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Peritoneal secretion of ovarian hormones and its consequences
Medical Hypotheses (2003) 60(6), 845–848 ª 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-9877(03)00029-X
Peritoneal secretion of ovarian hormones and its consequences Eugene A. Foster Charlottesville, Virginia, USA
Summary Secretion of ovarian hormones directly into the peritoneal cavity has been repeatedly demonstrated for 25 years, but the consequences of this pathway of secretion have not been fully considered. Circumstantial evidence suggests the following hypotheses: (1) Hormones enter the endometrial cavity through the tubes and influence the endometrial cycle. (2) Androgens are absorbed into the portal venous system and are inactivated in the liver. (3) In polycystic ovary syndrome, ovarian cortical fibrosis inhibits peritoneal secretion of androgens and contributes to hyperandrogenemia. (4) Bypass of the ovarian vein by peritoneal secretion leads to underestimation of ovarian hormone production rates. (5) Peritoneally secreted hormones are absorbed into the broad ligaments of the uterus and returned to the reproductive organs by veno-arterial countercurrent transfer. Some approaches to testing the hypotheses are outlined. If any of the hypotheses are supported by more direct evidence, some aspects of reproductive endocrinology will turn out be even more complicated than they have seemed. ª 2003 Elsevier Science Ltd. All rights reserved.
BACKGROUND In addition to their primary function as organs for the storage and development of ova, the ovaries secrete a number of steroid and polypeptide hormones, including estrogens and androgens. Many of the hormones are produced by the specialized tissues of developing follicles: granulosa, theca interna and theca externa. In addition to being secreted into the blood, these hormones are present in high concentration in the follicular fluid that surrounds the maturing ovum. Hormones, especially androgens, are also manufactured in the non-follicular cortical stroma, as well as in the interstitial cells of the ovarian medulla.
Received 8 October 2002 Accepted 11 November 2002 Correspondence to: Eugene A. Foster MD, 6 Gildersleeve Wood, Charlottesville, VA 22903, USA. Phone: +434-293-3683; Fax: +434-973-5208; E-mail: [email protected]
The ovaries lie within the abdominal cavity, suspended by vascularized mesenteries and rest on the posterior surfaces of the broad ligaments of the uterus, separated from the peritoneal cavity by a single layer of epithelial (mesothelial) cells. This unique anatomical situation and the fact that the ovaries are not encapsulated provide conditions that permit direct secretion into the peritoneal cavity in addition to the usual secretion into the blood. Persuasive evidence for such a direct peritoneal secretion pathway has been accumulated by a number of investigators since 1978. Hormones such as estradiol, progesterone, androstenedione, testosterone and inhibins have been detected in peritoneal fluid (PF) in higher concentrations than simultaneous systemic blood levels (1). During the ovarian cycle, levels of some hormones peak in PF before they do in blood (2). The most obvious way for the ovaries to deliver hormones to the peritoneal cavity is by spillage of the hormone-rich follicular fluid during ovulation. In addition, dropwise exudation of fluid from the bulging surfaces of postovulatory follicles has been observed culdoscopically (3). It is likely that direct secretion of hormones from the non-follicular ovarian cortical
845
846 Foster
stroma into PF also takes place. In one study, PF concentrations of androstenedione and testosterone were not significantly different during the pre- and post-ovulatory phases of the ovarian cycle suggesting that these androgens were secreted from the non-follicular stroma (4). HYPOTHESES Judging by the scant attention the peritoneal secretion pathway has received, it seems to have been regarded as no more than an interesting phenomenon, perhaps useful in helping to determine whether and when ovulation has occurred. Speculation on the possible fate of hormones that have entered the peritoneal cavity based on consideration of circumstantial evidence from a wide variety of sources has led me to believe that peritoneal secretion may play important roles in reproductive tract function and dysfunction. I propose the following hypotheses. (1) Ovarian hormones that have been secreted into the peritoneal fluid reach the uterine cavity by way of