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Steroids in ovarian and peripheral venous blood in a case of ovarian leydig cell tumor
GYNECOLOGIC ONCOLOGY 11, 240--245 (1981)
CASE REPORT
Steroids in Ovarian and Peripheral Venous Blood in a Case of
Ovarian Leydig Cell Tumor TIMO LAATIKAINEN,
M.D., DAN
APTER,
M.D.,
AND TORSTEN WAHLSTRO'M, M . D .
Department I of Obstetrics and Gynecology, University Central Hospital, and Department III of Pathology, University of Helsinki, Helsinki 29, Finland Accepted October 24, 1980 A 52-year-old woman was admitted to the hospital because of hirsutism and virilism which appeared 1 year previously. Pelvic examination did not reveal any ovarian tumor. Endocrinological evaluation showed a highly elevated serum level of testosterone (17.5 nmole/ liter). Urinary 17-ketosteroid excretion was normal. At laparotomy a bilateral centrally located ovarian tumor was found which histologically proved to be a Leydig cell tumor. In addition, there was a separate Brenner tumor in the left ovary. Serum concentrations of testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, pregnenolone, progesterone, 17a-hydroxyprogesterone, and estradiol were measured by a radioimmunoassay in peripheral and ovarian vein blood samples collected at laparotomy and compared to those in a control group of women without any ovarian abnormality. It was found that the Leydig cell tumor secreted large amounts of testosterone but concentrations of the other steroids did not differ significantly from those in the control group.
INTRODUCTION Leydig cell tumors of the ovary are very uncommon [ 1,2]. Most published cases have been associated with masculinization [1,2]. The tumor is often small, and therefore not easily detectable by pelvic examination. In a few cases highly elevated blood testosterone level has been an important sign leading to a suspicion of androgen secreting ovarian tumor [3-5], but data on other blood steroids in these patients is very limited. We have had the opportunity to study serum levels of androgens and a number of other steroids in a case of hirsutism and virilism resulting from bilateral ovarian Leydig cell tumors.
CASE REPORT A 52-year-old parous woman was admitted to the hospital in September 1979 for evaluation of hirsutism. Her menses had ceased 6 months previously. She had
observed increased hair growth on the face, neck, lower abdomen, and legs during 240 0090-8258/81/020240-06501.00/0 Copyright© 1981by AcademicPress, Inc, All rights of reproductionin any formreserved.
OVARIAN T U M O R S - - S T E R O I D CONCENTRATIONS
241
a period of 1 year. Physical examination showed increased hair growth on the upper lip, as well as in the abdominal and inner thigh areas. Pelvic examination revealed the clitoris to be enlarged, the uterus was at least double the normal size containing several swellings suggesting the presence of fibroids. No evidence of the presence of an ovarian tumor could be found. The urinary excretion of 17-ketosteroids was 25 /zmole/24 hr and that of 17hydroxycorticoids 33 /zmole/24 hr, both values being normal. Serum cortisol concentration at 8 AM was 0.47/xmole/liter and at 4 PM was 0.19 p~mole/liter; after the administration of a 1-mg dose of Dexamethasone it fell to 0.07/zmole/liter at 8 o'clock in the following morning which did not indicate any abnormality of the adrenal function. Urinary excretion of dehydroepiandrosterone, 0.7/.tmole/24 hr, was near the upper limit for postmenopausal women (0.6/zmole/24 hr). The serum level of androstenedione, 8.7 nmole/liter, was slightly elevated (normal <8.0), but the serum testosterone concentration was very high, 17.5 nmole/liter (normal <2.8). Because of uterine leiomyomas and the suspicion of androgen-secreting ovarian tumor, a laparotomy was carried out. At laparotomy blood samples were collected simultaneously from a peripheral and the ovarian vein 1-1.5 cm from the hilus. Both ovaries were of normal size and appearance, but sectioning of them revealed centrally located slightly yellow areas of tumor tissue, 0.5 x 1.0 cm in diameter in the left side and 0.5 x 0.5 cm in the right side, under the intact cortex. Several leiomyomas were seen in the uterus. Bilateral salpingo-oophorectomy and hysterectomy were performed. Histopathological examination revealed typical Leydig cell tumors in both ovaries. They consisted of cells with small round nuclei surrounded by a rather ample amount of cytoplasm. The cells did not form any regular configurations but grew as a loose fragile mass containing little connective tissue. No convincing crystalloids of Reinke were seen. In addition, the left ovary contained a Brenner tumor separated from the Leydig cell tumor by a rather thin wall of scarry connective tissue. These features are shown in Fig. 1. Serum concentrations of testosterone, dihydrotestosterone (DHT), androstenedione, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, and 17ct-hydroxyprogesterone were determined using a specific radioimmunoassay with chromatography described in detail previously [6,7]. Serum level of estradiol was determined by radioimmunoassay without chromatography using an antiserum donated by Dr. B. S. Lindberg (Uppsala, Sweden). The control group consisted of seven women aged 27 to 41 years who were operated on because of tubal sterilization or leiomyoma of the uterus and who did not show any evidence of disturbed ovarian function.
