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The link between norethynodrel and thromboembolism
The link between norethynodrel and thromboembolism MAX New
ROSENBERG, Orleans,
M.D.
Louisiana
day which was gradually increased to 15 mg. per day to control breakthrough bleeding. Approximately 3 months after beginning the medication the patient complained of chest pain and hemoptysis. The medication was discontinued. Five days later the patient developed increasingly severe chest pain with dyspnea and hemoptysis. She was admitted to Touro Infirmary with the diagnosis of pulmonary embolism. The patient’s history did not reveal any antecedent trauma or other possible cause of the thromboembolism. She received anticoagulants for 10 weeks including inpatient and outpatient therapy. Ten weeks after her hospital admission the diagnosis of an early uterine pregnancy was made.
A D E F I N IT E relationship between norethynodrel and thromboembolism has neither been proved nor disproved. Reports associating the two continue to be published. The following case reports are presented which seem to indicate that a relationship does exist. Case reports Case 1. M. F., a 20-year-old nulligravida, was seen as a sterility problem. She gave no history of previous pelvic pathology or other illness. She was placed on norethynodrel (with mestranol) 5 mg. per day and continued the medication for 3 months. Five days after discontinuing the medication she experienced sharp pleuritic pain and dyspnea. A chest plate was obtained and read as possible pneumonitis. Five days later the patient experienced more chest pain, dyspnea, and hemoptysis. She was admitted to Touro Infirmary with the diagnosis of pulmonary embolism. There was no history of trauma or other factor that might be associated with thromboembolism. She was treated with anticoagulants for 2 weeks in the hospital and 12 weeks as an outpatient. Approximately 9 weeks after discontinuing the anticoagulants, the diagnosis of an early uterine pregnancy was made. Case 2. H. B., a 28-year-old gravida i, para i (7 years previously), was placed on norethynodrel (with mestranol) because of involuntary barrenness after more than one year, some menstrual irregularity, and the possibility of endometriosis. She began with a dosage of 5 mg. per
Comment The occurrence of 2 cases of pulmonary embolism following the use of norethynodrel was startling since both cases occurred within a period of 4 months in healthy young women. Norethynodrel has been shown to be a very potent estrogenic substance since it is converted to estrogen, has biologic estrogenic effects, and acts syngeristically with other estrogens such as mestrano1.l It is this estrogenie quality of norethynodrel which may be responsible for its possible link to thromboembolism. Estrogens have been found to exert a profound effect on the metabolism of the adrenal cortical hormones; indeed, an estrogen effect has been defined. This effect results in a raised plasma level of hydrocortisone and an increased plasma binding of the hormone.2 The mean-level of unbound biologically active hydrocortisone is also elevated
From the Department of Obstetrics and Gynecology of Touro Infirmary nnd Louisiana State University School of Medicine.
745
746
Rosenberg
in estrogen treated individuals3 Not oniy is the hydrocortisone level elevated in individuals given estrogen, but there is marked potentiation of the biologic effects of hydrocortisone when it is administered to estrogentreated individuals.* At this point it should be noted that Layne and co-workers” demo,nstrated that norethynodrel also exerts an estrogenic effect upon hydrocortisone metabolism. This study is consistent with the findings of Metcalf and ReavenG who found that administration of other proges,tin-estrogen preparations resulted in highly significant increases in plasma corticosteroids. If we can assume that administration of a progestin-estrogen preparation such as norethynodrel produces an increased plasma hydrocortisone then the increased hydrocortisone may be the link between norethynodrel and thromboembolism. The reason for this statement is that elevating the level of adrenal cortical hormone by giving ACTH or a corticosteroid can produce thromboembolism through certain vascular effects OI by altering the actual clotting mechanism or both. Many reports have cited the effect of
adrenal cortical hormone in the production of nonspecific vasculitis.‘, ‘. B Others report that the adrenal cortical hormones cause thrombophlebitis, pulmonary embolism and other thromboembolic phenomena.‘“-‘” Cosgriff, Diefenbach, and \‘ogt’* reported that administration of ACTH or an analoguc of hydrocortisonc can potentially induce a prcthrombotic state. ,4 clinical correlation is found in postoperative patients. After almost all types of surgery, these individuals have distinct rlevations of adrenal cortical hormones and an acabnormal companying tendency toward thrombosis.’ L Summary
‘I‘wo cases of pulmonary embolism following the use of norethynodrel are presented. The linl, between norethynodrel and thromboembolism may exist wherein norrthynodrel by virtue of its strong estrogenic effect alters adrenal cortical hormone metabolism sufficiently to cause vasculitis, increased coagulability and thrombosis in susceptible individuals.