the tubes, diffuse into the endometrium and influence endometrial cyclical changes. Cyclical endometrial changes are largely confined to the thick superficial layer (functionalis) of the endometrium. The thinner, deep layer (basalis) of endometrium remains essentially unchanged (5). Perhaps one mechanism that contributes to the greater activity of the functionalis is that it is the first layer exposed to hormones transported from the peritoneal cavity and that its receptors have bound all or most of the hormones diffusing from the lumen before they can reach the basalis. Despite its inactivity the basalis has been shown to contain the same or higher concentrations of estrogen and progesterone receptors as the functionalis (6–8). If cyclical endometrial changes are influenced by peritoneally secreted hormones, endometrial function should be altered following tubal interruption. Although a review of a large number of studies of tubal sterilization did not reveal effects that were considered harmful, there was a significantly increased prevalence of innocuous menstrual abnormalities such as shortened duration of flow (9). A recent prospective multicenter study, based on follow-up of over 9000 women found that women sterilized by tubal interruption had menstrual changes that included decreased duration and amount of bleeding, less pain, and increased cycle irregularity (10). Studies of serum levels of ovarian hormones in women with menstrual abnormalities following tubal interruption have yielded conflicting results and have not adequately explained the abnormalities (11–13). (2) Ovarian androgens that have been secreted directly into the peritoneal cavity are absorbed across Medical Hypotheses (2003) 60(6), 845–848
intestinal peritoneum, enter the portal venous system and are inactivated in the liver before they enter the systemic circulation. According to this hypothesis, normal women would have higher systemic blood androgen levels if a high proportion of their ovarian androgen production were not secreted into the peritoneal cavity and inactivated in the liver. Thus, if a pathway from the peritoneal cavity to the liver through the portal vein were to be abnormally bypassed, systemic serum levels of androgens would be expected to rise disproportionately and might result in virilization. The effects of such a bypass of the liver have been reported recently. Two adolescent patients with congenital portosystemic venous shunts had elevated serum androgens and virilization as well as insulin-resistant hyperinsulinemia (14). The authors attributed the hyperandrogenism to increased adrenal production but one can also speculate that at least part of the increased serum androgen resulted from the failure of hepatic inactivation of ovarian androgens secreted into the peritoneal fluid. (3) The ovarian cortical fibrosis characteristic of polycystic ovary syndrome (PCOS) inhibits secretion of ovarian androgens into the peritoneal cavity and leads to increased secretion into the systemic blood, thus contributing to the abnormally high androgen levels. Despite decades of investigation and speculation, the causes of PCOS and the pathogenesis of the characteristic hyperandrogenemia remain unclear (15). Regardless of its initiating cause, it is well established that longstanding hyperandrogenemia results in thickening and collagenization of the superficial ovarian cortical stroma (16). Once such fibrosis has occurred, it could be part of a vicious circle in which a block to secretion into the peritoneal cavity augments the hyperandrogenemia. It is even possible that in some cases of PCOS ovarian cortical fibrosis of unknown etiology is the primary cause of hyperandrogenemia. Surgical removal of ovarian tissue by wedge resection has reduced hyperandrogenemia.in many cases of PCOS (17). The fact that thecal and stromal ovarian tissue from ovaries of patients with PCOS produce greatly increased amounts of androgen in vitro has suggested that removal of this hyperactive tissue accounts for the success of wedge resection (18). Destruction of small portions of the thickened superficial ovarian cortex without removal of significant amounts of ovarian tissue, however, is also successful in reducing or abolishing the hyperandrogenemia (19–21). In these cases, reduction of hyperandrogenemia could have resulted from restoration of the peritoneal pathway of androgen secretion with subsequent portal venous transport to the liver and inactivation there. ª 2003 Elsevier Science Ltd. All rights reserved.
