Medical Hypotheses Medrcd Ify~~rheses Q Longman Group
(1991) 34, 141 - 143 UK Ltd 1991
Acute Intermittent Disbalance H. KRSNJAVI, institute (Reprint
7
S. MILKOVIC-KRAUS
for Medical Research requests to HKI
Porphyria and Hormone
and D. PRPIC-MAJIC
and Occupational
Health,
M. Pijade
158,
4 1000
Zagreb,
Yugoslavia
Abstract - A study of acute intermittent porphyria (Alp) in three female patients indicates the necessity of stressing that in cases of clinical and laboratory exacerbation of the disease in patients of reproductive age the possibility of the existence of pathological changes in the ovaries (polycystic ovary, anovulatory cycle) should be taken into consideration. By examination of patients’ endocrinological status and on the basis of the experience of clinicians it can be concluded that in such cases of exacerbation of the disease, apart from conventional therapy with glucose, Panhematin, electrolyte correction and other symptomatic therapy, coexisting steroid deficiency should be corrected.
Introduction
Methods
Porphyria is rarely found in our clinical practice (1). Acute intermittent porphyria (AIP) is a hepatic enzymopathy of various clinical forms. Etiologically it includes genetic, chemical and occasionally hormonal factors (2). Porphyric crises were observed in a group of female patients of fertile age which occurred synchronously with the menstrual cycle (3 - 7), leading the investigators to the conclusion that a link exists between hormones and biochemical processes in the liver. It has been found that 5 fl -steroids induce synthesis of 6 aminolevulinic acid (ALA) in competition with the heme feed-back mechanism, resulting in increased levels of porphobilinogens (PBG), ALA, uro and coproporphyrins (8).
Three female patients with AIP, aged 27- 30 years, who had been frequently hospitalized seven days before menstruation due to exacerbation of the disease, were studied. Clinical, ultrasound and endocrinological examinations revealed ovarian cysts, and monitoring of ovulation showed an anovulatory cycle in all three cases. The most abnormal endocrine findings included marked elevations of estradiol, testosterone and dehydroepiandrosterone (DHS) sulphates. The follicle-stimulating hormone (FSH) and progesterone were within normal limits. During exacerbation of the disease, cortisol was markedly reduced, ALA increased, PBG significantly in-
Date received Date accepted
11 November 1989 22 June 1990
141
142 creased and sodium, magnesium and potassium reduced. We examined one female patient with AIP, with no clinical exacerbation in connection with the menstrual cycle. With regard to her hormonal status FSH was increased (238.1 IU/L) and estrogen was normal or decreased. Discussion
In three female patients in whom exacerbation of the disease occurred synchronously with the menstrual cycle, clinical and ultrasound examination confirmed ovarian cysts and increased estradiol and testosterone levels. In contrast, one female patient with AIP, but without exacerbation of the disease in connection with the menstrual cycle, had apparently normal steroid metabolism, as was also observed by Anderson in 1979 (7). In the patients with cysts it would be logical to expect that their removal would also remove the hormonal disbalance. However, such a conclusion is not correct. Female patients described by Schley, after ovariectomy and during the next exacerbation of the disease, died or committed suicide. It remains unexplained as to what caused a further exacerbation when the source of increased estrogen secretion had been removed. In the case of our patients we found reduced cortisol levels, which indicated hypofunction of the suprarenal glands. In adnexectomised patients, due to a lack of estrogens the organism reacts by peripheral conversion of androstediones to estrogen (9). In this way the liver again metabolizes a new amount of endogenous estrogen and the already exhausted suprarenal glands become still more depleted. The suprarenal glands in the patients described by Schley were probably hypofunctional as was the case in our patients as shown by a decreased level of cortisol and a clinical picture of lethargy and apathy. Androgens, which were increased in these patients, can also be transformed into estrogens by routes influenced neither by the suprarenal glands nor the ovary (10). Estrogens are eliminated from the body by excretion through the liver and gall-bladder. The negative ‘estrogenic effect’ on the liver function of these patients is known, although not completely explained (4). Such an outcome of the disease could be considered coincidental in AIP. However, the clinical aspects of these patients - adynamia, reduced level of potassium, sodium and magnesium, dark skin colour, and decreased values of cortisol -
