- Email: [email protected]
PERCUTANEOUS TESTOSTERONE CONTRACEPTION
276
clinically and in the test results, was seen between the 8th and 10th days in the patient on high-dose IFN, and between the 3rd and 4th weeks in the patients on low-dose IFN. The figure indicates the development of IFN-induced mental dysfunction monitored by simple measurement of logical memory function in two patients-one on high-dose followed by low-dose (above), and the other on low-dose treatment (below). The changes in logical memory were accompanied by changes in visuoconstructional function, slowing of fingertapping speed, and changes in psychomotor behaviour. The degree of dysfunction was influenced by IFN dose. On the discontinuation of IFN, the clinical and psychometric abnormalities disappeared within 2 weeks. Our experience suggests that psychometric tests can contribute to our knowledge about the action ofinterferons on the central nervous system, and that a selection of such simple tests might replace a large battery of neurophysiological investigations in the monitoring of interferon toxicity in clinical settings. Departments of Pulmonary Diseases and Neurology, Helsinki University Central Hospital, SF 00290 Helsinki 29, Finland
KARIN MATTSON AILA NIIRANEN RITVA LAAKSONEN
National Public Health Institute, Helsinki
KARI CANTELL
ANDROGENISATION OF FEMALE PARTNERS OF MEN ON MEDROXYPROGESTERONE ACETATE/PERCUTANEOUS TESTOSTERONE CONTRACEPTION
SiR,-We are evaluating a method of male hormonal contraception with medroxyprogesterone 20 mg daily by mouth (’Farlutal’; Laboratoires Farmitalia Carlo Erba, Paris) plus 100 percutaneous testosterone mg daily (’Percutacrine Laboratoires Besins-Isovesco, Paris).1,2 Forte’; Androgenique Seventeen men were started on this treatment between May, 1982, and.October, 1983. After a few months the female partners of some of the men using this form of contraception noted moderate hair growth on the upper lip (ie,a moustache) andon the inner side of the thighs. Because of this the female partners of men under treatment and those of men requesting treatment (ie, before it had started, three cases) were systematically investigated. In the 12 couples evaluated there were 5 cases of moderate hirsutism; the other 7 women were free of unwanted facial and body hair. Hormone levels were measured at the Fondation de Recherches en Hormonologie, Paris. There were 11 women with increased plasma-testosterone levels, associated with hirsutism in 4; the other 7 showed no clinical signs after their partners had been on treatment for between 3 and 12 months. Testosterone levels ranged from 3 -3 (close to the lower limit for males) to 0 -80 ng/ml; the average level was 1’ 87 ng/ml. In 2 cases testosterone levels were measured before treatment: they rose from 0 - 15 to 0-80 ng/ml after 5 months and from 0 - 20 to 2-55 ng/ml after 1/2 months. In one case, the level remained constant at 0 -50 ng/ml at 2 months of treatment, while in another case the plasma testosterone level fell from 1 -2 ng/ml during treatment of the male partner to 0.4ng/ml 1 month treatment stopped. Normal testosterone levels in females are 0 -15-0’75 ng/ml. A4-androstenedione levels remained consistently normal, which excludes an ovarian or adrenal cause for this
androgenic effect. has remained free of hirsutism and has normal after 2 months of hormonal contraception by her male partner. Another couple has reported a moderate hirsutism but cannot be contacted for further examination. Percutacrine (100 mg testosterone in an alcoholic solvent) is applied daily as an ointment to the abdomen or buttocks. 10 mg is absorbed in a few minutes and the other 90 mg stays on the surface of the skin as presumably inactive crystals after the evaporation of the 1
woman
testosterone values
JF, Rollet J, Czyba J-C, Claustrat B, Morville R Essai d’une contraception hormonale masculine associant l’acétate de médroxyprogestérone et un androgène naturel. Méd Hyg 1982, no 1465: 1286.
