1. STEROIDS IN EPILEPSIES
Effects and mechanisms of progestogens and androgens in
ictal activity
dr. I Komang Sri Mahendra putra
dr. Anna Marita Gelgel, Sp.S (K)

2. INTRODUCTIONS
 Steoids hormones may have a role in:
 Etiology
 pathophysiology
 Management of seizure
 High levels steroids in woman in epilepsy reduce
seizure
 Incidens of several epileptic syndrome peak in
adolescence

3.  The nature of epilepsy may change in early adolescent
years
 Changing seizure patterns of same epileptic children
as they became adolescent may difficulties normally
associated with adolescence.
 Role dan mechanism of steroids in ictal activity

4. TRADITIOANAL VIEW OF STEROID HORMONE
SECRETION AND ACTION
 Progestogens and androgens → sex steroid hormones
 Small, fat soluble, chemicals, →secretions by
peripheral glands (ovaries, testes,adrenals)
 Progestogens → Progestin reseptors (PRs)
 Androgens → Androgen reseptors (ARs)

5. DE NOVO PRODUCTION OF NEUROSTEROIDS AND
ACTIONS INDEPENDENT OF COGNATE STEROID
RECEPTORS
 Steroids hormones derived from cholesterol
 Released by neuronal/glial cells in brain and
peripheral endocrine sources
 Steroids have rapid effect on neuronal signaling
 Steroids receptors have been localized in terminal
buttons and arround post synaptic.

6. REPRODUCTIVE FUNCTION AND PROGESTOGENS
 Sex steroids influence
- peripheral tissue (genitals ) to prepare for mating
- Brain : regulate arrousal, appetitive, reproductive
behaviors

7. PROGESTOGENS MAY EXERT ANTISEIZURE
EFFECTS AMONG SOME WOMAN
 Seizure frequency decreases during the midluteal
phase and pregnancy
 Woman with epilepsy, seizure align with menstrual
cycle, increase in the preovulatory and inadequate
lutheal phase
 Progestogen therapy reduces seizure
 Natural progesterone (P4) consistently decreases
complex partial or secondary generalized motor
seizure.
 Progesterone (P4) and 5@ reductaced metabolites
have anti epileptogenic effect among same woman

8. IN RODENT MODELS, THE ANTISEIZURE EFFECT
OF P4 REQUIRE 5@ REDUCTION
 Protective effect of P4 related to 5@ reduction
 Kainic acid, pantylenetherazole (PTZ), pilocarpine →
elevated of 5@ reduced progestogen are elevated
 Medroxyprogesterone acetate (MPA) can not be 5@
reduced

9. SOME OF THE ANTISEIZURE EFFECTS OF PROGESTOGEN
MAY ACCUR INDEPENDENT OF PRs
 Antiseizure effect of P4 can,t all be explained by
“Genomic” action via PRs
 P4’s 5a-reduced metabolite,5α-pregnan-3α-ol-20-one
(3α,5α-THP, or allopregnanolone) is devoid of affinity
at intracellular PRs
 3α,5α-THP produces rapid anesthetic → involve GABA
and neurotransmitters

10.  P4 to PR replete
wild-type
(WT), or PR
mutant (PRKO)
mice significantly
increases
latencies to PTZ-
induced death
compared to
vehicle

11. ANDROGENS INFLUENCE ON
SEIZURES
 Androgens may play role in seizure
 Childrens in sexual development with epilepsy
 More sensitive In puberty
 Androgens supress release of adrenal stress hormones
 Several type of epilepsy fist present during adolescence

12. REPRODUCTIVE FUNCTION AND ANDROGEN
MILLEU AMONG MEN WITH EPILEPSY
 Deficiencies in androgens and infertility are over
presented among men with epilepsy
 Men with epilepsy have fewer offspring,lower score for
sexual interest & reduce bioactive testosterone (T)
 Alchoholic men with lower concentration of T have
more seizure

13. ANDROGENS ADMINISTRATION CAN MITIGATE
SEIZURE AMONG MEN
 Androgens treatment can decrease seizure
susceptability
 T administration to a young man with post traumatic
seizures reduced seizure frequency compared to the
number of seizures prior (Frye, 2006; Frye & Rhodes,
2009)
 5@-reduced androgens may play a role in mediating
seizures of men

14. ANDROGENS CAN HAVE ANTISEIZURE EFFECT IN
ANIMAL MODELS

15.  Androgens may have protective effects against
neuronal overexitation

16. The Role of Androgen Metabolism
on Seizure Susceptibility
 T is aromatized to estradiol (E2), which can have
neuroexcitatory, pro convulsant or anti seizure effects
(Frye & Rhodes, 2009a).
 T is metabolized by the 5a-reductase enzyme to
dihydrotestosterone (DHT) and 3α-diol
 some antiepileptic drugs (AEDs) may alter the
metabolism of T to E2, and DHT or 3α-diol
 Androgens modulation of seizures may occur as a
result of the ratio of 5a-reduced to aromatized
metabolites

17. 3α-Diol Has Anti Seizure Effects
in Female and Male Rodents
 Elevations in 3α-diol levels reduce chemoconvulsant
induced seizure
 Male rodents, juvenile (1 month) or aged rats (24
months), which have lower 3a-diol levels in the
hippocampus VS young adults →
Greater incidence of chemoconvulsant-induced
tonic–clonic seizures than do 9-month-old rats
(Rhodes et al., 2004).
 5α-reduced androgens may have an important role in
mediating seizure activity

18. Substrates for Androgen’s
Actions
 Androgens bind with Ars
 Androgens may influence ictal activity in part by
activating GABA A receptors to open the central
chloride channel, repolarize neuronal membranes,
and inhibit neuronal firing
 Androgens may also influence ictal activity in part by
decreasing excitatory actions of glutamatergic neurons
 Decreasing excitatory actions of glutamatergic
neurons.

19. Steroidal Actions of AEDs
 Steroids may influence seizures via AEDs through
alteration of cytochrome P-450 enzymes
 Enzyme-inducing AEDs include phenobarbital,
phenytoin, and carbamazepine, whereas valproic acid
inhibits CYP system enzymes
 Incidence of reproductive endocrine disorders among
persons with epilepsy is higher than among those
without seizure disorder

20. Role of Other Factors
 Hormones, are ictal activity, stress, or other activators
of the hypothalamus–pituitary–adrenal (HPA) axis
 Androgens and HPA function may have an important
role in neuronal excitability
 Effects of seizures on androgens or stress hormones
has not been clearly established

21. THANK YOU