MEDICAL HYPOTHESES
indicate Addison’s disease. The suicidal reactions of patients reported by Schley in 1976 also indicate this syndrome. This was probably not noticed by previous investigators, and in their reviews they do not mention findings in the suprarenal glands in their descriptions of autopsy results. Consequently this experience should be a warning to clinicians that overiectomy can have a fatal outcome. In an effort to avoid the administration of estrogens and progesterones, in 1979 Lamon (10) attempted to treat such patients with a gonadotropic blocker with an androgenic component (Danazol), although this is contraindicated in liver disease. Because of the drug’s characteristics it was anticipated that the results would not be satisfactory, and this was confirmed in practice. In 1966 Zimmerman (12) reported treatment with testosterone with varied results. Some doubt exists with regard to the application of such treatment for two reasons: the possibility of peripheral conversion of testosterones into estrogen and deficient 5-a reduction of testosterones in the liver (2, 13) which unfavourably acts in two ways on the already deficient enzymatic function of the liver. The latest attempts of Anderson et al in 1984 (14) to apply the antagonist of luteinizing hormone releasing hormone (LHRH) in order to block the secretion of gonadotropins at the level of the pituitary gland, showed good results in one female patient. The effect is similar to that of oral contraceptives but is much more specific. As is well known, oral contraceptives increase the level of glucose and cortisol in the blood, which favourably influences the deficit in female patients with porphyria, and also reduces increased concentrations of testosterones in the blood (10). We are of the opinion that treatment of such female patients should consist of the foregoing methods together with cortisol compensation. The problem of the dysfunction of the suprarenal glands has been raised (15) with regard to the increased DHA-sulphate found in our patients, together with increased testosterone and a frequent clinical picture of virilization. Recently it has been found that ovarian insufficiency (polycystic ovary), which can be considered as autoimmunoendocrinopathy, is very frequently combined with autoimmunoadrenalitis, resulting in Addison’s disease (15), may be confirmation that we are closer to solving one of the aspects of the clinical enigmas of AIP. The empirical results of the application of 8glucocorticoid treatment of some
143
AlP AND HORMONE DISBALANCE
of our investigators (16).
corroborate
our hypothesis
Conclusion From the foregoing it can be assumed that exacerbation of AIP can be prevented in women with polycystic ovaries by hormonal therapy (LHRH). The need for intensive diagnostic follow-up of the function of the suprarenal glands has proved necessary in patients with this disease, as in our survey it can be seen that low values of cortisol represent one more unexplained hormonal deficiency in a group of women with AIP, whose porphyric crises are synchronous with the menstrual cycle. References 1. Beritic T. PrpiC-PajiC D. Porfirije. Lijecnicki vjesnik 91: 203, 1969. 2. Kappas A. Bradlow HL. Bickers DR. Alvares AP. Induction of a deficiency of steroid A 4 - 5 (I reductase activity in liver by porphyrinogenic drug. Journal of Clinical Investigations 59: 159, 1977. 3. Mustajoki P. Acute Intemittent Porphyria. Seminars in Dermatology 155, 1988. 4. Tschudy DP, Valsmais M, Magmusen CR. Acute Intermittent Porphyria: Clinical and Selected Research Aspects. Annals of Internal Medicine 83: 420, 1975. 5. Gerlis LS, Chir B. Acute Intermittent Porphyria on Withdrawal of Oral Contraceptives. Journal of International Medical Research 6: 255, 1978. 6. Schley G, Hengstebeck W, Bock KD. Therapy of Acute Intermittent Porphyria with Ovulation Inhibitors in Women. international Symposium of Clinical Biochemistry 74, 1978.
