Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism

Herzog, Andrew G.; Klein, Pavel; Jacobs, Alan R.

doi:10.1212/wnl.50.3.782

Cited by 87 publications

(52 citation statements)

References 4 publications

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“…Alternatively, testosterone might have a biphasic effect on seizures: proconvulsant at higher doses, anticonvulsant at lower doses. Further, notwithstanding the modest antiseizure activity of testosterone in animals (Pesce et al, 2000;Frye et al, 2001b), testosterone itself has not been reported to improve seizures clinically (Herzog et al, 1998). Reductions of seizures were observed only when testosterone was given together with an estrogen synthesis inhibitor, suggesting the estradiol modulation of seizure activity.…”

Section: Resolving Bimodal Effects Of Testosterone On Seizure Susceptmentioning

confidence: 97%

“…Testosterone is known to produce both proconvulsant and anticonvulsant effects depending on the animal model and the seizure type (Werboff and Havlena, 1968;Thomas and McLean, 1991;Frye and Reed, 1998;Pesce et al, 2000;Mejias-Aponte et al, 2002). Both animal and clinical studies show that testosterone enhances seizure activity by metabolism to estrogens (Isojarvi et al, 1988;Thomas and Yang, 1991;Herzog et al, 1998;Edwards et al, 1999;El-Khayat et al, 2003). Epidemiological data indicate that the occurrence of focal and tonic-clonic epileptic seizures is ~50% higher in intact than in castrated dogs (VMDB Report, 2003).…”

Section: Effect Of Testosterone On Seizure Susceptibilitymentioning

confidence: 99%

“…Alterations in testosterone levels, therefore, may possibly contribute to exacerbation of seizures. Despite the testosterone-derived 3α-androstanediol's antiseizure effects in animals (Table 1) (Frye and Reed, 1998), however, testosterone itself has not been reported to improve seizures clinically (Herzog et al, 1998). One possible explanation is that antiepileptic drugs that induce enzyme synthesis may enhance the conversion of testosterone to 17β-estradiol, and presumably reduce the net availability of testosterone for the synthesis of 3α-androstanediol.…”

Section: Androgenic Neurosteroids In Epilepsymentioning

confidence: 99%

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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: Resolving Bimodal Effects Of Testosterone On Seizure Susceptmentioning

confidence: 97%

Section: Effect Of Testosterone On Seizure Susceptibilitymentioning

confidence: 99%

Section: Androgenic Neurosteroids In Epilepsymentioning

confidence: 99%

See 1 more Smart Citation

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Reddy¹

2008

Neurochemistry International

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“…5,40 This possibility is supported by the previously reported improved seizure control achieved with the adjunctive use of the aromatase inhibitor testolactone or the antiestrogen clomiphene than testosterone alone. 41 (2) Poor seizure control and untreated groups of epileptics exhibited more hormonal abnormalities than the controlled group on AED(s). Many evidences support our findings, including the following: free testosterone levels are usually low in reproductive endocrine disorders that are associated with TLE in men and therefore favor the occurrence of epileptiform activity, 26 testosterone has been found to raise the threshold of some induced seizures in experimental animals, 15,16 and previous studies demonstrated that patients with refractory epilepsy had improved sexual performance after temporal lobectomy.…”

Section: Discussionmentioning

confidence: 99%

The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation

et al. 2005

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EgyptThis study was specifically aimed to evaluate the sexual and reproductive health in a group of men with generalized epilepsy. In total, 44 men with generalized epilepsy were included in this study, their ages between 18 and 48 years (29.279.9) and duration of illness between 2 and 35 years (11.277.4); 34 patients were treated with conventional antiepileptic drugs (AEDs). Sexological and psychological interviews together with serum total testosterone, E 2 , FSH, LH and prolactin were determined. Hyposexuality was diagnosed in 61.4%. Erectile dysfunction (ED) and premature ejaculation represented 70.4 and 66.7%, respectively. Variables such as hyposexuality, seizure duration and its poor control on AEDs were significantly associated with depressive symptoms. Compared to the normal control group, all patients reported elevated E 2 levels (Po0.001), 10 had FSH (n ¼ 4) and LH (n ¼ 6) levels exceeding that of the normal range for controls and two had hyperprolactinemia. Although the patients' mean value of total testosterone remained within the normal range, but it was significantly lower in hyposexual men compared to nonhyposexual (Po0.002), only two epileptic patients had markedly reduced level of total testosterone beyond normal control levels. This study strongly supports that: (1) The risk of hyposexuality and reproductive disturbances is high in epileptic patients with GTC convulsions despite the AEDs utilized. The risk for SD is further increased by poor seizure control and the frequently accompanied depressive manifestations. (2) It is possible that elevated E2 could increase the risk of SD by reducing active testosterone through negative feedback and the reduction of active testosterone could increase seizure intractability to antiepileptic medications.

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“…7,8 Estrogens have been shown to have important beneficial effects on bone density, even in males; 8 however, the long-term effects on bone density in men receiving both testosterone supplementation and an anti-estrogen such as anastrozole are uncertain. However, no large-scale studies of anastrozole have been performed in men, and so there is limited information regarding its side effects in this population.…”

Section: Discussionmentioning

confidence: 99%

Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole

Rhoden

Morgentaler

2004

Int J Impot Res

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Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism

Cited by 87 publications

References 4 publications

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation

Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole

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