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The Chiari-Frommel syndrome
The Chiari-Frommel syndrome C. H. LIPPARD. M.D. Lynchburg, Virginia
A s Y N D R o M E consisting of amenorrhea, persistent lactation, and uterine-ovarian atrophy in otherwise normal postpartum women was first described by Chiari in 1855. 7 He described 2 such patients and expressed the opinion that the condition was due to the poor nutrition and general health of the patients. Fromme!, in 1882, reported a similar case. 16 Since these original descriptions further reports have raised the total of known cases of this syndrome to 18.1-3, 8 • 0 • 17 • 22 • 23 • 28 Four patients have been reported to have stopped lactating or to have resumed menstruation. 1 • 3 • 22 • 23 Of these, 2 were reported to have become pregnant again.a· 23 The shortest duration of the syndrome reported with subsequent resumption of menstruation was 18 months but lactation persisted. 22 The longest duration with recovery was 8 years, with resumption of menstruation and no further lactation. 3 Long-term follow-ups are sparse and no autopsy reports are available. A case has recently been studied which fits this syndrome, and the patient subsequently became pregnant and was delivered.
and her breasts subsided promptly. She was delivered of her second child in September, 1956. She breastfed this infant for 3 weeks, then changed to bottle feeding because of a sore breast. Profuse galactorrhea persisted in spite of attempts to terminate lactation by full estrogen and androgen therapy. Amenorrhea also persisted. There was no headache, visual impairment, or hirsutism. The patient noted periods of marked depression. Physical examination showed the uterus to be smaller than normal and the breasts to be engorged with milk. Axillary and pubic hair were normal in amount, and pubic hair was feminine in distribution. The external genitals did not show atrophy, and the clitoris was normal in size. Studies done at the University of Virginia Hospital in February, 1959, were as follows: Visual field determinations were normal. The pituitary sella appeared normal. Results of endocrine studies were considered normal except for a slightly elevated 17-hydroxycorticosteroid excretion of 19.4 and 19.1 mg. per 24 hours. The plasma 17-hydroxycorticosteroid level was 13.8 mg. per 100 c.c. with a rise to 52.3 mg. per 100 c.c. 4 hours later in response to 25 units of ACTH given intravenously. Urinary 17-ketosteroid excretion ·was 11.7 and 8.6 mg. per 24 hours. Pituitary gonadotropin excretion was positive for 6.6 M.U., negative for 100 M.U. Protein-bound iodine level was 5.4 p.g per 100 c.c. Fasting blood sugar level was 92 mg. per !(JO c.c.; 2 hours after glucose administration it was 95 mg. per 100 c.c. The hemogram findings were normal except for 9 per cent eosinophils. An endometrial biopsy showed only ciliated columnar epithelium, presumably endocervical in origin. Routine urinalysis, urea, stool, serology, and chest films were normal. No treatment was instituted at that time. One month later, in March, 1959, she had the first vaginal bleeding since the birth of her child 20z
Case report
Mrs. J. D., a 31-year-old white woman, was first seen in January, 1959, complaining of amenorrhea and galactorrhea since the birth of her second child 2 years and 4 months before. She had an abortion at 3 months' gestation in 1953, and was delivered of her first child in March, 1955. She did not breast feed the infant From the Virginia Baptist Hospital. Presented at the Twenty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, Feb. 15-18, 1961.
724
Volume 82 :>lumber -l
years before, and had scant bleeding of 3 or 4 days' duration at monthly intervals until July, 1959. The galactorrhea lessened although milk was still expressible from both nipples. When seen in October, 1959, she was found to be approximately 2 months pregnant. Galactorrhea persisted during the pregnancy though less than just prior to pregnancy. The last 2 weeks of pregnancy were marked by albuminuria and hypertension, and labor was induced. A 4 pound, 3 ounce female infant was delivered under continuous caudal anesthesia in May, 1960. The infant was not breastfed. Stilbestrol was given to the patient for 2 weeks postpartum but galactorrhea persists, more than during the pregnancy but less than at a comparable time following delivery of the second child. She n'mains amenorrheic to date, now 9 months post partum. Comment
A consideration of abnormal lactation cannot be pursued with exactness because the mechanism of initiation and maintenance of normal lactation is not completely understood. One of the major difficulties is the absence of accurate and readily reproducible methods for the assay of prolactin in the human. There is no doubt that the pituitary is essential to lactogenesis. When the lactating rat is hypophysectomized, no milk can be obtained 16 hours later by suckling rat pups. 6 It is further established that the anterior pituitary gland secretes a hormone with lactogenic properties/ 9 • 21 • :: 7 prolactin, which is produced by the eosinophilic cells. 26 In the rat, these cells are increased by 3 days post partum almost 100 per cent over the number present in pregnant anirnals.H This increase appears to be due to conversion of chromophobe cells. The basophilic cells are not increased during lactation. The mechanism of initiation of lactation is not entirely clear. Folley postulates that low levels of estrogen activate lactogenic function v;hereas higher levels inhibit it. 5 He suggests that progesterone, in the levels found in pregnancy, inhibits the lactogenic stimulus of estrogen, and the fall in the ratio of progesterone to estrogen at delivery releases this inhibition and the positive lactogenic effect of estrogen asserts itself.
