Estrogens in the Post-Menopause. Front. Hormone Res., vol. 3, pp. 199-207 (Karger, Basel 1975)
Estrogens and Vitamin Β6 Α. Α. HASPELS, Η. J. Τ. COELINGH BENNINK, Ρ. Α. iAl KEEP and W. Η. Ρ. SCHREURS Department of Obstetrics and Gynaecology, WHO Clinical Research Centre, Academic Hospital, University of Utrecht, Utrecht
Introduction
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The interference of oral contraceptives with the metabolism of tryptophane was reported by ROSE [1966]. Later ADAMS et al. [1973] reported on the effect of vitamin Β0 on the depression associated with oral contraception. The abnormality in the tryptophane metabolism is characterized by an increased excretion of tryptophane metabolites, particularly xanthurenic acid. The result is a deficiency or a `dependency' of pyrodoxíne (vitamin Β6). This disturbance appears to be caused by the synthetic estrogens in oral contraceptives and it can rapidly be corrected by the administration of pyridoxine, as has been shown earlier by the group in Utrecht. This disturbance — which can be detected by measuring xanthurenic acid after an oral load of tryptophane — is reported to have clinical consequences, such as depression, emotional instability, irritability, fatigue, disturbances in concentration and in sleep, and loss of libido. ADAMS and his group have reported that half of a group of women taking oral contraceptives and complaining of depression were found to have a vitamin Β6 deficiency. These women reacted favourably to the administration of vitamin Β6. Apart from the many women taking estrogens in oral contraceptives, there is a second group of women — a rapidly growing one — taking estrogens regularly. These are the women who take estrogens to prevent estrogen deficiency symptoms in the post-menopause. The estrogens used for this unquestionably important therapy, however, are in most cases different from the ones used in oral contraceptives in that, being estriol (or its
HASPELS/COELlNGH Βεκκπηt/νπκ Κεεr/ScØUxs
200
succinate), or conjugated estrogens, they are natural estrogens. Many secondary effects observed in women taking oral contraceptives are not observed in post-menopausal women taking estrogens. It was thought interesting to see whether or not the natural estrogens also had a different influence on tryptophane metabolism. This report summarizes the results obtained so far, but it must be remembered that the number of post-menopausal women involved in this study to date is very small. Material and Methods
Downloaded by: Université de Paris 193.51.85.197 - 2/1/2020 5:10:54 PM
The first part of the study involved 177 healthy women between the ages of 18 and 40 — a-selectively taken from out-patients visiting the University Hospital of Utrecht for fertility regulation. One hundred were using oral contraceptives and had been doing so for at least 3 months. Thirty used Neogynon or Stediríl-d (0.050 mg ethinyl estradiol and 0.25 mg d-norgestrel), 32 used Lyndiol (0.050 mg ethinyl estradiol and 2.5 mg lynestrenol). The others used a variety of different preparations, but in all but three these were preparations containing no more than 0.050 mg ethinyl estradiol. Twenty-five were having intramuscular injections of 150 mg medroxyprogesterone acetate every 12 weeks. The control group consisted of 52 women fitted with an intrauterine device. Two main tests were conducted. The first, to determine the serum vitamin ΒB concentration, involved 50 women using oral contraceptives, 24 receiving medroxyprogesterone acetate injections, and 14 using an IUD. The second test, to determine the urinary xanthurenic acid excretion in the 8-hour period following the oral administration of 2 g L-tryptophane, was done on 100 women using oral contraceptives, 15 receiving medroxyprogesterone acetate injections, and 52 using an IUD. In 38 women on oral contraceptives this test was repeated after a 4-week therapy of 100 mg pyridoxine hydrochloride/day had been added to the contraceptive therapy. The second part of the study involved nine women in the post-menopause who had been on estrogens for a prolonged period — in most cases conjugated estrogens 2.50-3.75 mg/day, or estriol succinate 4 mg/day. In these women xanthurenic excretion in the 8-hour period following the oral administration of 2 g L-tryptophane was determined
Estrogens and Vitamin Β6
201
Table Ι. Xanthurenic acid excretion during 8 h after oral administration of 2 g L-tryptlphane Oral contraceptives
Medroxyprogesterone acetate
Controls
Number of women
100
15
52
Mean xanthurenic acid excretion in µmοl/8 h with standard deviation
235 ± 224
74±51
40 ± 19
Range, µmol/8 h
19-885
22-245
11-112
Percentage with increased xanthurenic acid excretion, 60 µmοl/8 h
80%*
33%**
77%
Significance compared with controls: * highly significant, p extremely small (2 x 2 contingency table — Fisher); ** significant, p 60 µmο1/8 h prior to pyridoxine administration (n=30)
271 (61-720)
30**
43 (4-76)