Peritoneal secretion of ovarian hormones and its consequences
847
(4) Ovarian hormones that have entered the peritoneal cavity are absorbed across the parietal and visceral peritoneum and are transported to the systemic and portal venous streams without traversing the ovarian vein, thus leading to underestimation of the ovarian contribution to the production of hormones that are also produced in the adrenals and other sites. Estimates of the ovarian contribution to a hormone’s production are often partly based on determination of hormone levels in ovarian venous blood. Such determinations of production of various hormones by the ovaries have not always been consistent with their production rates in vitro or their follicular fluid concentrations (22,23). Perhaps these discrepancies can be partly accounted for by peritoneal secretion that has bypassed the ovarian vein. (5) Ovarian hormones that have been secreted into the peritoneal cavity are absorbed across the peritoneum of the broad ligaments, enter uterine veins by veno-arterial countercurrent transfer and are returned to the reproductive organs, thus augmenting their hormone concentrations. Because of the intimate anatomical relationship of the ovaries to the broad ligaments, it is likely that the posterior peritoneal surfaces of the broad ligaments are exposed to high concentrations of ovarian hormones, some of which would be absorbed into the interstitial tissue of the broad ligaments and then into their venous plexuses. Numerous studies have demonstrated countercurrent transfer of a wide variety of substances, including ovarian steroids, between veins and arteries in the broad ligaments (24). Substances flowing through the extensive uteroovarian venous plexuses of the broad ligaments, are transferred, in part, to adjacent arteries and are returned to the reproductive organs. Such transfer results in augmented concentrations of these substances in arteries supplying the uterus, tubes and ovaries. Transfer of a hormone from the interstitium to arteries has been demonstrated by investigators who injected radioactively labeled testosterone into muscle of the mesovarium of the sow and then detected a gradually rising level of radioactivity in the ovarian artery (25).
without using tracers by performing simultaneous assays of ovarian hormones in endometrial flushings and blood at various times during the endometrial cycle. Direct evidence bearing on the second, third and fourth hypotheses could be obtained by performing hormonal assays in blood from appropriate vessels during a wide variety of surgical procedures such as hysterectomy, salpingo-oophorectomy, various bowel resections, gastric procedures, portacaval and other portal-systemic shunts. These would be compared to simultaneous assays in mixed systemic venous blood. Since the surgical procedures usually require ligation of the vessels of interest, blood could be obtained with little or no risk to the patient. The second hypothesis (Androgens absorbed across the visceral peritoneum of the bowel enter the hepatic portal venous system and are inactivated in the liver.) and the third hypothesis (Ovarian cortical fibrosis in PCOS inhibits peritoneal secretion of androgens and leads to increased ovarian vein secretion.) could be tested by comparison of androgen levels in blood from mesenteric veins and/or the portal vein with levels in mixed systemic venous blood. Comparison of androgen levels in culdoscopically obtained peritoneal fluid from normal women and those with PCOS could also also provide useful information. Evidence for or against the fourth hypothesis (Production rates of ovarian hormones based on ovarian venous levels have been underestimated because some of the ovarian hormones bypass the ovarian veins by way of the peritoneal cavity.) could be gotten by assays of blood from the portal vein and the inferior vena cava below the influx of ovarian vein blood (below the entrances of the right ovarian vein and the left renal vein, into which the left ovarian vein drains). The fifth hypothesis (Hormones secreted into the peritoneal cavity are absorbed into the interstitial tissue of the broad ligament and are returned to the reproductive organs by means of venoarterial transfer.) could be tested by introduction of radioactively tagged hormones into the peritoneal cavity before hysterectomy followed by assays in venous and arterial blood in vessels within the broad ligament.
TESTING THE HYPOTHESES
COMMENT
The availability of a simple method for flushing the endometrial cavity (26) suggests at least two approaches to the first hypothesis (Significant amounts of hormones flow from the peritoneal cavity into the endometrial cavity.). The most direct method would be to introduce a tagged hormone or other tracer into the peritoneal cavity and then perform assays in endometrial flushings at intervals. One could also obtain useful information
The fundamental concept underlying these hypotheses is that it is very unlikely that ovarian hormones secreted into the peritoneal cavity simply disappear without a trace and have no effects on potential targets. The hypotheses are a first attempt at trying to understand what pathways the hormones might follow as they leave the peritoneal cavity and what the consequences might be. If one or more of the hypotheses are borne out by
ª 2003 Elsevier Science Ltd. All rights reserved.