REFERENCES
Paulsen, A. C., Leach, P. B., Lanman, J., Goldston, N., Maddock, W. D., and He&r, C. G.: J. Clin. Endocrinol. 22: 1033, 1962. 2. Peterson, R. E., Nokes, G., Chen, P. S., and Black, R. L.: J. Clin. Endocrinol. 20: 495, 1960. 3. Doe, R. P., Zinneman, II. H., Flink, E. B., and Ulstrom, R. A.: J. Clin. Endocrinol. 20: 1.
4.
1484, 1960. Nelson, D. H., Tanney, H., Gieschen, V. W., and Wilson,
6. 7. 8.
C.
II.:
Ann.
M.
C.,
Garvey,
Int.
Med. J.,
46:
Welsh,
831, E.
C.,
Koenig, R. R., and Polcyn, B. M.: Wisconsin M. J. 58: 557, 1959. 10.
Cecil, 1963.
11.
Kern, F., Vinnik,
Mestman, G., I,. D.: J. Clin.
12. 13.
Layne, D. S., Meyer, C. J., Vaishwanar, P. S., and Pincus, G.: J. Clin. Endocrinol. 22: 107, 1962. Metcalf, M., and Beaven, D. W.: Lancet 2: 1095, 1963. Berntsen, C. A., and Freyberg, R. H.: Ann. Int. Med. 54: 938, 1961. Kemper, J. W., Baggenstoss, A. H., and
14.
Endocrinol. 5.
9.
Slocumb, 1957. Borman,
23: 261, 1963. 15.
R.
I,.:
J.
Mississippi
M.
A.
4:
189,
1. E., Struthers, J. E., Jr.,
and Hill, R. B.: Am. J. Med. 35: 310, 1963. Cosgriff, S. W.: J. A. M. A. 147: 924, 1951. Hartman, M. M.: California Med. 98: 27, 1963. Cosgriff, S. W., Diefenbach, A. F., and Vogt, W., Jr.: Am. J. Med. 9: 752, 1950. Moore, F. D.: Metabolic care of the surgical patient, Philadelphia and London, 1959, W. B. Saunders Company, p. 75. 404 Medical Nea Orleans,
Art.r Ruilding Loui.riana 10115
ROSENBERG, Orleans,
M.D.
Louisiana
day which was gradually increased to 15 mg. per day to control breakthrough bleeding. Approximately 3 months after beginning the medication the patient complained of chest pain and hemoptysis. The medication was discontinued. Five days later the patient developed increasingly severe chest pain with dyspnea and hemoptysis. She was admitted to Touro Infirmary with the diagnosis of pulmonary embolism. The patient’s history did not reveal any antecedent trauma or other possible cause of the thromboembolism. She received anticoagulants for 10 weeks including inpatient and outpatient therapy. Ten weeks after her hospital admission the diagnosis of an early uterine pregnancy was made.
A D E F I N IT E relationship between norethynodrel and thromboembolism has neither been proved nor disproved. Reports associating the two continue to be published. The following case reports are presented which seem to indicate that a relationship does exist. Case reports Case 1. M. F., a 20-year-old nulligravida, was seen as a sterility problem. She gave no history of previous pelvic pathology or other illness. She was placed on norethynodrel (with mestranol) 5 mg. per day and continued the medication for 3 months. Five days after discontinuing the medication she experienced sharp pleuritic pain and dyspnea. A chest plate was obtained and read as possible pneumonitis. Five days later the patient experienced more chest pain, dyspnea, and hemoptysis. She was admitted to Touro Infirmary with the diagnosis of pulmonary embolism. There was no history of trauma or other factor that might be associated with thromboembolism. She was treated with anticoagulants for 2 weeks in the hospital and 12 weeks as an outpatient. Approximately 9 weeks after discontinuing the anticoagulants, the diagnosis of an early uterine pregnancy was made. Case 2. H. B., a 28-year-old gravida i, para i (7 years previously), was placed on norethynodrel (with mestranol) because of involuntary barrenness after more than one year, some menstrual irregularity, and the possibility of endometriosis. She began with a dosage of 5 mg. per
Comment The occurrence of 2 cases of pulmonary embolism following the use of norethynodrel was startling since both cases occurred within a period of 4 months in healthy young women. Norethynodrel has been shown to be a very potent estrogenic substance since it is converted to estrogen, has biologic estrogenic effects, and acts syngeristically with other estrogens such as mestrano1.l It is this estrogenie quality of norethynodrel which may be responsible for its possible link to thromboembolism. Estrogens have been found to exert a profound effect on the metabolism of the adrenal cortical hormones; indeed, an estrogen effect has been defined. This effect results in a raised plasma level of hydrocortisone and an increased plasma binding of the hormone.2 The mean-level of unbound biologically active hydrocortisone is also elevated
From the Department of Obstetrics and Gynecology of Touro Infirmary nnd Louisiana State University School of Medicine.