Chiari-Frommel syndrome
725
Recent evidence suggests that the hypothalamus may exert an inhibitory influence on the secretion of prolactin. Eckles and associates reported long-continuing lactation in women treated for breast carcinoma by pituitary stalk section with insertion of polyethylene plates between the cut ends. 13 The Chiari-Frommel syndrome is presumed to result from either an increase in prolactin secretion or a disruption of an inhibitory factor which would normally prevent the eosinophilic cells from producing large amounts of prolactin. Until a reliable assay method for prolactin in the human is available, such considerations must remain highly theoretical. Some believe that prolactin and luteotropin are identical and report assays for prolactin on this basis, but this is questioned by others. 12 A similar syndrome with amenorrhea and galactorrhea has recently been described by Argonz and del Castillo, 2 and Forbes and associatesY This syndrome differs from that of Chiari-Frommel in several respects. These cases were unrelated to pregnancy. They demonstrated a lower than normal folliclestimulating hormone excretion in almost all of their cases, whereas this finding has not been consistent in the Chiari-Frommel syndrome. Of particular interest was the finding of evidence of pituitary tumor in many of these patients. Forbes reported 15 such cases, 8 of which had evidence of tumor, and in the 3 of these operated upon, a chromophobe adenoma was found. Forbes believes that all these cases, with or without tumor, have an overproduction of prolactin, so the fundamental mechanism of this syndrome and that of Chiari-Frommel may be the same. Lactation also occurs in acromegaly,11 in which condition there is known to be an overproduction of hormone by the eosinophilic cells. The one distinguishing feature of the
Chiari-Frommel syndrome is that it occurs only immediately following a pregnancy. When the syndrome appears at this time, but in addition shows evidence of a pituitary tumor, it becomes indeed confusing as to how the case should be classified. Two such
726
Lippard
October, 1!!61
.\m. JObst. & Gynec.
cases'• 17 have been reported. In the interest of clearer classification, it would seem preferable to classify such cases with those of Forbes and restrict the Chiari-Frommel syndrome classification to cases of postpartum amenorrhea, lactation, and uterine atrophy in which a pituitary tumor or other cause of abnormal lactation has been ruled out. It must be remembered as well that lactation has been reported in a variety of other conditions; following thoracoplasty and pneumonectomy, presumably due to stimulation of the same nerve fibers in the chest wall as mediate the suckling stimulus to lactation 25 ; following encephalitis10 and pneumoencephalography/ presumably on the basis of damage to the hypophysis or hypothalamus. It has also been reported following hysterectomy 24 and partial ovarian resection.18 Chlorpromazine 5 and reserpine 20 have been reported to induce lactation, believed to be due to their action on the hypothalamus. Summary
1. A case is reported which fits the ChiariFrommel syndrome. 2. This is the nineteenth case reported of this syndrome, and the third in which a subsequent pregnancy has ensued. 3. Endocrinological considerations pertinent to this and other causes of abnormal lactation have been discussed. 4. This syndrome designation should be restricted to situations immediately following pregnancy in which no evidence of pituitary tumor or other cause of abnormal lactation is found. I wish to thank Dr. William Parson of the Department of Internal Medicine, University of Virginia Hospital, Charlottesville, Virginia, for his kind assistance in working up this case and preparing this report.
REFERENCES
I. Aguilar, R. F.: Am. Pract. & Digest. Treat.
11: 509, 1960.