Medical Hypotheses (2003) 60(6), 845–848
848 Foster
subsequent investigations, another layer of complexity of some aspects of reproductive endocrinology will have been uncovered.
REFERENCES 1. Maathuis J. B., Van Look P. F. A., Michie E. A. Changes in volume, total protein and ovarian steroid concentrations of peritoneal fluid throughout the human menstrual cycle. J Endocr 1978; 76: 123–133. 2. Koninckx P. R., Heyns W., Verhoeven G. et al. Biochemical characterization of peritoneal fluid in women during the menstrual cycle. J Clin Endocrinol Metab 1980; 51: 1239–1244. 3. Donnez J., Langerock S., Thomas K. Peritoneal fluid volume and 17b-estradiol and progesterone concentrations in ovulatory, anovulatory and postmenopausal women. Obstet Gynecol 1982; 59: 687–692. 4. Lesorgen P. R., Wu C. H., Green P. J., Gocial B., Lerner L. J. Peritoneal fluid and serum steroids in infertility patients. Fertil Steril 1984; 42: 237–242. 5. Cormack D. H. In: Ham’s Histology, 3rd ed. Philadelphia: Lippincott, 1987: 633. 6. Press M. F., Nousek-Goebl N., King W. J., Herbst A. L., Greene G. L. Immuno-histochemical assessment of estrogen receptor distribution in the human endometrium throughout the menstrual cycle. Lab Invest 1984; 51: 495–503. 7. Coppens M. T., Dhont M. A., De Boever J. G., Serreyn R. F., Vandekerckhove D. A., Roels H. J. The distribution of estrogen and progesterone receptors in the human endometrial basal and functional layers during the normal menstrual cycle. An immunocytochemical study. Histochemistry 1993; 99: 121–126. 8. Press M. F., Nousek-Goebl N. A., Bur M., Greene G. L. Estrogen localization in the female genital tract. Am J Pathol 1986; 123: 280–292. 9. Gentile G. W., Kaufman S. C., Helbig D. W. Is there any evidence for a post-tubal sterilization syndrome? Fertil Steril 1998; 69: 179–186. 10. Peterson H. B., Jeng G., Folger S. G., Hillis S. A., Marchbanks P. A., Wilcox L. S. The risk of menstrual abnormalities after tubal sterilization. N Engl J Med 2000; 343: 1681–1687. 11. Corson S. L., Levinson C. J., Batzer F. R., Otis C. Hormonal levels following sterilization and hysterectomy. J Reprod Med 1981; 26: 363–370. 12. Alvarez-Sanchez F., Segal S. J., Brache V., Adejuwon C. A., Leon P., Faundes A. Pituitary-ovarian function after tubal ligation. Fertil Steril 1981; 36: 606–609.
Medical Hypotheses (2003) 60(6), 845–848
13. Radwanska E., Headley S. K., Dmowski P. Evaluation of ovarian function after tubal sterilization. J Reprod Med 1982; 27: 376–384. 14. Satoh M., Yokoya S., Hachiya Y. et al. Two hyperandrogenic adolescent girls with congenital portosystemic shunt. Eur J Pediatr 2001; 160: 307–311. 15. Goldzieher J. W., Young Y. Selected aspects of polycystic ovarian disease. Endocrinol Metab Clin North Am 1992; 21: 141–171. 16. Pache T. D., Chadha S., Goorens L. J. G. et al. Ovarian morphology in long-term androgen treated female to male transsexuals: a human model for the study of polycystic ovarian syndrome?. Histopathology 1991; 19: 445–452. 17. Judd W. L., Rigg L. A., Anderson D. C., Yen S. S. C. The effects of ovarian wedge resection on circulating gonadotrophin and ovarian steroid levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 1976; 43: 347–355. 18. Barnes R., Rosenfield R. L. The polycystic ovary syndrome: pathogenesis and treatment. Ann Int Med 1989; 110: 386–389. 