7. Anderson KE, Bradlow HL, Sassa S, Kappas A. Studies in Porphyria. VIII Relationship of the 5 (1 Reductive Metabolism of Steroid Hormones of Clinical Expression of the Genetic Defect in Acute Intermittent Porphyria. The American Journal of Medicine 66: 644, 1979. 8. Rossi E. Chiodi S. Acute Intermittent Porphyria and Pregnancy. Journal of Obstetrics and Gynaecology 8: 262, 1988. 9. Donald MC PC, Grodin JM, Suteri PK. The Utilization of Plasme Androstenodione for Estrone Production in Women. Proceedings of International Congress of Endocrinology 184: 770, 1969. 10. Speroff L, Glass RH, Kase NC. Clinical Gynecology and Infetility p. 53 - 66 Medicinska knjiga, Beograd-Zagreb, 1978. 11. Lamon JM, Frykholm BC, Herrera W, Tschudy DP. Danasol Administration to Females with Menses-Associated Exacerbations of Acute Intermittent Porphyria. Journal of Clinical Endocrinology 48: 123, 1979. 12. Zimmerman TS, McMiIIin JM, Watson CJ. Onset of Manifestations of Hepatic Porphyria in Relation to the Influence of Female Sex Hormones, Archives of Internal Medicine 118: 229, 1966. 13. Braunwold E, Issclabcler KJ, Petersdort RG, Wilson JD, Martin JB, Fanci AS. P0rphyrias.p. 1641- 1643 in Harrison’s Principles of Internal Medicine. Bd XI/2 (McGrawHi11Book Company) New York, St Louis, San Francisco, 1987. 14. Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of Cyclical Attacks of Acute Intermittent Porphyria with a Long-acting agonist of Luteinizing Hormone - Releasing Hormone. New England Journal of Medicine 31 I: 634, 1984. 15. MiiIIer CA. Nebennierenerkrankungen - und Umgang in der taglichen Praxis. Miinchener Medizinische Wochenschrift 130: 442, 1988. 16. Jusic A, Sostarsko M, PrpiC-Majic D. Long-term and Corticosteroid Therapy in Two Siblings with Polyneuropathy due to Acute Intermittent Porphyria. European Neurology 14: 294, 1976.
(1991) 34, 141 - 143 UK Ltd 1991
Acute Intermittent Disbalance H. KRSNJAVI, institute (Reprint
7
S. MILKOVIC-KRAUS
for Medical Research requests to HKI
Porphyria and Hormone
and D. PRPIC-MAJIC
and Occupational
Health,
M. Pijade
158,
4 1000
Zagreb,
Yugoslavia
Abstract - A study of acute intermittent porphyria (Alp) in three female patients indicates the necessity of stressing that in cases of clinical and laboratory exacerbation of the disease in patients of reproductive age the possibility of the existence of pathological changes in the ovaries (polycystic ovary, anovulatory cycle) should be taken into consideration. By examination of patients’ endocrinological status and on the basis of the experience of clinicians it can be concluded that in such cases of exacerbation of the disease, apart from conventional therapy with glucose, Panhematin, electrolyte correction and other symptomatic therapy, coexisting steroid deficiency should be corrected.
Introduction
Methods
Porphyria is rarely found in our clinical practice (1). Acute intermittent porphyria (AIP) is a hepatic enzymopathy of various clinical forms. Etiologically it includes genetic, chemical and occasionally hormonal factors (2). Porphyric crises were observed in a group of female patients of fertile age which occurred synchronously with the menstrual cycle (3 - 7), leading the investigators to the conclusion that a link exists between hormones and biochemical processes in the liver. It has been found that 5 fl -steroids induce synthesis of 6 aminolevulinic acid (ALA) in competition with the heme feed-back mechanism, resulting in increased levels of porphobilinogens (PBG), ALA, uro and coproporphyrins (8).
