Hormones and their Relationships to Epilepsy and Pre-Menstrual Disorders in Young Women

Despite the controversy currently surrounding the use of hormone therapy in women, there are two unique theories regarding epilepsy and hormones according to researchers Constance Guille, MD, at the Yale Department of Psychiatry and Pavel Klein, MD, from the Mid-Atlantic Sleep Center in Bethesda. Dr. Klein suggests that hormones may be used to treat young women with epilepsy or at risk of developing epilepsy who have reached puberty.

While hormone therapy has received bad press as possibly linked with significant risks in women, Dr. Klein points out that “Not all hormones are the same.”

Dr. Guille agrees and is first author on a paper currently in press with Epilepsy & Behavior, called “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment.”

The article focuses on the preclinical and clinical research investigating the role of female hormones such as estradiol and progesterone, via its metabolite allopregnanonlone, in the etiology of Premenstrual Dysphoric Disorder (PMDD) and Catamenial Epilepsy (CE). The paper discussed the phenomenologic and neurobiologic overlap between CE and PMDD, and highlights areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders.

Possible protective benefit

At the 2007 annual American Epilepsy Society meeting, Dr. Klein noted that in some girls, epilepsy begins or worsens at the time of puberty. He hypothesizes that this could be due to the effect of hormones and their metabolites on the brain.

He said, “In animals, estrogens increase neuronal excitability and may bring on seizures. Progesterone, via one of its metabolites, allopregnanolone (ALLO), does the opposite: it blunts neuronal activity and blocks seizures, just like diazepam or barbiturates. At the start of puberty, the ovary produces estrogens, which cause some of the early hallmarks of female puberty such as breast development. A couple of years after breasts begin to develop, girls begin to menstruate.

“At first, menstrual cycles occur without the release of the egg from the ovary (ovulation). Ovulation starts at the very end of the process of sexual maturation, often 3-5 years after the beginning of puberty. It is only at this late stage that the ovary begins to produce progesterone,” he said.

Dr. Klein questions whether the prolonged production of estrogen without progesterone during early and mid-puberty could affect the brain so as to either cause the onset of seizures in susceptible girls or make seizures worse in some girls with epilepsy that began before puberty. He speculates that “Physiological replacement of progesterone, during this period, could perhaps protect girls from developing epileptic seizures or treat seizures that worsen during this period.”

Steroid hypothesis and Phase II trials

The steroid hypothesis of seizure onset during puberty is as follows:

• Ovarian secretion of estrogens starts during stage two of puberty (average age 9.8 years), rising until the onset of ovulation
• Ovarian secretion of progesterone only starts with ovulation, 3-4 years after ovarian secretion begins
• Excitatory neuroactive gonadal and adrenal steroids are produced for a period of time during perimenarche before inhibitory neuroactive steroids begin to be produced

As Dr. Klein stated, “This steroid production may facilitate kindling of a pre-existing central nervous system lesion into an epileptiform focus (or lower seizure threshold in a person with a genetic predisposition to epilepsy), acting as a “second hit” and thereby resulting in epilepsy. Our premise is to treat with the hormone progesterone and prevent the seizure.”

In fact, a synthetic version of ALLO called ganaxolone, which has the same action on the brain but has no hormonal effects, is under development for treatment of epilepsy. At present, Phase II trials are underway to determine the efficacy and tolerability of ganaxolone in the treatment of diverse forms of epilepsy in children and adults. Ganaxolone is being developed by Marius Pharmaceuticals, which has received grant funding from the Epilepsy Therapy Project.

Agreement on allopregnanolone

Dr. Guille said, “I think we are both in agreement that allopregnanolone has the potential to be a therapeutic treatment for epilepsy with a catamenial pattern. Currently the National Institute of Mental Health is funding a prospective, randomized, placebo-controlled, double-blind investigation to evaluate the efficacy and tolerability of natural progesterone for the treatment of CE. Hopefully these data will clarify some of the misconceptions regarding the safety of hormone therapy and delineate its potential for therapeutic use.”

Dr. Guille is interested in an area of psychiatry addressing issues related to women’s reproductive behavioral health. In particular she is interested in investigating the role of hormones in menstrual cycle-linked neuropsychiatric disorders.

She added, “Despite our understanding of hormonal influences on brain function, there is still much to learn about the pathogenesis and treatment of menstrual cycle-linked disorders. Our paper in press with Epilepsy & Behavior reviews what we know regarding the effects of hormones on the central nervous system in patients with PMDD and CE and explores the theoretical basis for a shared etiology. The paper is meant to stimulate discussion regarding this overlap and the potential implications for novel treatments for PMDD and CE.”

Concerns about hormones

Dr. Klein reiterated: “People have concerns about hormone replacement therapy (HRT) but this is not just one thing although it is commonly perceived as such. Hormones are not all the same. For instance HRT that is most commonly used in menopausal women consists of two components -- estrogens and progesterone. These have different effects, but in the public mind they get lumped together. Generally speaking, there is a fear when suggesting hormonal treatment. That fear is greater in adolescents because of the young ages of the girls we would be treating.” The Women’s Health Initiative (WHI), an NIH study which evaluated the effects of HRT in postmenopausal women and whose main findings were published in 2003, has cautioned about using HRT. It suggested that HRT is associated with increased risk of breast cancer, heart disease and other diseases.

Dr. Klein said, “Unfortunately, the conclusions did not draw distinction between the possible effects of the estrogens and progesterone, the two hormones used in HRT. The effects of estrogens and of progesterone may differ in the body as well as in the brain. For instance, there is very good evidence that long term HRT with estrogen alone clearly increases the risk of cancer of the uterus. Progesterone, however, protects against that risk.”

Differences not well known among the public

He also pointed out that “There is also reasonable evidence for an increased risk of breast cancer in women using the hormones for five years or longer. However the effect of progesterone on breast cancer is not clear. Furthermore, the effect of synthetic progesterone used in the WHI study may have different effects from natural progesterone, which is also available. The natural and synthetic forms of hormones such as progesterone are different compounds with often quite different effects.”

What Dr. Klein stressed is that these differences are not generally known by the public. “There is little evidence of increased risk of breast cancer when estrogen with progesterone is used short term. Furthermore, there is no evidence of this risk concerning natural progesterone. The WHI concluded simplistically that HRT is harmful. These conclusions were sensationalized, both by the medical communities and lay press, and caused great concern to women as well as physicians to shun HRT. The conclusions have since then been qualified and disputed. Now the pendulum is beginning to swing back.”

“Nevertheless,” says Dr. Klein, who uses progesterone and estrogens to treat worsening of mood disorders during peri-menopause, “there is still a great fear of cancer associated with estrogen among the public, which transfers without reason to progesterone also..”

Dr. Guille is currently a third-year resident in Adult Psychiatry at Yale University-Yale New Haven Hospital.

Dr. Klein completed a neurology residency and epilepsy fellowship at the University of Virginia, and a fellowship in neuroendocrinology at the Beth Israel Deaconess Medical Center in Boston. He was the director of Georgetown University Epilepsy Center before assuming his current position as the Director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, MD.

Back to top

Return to Articles and Publications