19. Aakvaag A., Gjønnæss H. Hormonal response to electro-cautery of the ovary in patients with polycystic ovarian disease. Br J Obstet Gynaecol 1985; 92: 1258–1264. 20. Greenblatt E., Casper R. F. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987; 156: 279–285. 21. Gjønnæss H. Late endocrine effects of ovarian electrocautery in women with polycystic ovarian syndrome. Fertil Steril 1998; 69: 697–701. 22. de Jong F. H., Baird D. T., van der Molen H. J. Ovarian secretion rates of oestrogens, androgens and progesterone in normal women and in women with persistent ovarian follicles. Acta Endocr 1974; 77: 575–587. 23. McNatty K. P., Baird D. T., Bolton A., Chambers P., Corker C. S., McLean H. Concentration of oestrogens and androgens in human ovarian venous plasma and follicular fluid throughout the menstrual cycle. J Endocr 1976; 71: 77–85. 24. Einer-Jensen N., Hunter R. H. F. Physiological and pharmacological aspects of local transfer of substances in the ovarian adnexa in women. Hum Reprod Update 2000; 6: 132–138. 25. Krzymowski T., Kotwica J., Stefanczyk S., Czarnocki J., Debek J. A subovarian exchange mechanism for the countercurrent transfer of ovarian steroid hormones in the pig. J Reprod Fert 1982; 65: 457–465. 26. Dawood M. Y., Fazleabas A. T. A simple method for the collection of human uterine flushing. Fertil Steril 1986; 45: 886–888.
ª 2003 Elsevier Science Ltd. All rights reserved.
Peritoneal secretion of ovarian hormones and its consequences Eugene A. Foster Charlottesville, Virginia, USA
Summary Secretion of ovarian hormones directly into the peritoneal cavity has been repeatedly demonstrated for 25 years, but the consequences of this pathway of secretion have not been fully considered. Circumstantial evidence suggests the following hypotheses: (1) Hormones enter the endometrial cavity through the tubes and influence the endometrial cycle. (2) Androgens are absorbed into the portal venous system and are inactivated in the liver. (3) In polycystic ovary syndrome, ovarian cortical fibrosis inhibits peritoneal secretion of androgens and contributes to hyperandrogenemia. (4) Bypass of the ovarian vein by peritoneal secretion leads to underestimation of ovarian hormone production rates. (5) Peritoneally secreted hormones are absorbed into the broad ligaments of the uterus and returned to the reproductive organs by veno-arterial countercurrent transfer. Some approaches to testing the hypotheses are outlined. If any of the hypotheses are supported by more direct evidence, some aspects of reproductive endocrinology will turn out be even more complicated than they have seemed. ª 2003 Elsevier Science Ltd. All rights reserved.
BACKGROUND In addition to their primary function as organs for the storage and development of ova, the ovaries secrete a number of steroid and polypeptide hormones, including estrogens and androgens. Many of the hormones are produced by the specialized tissues of developing follicles: granulosa, theca interna and theca externa. In addition to being secreted into the blood, these hormones are present in high concentration in the follicular fluid that surrounds the maturing ovum. Hormones, especially androgens, are also manufactured in the non-follicular cortical stroma, as well as in the interstitial cells of the ovarian medulla.