2. Argonz, J. and del Castillo, E. B.: ]. Clin. Endocrinol. 13: 79, 1953. 3. Ashkar, P. A.: J. Obst. & Gynaec. Brit. Emp. 57: 78, 1950. 4. Bellut, H.: Quoted by Sachs.24 5. Benson, G. H., Cowie, A. T., Folley, S. ]., and Tindall, J. S.: In Lloyd, C. W., editor: Recent Progress in the Endocrinology of Reproduction. New York, 1959, Academic Press, Inc., p. 457. 6. Bradley, T. R., and Cowie, A. T.: J. Endoerinol. 14: 8, 1956. 7. Chiari, J.: Quoted by Mendel.22 8. Christiansen, E. G.: Acta endocrinol. 24: 407, 1957. 9. Cohen, A.: Australas. Ann. Med. 8: 77, 1959. 10. Dadey, J. L., and Hurxthal, L. M.: Lahey Clin. Bull. 10: 166, 1957. ll. Davidoff, L. M.: Endocrinology 10: 461, 1926. 12. Eastman, N. ]., Jones, H. W., Jr., and Jones, G. S.: Obst. & Gynec. Surv. 12: 894, 1957. 13. Eckles, N. E., Ehni, G., and Kirschbaum, A.: Anat. Rec. 130: 295, 1958. 14. Everett, N. B., and Baker, B. L.: Endocrinology 37: 83, 1945. 15. Forbes, A. P., Henneman, P. H., Griswold, G. C., and Albright, F.: J. Clin. Endocrinol. 14: 265, 1954. 16. Fromme!, R.: Quoted by Mendel.22 17. Greenblatt, R. B., Carmona, N., and Hagler, W. S.: Obst. & Gynec. 7: 165, 1956. 18. Langeron, L., and Barbary, A.: Quoted by Sachs. 24 19. Lyons, W. R.: Proc. Soc. Exper. Bioi. & Med. 51: 308, 1942. 20. Meites, J.: Proc. Soc. Exper. Bioi. & Med. 96: 728, 1957. 21. Meites, J., and Turner, C. W.: Am. J. Physiol. 150: 394, 1947. 22. Mendel, E. B.: AM. J. 0BsT. & GYNEC. 51: 889, 1946. 23. Potter, J. C.: AM. J. OBsT. & GYNEC. 47: 276, 1944. 24. Sachs, H. B.: AM. J. OssT. & GYNEC. 78: 204, 1959. 25. Salkin, D., and Davis, E. W.: ]. Thoracic Surg. 18: 580, 1949. 26. Schooley, J. P., and Riddle, 0.: Am. J. Anat. 62: 313, 1938. 27. Schooley, J. P., Riddle, 0., and Bates, R. W.: Proc. Soc. Exper. Bioi. & Med. 36: 408, 1937. 28. Sharp, E. A.: AM. J. OssT, & GYNEC. 30: 4-11, 1935.
A s Y N D R o M E consisting of amenorrhea, persistent lactation, and uterine-ovarian atrophy in otherwise normal postpartum women was first described by Chiari in 1855. 7 He described 2 such patients and expressed the opinion that the condition was due to the poor nutrition and general health of the patients. Fromme!, in 1882, reported a similar case. 16 Since these original descriptions further reports have raised the total of known cases of this syndrome to 18.1-3, 8 • 0 • 17 • 22 • 23 • 28 Four patients have been reported to have stopped lactating or to have resumed menstruation. 1 • 3 • 22 • 23 Of these, 2 were reported to have become pregnant again.a· 23 The shortest duration of the syndrome reported with subsequent resumption of menstruation was 18 months but lactation persisted. 22 The longest duration with recovery was 8 years, with resumption of menstruation and no further lactation. 3 Long-term follow-ups are sparse and no autopsy reports are available. A case has recently been studied which fits this syndrome, and the patient subsequently became pregnant and was delivered.
and her breasts subsided promptly. She was delivered of her second child in September, 1956. She breastfed this infant for 3 weeks, then changed to bottle feeding because of a sore breast. Profuse galactorrhea persisted in spite of attempts to terminate lactation by full estrogen and androgen therapy. Amenorrhea also persisted. There was no headache, visual impairment, or hirsutism. The patient noted periods of marked depression. Physical examination showed the uterus to be smaller than normal and the breasts to be engorged with milk. Axillary and pubic hair were normal in amount, and pubic hair was feminine in distribution. The external genitals did not show atrophy, and the clitoris was normal in size. Studies done at the University of Virginia Hospital in February, 1959, were as follows: Visual field determinations were normal. The pituitary sella appeared normal. Results of endocrine studies were considered normal except for a slightly elevated 17-hydroxycorticosteroid excretion of 19.4 and 19.1 mg. per 24 hours. The plasma 17-hydroxycorticosteroid level was 13.8 mg. per 100 c.c. with a rise to 52.3 mg. per 100 c.c. 4 hours later in response to 25 units of ACTH given intravenously. Urinary 17-ketosteroid excretion ·was 11.7 and 8.6 mg. per 24 hours. Pituitary gonadotropin excretion was positive for 6.6 M.U., negative for 100 M.U. Protein-bound iodine level was 5.4 p.g per 100 c.c. Fasting blood sugar level was 92 mg. per !(JO c.c.; 2 hours after glucose administration it was 95 mg. per 100 c.c. The hemogram findings were normal except for 9 per cent eosinophils. An endometrial biopsy showed only ciliated columnar epithelium, presumably endocervical in origin. Routine urinalysis, urea, stool, serology, and chest films were normal. No treatment was instituted at that time. One month later, in March, 1959, she had the first vaginal bleeding since the birth of her child 20z
Case report
Mrs. J. D., a 31-year-old white woman, was first seen in January, 1959, complaining of amenorrhea and galactorrhea since the birth of her second child 2 years and 4 months before. She had an abortion at 3 months' gestation in 1953, and was delivered of her first child in March, 1955. She did not breast feed the infant From the Virginia Baptist Hospital. Presented at the Twenty-third Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Atlanta, Georgia, Feb. 15-18, 1961.