alcoholic solvent, which takes about 5 min. These crystals may dissolve in sweat, creating a reconstituted testosterone solution that may infiltrate the skin of the female partner during the intercourse. We now advise men to apply percutacrine, not in the evening as formerly, but in the morning, and we suggest that they take a shower 10 min later. This measure should eliminate any unabsorbed testosterone. It has been effective in three cases but ineffective in’ another three. Testosterone levels in the woman fell from 2 -7ng/ml to 0 - 75 ng/ml 1 month after the revised percutacrine schedule was adopted in one couple. In another woman the testosterone level was only 0 -30 ng/ml in the 17th month of the treatment; hirsutism had been observed since the 8th month, and a shower was taken from the 15th month. In another woman, with a testosterone level of 0’ 50 ng/ml before treatment, the plasma testosterone was unchanged after her male partner had been on the amended contraception regimen for 2 months. Plasma testosterone levels at the I Ith month of treatment (after 1 month of post-treatment showers) was 1’7 ng/ml, falling to 0-45 ng/ml 40 days later. However, despite thorough showering after application of testosterone levels in the partner only fell from 211 nglml to 1.4 4 ng/ml within 3 months in 1 case and from 3.3 3 to 1-1 ng/ml within 2 months in another. In the third failure testosterone levels rose from 0 - 15 ng/ml before treatment to 0 - 80 ng/ml at the 5th month. This female hirsutism prompted 4 couples to abandon treatment. It seems to make no difference whether the hormone is applied to the man’s abdomen or his buttocks. In only 1 case did the woman apply percutacrine to her partner. Since showering cannot be guaranteed to prevent hirsutism developing this male contraceptive agent must be used with utmost care and only where regular surveillance of the female partner can be achieved. We thank Dr M. Roger, Fondation de Recherches en Hormonologie (Paris) for his advice and for measuring hormone levels and Dr B. de Lignieres (Laboratoires Besins-Isovesco) for information. AREIRH Centre de Contraception et d’IVG, Service de Professeur Engelman, Hôpital Louis Mourier, 92701 Colombes, France
D. DELANOE B. FOUGEYROLLAS L. MEYER P. THONNEAU
NOT SO BENIGN LONG-TERM IMMUNOSUPPRESSION IN MULTIPLE SCLEROSIS?
SIR,-An increased risk of malignancy is a well-known side-effect such of immunosuppressive therapy in renal transplant recipients; has been a risk feared, but not yet demonstrated, in multiple sclerosis patients treated in the long term with immunosuppressive 2
drugs.
We have evaluated all our multiple sclerosis patients who had been on continuous long-term azathioprine therapy since 1967. 131 patients met the following criteria: diagnosis of multiple sclerosis probable or definite,3 treatment for at least a year, no immunosuppressive treatment other than azathioprine ever used, follow-up until death or Dec 31, 1982. 27 patients were male, 104 female; mean age at clinical onset of disease 27 years (range 15-49); mean duration of treatment 73 months (range 12-184), mean follow-up from onset of treatment 121 months (range 30-187). The average daily dose of azathioprine was 100 mg. Steroids were used in most patients, but only short term during exacerbations. 10 cancers, all epitheliomas (breast 5; ovary, cervix uteri, colon, stomach, skin 1 each) were diagnosed during the study. The age of patients and duration of treatment did not differ from those of the other patients in this group. 8 of these 10 cancers were diagnosed during the last three years of the study. The frequency of malignancy was almost 10% in the subgroup of patients followed up for 5 years or longer. Cancer was the cause of 4 of the 6 deaths in the subgroup of patients with the exacerbating-remitting form of the disease (65% of this subgroup had a stable disability score during treatment). In a control group of 131 patients with same diagnostic and follow-up criteria and same age and sex stratification but
1. Guerin
2
Soufir JC, Jouannet P, Marson J, Soumah A. Reversible inhibition of sperm production and gonadotrophin secretion in men following combined oral medroxyprogesterone acetate
625-32.
and percutaneous
testosterone
treatment.
Acta Endocrinol 1983; 102:
1.
Penn I. Malignancies associated with immunosuppressive or cytotoxic therapy. Surgery 1978; 83: 442-501
Myers LM. Immunosuppressive drugs in multiple sclerosis: Pro and con. Neurology 1980; 30: 28-32. McAlpine D, Lumsden CE, Acheson ED. Multiple sclerosis: a reappraisal, 2nd ed. Edinburgh: Churchill Livingstone, 1972.
