Circulating Hormones and Pituitary Responsiveness in Young Epileptic Men Receiving Long‐Term Antiepileptic Medication

Macphee, G. J. A.; Larkin, John G.; Butler, Elaine; Beastall, G. H.; Brodie, Martin J.

doi:10.1111/j.1528-1157.1988.tb03747.x

Cited by 106 publications

(88 citation statements)

References 28 publications

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“…In many men with epilepsy, testosterone deficiency is an unusually common clinical observation (MacPhee et al, 1988;Herzog, 1991;El-Khayat et al, 2003). Temporal lobe epilepsy surgery has been shown to reduce seizure occurrence and normalize serum androgen concentrations in men with epilepsy (Bauer et al, 2000).…”

Section: Androgenic Neurosteroids In Epilepsymentioning

confidence: 99%

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Reddy¹

2008

Neurochemistry International

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Steroid hormones play a key role in the pathophysiology of several brain disorders. Testosterone modulates neuronal excitability, but the underlying mechanisms are obscure. There is emerging evidence that testosterone-derived "androgenic neurosteroids", 3α-androstanediol and 17β-estradiol, mediate the testosterone effects on neural excitability and seizure susceptibility. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone, which is then converted to 3α-androstanediol, a powerful GABA A receptormodulating neurosteroid with anticonvulsant properties. Although the 3α-androstanediol is an emerging neurosteroid in the brain, there is no specific and sensitive assay for determination of 3α-androstanediol in biological samples. This article describes the development and validation of mass spectrometric assay of 3α-androstanediol, and the molecular mechanisms underlying the testosterone modulation of seizure susceptibility. A liquid chromatography-tandem mass spectrometry assay to measure 3α-androstanediol is validated with excellent linearity, specificity, sensitivity, and reproducibility. Testosterone modulation of seizure susceptibility is demonstrated to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. The proconvulsant effect of testosterone is associated with increases in plasma 17β-estradiol concentrations. The 5α-reduced metabolites of testosterone, 5α-dihydrotestosterone and 3α-androstanediol, had powerful anticonvulsant activity. Overall, the testosterone-derived neurosteroids 3α-androstanediol and 17β-estradiol could contribute to the net cellular actions of testosterone in the brain. Because 3α-androstanediol is a potent positive allosteric modulator of GABA A receptors, it could serve as an endogenous neuromodulator of neuronal excitability in men. The 3α-androstanediol assay is an important tool in this area because of the growing interest in the potential to use adjuvant aromatase inhibitor therapy to improve treatment of epilepsy.

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Section: Androgenic Neurosteroids In Epilepsymentioning

confidence: 99%

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Reddy¹

2008

Neurochemistry International

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“…The extent of this process contributes to the three-fold variation in trough and peak plasma CBZ concentrations in patients receiving the same daily dose (Macphee et al, 1987). The metabolism of other lipid-soluble drugs including anticonvulsants can be similarly induced (Baciewiez, 1986) and circulating concentrations of endogenous hormones are also affected (Connell et al, 1984;Larkin et al, 1989b;Macphee et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin

Mckee

Forrest

et al. 1991

Brit J Clinical Pharma

114

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1 Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2 Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 ± 2.2 ,umol 1-1) were higher than predicted (16.5 + 4 ,umol 1-1).5 Antipyrine metabolism, urinary 6-13-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6 OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

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“…Another possible factor is the deleterious effects that a seizure disorder can have on normal psychosexual development because of the social stigma the condition carries (14,15). Last, the effects of enzyme-inducing antiepileptic drugs (AEDs) on free testosterone (FT) levels have been suggested as a cause for loss of libido (5,(16)(17)(18).…”

mentioning

confidence: 99%

Sexual Function in Women with Epilepsy

et al. 1997

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Summary:Purpose: To examine certain aspects of sexual behaviour and attitudes in a group of women with epilepsy using a validated questionnaire (Sexuality Experience Scales), and effects of antiepileptic drugs (AEDs) on sex hormone binding globulin (SHBG), total testosterone (TT), and free testosterone (FT).Methods: One hundred ninety-five women all attending a hospital-based epilepsy clinic were recruited. One hundred fifty-nine received AED therapy and 36 women did not. A control group of 48 women was also recruited. All women completed the first two Sexuality Experience Scales (SES 1 and SES 2), and those women in stable heterosexual relationships completed SES 3 and SES 4. At the same time blood was taken for TT and SHBG 1evels.FT was calculated using the method of Nanjee and Wheeler (22).Results: Women receiving AED therapy achieved significantly higher SES 1 and SES 2 scores than the rest of the women, suggesting that they adhered to a stricter sexual morality and were less open to psychosexual stimulation than the rest of the women treated. Women in the treated group were less likely to have received further education than the controls, a factor that influences SES 1 and SES 2 scores. There were no significant differences between the three groups on SES 3 or SES 4, with the exception of the orgasmic adequacy (OE) scale of SES 3 where those women in the treated group attained a higher mean score than the controls, suggesting that they found orgasm less satisfying. Women receiving AEDs had significantly higher SHBG and TT than controls and untreated patients. There were no differences in FT between the groups. Those women receiving AEDs also exhibited the expected midcycle rise in FT. There was no significant correlation between FT and the desired frequency of intercourse or enjoyment of it for the three groups.Conclusions: Women in the treated group appeared to be more "moral" and less open to sexual approach, but those who had regular partners appeared to desire and enjoy intercourse as much as the control and untreated groups. This could be explained by differences in demographic characteristics of the study groups or be indicative of a bimodal distribution of sexual interest in these women. As FT was within physiological norms for each study group this cannot be cited as a cause for hyposexuality .

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Circulating Hormones and Pituitary Responsiveness in Young Epileptic Men Receiving Long‐Term Antiepileptic Medication

Cited by 106 publications

References 28 publications

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Sexual Function in Women with Epilepsy

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