RESULTS Table 1 shows serum concentrations of steroids in the peripheral and ovarian vein blood in the patient and the control group. The patient had highly elevated values of testosterone both in the ovarian and peripheral vein blood. In the ovarian veins, concentrations of androstenedione and 17ot-hydroxyprogesterone were also elevated, but the peripheral blood levels did not differ from those of the controls. One week after operation (Table 1) all steroid levels had fallen, and that of testosterone most strikingly.
242
LAATIKAINEN,
APTER,
AND
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OVARIAN
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244
LAATIKAINEN, APTER, AND WAHLSTROM
DISCUSSION There is often a long time interval between the onset of symptoms and the diagnosis in patients with androgen-secreting tumors [8]. Because some of these, e.g., 20% of arrhenoblastomas [8], prove to be malignant, a delay in the diagnosis may be crucial to the fate of the patient. A factor which contributes to the delay in the diagnosis is the small size of many of these tumors, e.g., over 80% of hilar cell tumors have been reported to be less than 6 cm in diameter [1]. Such a small tumor is not easily detected even at laparoscopy because the appearance of the ovary may be normal. Hancock et al. [3] and Judd et al. [4] have reported cases with virilizing ovarian tumors where laparoscopy failed to disclose a small intraovarian tumor. Hilus cell tumors are usually unilateral and benign [ 1,2,11], although two malignant cases have been reported [9,10]. In the present patient a bilateral tumor was found which was histologically benign. A highly elevated blood testosterone concentration in a virilized woman in whom urinary 17-ketosteroid excretion is normal or only slightly elevated has been regarded to suggest the presence of androgen-secreting ovarian tumor. Recently, Meldrum and Abraham [5] came to the conclusion that a testosterone level of over 7 nmole/liter (2 ng/ml) should be considered highly suspicious of such a tumor. A possibility of a testosterone secreting adrenal tumor must be taken into account, although only few such cases have been reported [12-14]. In these particular cases the high blood testosterone level has been found to associate with normal urinary 17-ketosteroid excretion. Generally, patients with a virilizing adrenal tumor show increased excretion of 17-ketosteroids. Measurement of the levels of other androgens and their precursors in addition to testosterone may prove helpful in differentiating the source of increased androgen production. For example, highly elevated plasma concentrations of DHEA and DHEA-sulfate have been found in patients with a virilizing adrenal tumor [15]. In the present patient whose increased androgen production was of ovarian origin, the serum DHEA level was normal (Table 1). The value of adrenal and ovarian stimulation and suppression tests in differentiating ovarian or adrenal etiology in hirsutism is limited [16]. Selective catheterization of ovarian and adrenal veins through the femoral vein has been used for detection of the source of increased androgen secretion [17,18]. The usefulness of this method has, however, been considered questionable [19]~ It is possible that in some virilized women the source of androgens still remains elusive in spite of current endocrinological methods. In these patients exploratory laparotomy should be considered.
