A Relationship Between Seizures and the Menstrual Cycle

By Andrew G. Herzog, M.D., M.Sc.
Special to EpilepsyUSA
Posted: August 15, 2006

The pattern of seizure occurrence in women may not be entirely random. Seizure occurrence may vary in relation to the menstrual cycle. In fact, a relationship between seizures and the menstrual cycle is evident in about 70% of women with epilepsy. In about one third of women with seizures, there is a substantial relationship in which seizure frequency may more than double at certain times of the cycle. This is often called catamenial seizure exacerbation or catamenial epilepsy.

Catamenial Epilepsy

Catamenial epilepsy may result from the effects of hormones on the brain and from the natural variation of hormones during the menstrual cycle. The most common sites of origin of seizures in the brain, such as the temporal lobe, may be sensitive to hormonal influence.

Estrogen and progesterone are two hormones that affect the excitability of brain cells. In general, estrogen tends to excite them; progesterone calms them. During the course of a menstrual cycle, the levels of these hormones change in the blood.

These changes are illustrated in Figure 1. Day 1 of the cycle is the first day of menstrual flow. Ovulation, when the egg is released from the ovary, generally occurs 14 days before the onset of menses and is, therefore, labeled Day -14. The part of the cycle between the onset of menstruation and ovulation is called the follicular phase. The part between ovulation and menstruation is called the luteal phase.

A steep elevation of estrogen occurs just before ovulation. This can trigger seizures. Seizure worsening at this time is referred to as catamenial pattern 2.

A steep decline of progesterone occurs during the three days before the first day of menstrual flow. This too can trigger seizures (catamenial pattern 1).

Generally, seizures are least likely to occur during the mid luteal phase of ovulatory cycles when progesterone levels are the highest around Day -8 of the cycle.

Anovulatory cycles, where ovulation does not occur, are more common among women with epilepsy than among women in the general population. They may make up one-third of all cycles. Anovulatory cycles are associated with approximately 28% more seizures than ovulatory cycles. Progesterone level does not rise substantially during the luteal phase of the anovulatory cycle, although the estrogen level does. The high estrogen to progesterone ratio may increase the excitability of brain cells. It is thought that this may be the cause of the increase of seizures in the second half of the anovulatory cycle. This pattern is known as catamenial pattern 3.

There is statistical evidence to support the concept of catamenial epilepsy and the existence of these three distinct patterns of seizure worsening in relation to the menstrual cycle. If hormones play a role in seizure occurrence, there may also be a role for hormones in treatment. To date, there are no FDA approved hormonal treatments for seizures. Investigations are underway, however, to develop hormonal therapies. These therapies fall into two general categories: cyclic hormonal treatment and suppressive hormonal treatment.

Cyclic Hormonal Treatment

Cyclic hormone treatment aims to raise the progesterone level a little during the luteal phase in order to balance the excitatory effects of estrogen and then to reduce it gradually premenstrually, more gradually than occurs naturally. The results of preliminary investigations raise the possibility that natural progesterone, but not synthetic progestins, may lessen seizures in women with catamenial epilepsy when given orally according to a specified schedule during the second half of each cycle.

We have conducted two open-label trials (which mean they are trials in which the subjects and investigators knew that progesterone, not placebo, was being administered). In both trials, the addition of progesterone to the best antiepileptic drug treatment for that person, was associated with substantially and statistically significantly lower numbers of seizures (over 50% reduction) than the previously best antiepileptic drug therapy alone.

In other words, the progesterone therapy seemed to be effective in lowering the numbers of seizures that the women had. In contrast, oral synthetic, non-natural, manufactured progestins, administered in a similar manner, have not proven to be effective. While cyclic natural progesterone use is generally well tolerated, potential side effects such as sedation and depression may occur.

However, these side effects do subside rapidly when treatment is stopped or when the dosage is reduced. Spotting may also develop although cyclic progesterone use often helps to improve cycle regularity. Other potential side effects are uncommon. A multicenter progesterone treatment trial, sponsored by the National Institutes of Health, is currently under way and accepting subjects who can contact the author for further information (see below).

Suppressive Hormonal Therapy

Suppressive hormonal therapies have as their goal the elimination of reproductive hormone production and the menstrual cycle. Elimination of menstrual cycles using DepoProvera (depomedroxyprogesterone) injections every one to three months has been associated with a one third reduction in seizure numbers. Menses are generally eliminated but spotting, hot flashes and night sweats may occur. Other side effects are similar to the ones listed above for natural progesterone.

Additionally, it may take months or sometimes a couple of years for normal ovulatory cycles to return upon discontinuation of this type of hormone therapy. As noted above, anovulatory cycles may be associated with more seizures. In some cases, a prolonged course of anovulatory cycles may pose a long-term problem for seizure management following the discontinuation of DepoProvera treatment.

Suppression of the menstrual cycle may also be achieved with a medication that blocks the pituitary regulation of the ovary (GnRH analogue, leuprolide, Lupron Depot). There are preparations that can be injected once a month or once every three months. Side effects are similar to the symptoms of menopause (hot flashes, night sweats, and vaginal dryness) unless estrogen and progesterone are replaced in a balanced daily fashion. Although replacement of these hormones would seem to defeat the purpose of the GnRH analogue, stable hormone supplement may not be as much of a trigger for seizures as is the rapid rise of estrogen or fall of progesterone.

Selected References

• Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997; 38:1082-1088.
• Herzog AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurol 1995; 45:1660-1662.
• Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow up. Neurol 1999; 52:1917-1918.
• Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology 1984;34:1255-1258.
• Bauer J, Wildt L, Flugel D, Stefan H. The effect of a synthetic GnRH analogue on catamenial epilepsy: a study in ten patients. J Neurol 1992;239:284-286.

Harvard Neuroendocrine Unit Investigation of Progesterone Therapy for Women with Intractable Seizures

Progesterone Therapy for Women with Seizure Disorder
Hormones can affect brain excitability and seizures. Many women with seizures experience worsening of seizures premenstrually or at other times during the menstrual cycle. There is evidence to suggest that hormonal fluctuations during the cycle, especially premenstrual progesterone withdrawal, may play a role. The use of natural progesterone during the second half of each cycle may lessen seizures.

This study is being done to determine if progesterone supplement during the second half of each cycle lessens seizures. This is a 6-month study. Following a 3-month baseline phase, women will have a two out of three chance of receiving progesterone as opposed to placebo during the 3-month treatment phase. Women will not be expected to stop taking their regular seizure medication.

Inclusion criteria: women must be1) between the ages of 13 and 45; 2) have at least 2 seizures per month; 3) on a stable antiepileptic drug regimen for at least 2 months.
Exclusion criteria: women must not be pregnant, lactating or taking reproductive hormones during the past 3 months.

For more information, please call Andrew Herzog, M.D., at the Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center at (781) 431-0273 and ask for Ms. Kristen Fowler, the study coordinator.