Three female patients with AIP, aged 27- 30 years, who had been frequently hospitalized seven days before menstruation due to exacerbation of the disease, were studied. Clinical, ultrasound and endocrinological examinations revealed ovarian cysts, and monitoring of ovulation showed an anovulatory cycle in all three cases. The most abnormal endocrine findings included marked elevations of estradiol, testosterone and dehydroepiandrosterone (DHS) sulphates. The follicle-stimulating hormone (FSH) and progesterone were within normal limits. During exacerbation of the disease, cortisol was markedly reduced, ALA increased, PBG significantly in-
Date received Date accepted
11 November 1989 22 June 1990
141
142 creased and sodium, magnesium and potassium reduced. We examined one female patient with AIP, with no clinical exacerbation in connection with the menstrual cycle. With regard to her hormonal status FSH was increased (238.1 IU/L) and estrogen was normal or decreased. Discussion
In three female patients in whom exacerbation of the disease occurred synchronously with the menstrual cycle, clinical and ultrasound examination confirmed ovarian cysts and increased estradiol and testosterone levels. In contrast, one female patient with AIP, but without exacerbation of the disease in connection with the menstrual cycle, had apparently normal steroid metabolism, as was also observed by Anderson in 1979 (7). In the patients with cysts it would be logical to expect that their removal would also remove the hormonal disbalance. However, such a conclusion is not correct. Female patients described by Schley, after ovariectomy and during the next exacerbation of the disease, died or committed suicide. It remains unexplained as to what caused a further exacerbation when the source of increased estrogen secretion had been removed. In the case of our patients we found reduced cortisol levels, which indicated hypofunction of the suprarenal glands. In adnexectomised patients, due to a lack of estrogens the organism reacts by peripheral conversion of androstediones to estrogen (9). In this way the liver again metabolizes a new amount of endogenous estrogen and the already exhausted suprarenal glands become still more depleted. The suprarenal glands in the patients described by Schley were probably hypofunctional as was the case in our patients as shown by a decreased level of cortisol and a clinical picture of lethargy and apathy. Androgens, which were increased in these patients, can also be transformed into estrogens by routes influenced neither by the suprarenal glands nor the ovary (10). Estrogens are eliminated from the body by excretion through the liver and gall-bladder. The negative ‘estrogenic effect’ on the liver function of these patients is known, although not completely explained (4). Such an outcome of the disease could be considered coincidental in AIP. However, the clinical aspects of these patients - adynamia, reduced level of potassium, sodium and magnesium, dark skin colour, and decreased values of cortisol -
MEDICAL HYPOTHESES
indicate Addison’s disease. The suicidal reactions of patients reported by Schley in 1976 also indicate this syndrome. This was probably not noticed by previous investigators, and in their reviews they do not mention findings in the suprarenal glands in their descriptions of autopsy results. Consequently this experience should be a warning to clinicians that overiectomy can have a fatal outcome. In an effort to avoid the administration of estrogens and progesterones, in 1979 Lamon (10) attempted to treat such patients with a gonadotropic blocker with an androgenic component (Danazol), although this is contraindicated in liver disease. Because of the drug’s characteristics it was anticipated that the results would not be satisfactory, and this was confirmed in practice. In 1966 Zimmerman (12) reported treatment with testosterone with varied results. Some doubt exists with regard to the application of such treatment for two reasons: the possibility of peripheral conversion of testosterones into estrogen and deficient 5-a reduction of testosterones in the liver (2, 13) which unfavourably acts in two ways on the already deficient enzymatic function of the liver. The latest attempts of Anderson et al in 1984 (14) to apply the antagonist of luteinizing hormone releasing hormone (LHRH) in order to block the secretion of gonadotropins at the level of the pituitary gland, showed good results in one female patient. The effect is similar to that of oral contraceptives but is much more specific. As is well known, oral contraceptives increase the level of glucose and cortisol in the blood, which favourably influences the deficit in female patients with porphyria, and also reduces increased concentrations of testosterones in the blood (10). We are of the opinion that treatment of such female patients should consist of the foregoing methods together with cortisol compensation. The problem of the dysfunction of the suprarenal glands has been raised (15) with regard to the increased DHA-sulphate found in our patients, together with increased testosterone and a frequent clinical picture of virilization. Recently it has been found that ovarian insufficiency (polycystic ovary), which can be considered as autoimmunoendocrinopathy, is very frequently combined with autoimmunoadrenalitis, resulting in Addison’s disease (15), may be confirmation that we are closer to solving one of the aspects of the clinical enigmas of AIP. The empirical results of the application of 8glucocorticoid treatment of some
143
AlP AND HORMONE DISBALANCE
of our investigators (16).