Received 8 October 2002 Accepted 11 November 2002 Correspondence to: Eugene A. Foster MD, 6 Gildersleeve Wood, Charlottesville, VA 22903, USA. Phone: +434-293-3683; Fax: +434-973-5208; E-mail: [email protected]
The ovaries lie within the abdominal cavity, suspended by vascularized mesenteries and rest on the posterior surfaces of the broad ligaments of the uterus, separated from the peritoneal cavity by a single layer of epithelial (mesothelial) cells. This unique anatomical situation and the fact that the ovaries are not encapsulated provide conditions that permit direct secretion into the peritoneal cavity in addition to the usual secretion into the blood. Persuasive evidence for such a direct peritoneal secretion pathway has been accumulated by a number of investigators since 1978. Hormones such as estradiol, progesterone, androstenedione, testosterone and inhibins have been detected in peritoneal fluid (PF) in higher concentrations than simultaneous systemic blood levels (1). During the ovarian cycle, levels of some hormones peak in PF before they do in blood (2). The most obvious way for the ovaries to deliver hormones to the peritoneal cavity is by spillage of the hormone-rich follicular fluid during ovulation. In addition, dropwise exudation of fluid from the bulging surfaces of postovulatory follicles has been observed culdoscopically (3). It is likely that direct secretion of hormones from the non-follicular ovarian cortical
845
846 Foster
stroma into PF also takes place. In one study, PF concentrations of androstenedione and testosterone were not significantly different during the pre- and post-ovulatory phases of the ovarian cycle suggesting that these androgens were secreted from the non-follicular stroma (4). HYPOTHESES Judging by the scant attention the peritoneal secretion pathway has received, it seems to have been regarded as no more than an interesting phenomenon, perhaps useful in helping to determine whether and when ovulation has occurred. Speculation on the possible fate of hormones that have entered the peritoneal cavity based on consideration of circumstantial evidence from a wide variety of sources has led me to believe that peritoneal secretion may play important roles in reproductive tract function and dysfunction. I propose the following hypotheses. (1) Ovarian hormones that have been secreted into the peritoneal fluid reach the uterine cavity by way of the tubes, diffuse into the endometrium and influence endometrial cyclical changes. Cyclical endometrial changes are largely confined to the thick superficial layer (functionalis) of the endometrium. The thinner, deep layer (basalis) of endometrium remains essentially unchanged (5). Perhaps one mechanism that contributes to the greater activity of the functionalis is that it is the first layer exposed to hormones transported from the peritoneal cavity and that its receptors have bound all or most of the hormones diffusing from the lumen before they can reach the basalis. Despite its inactivity the basalis has been shown to contain the same or higher concentrations of estrogen and progesterone receptors as the functionalis (6–8). If cyclical endometrial changes are influenced by peritoneally secreted hormones, endometrial function should be altered following tubal interruption. Although a review of a large number of studies of tubal sterilization did not reveal effects that were considered harmful, there was a significantly increased prevalence of innocuous menstrual abnormalities such as shortened duration of flow (9). A recent prospective multicenter study, based on follow-up of over 9000 women found that women sterilized by tubal interruption had menstrual changes that included decreased duration and amount of bleeding, less pain, and increased cycle irregularity (10). Studies of serum levels of ovarian hormones in women with menstrual abnormalities following tubal interruption have yielded conflicting results and have not adequately explained the abnormalities (11–13). (2) Ovarian androgens that have been secreted directly into the peritoneal cavity are absorbed across Medical Hypotheses (2003) 60(6), 845–848
intestinal peritoneum, enter the portal venous system and are inactivated in the liver before they enter the systemic circulation. According to this hypothesis, normal women would have higher systemic blood androgen levels if a high proportion of their ovarian androgen production were not secreted into the peritoneal cavity and inactivated in the liver. Thus, if a pathway from the peritoneal cavity to the liver through the portal vein were to be abnormally bypassed, systemic serum levels of androgens would be expected to rise disproportionately and might result in virilization. The effects of such a bypass of the liver have been reported recently. Two adolescent patients with congenital portosystemic venous shunts had elevated serum androgens and virilization as well as insulin-resistant hyperinsulinemia (14). The authors attributed the hyperandrogenism to increased adrenal production but one can also speculate that at least part of the increased serum androgen resulted from the failure of hepatic inactivation of ovarian androgens secreted into the peritoneal fluid. (3) The ovarian cortical fibrosis characteristic of polycystic ovary syndrome (PCOS) inhibits secretion of ovarian androgens into the peritoneal cavity and leads to increased secretion into the systemic blood, thus contributing to the abnormally high androgen levels. Despite decades of investigation and speculation, the causes of PCOS and the pathogenesis of the characteristic hyperandrogenemia remain unclear (15). Regardless of its initiating cause, it is well established that longstanding hyperandrogenemia results in thickening and collagenization of the superficial ovarian cortical stroma (16). Once such fibrosis has occurred, it could be part of a vicious circle in which a block to secretion into the peritoneal cavity augments the hyperandrogenemia. It is even possible that in some cases of PCOS ovarian cortical fibrosis of unknown etiology is the primary cause of hyperandrogenemia. Surgical removal of ovarian tissue by wedge resection has reduced hyperandrogenemia.in many cases of PCOS (17). The fact that thecal and stromal ovarian tissue from ovaries of patients with PCOS produce greatly increased amounts of androgen in vitro has suggested that removal of this hyperactive tissue accounts for the success of wedge resection (18). Destruction of small portions of the thickened superficial ovarian cortex without removal of significant amounts of ovarian tissue, however, is also successful in reducing or abolishing the hyperandrogenemia (19–21). In these cases, reduction of hyperandrogenemia could have resulted from restoration of the peritoneal pathway of androgen secretion with subsequent portal venous transport to the liver and inactivation there. ª 2003 Elsevier Science Ltd. All rights reserved.