REFERENCES l. Dunnihoo, D. R., Grieme, D. L., and Woolf, R. B, Hilar-ceU tumors of the ovary, Obstet. Gynecol. 27, 703-716 (1966). 2. Ireland, K., and Woodruff, J. D. Masculinizing ovarian tumors, Obstet. Gynecol. Surv. 31, 83-111 (1976). 3. Hancock, K. W., Levell, M. J., and Coulson, A. The value of plasma testosterone estimation in the diagnosis of virilizing ovarian neoplasia, Brit. J. Obstet. Gynaecol. "/9, 846-848 (1972). 4. Judd, H. L., Spore, W. W., Talner, L. B., Rigg, L. A., Yen, S. S. C., and Benirschke, K. Preoperative localization of a testosterone-secreting ovarian tumor by retrograde venous catheterization and selective sampling, Amer. J. Obstet. Gynecol. 120, 91-96 (1974).
OVARIAN TUMORS--STEROID CONCENTRATIONS
245
5. Meldrum, D. R., and Abraham, G. E. Peripheral and ovarian venous concentrations of various steroid hormones in virilizing ovarian tumors, Obstet. Gynecol. 53, 36-43 (1979). 6. Apter, D., J/inne, O., Karvonen, P., and Vihko, R. Simultaneous determination of five sex hormones in human serum by radioimmunoassay after chromatography on Lipidex-5000, Clin. Chem. 22, 32-38 (1976). 7. Hammond, G. L., Ruokonen, A., Kontturi, M., Koskela, E., and Vihko, R. The simultaneous radioimmunoassay of seven steroids in human spermatic and peripheral venous blood, J. Clin. Endocrinol. Metab. 45, 16-24 (1976). 8. Novak, E. R., and Long, J. H. Arrhenoblastoma of the ovary. A review of the ovarian tumor registry, Amer. J. Obstet. Gyneeol. 92, 1082-1093 (1965). 9. Stewart, R. S., and Woodard, D. R. Malignant ovarian hilus cell tumor. The first reported case, Arch. Pathol. 73, 91-99 (1962). 10. Echt, C. R., and Hadd, H. E. Androgen excretion patterns in a patient with a metastatic hilus cell tumor of the ovary, Amer. J. Obstet. Gynecol. 100, 1055-1061 (1966). 11. Mori, H. Hilus cell hyperplasia of ovary with virilization, Obstet. Gynecol. 24, 606-608 (1964). 12. Chakmakjian, Z. H., and Abraham, G. E. Peripheral steroid levels in a patient with virilizing adrenal adenoma, Obstet. Gynecol. 46, 544-548 (1975). 13. Larson, B. A., Vanderlaan, W. P., Judd, H. L., and McGullough, D. L. A testosterone producing adrenal cortical adenoma in an elderly woman, J. Clin. Endocrinol. Metab. 42, 882-887 (1976). 14. Kable, W. T., and Yussman, M. A. Testosterone-secreting adrenal adenoma, Fert. Steril. 32, 610-611 (1979). 15. Nogiere, C., Fukushima, D. K., Hellman, L., and Boyar, R. M. Virilizing adrenal cortical carcinoma, Cancer 40, 307-313 (1977). 16. Forbes, A. P. Endocrine function in hirsute women, N. Engl. J. Med. 294, 665-667 (1976). 17. Kirschner, M. A., and Jacobs, J. B. Combined ovarian and adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women, J. Clin. Endocrinol. Metab. 33, 199-209 (1971). 18. Stahl, N. L., Teeslink, V. R., Beauchamps, G., and Greenblatt, R. B. Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values, Obstet. Gynecol. 41, 650-654 (1973). 19. Wentz, A. C., White, R. I., Jr., Migeon, C. J., Hsu, T. H., Barnes, H. V., and Jones, G. S. Differential ovarian and adrenal vein catheterization, Amer. J. Obstet. Gynecol. 125, 100-107 (1976).