corroborate
our hypothesis
Conclusion From the foregoing it can be assumed that exacerbation of AIP can be prevented in women with polycystic ovaries by hormonal therapy (LHRH). The need for intensive diagnostic follow-up of the function of the suprarenal glands has proved necessary in patients with this disease, as in our survey it can be seen that low values of cortisol represent one more unexplained hormonal deficiency in a group of women with AIP, whose porphyric crises are synchronous with the menstrual cycle. References 1. Beritic T. PrpiC-PajiC D. Porfirije. Lijecnicki vjesnik 91: 203, 1969. 2. Kappas A. Bradlow HL. Bickers DR. Alvares AP. Induction of a deficiency of steroid A 4 - 5 (I reductase activity in liver by porphyrinogenic drug. Journal of Clinical Investigations 59: 159, 1977. 3. Mustajoki P. Acute Intemittent Porphyria. Seminars in Dermatology 155, 1988. 4. Tschudy DP, Valsmais M, Magmusen CR. Acute Intermittent Porphyria: Clinical and Selected Research Aspects. Annals of Internal Medicine 83: 420, 1975. 5. Gerlis LS, Chir B. Acute Intermittent Porphyria on Withdrawal of Oral Contraceptives. Journal of International Medical Research 6: 255, 1978. 6. Schley G, Hengstebeck W, Bock KD. Therapy of Acute Intermittent Porphyria with Ovulation Inhibitors in Women. international Symposium of Clinical Biochemistry 74, 1978.
7. Anderson KE, Bradlow HL, Sassa S, Kappas A. Studies in Porphyria. VIII Relationship of the 5 (1 Reductive Metabolism of Steroid Hormones of Clinical Expression of the Genetic Defect in Acute Intermittent Porphyria. The American Journal of Medicine 66: 644, 1979. 8. Rossi E. Chiodi S. Acute Intermittent Porphyria and Pregnancy. Journal of Obstetrics and Gynaecology 8: 262, 1988. 9. Donald MC PC, Grodin JM, Suteri PK. The Utilization of Plasme Androstenodione for Estrone Production in Women. Proceedings of International Congress of Endocrinology 184: 770, 1969. 10. Speroff L, Glass RH, Kase NC. Clinical Gynecology and Infetility p. 53 - 66 Medicinska knjiga, Beograd-Zagreb, 1978. 11. Lamon JM, Frykholm BC, Herrera W, Tschudy DP. Danasol Administration to Females with Menses-Associated Exacerbations of Acute Intermittent Porphyria. Journal of Clinical Endocrinology 48: 123, 1979. 12. Zimmerman TS, McMiIIin JM, Watson CJ. Onset of Manifestations of Hepatic Porphyria in Relation to the Influence of Female Sex Hormones, Archives of Internal Medicine 118: 229, 1966. 13. Braunwold E, Issclabcler KJ, Petersdort RG, Wilson JD, Martin JB, Fanci AS. P0rphyrias.p. 1641- 1643 in Harrison’s Principles of Internal Medicine. Bd XI/2 (McGrawHi11Book Company) New York, St Louis, San Francisco, 1987. 14. Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of Cyclical Attacks of Acute Intermittent Porphyria with a Long-acting agonist of Luteinizing Hormone - Releasing Hormone. New England Journal of Medicine 31 I: 634, 1984. 15. MiiIIer CA. Nebennierenerkrankungen - und Umgang in der taglichen Praxis. Miinchener Medizinische Wochenschrift 130: 442, 1988. 16. Jusic A, Sostarsko M, PrpiC-Majic D. Long-term and Corticosteroid Therapy in Two Siblings with Polyneuropathy due to Acute Intermittent Porphyria. European Neurology 14: 294, 1976.