2. Ellison GW, 3.
clinically and in the test results, was seen between the 8th and 10th days in the patient on high-dose IFN, and between the 3rd and 4th weeks in the patients on low-dose IFN. The figure indicates the development of IFN-induced mental dysfunction monitored by simple measurement of logical memory function in two patients-one on high-dose followed by low-dose (above), and the other on low-dose treatment (below). The changes in logical memory were accompanied by changes in visuoconstructional function, slowing of fingertapping speed, and changes in psychomotor behaviour. The degree of dysfunction was influenced by IFN dose. On the discontinuation of IFN, the clinical and psychometric abnormalities disappeared within 2 weeks. Our experience suggests that psychometric tests can contribute to our knowledge about the action ofinterferons on the central nervous system, and that a selection of such simple tests might replace a large battery of neurophysiological investigations in the monitoring of interferon toxicity in clinical settings. Departments of Pulmonary Diseases and Neurology, Helsinki University Central Hospital, SF 00290 Helsinki 29, Finland
KARIN MATTSON AILA NIIRANEN RITVA LAAKSONEN
National Public Health Institute, Helsinki
KARI CANTELL
ANDROGENISATION OF FEMALE PARTNERS OF MEN ON MEDROXYPROGESTERONE ACETATE/PERCUTANEOUS TESTOSTERONE CONTRACEPTION
SiR,-We are evaluating a method of male hormonal contraception with medroxyprogesterone 20 mg daily by mouth (’Farlutal’; Laboratoires Farmitalia Carlo Erba, Paris) plus 100 percutaneous testosterone mg daily (’Percutacrine Laboratoires Besins-Isovesco, Paris).1,2 Forte’; Androgenique Seventeen men were started on this treatment between May, 1982, and.October, 1983. After a few months the female partners of some of the men using this form of contraception noted moderate hair growth on the upper lip (ie,a moustache) andon the inner side of the thighs. Because of this the female partners of men under treatment and those of men requesting treatment (ie, before it had started, three cases) were systematically investigated. In the 12 couples evaluated there were 5 cases of moderate hirsutism; the other 7 women were free of unwanted facial and body hair. Hormone levels were measured at the Fondation de Recherches en Hormonologie, Paris. There were 11 women with increased plasma-testosterone levels, associated with hirsutism in 4; the other 7 showed no clinical signs after their partners had been on treatment for between 3 and 12 months. Testosterone levels ranged from 3 -3 (close to the lower limit for males) to 0 -80 ng/ml; the average level was 1’ 87 ng/ml. In 2 cases testosterone levels were measured before treatment: they rose from 0 - 15 to 0-80 ng/ml after 5 months and from 0 - 20 to 2-55 ng/ml after 1/2 months. In one case, the level remained constant at 0 -50 ng/ml at 2 months of treatment, while in another case the plasma testosterone level fell from 1 -2 ng/ml during treatment of the male partner to 0.4ng/ml 1 month treatment stopped. Normal testosterone levels in females are 0 -15-0’75 ng/ml. A4-androstenedione levels remained consistently normal, which excludes an ovarian or adrenal cause for this
androgenic effect. has remained free of hirsutism and has normal after 2 months of hormonal contraception by her male partner. Another couple has reported a moderate hirsutism but cannot be contacted for further examination. Percutacrine (100 mg testosterone in an alcoholic solvent) is applied daily as an ointment to the abdomen or buttocks. 10 mg is absorbed in a few minutes and the other 90 mg stays on the surface of the skin as presumably inactive crystals after the evaporation of the 1
woman
testosterone values
JF, Rollet J, Czyba J-C, Claustrat B, Morville R Essai d’une contraception hormonale masculine associant l’acétate de médroxyprogestérone et un androgène naturel. Méd Hyg 1982, no 1465: 1286.