CASE REPORT
Steroids in Ovarian and Peripheral Venous Blood in a Case of
Ovarian Leydig Cell Tumor TIMO LAATIKAINEN,
M.D., DAN
APTER,
M.D.,
AND TORSTEN WAHLSTRO'M, M . D .
Department I of Obstetrics and Gynecology, University Central Hospital, and Department III of Pathology, University of Helsinki, Helsinki 29, Finland Accepted October 24, 1980 A 52-year-old woman was admitted to the hospital because of hirsutism and virilism which appeared 1 year previously. Pelvic examination did not reveal any ovarian tumor. Endocrinological evaluation showed a highly elevated serum level of testosterone (17.5 nmole/ liter). Urinary 17-ketosteroid excretion was normal. At laparotomy a bilateral centrally located ovarian tumor was found which histologically proved to be a Leydig cell tumor. In addition, there was a separate Brenner tumor in the left ovary. Serum concentrations of testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, pregnenolone, progesterone, 17a-hydroxyprogesterone, and estradiol were measured by a radioimmunoassay in peripheral and ovarian vein blood samples collected at laparotomy and compared to those in a control group of women without any ovarian abnormality. It was found that the Leydig cell tumor secreted large amounts of testosterone but concentrations of the other steroids did not differ significantly from those in the control group.
INTRODUCTION Leydig cell tumors of the ovary are very uncommon [ 1,2]. Most published cases have been associated with masculinization [1,2]. The tumor is often small, and therefore not easily detectable by pelvic examination. In a few cases highly elevated blood testosterone level has been an important sign leading to a suspicion of androgen secreting ovarian tumor [3-5], but data on other blood steroids in these patients is very limited. We have had the opportunity to study serum levels of androgens and a number of other steroids in a case of hirsutism and virilism resulting from bilateral ovarian Leydig cell tumors.
CASE REPORT A 52-year-old parous woman was admitted to the hospital in September 1979 for evaluation of hirsutism. Her menses had ceased 6 months previously. She had
observed increased hair growth on the face, neck, lower abdomen, and legs during 240 0090-8258/81/020240-06501.00/0 Copyright© 1981by AcademicPress, Inc, All rights of reproductionin any formreserved.
OVARIAN T U M O R S - - S T E R O I D CONCENTRATIONS
241
a period of 1 year. Physical examination showed increased hair growth on the upper lip, as well as in the abdominal and inner thigh areas. Pelvic examination revealed the clitoris to be enlarged, the uterus was at least double the normal size containing several swellings suggesting the presence of fibroids. No evidence of the presence of an ovarian tumor could be found. The urinary excretion of 17-ketosteroids was 25 /zmole/24 hr and that of 17hydroxycorticoids 33 /zmole/24 hr, both values being normal. Serum cortisol concentration at 8 AM was 0.47/xmole/liter and at 4 PM was 0.19 p~mole/liter; after the administration of a 1-mg dose of Dexamethasone it fell to 0.07/zmole/liter at 8 o'clock in the following morning which did not indicate any abnormality of the adrenal function. Urinary excretion of dehydroepiandrosterone, 0.7/.tmole/24 hr, was near the upper limit for postmenopausal women (0.6/zmole/24 hr). The serum level of androstenedione, 8.7 nmole/liter, was slightly elevated (normal <8.0), but the serum testosterone concentration was very high, 17.5 nmole/liter (normal <2.8). Because of uterine leiomyomas and the suspicion of androgen-secreting ovarian tumor, a laparotomy was carried out. At laparotomy blood samples were collected simultaneously from a peripheral and the ovarian vein 1-1.5 cm from the hilus. Both ovaries were of normal size and appearance, but sectioning of them revealed centrally located slightly yellow areas of tumor tissue, 0.5 x 1.0 cm in diameter in the left side and 0.5 x 0.5 cm in the right side, under the intact cortex. Several leiomyomas were seen in the uterus. Bilateral salpingo-oophorectomy and hysterectomy were performed. Histopathological examination revealed typical Leydig cell tumors in both ovaries. They consisted of cells with small round nuclei surrounded by a rather ample amount of cytoplasm. The cells did not form any regular configurations but grew as a loose fragile mass containing little connective tissue. No convincing crystalloids of Reinke were seen. In addition, the left ovary contained a Brenner tumor separated from the Leydig cell tumor by a rather thin wall of scarry connective tissue. These features are shown in Fig. 1. Serum concentrations of testosterone, dihydrotestosterone (DHT), androstenedione, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, and 17ct-hydroxyprogesterone were determined using a specific radioimmunoassay with chromatography described in detail previously [6,7]. Serum level of estradiol was determined by radioimmunoassay without chromatography using an antiserum donated by Dr. B. S. Lindberg (Uppsala, Sweden). The control group consisted of seven women aged 27 to 41 years who were operated on because of tubal sterilization or leiomyoma of the uterus and who did not show any evidence of disturbed ovarian function.