Peritoneal secretion of ovarian hormones and its consequences
847
(4) Ovarian hormones that have entered the peritoneal cavity are absorbed across the parietal and visceral peritoneum and are transported to the systemic and portal venous streams without traversing the ovarian vein, thus leading to underestimation of the ovarian contribution to the production of hormones that are also produced in the adrenals and other sites. Estimates of the ovarian contribution to a hormone’s production are often partly based on determination of hormone levels in ovarian venous blood. Such determinations of production of various hormones by the ovaries have not always been consistent with their production rates in vitro or their follicular fluid concentrations (22,23). Perhaps these discrepancies can be partly accounted for by peritoneal secretion that has bypassed the ovarian vein. (5) Ovarian hormones that have been secreted into the peritoneal cavity are absorbed across the peritoneum of the broad ligaments, enter uterine veins by veno-arterial countercurrent transfer and are returned to the reproductive organs, thus augmenting their hormone concentrations. Because of the intimate anatomical relationship of the ovaries to the broad ligaments, it is likely that the posterior peritoneal surfaces of the broad ligaments are exposed to high concentrations of ovarian hormones, some of which would be absorbed into the interstitial tissue of the broad ligaments and then into their venous plexuses. Numerous studies have demonstrated countercurrent transfer of a wide variety of substances, including ovarian steroids, between veins and arteries in the broad ligaments (24). Substances flowing through the extensive uteroovarian venous plexuses of the broad ligaments, are transferred, in part, to adjacent arteries and are returned to the reproductive organs. Such transfer results in augmented concentrations of these substances in arteries supplying the uterus, tubes and ovaries. Transfer of a hormone from the interstitium to arteries has been demonstrated by investigators who injected radioactively labeled testosterone into muscle of the mesovarium of the sow and then detected a gradually rising level of radioactivity in the ovarian artery (25).
without using tracers by performing simultaneous assays of ovarian hormones in endometrial flushings and blood at various times during the endometrial cycle. Direct evidence bearing on the second, third and fourth hypotheses could be obtained by performing hormonal assays in blood from appropriate vessels during a wide variety of surgical procedures such as hysterectomy, salpingo-oophorectomy, various bowel resections, gastric procedures, portacaval and other portal-systemic shunts. These would be compared to simultaneous assays in mixed systemic venous blood. Since the surgical procedures usually require ligation of the vessels of interest, blood could be obtained with little or no risk to the patient. The second hypothesis (Androgens absorbed across the visceral peritoneum of the bowel enter the hepatic portal venous system and are inactivated in the liver.) and the third hypothesis (Ovarian cortical fibrosis in PCOS inhibits peritoneal secretion of androgens and leads to increased ovarian vein secretion.) could be tested by comparison of androgen levels in blood from mesenteric veins and/or the portal vein with levels in mixed systemic venous blood. Comparison of androgen levels in culdoscopically obtained peritoneal fluid from normal women and those with PCOS could also also provide useful information. Evidence for or against the fourth hypothesis (Production rates of ovarian hormones based on ovarian venous levels have been underestimated because some of the ovarian hormones bypass the ovarian veins by way of the peritoneal cavity.) could be gotten by assays of blood from the portal vein and the inferior vena cava below the influx of ovarian vein blood (below the entrances of the right ovarian vein and the left renal vein, into which the left ovarian vein drains). The fifth hypothesis (Hormones secreted into the peritoneal cavity are absorbed into the interstitial tissue of the broad ligament and are returned to the reproductive organs by means of venoarterial transfer.) could be tested by introduction of radioactively tagged hormones into the peritoneal cavity before hysterectomy followed by assays in venous and arterial blood in vessels within the broad ligament.