724
Volume 82 :>lumber -l
years before, and had scant bleeding of 3 or 4 days' duration at monthly intervals until July, 1959. The galactorrhea lessened although milk was still expressible from both nipples. When seen in October, 1959, she was found to be approximately 2 months pregnant. Galactorrhea persisted during the pregnancy though less than just prior to pregnancy. The last 2 weeks of pregnancy were marked by albuminuria and hypertension, and labor was induced. A 4 pound, 3 ounce female infant was delivered under continuous caudal anesthesia in May, 1960. The infant was not breastfed. Stilbestrol was given to the patient for 2 weeks postpartum but galactorrhea persists, more than during the pregnancy but less than at a comparable time following delivery of the second child. She n'mains amenorrheic to date, now 9 months post partum. Comment
A consideration of abnormal lactation cannot be pursued with exactness because the mechanism of initiation and maintenance of normal lactation is not completely understood. One of the major difficulties is the absence of accurate and readily reproducible methods for the assay of prolactin in the human. There is no doubt that the pituitary is essential to lactogenesis. When the lactating rat is hypophysectomized, no milk can be obtained 16 hours later by suckling rat pups. 6 It is further established that the anterior pituitary gland secretes a hormone with lactogenic properties/ 9 • 21 • :: 7 prolactin, which is produced by the eosinophilic cells. 26 In the rat, these cells are increased by 3 days post partum almost 100 per cent over the number present in pregnant anirnals.H This increase appears to be due to conversion of chromophobe cells. The basophilic cells are not increased during lactation. The mechanism of initiation of lactation is not entirely clear. Folley postulates that low levels of estrogen activate lactogenic function v;hereas higher levels inhibit it. 5 He suggests that progesterone, in the levels found in pregnancy, inhibits the lactogenic stimulus of estrogen, and the fall in the ratio of progesterone to estrogen at delivery releases this inhibition and the positive lactogenic effect of estrogen asserts itself.
Chiari-Frommel syndrome
725
Recent evidence suggests that the hypothalamus may exert an inhibitory influence on the secretion of prolactin. Eckles and associates reported long-continuing lactation in women treated for breast carcinoma by pituitary stalk section with insertion of polyethylene plates between the cut ends. 13 The Chiari-Frommel syndrome is presumed to result from either an increase in prolactin secretion or a disruption of an inhibitory factor which would normally prevent the eosinophilic cells from producing large amounts of prolactin. Until a reliable assay method for prolactin in the human is available, such considerations must remain highly theoretical. Some believe that prolactin and luteotropin are identical and report assays for prolactin on this basis, but this is questioned by others. 12 A similar syndrome with amenorrhea and galactorrhea has recently been described by Argonz and del Castillo, 2 and Forbes and associatesY This syndrome differs from that of Chiari-Frommel in several respects. These cases were unrelated to pregnancy. They demonstrated a lower than normal folliclestimulating hormone excretion in almost all of their cases, whereas this finding has not been consistent in the Chiari-Frommel syndrome. Of particular interest was the finding of evidence of pituitary tumor in many of these patients. Forbes reported 15 such cases, 8 of which had evidence of tumor, and in the 3 of these operated upon, a chromophobe adenoma was found. Forbes believes that all these cases, with or without tumor, have an overproduction of prolactin, so the fundamental mechanism of this syndrome and that of Chiari-Frommel may be the same. Lactation also occurs in acromegaly,11 in which condition there is known to be an overproduction of hormone by the eosinophilic cells. The one distinguishing feature of the
Chiari-Frommel syndrome is that it occurs only immediately following a pregnancy. When the syndrome appears at this time, but in addition shows evidence of a pituitary tumor, it becomes indeed confusing as to how the case should be classified. Two such
726
Lippard
October, 1!!61
.\m. JObst. & Gynec.
