Do the emotional side-effects of hormonal contraceptives come from pharmacologic or psychological mechanisms?

Hormonal preparations have become one of the most popular methods used for controlling fertility. The literature over the last 40 years continues to reveal how their numerous side effects negatively impact many users and even society at large. Three large cohort trials were the first to demonstrate, on a grand scale, certain emotional and behavioral associations with contraceptive use. Current contraceptive use was associated with an increase rate in depression, divorce, tranquilizer use, sexual dysfunction, and suicide and other violent and accidental deaths. Despite the advent of more "user friendly" contraceptives, the discontinuation rate secondary to side effects has changed little through the years. While in rare cases hormonal preparations can be deadly to the user, there is substantial evidence that their negative effect issues more from their emotional and behavioral properties. This paper reviews the results of over seven studies which further characterize these prominent associations, particularly with hormonal contraception, in an attempt to demonstrate their association with the intrinsic pharmacologic properties of hormonal preparations. Hormonal contraceptive users, in contrast with non users, were found to have higher rates of depression, anxiety, fatigue, neurotic symptoms, sexual disturbances, compulsion, anger, and negative menstrual effects. The question of whether the association of these maladies is directly due to the effect of taking exogenous hormones versus the psychological impact of the contraceptive behavior itself had yet to be studied. Seven small randomized-controlled trials were found in a review of the literature which studied this hypothesis in a direct way. They do not support the origination of these side effects being from the pharmacological properties of hormones. No association was found between hormone levels and emotional functioning in females. Psychiatric evaluations among IUD and oral contraceptive pill (OCP) users reveal no significant differences. Women who were given an OCP placebo experienced a similar side effect profile of OCP users. Different hormonal concentrations and combinations made no significant difference in the side effect profile. A study of women who were given either "weak female hormones" or a placebo failed to duplicate the side effect profile found in all of the other studies where the hormones were labeled as contraceptives. The evidence suggests that most of the side effects of hormonal contraception are a result of a psychological response to the practice of contraception. More study is warranted to further understand this psychological phenomenon, especially now that an effective non-contraceptive method of fertility regulation and more reliable psychological instruments are available. Furthermore, it is reasonable to hypothesize, given the present data, that contraceptive activity itself is inherently damaging to women.

Dose responses for DNA adduct formation in tissues of rats and mice exposed by inhalation to low concentrations of 1,3-[2,3-[(14)C]-butadiene.

Male Sprague-Dawley rats and B6C3F1 mice were exposed to either a single 6h or a multiple (5) daily (6h) nose-only dose of 1,3-[2,3-(14)C]-butadiene at exposure concentrations of nominally 1, 5 or 20 ppm. The aim was to compare the results with those from a similar previous study at 200 ppm. DNA isolated from liver, lung and testis of exposed rats and mice was analysed for the presence of butadiene related adducts, especially the N7-guanine adducts. Total radioactivity present in the DNA from liver, lung and testis was quantified and indicated more covalent binding of radioactivity for mouse tissue DNA than rat tissue DNA. Following release of the depurinating DNA adducts by neutral thermal hydrolysis, the liberated depurinated DNA adducts were measured by reverse phase HPLC coupled with liquid scintillation counting. The guanine adduct G4, assigned as N7-(2,3,4-trihydroxybutyl)- guanine, was the major adduct measured in liver, lung and testis DNA in both rats and mice. Higher levels of G4 were detected in all mouse tissues compared with rat tissue. The dose-response relationship for the formation of adduct G4 was approximately linear for all tissues studied for both rats and mice exposed in the 1-20 ppm range. The formation of G4 in liver tissue was about three times more effective for mouse than rat in this exposure range. Average levels of adduct G4 measured in liver DNA of rats and mice exposed to 5 x 6 h 1, 5 and 20 ppm 1,3-[2,3-(14)C]-butadiene were, respectively, for rats: 0.79 +/- 0.30, 2.90 +/- 1.19, 16.35 +/- 4.8 adducts/10(8) nucleotides and for mice: 2.23 +/- 0.71, 12.24 +/- 2.15, 48.63 +/- 12.61 adducts/10(8) nucleotides. For lung DNA the corresponding values were for rats: 1.02 +/- 0.44, 3.12 +/- 1.06, 17.02 +/- 4.07 adducts/10(8) nucleotides, and for mice: 3.28 +/- 0.32, 14.04 +/- 1.55, 42.47 +/- 13.12 adducts/10(8) nucleotides. Limited comparative data showed that the levels of adduct G4 formed in liver and lung DNA of mice exposed to a single exposure to butadiene in the present 20 ppm study and earlier 200 ppm study were approximately directly proportional across dose, but this was not observed in the case of rats. From the available evidence it is most likely that adduct G4 was formed from a specific isomer of the diol-epoxide metabolite, 3,4-epoxy-1,2-butanediol rather than the diepoxide, 1,2,3,4-diepoxybutane. Another adduct G3, possibly a diastereomer of N7-(2,3,4-trihydroxybutyl)-guanine or most likely the regioisomer N7-(1-hydroxymethyl-2,3-dihydroxypropyl)-guanine, was also detected in DNA of mouse tissues but was essentially absent in DNA from rat tissue. Qualitatively similar profiles of adducts were observed following exposures to butadiene in the present 20 ppm study and the previous 200 ppm study. Overall the DNA adduct levels measured in tissues of both rats and mice were very low. The differences in the profiles and quantity of adducts seen between mice and rats were considered insufficient to explain the large difference in carcinogenic potency of butadiene to mice compared with rats.