TESTING THE HYPOTHESES
COMMENT
The availability of a simple method for flushing the endometrial cavity (26) suggests at least two approaches to the first hypothesis (Significant amounts of hormones flow from the peritoneal cavity into the endometrial cavity.). The most direct method would be to introduce a tagged hormone or other tracer into the peritoneal cavity and then perform assays in endometrial flushings at intervals. One could also obtain useful information
The fundamental concept underlying these hypotheses is that it is very unlikely that ovarian hormones secreted into the peritoneal cavity simply disappear without a trace and have no effects on potential targets. The hypotheses are a first attempt at trying to understand what pathways the hormones might follow as they leave the peritoneal cavity and what the consequences might be. If one or more of the hypotheses are borne out by
ª 2003 Elsevier Science Ltd. All rights reserved.
Medical Hypotheses (2003) 60(6), 845–848
848 Foster
subsequent investigations, another layer of complexity of some aspects of reproductive endocrinology will have been uncovered.
REFERENCES 1. Maathuis J. B., Van Look P. F. A., Michie E. A. Changes in volume, total protein and ovarian steroid concentrations of peritoneal fluid throughout the human menstrual cycle. J Endocr 1978; 76: 123–133. 2. Koninckx P. R., Heyns W., Verhoeven G. et al. Biochemical characterization of peritoneal fluid in women during the menstrual cycle. J Clin Endocrinol Metab 1980; 51: 1239–1244. 3. Donnez J., Langerock S., Thomas K. Peritoneal fluid volume and 17b-estradiol and progesterone concentrations in ovulatory, anovulatory and postmenopausal women. Obstet Gynecol 1982; 59: 687–692. 4. Lesorgen P. R., Wu C. H., Green P. J., Gocial B., Lerner L. J. Peritoneal fluid and serum steroids in infertility patients. Fertil Steril 1984; 42: 237–242. 5. Cormack D. H. In: Ham’s Histology, 3rd ed. Philadelphia: Lippincott, 1987: 633. 6. Press M. F., Nousek-Goebl N., King W. J., Herbst A. L., Greene G. L. Immuno-histochemical assessment of estrogen receptor distribution in the human endometrium throughout the menstrual cycle. Lab Invest 1984; 51: 495–503. 7. Coppens M. T., Dhont M. A., De Boever J. G., Serreyn R. F., Vandekerckhove D. A., Roels H. J. The distribution of estrogen and progesterone receptors in the human endometrial basal and functional layers during the normal menstrual cycle. An immunocytochemical study. Histochemistry 1993; 99: 121–126. 8. Press M. F., Nousek-Goebl N. A., Bur M., Greene G. L. Estrogen localization in the female genital tract. Am J Pathol 1986; 123: 280–292. 9. Gentile G. W., Kaufman S. C., Helbig D. W. Is there any evidence for a post-tubal sterilization syndrome? Fertil Steril 1998; 69: 179–186. 10. Peterson H. B., Jeng G., Folger S. G., Hillis S. A., Marchbanks P. A., Wilcox L. S. The risk of menstrual abnormalities after tubal sterilization. N Engl J Med 2000; 343: 1681–1687. 11. Corson S. L., Levinson C. J., Batzer F. R., Otis C. Hormonal levels following sterilization and hysterectomy. J Reprod Med 1981; 26: 363–370. 12. Alvarez-Sanchez F., Segal S. J., Brache V., Adejuwon C. A., Leon P., Faundes A. Pituitary-ovarian function after tubal ligation. Fertil Steril 1981; 36: 606–609.
Medical Hypotheses (2003) 60(6), 845–848
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