust to concurrent changes in secretion of prorenin from extraovarian sources. In this regard, the report [38] that circulating prorenin may not have the
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complete prosequence, as found in the kidney, is intriguing, since receptor binding could perhaps be altered by the presence of different portions of the prorenin segment. Since angiotensin II affects intracellular calcium and phospholipase activity, there are many potential roles for prorenin via angiotensin II action, ranging from an effect on pituitary luteinizing hormone release [ 151 to facilitation of egg extrusion [39] or alteration of ovarian steroid biosynthesis in a manner similar to the known action of angiotensin on adrenal cortical steroid biosynthesis [40]. The coming years should see exciting new research in this regard. Renin has been found in the male reproductive
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system [41,42], but it remains to be determined whether prorenin is synthesized in the testes in a manner analogous to that in the ovary. To date, the results in rodents suggest that active renin, not prorenin, is formed in the Leydig cells of the testes. Whatever the outcome, it seems likely that a new form and function of the reninangiotensin system exist that operate independently of changes in circulating active renin, and the effect of which is regulated by changes in prorenin. This new prorenin system seems to be involved in reproductive function. Future work to elucidate ovarian prorenin function may have clinical implications in the fields of birth control, infertility, a.nd toxemia of pregnancy.
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