cases'• 17 have been reported. In the interest of clearer classification, it would seem preferable to classify such cases with those of Forbes and restrict the Chiari-Frommel syndrome classification to cases of postpartum amenorrhea, lactation, and uterine atrophy in which a pituitary tumor or other cause of abnormal lactation has been ruled out. It must be remembered as well that lactation has been reported in a variety of other conditions; following thoracoplasty and pneumonectomy, presumably due to stimulation of the same nerve fibers in the chest wall as mediate the suckling stimulus to lactation 25 ; following encephalitis10 and pneumoencephalography/ presumably on the basis of damage to the hypophysis or hypothalamus. It has also been reported following hysterectomy 24 and partial ovarian resection.18 Chlorpromazine 5 and reserpine 20 have been reported to induce lactation, believed to be due to their action on the hypothalamus. Summary
1. A case is reported which fits the ChiariFrommel syndrome. 2. This is the nineteenth case reported of this syndrome, and the third in which a subsequent pregnancy has ensued. 3. Endocrinological considerations pertinent to this and other causes of abnormal lactation have been discussed. 4. This syndrome designation should be restricted to situations immediately following pregnancy in which no evidence of pituitary tumor or other cause of abnormal lactation is found. I wish to thank Dr. William Parson of the Department of Internal Medicine, University of Virginia Hospital, Charlottesville, Virginia, for his kind assistance in working up this case and preparing this report.
REFERENCES
I. Aguilar, R. F.: Am. Pract. & Digest. Treat.
11: 509, 1960.
2. Argonz, J. and del Castillo, E. B.: ]. Clin. Endocrinol. 13: 79, 1953. 3. Ashkar, P. A.: J. Obst. & Gynaec. Brit. Emp. 57: 78, 1950. 4. Bellut, H.: Quoted by Sachs.24 5. Benson, G. H., Cowie, A. T., Folley, S. ]., and Tindall, J. S.: In Lloyd, C. W., editor: Recent Progress in the Endocrinology of Reproduction. New York, 1959, Academic Press, Inc., p. 457. 6. Bradley, T. R., and Cowie, A. T.: J. Endoerinol. 14: 8, 1956. 7. Chiari, J.: Quoted by Mendel.22 8. Christiansen, E. G.: Acta endocrinol. 24: 407, 1957. 9. Cohen, A.: Australas. Ann. Med. 8: 77, 1959. 10. Dadey, J. L., and Hurxthal, L. M.: Lahey Clin. Bull. 10: 166, 1957. ll. Davidoff, L. M.: Endocrinology 10: 461, 1926. 12. Eastman, N. ]., Jones, H. W., Jr., and Jones, G. S.: Obst. & Gynec. Surv. 12: 894, 1957. 13. Eckles, N. E., Ehni, G., and Kirschbaum, A.: Anat. Rec. 130: 295, 1958. 14. Everett, N. B., and Baker, B. L.: Endocrinology 37: 83, 1945. 15. Forbes, A. P., Henneman, P. H., Griswold, G. C., and Albright, F.: J. Clin. Endocrinol. 14: 265, 1954. 16. Fromme!, R.: Quoted by Mendel.22 17. Greenblatt, R. B., Carmona, N., and Hagler, W. S.: Obst. & Gynec. 7: 165, 1956. 18. Langeron, L., and Barbary, A.: Quoted by Sachs. 24 19. Lyons, W. R.: Proc. Soc. Exper. Bioi. & Med. 51: 308, 1942. 20. Meites, J.: Proc. Soc. Exper. Bioi. & Med. 96: 728, 1957. 21. Meites, J., and Turner, C. W.: Am. J. Physiol. 150: 394, 1947. 22. Mendel, E. B.: AM. J. 0BsT. & GYNEC. 51: 889, 1946. 23. Potter, J. C.: AM. J. OBsT. & GYNEC. 47: 276, 1944. 24. Sachs, H. B.: AM. J. OssT. & GYNEC. 78: 204, 1959. 25. Salkin, D., and Davis, E. W.: ]. Thoracic Surg. 18: 580, 1949. 26. Schooley, J. P., and Riddle, 0.: Am. J. Anat. 62: 313, 1938. 27. Schooley, J. P., Riddle, 0., and Bates, R. W.: Proc. Soc. Exper. Bioi. & Med. 36: 408, 1937. 28. Sharp, E. A.: AM. J. OssT, & GYNEC. 30: 4-11, 1935.