Number of women with ΧΑ excretion
Estrogens and Vitamin Β6 Α. Α. HASPELS, Η. J. Τ. COELINGH BENNINK, Ρ. Α. iAl KEEP and W. Η. Ρ. SCHREURS Department of Obstetrics and Gynaecology, WHO Clinical Research Centre, Academic Hospital, University of Utrecht, Utrecht
Introduction
Downloaded by: Université de Paris 193.51.85.197 - 2/1/2020 5:10:54 PM
The interference of oral contraceptives with the metabolism of tryptophane was reported by ROSE [1966]. Later ADAMS et al. [1973] reported on the effect of vitamin Β0 on the depression associated with oral contraception. The abnormality in the tryptophane metabolism is characterized by an increased excretion of tryptophane metabolites, particularly xanthurenic acid. The result is a deficiency or a `dependency' of pyrodoxíne (vitamin Β6). This disturbance appears to be caused by the synthetic estrogens in oral contraceptives and it can rapidly be corrected by the administration of pyridoxine, as has been shown earlier by the group in Utrecht. This disturbance — which can be detected by measuring xanthurenic acid after an oral load of tryptophane — is reported to have clinical consequences, such as depression, emotional instability, irritability, fatigue, disturbances in concentration and in sleep, and loss of libido. ADAMS and his group have reported that half of a group of women taking oral contraceptives and complaining of depression were found to have a vitamin Β6 deficiency. These women reacted favourably to the administration of vitamin Β6. Apart from the many women taking estrogens in oral contraceptives, there is a second group of women — a rapidly growing one — taking estrogens regularly. These are the women who take estrogens to prevent estrogen deficiency symptoms in the post-menopause. The estrogens used for this unquestionably important therapy, however, are in most cases different from the ones used in oral contraceptives in that, being estriol (or its
HASPELS/COELlNGH Βεκκπηt/νπκ Κεεr/ScØUxs
200
succinate), or conjugated estrogens, they are natural estrogens. Many secondary effects observed in women taking oral contraceptives are not observed in post-menopausal women taking estrogens. It was thought interesting to see whether or not the natural estrogens also had a different influence on tryptophane metabolism. This report summarizes the results obtained so far, but it must be remembered that the number of post-menopausal women involved in this study to date is very small. Material and Methods
Downloaded by: Université de Paris 193.51.85.197 - 2/1/2020 5:10:54 PM
The first part of the study involved 177 healthy women between the ages of 18 and 40 — a-selectively taken from out-patients visiting the University Hospital of Utrecht for fertility regulation. One hundred were using oral contraceptives and had been doing so for at least 3 months. Thirty used Neogynon or Stediríl-d (0.050 mg ethinyl estradiol and 0.25 mg d-norgestrel), 32 used Lyndiol (0.050 mg ethinyl estradiol and 2.5 mg lynestrenol). The others used a variety of different preparations, but in all but three these were preparations containing no more than 0.050 mg ethinyl estradiol. Twenty-five were having intramuscular injections of 150 mg medroxyprogesterone acetate every 12 weeks. The control group consisted of 52 women fitted with an intrauterine device. Two main tests were conducted. The first, to determine the serum vitamin ΒB concentration, involved 50 women using oral contraceptives, 24 receiving medroxyprogesterone acetate injections, and 14 using an IUD. The second test, to determine the urinary xanthurenic acid excretion in the 8-hour period following the oral administration of 2 g L-tryptophane, was done on 100 women using oral contraceptives, 15 receiving medroxyprogesterone acetate injections, and 52 using an IUD. In 38 women on oral contraceptives this test was repeated after a 4-week therapy of 100 mg pyridoxine hydrochloride/day had been added to the contraceptive therapy. The second part of the study involved nine women in the post-menopause who had been on estrogens for a prolonged period — in most cases conjugated estrogens 2.50-3.75 mg/day, or estriol succinate 4 mg/day. In these women xanthurenic excretion in the 8-hour period following the oral administration of 2 g L-tryptophane was determined
Estrogens and Vitamin Β6
201
Table Ι. Xanthurenic acid excretion during 8 h after oral administration of 2 g L-tryptlphane Oral contraceptives
Medroxyprogesterone acetate
Controls
Number of women
100
15
52
Mean xanthurenic acid excretion in µmοl/8 h with standard deviation
235 ± 224
74±51
40 ± 19
Range, µmol/8 h
19-885
22-245
11-112
Percentage with increased xanthurenic acid excretion, 60 µmοl/8 h
80%*
33%**
77%
Significance compared with controls: * highly significant, p extremely small (2 x 2 contingency table — Fisher); ** significant, p 60 µmο1/8 h prior to pyridoxine administration (n=30)
271 (61-720)
30**
43 (4-76)
Number of women with ΧΑ excretion