745
746
Rosenberg
in estrogen treated individuals3 Not oniy is the hydrocortisone level elevated in individuals given estrogen, but there is marked potentiation of the biologic effects of hydrocortisone when it is administered to estrogentreated individuals.* At this point it should be noted that Layne and co-workers” demo,nstrated that norethynodrel also exerts an estrogenic effect upon hydrocortisone metabolism. This study is consistent with the findings of Metcalf and ReavenG who found that administration of other proges,tin-estrogen preparations resulted in highly significant increases in plasma corticosteroids. If we can assume that administration of a progestin-estrogen preparation such as norethynodrel produces an increased plasma hydrocortisone then the increased hydrocortisone may be the link between norethynodrel and thromboembolism. The reason for this statement is that elevating the level of adrenal cortical hormone by giving ACTH or a corticosteroid can produce thromboembolism through certain vascular effects OI by altering the actual clotting mechanism or both. Many reports have cited the effect of
adrenal cortical hormone in the production of nonspecific vasculitis.‘, ‘. B Others report that the adrenal cortical hormones cause thrombophlebitis, pulmonary embolism and other thromboembolic phenomena.‘“-‘” Cosgriff, Diefenbach, and \‘ogt’* reported that administration of ACTH or an analoguc of hydrocortisonc can potentially induce a prcthrombotic state. ,4 clinical correlation is found in postoperative patients. After almost all types of surgery, these individuals have distinct rlevations of adrenal cortical hormones and an acabnormal companying tendency toward thrombosis.’ L Summary
‘I‘wo cases of pulmonary embolism following the use of norethynodrel are presented. The linl, between norethynodrel and thromboembolism may exist wherein norrthynodrel by virtue of its strong estrogenic effect alters adrenal cortical hormone metabolism sufficiently to cause vasculitis, increased coagulability and thrombosis in susceptible individuals.
REFERENCES
Paulsen, A. C., Leach, P. B., Lanman, J., Goldston, N., Maddock, W. D., and He&r, C. G.: J. Clin. Endocrinol. 22: 1033, 1962. 2. Peterson, R. E., Nokes, G., Chen, P. S., and Black, R. L.: J. Clin. Endocrinol. 20: 495, 1960. 3. Doe, R. P., Zinneman, II. H., Flink, E. B., and Ulstrom, R. A.: J. Clin. Endocrinol. 20: 1.
4.
1484, 1960. Nelson, D. H., Tanney, H., Gieschen, V. W., and Wilson,
6. 7. 8.
C.
II.:
Ann.
M.
C.,
Garvey,
Int.
Med. J.,
46:
Welsh,
831, E.
C.,
Koenig, R. R., and Polcyn, B. M.: Wisconsin M. J. 58: 557, 1959. 10.
Cecil, 1963.
11.
Kern, F., Vinnik,
Mestman, G., I,. D.: J. Clin.
12. 13.
Layne, D. S., Meyer, C. J., Vaishwanar, P. S., and Pincus, G.: J. Clin. Endocrinol. 22: 107, 1962. Metcalf, M., and Beaven, D. W.: Lancet 2: 1095, 1963. Berntsen, C. A., and Freyberg, R. H.: Ann. Int. Med. 54: 938, 1961. Kemper, J. W., Baggenstoss, A. H., and
14.
Endocrinol. 5.
9.
Slocumb, 1957. Borman,
23: 261, 1963. 15.
R.
I,.:
J.
Mississippi
M.
A.
4:
189,
1. E., Struthers, J. E., Jr.,
and Hill, R. B.: Am. J. Med. 35: 310, 1963. Cosgriff, S. W.: J. A. M. A. 147: 924, 1951. Hartman, M. M.: California Med. 98: 27, 1963. Cosgriff, S. W., Diefenbach, A. F., and Vogt, W., Jr.: Am. J. Med. 9: 752, 1950. Moore, F. D.: Metabolic care of the surgical patient, Philadelphia and London, 1959, W. B. Saunders Company, p. 75. 404 Medical Nea Orleans,
Art.r Ruilding Loui.riana 10115