RESULTS Table 1 shows serum concentrations of steroids in the peripheral and ovarian vein blood in the patient and the control group. The patient had highly elevated values of testosterone both in the ovarian and peripheral vein blood. In the ovarian veins, concentrations of androstenedione and 17ot-hydroxyprogesterone were also elevated, but the peripheral blood levels did not differ from those of the controls. One week after operation (Table 1) all steroid levels had fallen, and that of testosterone most strikingly.
242
LAATIKAINEN,
APTER,
AND
WAHLSTROM
eu)
.=. t~ ~D [-,4
¢9
,.d '-'
O
~E
,--, e-,
>.. e.~
~',j=
e~
OVARIAN
TUMORS--STEROID
CONCENTRATIONS
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Z <
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243
244
LAATIKAINEN, APTER, AND WAHLSTROM
DISCUSSION There is often a long time interval between the onset of symptoms and the diagnosis in patients with androgen-secreting tumors [8]. Because some of these, e.g., 20% of arrhenoblastomas [8], prove to be malignant, a delay in the diagnosis may be crucial to the fate of the patient. A factor which contributes to the delay in the diagnosis is the small size of many of these tumors, e.g., over 80% of hilar cell tumors have been reported to be less than 6 cm in diameter [1]. Such a small tumor is not easily detected even at laparoscopy because the appearance of the ovary may be normal. Hancock et al. [3] and Judd et al. [4] have reported cases with virilizing ovarian tumors where laparoscopy failed to disclose a small intraovarian tumor. Hilus cell tumors are usually unilateral and benign [ 1,2,11], although two malignant cases have been reported [9,10]. In the present patient a bilateral tumor was found which was histologically benign. A highly elevated blood testosterone concentration in a virilized woman in whom urinary 17-ketosteroid excretion is normal or only slightly elevated has been regarded to suggest the presence of androgen-secreting ovarian tumor. Recently, Meldrum and Abraham [5] came to the conclusion that a testosterone level of over 7 nmole/liter (2 ng/ml) should be considered highly suspicious of such a tumor. A possibility of a testosterone secreting adrenal tumor must be taken into account, although only few such cases have been reported [12-14]. In these particular cases the high blood testosterone level has been found to associate with normal urinary 17-ketosteroid excretion. Generally, patients with a virilizing adrenal tumor show increased excretion of 17-ketosteroids. Measurement of the levels of other androgens and their precursors in addition to testosterone may prove helpful in differentiating the source of increased androgen production. For example, highly elevated plasma concentrations of DHEA and DHEA-sulfate have been found in patients with a virilizing adrenal tumor [15]. In the present patient whose increased androgen production was of ovarian origin, the serum DHEA level was normal (Table 1). The value of adrenal and ovarian stimulation and suppression tests in differentiating ovarian or adrenal etiology in hirsutism is limited [16]. Selective catheterization of ovarian and adrenal veins through the femoral vein has been used for detection of the source of increased androgen secretion [17,18]. The usefulness of this method has, however, been considered questionable [19]~ It is possible that in some virilized women the source of androgens still remains elusive in spite of current endocrinological methods. In these patients exploratory laparotomy should be considered.