alcoholic solvent, which takes about 5 min. These crystals may dissolve in sweat, creating a reconstituted testosterone solution that may infiltrate the skin of the female partner during the intercourse. We now advise men to apply percutacrine, not in the evening as formerly, but in the morning, and we suggest that they take a shower 10 min later. This measure should eliminate any unabsorbed testosterone. It has been effective in three cases but ineffective in’ another three. Testosterone levels in the woman fell from 2 -7ng/ml to 0 - 75 ng/ml 1 month after the revised percutacrine schedule was adopted in one couple. In another woman the testosterone level was only 0 -30 ng/ml in the 17th month of the treatment; hirsutism had been observed since the 8th month, and a shower was taken from the 15th month. In another woman, with a testosterone level of 0’ 50 ng/ml before treatment, the plasma testosterone was unchanged after her male partner had been on the amended contraception regimen for 2 months. Plasma testosterone levels at the I Ith month of treatment (after 1 month of post-treatment showers) was 1’7 ng/ml, falling to 0-45 ng/ml 40 days later. However, despite thorough showering after application of testosterone levels in the partner only fell from 211 nglml to 1.4 4 ng/ml within 3 months in 1 case and from 3.3 3 to 1-1 ng/ml within 2 months in another. In the third failure testosterone levels rose from 0 - 15 ng/ml before treatment to 0 - 80 ng/ml at the 5th month. This female hirsutism prompted 4 couples to abandon treatment. It seems to make no difference whether the hormone is applied to the man’s abdomen or his buttocks. In only 1 case did the woman apply percutacrine to her partner. Since showering cannot be guaranteed to prevent hirsutism developing this male contraceptive agent must be used with utmost care and only where regular surveillance of the female partner can be achieved. We thank Dr M. Roger, Fondation de Recherches en Hormonologie (Paris) for his advice and for measuring hormone levels and Dr B. de Lignieres (Laboratoires Besins-Isovesco) for information. AREIRH Centre de Contraception et d’IVG, Service de Professeur Engelman, Hôpital Louis Mourier, 92701 Colombes, France
D. DELANOE B. FOUGEYROLLAS L. MEYER P. THONNEAU
NOT SO BENIGN LONG-TERM IMMUNOSUPPRESSION IN MULTIPLE SCLEROSIS?
SIR,-An increased risk of malignancy is a well-known side-effect such of immunosuppressive therapy in renal transplant recipients; has been a risk feared, but not yet demonstrated, in multiple sclerosis patients treated in the long term with immunosuppressive 2
drugs.
We have evaluated all our multiple sclerosis patients who had been on continuous long-term azathioprine therapy since 1967. 131 patients met the following criteria: diagnosis of multiple sclerosis probable or definite,3 treatment for at least a year, no immunosuppressive treatment other than azathioprine ever used, follow-up until death or Dec 31, 1982. 27 patients were male, 104 female; mean age at clinical onset of disease 27 years (range 15-49); mean duration of treatment 73 months (range 12-184), mean follow-up from onset of treatment 121 months (range 30-187). The average daily dose of azathioprine was 100 mg. Steroids were used in most patients, but only short term during exacerbations. 10 cancers, all epitheliomas (breast 5; ovary, cervix uteri, colon, stomach, skin 1 each) were diagnosed during the study. The age of patients and duration of treatment did not differ from those of the other patients in this group. 8 of these 10 cancers were diagnosed during the last three years of the study. The frequency of malignancy was almost 10% in the subgroup of patients followed up for 5 years or longer. Cancer was the cause of 4 of the 6 deaths in the subgroup of patients with the exacerbating-remitting form of the disease (65% of this subgroup had a stable disability score during treatment). In a control group of 131 patients with same diagnostic and follow-up criteria and same age and sex stratification but
1. Guerin
2
Soufir JC, Jouannet P, Marson J, Soumah A. Reversible inhibition of sperm production and gonadotrophin secretion in men following combined oral medroxyprogesterone acetate
625-32.
and percutaneous
testosterone
treatment.
Acta Endocrinol 1983; 102:
1.
Penn I. Malignancies associated with immunosuppressive or cytotoxic therapy. Surgery 1978; 83: 442-501
Myers LM. Immunosuppressive drugs in multiple sclerosis: Pro and con. Neurology 1980; 30: 28-32. McAlpine D, Lumsden CE, Acheson ED. Multiple sclerosis: a reappraisal, 2nd ed. Edinburgh: Churchill Livingstone, 1972.
2. Ellison GW, 3.