REFERENCES l. Dunnihoo, D. R., Grieme, D. L., and Woolf, R. B, Hilar-ceU tumors of the ovary, Obstet. Gynecol. 27, 703-716 (1966). 2. Ireland, K., and Woodruff, J. D. Masculinizing ovarian tumors, Obstet. Gynecol. Surv. 31, 83-111 (1976). 3. Hancock, K. W., Levell, M. J., and Coulson, A. The value of plasma testosterone estimation in the diagnosis of virilizing ovarian neoplasia, Brit. J. Obstet. Gynaecol. "/9, 846-848 (1972). 4. Judd, H. L., Spore, W. W., Talner, L. B., Rigg, L. A., Yen, S. S. C., and Benirschke, K. Preoperative localization of a testosterone-secreting ovarian tumor by retrograde venous catheterization and selective sampling, Amer. J. Obstet. Gynecol. 120, 91-96 (1974).
OVARIAN TUMORS--STEROID CONCENTRATIONS
245
5. Meldrum, D. R., and Abraham, G. E. Peripheral and ovarian venous concentrations of various steroid hormones in virilizing ovarian tumors, Obstet. Gynecol. 53, 36-43 (1979). 6. Apter, D., J/inne, O., Karvonen, P., and Vihko, R. Simultaneous determination of five sex hormones in human serum by radioimmunoassay after chromatography on Lipidex-5000, Clin. Chem. 22, 32-38 (1976). 7. Hammond, G. L., Ruokonen, A., Kontturi, M., Koskela, E., and Vihko, R. The simultaneous radioimmunoassay of seven steroids in human spermatic and peripheral venous blood, J. Clin. Endocrinol. Metab. 45, 16-24 (1976). 8. Novak, E. R., and Long, J. H. Arrhenoblastoma of the ovary. A review of the ovarian tumor registry, Amer. J. Obstet. Gyneeol. 92, 1082-1093 (1965). 9. Stewart, R. S., and Woodard, D. R. Malignant ovarian hilus cell tumor. The first reported case, Arch. Pathol. 73, 91-99 (1962). 10. Echt, C. R., and Hadd, H. E. Androgen excretion patterns in a patient with a metastatic hilus cell tumor of the ovary, Amer. J. Obstet. Gynecol. 100, 1055-1061 (1966). 11. Mori, H. Hilus cell hyperplasia of ovary with virilization, Obstet. Gynecol. 24, 606-608 (1964). 12. Chakmakjian, Z. H., and Abraham, G. E. Peripheral steroid levels in a patient with virilizing adrenal adenoma, Obstet. Gynecol. 46, 544-548 (1975). 13. Larson, B. A., Vanderlaan, W. P., Judd, H. L., and McGullough, D. L. A testosterone producing adrenal cortical adenoma in an elderly woman, J. Clin. Endocrinol. Metab. 42, 882-887 (1976). 14. Kable, W. T., and Yussman, M. A. Testosterone-secreting adrenal adenoma, Fert. Steril. 32, 610-611 (1979). 15. Nogiere, C., Fukushima, D. K., Hellman, L., and Boyar, R. M. Virilizing adrenal cortical carcinoma, Cancer 40, 307-313 (1977). 16. Forbes, A. P. Endocrine function in hirsute women, N. Engl. J. Med. 294, 665-667 (1976). 17. Kirschner, M. A., and Jacobs, J. B. Combined ovarian and adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women, J. Clin. Endocrinol. Metab. 33, 199-209 (1971). 18. Stahl, N. L., Teeslink, V. R., Beauchamps, G., and Greenblatt, R. B. Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values, Obstet. Gynecol. 41, 650-654 (1973). 19. Wentz, A. C., White, R. I., Jr., Migeon, C. J., Hsu, T. H., Barnes, H. V., and Jones, G. S. Differential ovarian and adrenal vein catheterization, Amer. J. Obstet. Gynecol. 125, 100-107 (1976).