Estrogen and Epilepsy research

Women and Epilepsy Approximately two million Americans (1%) have epilepsy, and about 180,000 new cases develop each year, according to the National Institute of Neurological Disorders and Stroke (NINDS). Half of the epilepsy patients are girls and women, however only 5% of epilepsy research goes to women and epilepsy even though epilepsy is one of the most common chronic health conditions affecting reproductive aged women. Seizure frequency and severity may change at puberty, over the menstrual cycle, with pregnancy, and at menopause. Estrogen is known to increase the risk of seizures, while progesterone has an inhibitory effect. Even after menopause women remain under the influence of hormones.1 Women with epilepsy also have lower fertility rates and are more likely to have anovulatory menstrual cycles where ovulation doesn’t occur, polycystic ovaries, and sexual dysfunction. Some anti-seizure drugs can interfere with the normal activity of female hormones. These drugs can also interfere with the effectiveness of medications containing those hormones, like birth control pills or hormone-replacement drugs. Ovarian steroid hormones alter excitability of neurons of the central nervous system. Estrogen reduces inhibition at the gamma-aminobutyric acid (GABA-A) receptor, enhances excitation at the glutamate receptor, and increases the number of excitatory neuronal synapses. Progesterone enhances GABA-A mediated inhibition, increases GABA synthesis, and increases the number of GABA-A receptors. In animal studies of epilepsy, estrogen increases and progesterone decreases the likelihood that a seizure will occur. That is why women may experience changes in seizure activity at puberty, during their menstrual cycles, and at menopause. An astonishing 30% to 50% of women with epilepsy experience menstrual cycle-related seizures. Seizures can be caused by infections, head injuries, brain tumors, and inherited disease. The two most common are called partial seizures, which affect one hemisphere of the brain, and generalized seizures, which start in both sides of the brain at the same time causing an immediate loss of consciousness. The length and severity of seizures varies from a few seconds to several minutes, and includes symptoms ranging from blank stares and lip smacking to extreme jerking of the arms and legs. Juvenile myoclonic epilepsy is a common epilepsy syndrome occurring primarily in girls at puberty and characterized by body jerks usually right after awakening. Another type of seizure is called juvenile absence seizures (having a blank stare) is common in girls at puberty. Generalized tonic-clonic (Grand-mal) seizures are also common. None of these types of seizures are likely to remit. Seizure control may also change during perimenopause because of fluctuations in estrogen and progesterone. Although 30% of women experience improvement in seizure control after menopause, another 30% describe a worsening in seizure control, many after beginning hormone replacement therapy with estrogen. REPRODUCTIVE FUNCTIONING Fertility rates in women with epilepsy are lower by one to two thirds when compared with their non-epileptic female siblings. Lower birth rates may also be caused by some of the social and psychological pressures experienced by women with epilepsy. Some women with epilepsy are afraid and do not to have children because of the fear of transmitting epilepsy or the belief that seizures will keep them from becoming safe and fit parents. Misinformation about epilepsy fuels many of these fears, however side effects from certain seizure drugs can have negative effects on a fetus. In addition to these social pressures, there is a physiologic basis for infertility in women with epilepsy. Up to one third of women with epilepsy have an abnormal menstrual cycle length (less that 23 days or more than 35 days). Almost one third of the women with epilepsy have cycles where they don’t ovulate regularly. Reproductive endocrine disorders, including disturbances in luteinizing hormone concentration and pulsatile release and abnormalities in prolactin and steroid hormone levels. Pituitary hormone abnormalities are probably associated with disruptions in hypothalamic input to the pituitary as a consequence of seizures. Potential health risks for women with seizure disorders include: · Increased risk of conceiving children born with birth defects · Sexual dysfunction · Ovarian cysts · Hormone related seizures · Irregular or absent menstruation · Unwanted changes in body and facial hair STEROID METABOLISM Changes in steroid metabolism related to the use of anti-epileptic drugs are another factor that affects ovarian hormone levels and reproductive functioning. Anti-epileptic drugs that induce certain enzymes enhance steroid metabolism. Polycistic ovaries are described in 20% to 40% of women with epilepsy. These women often have an elevated body mass index (more than 25 kg per m2 ), abnormal menstrual cycle length, and irregular ovulation cycles. It is not known whether this condition is the same as polycystic ovary syndrome. If there is a suspicion of anti-epileptic drug-induced polycystic ovarian syndrome it may warrant an endocrine screen, including luteinizing hormone, testosterone and prolactin levels, pelvic examination, and ovarian ultrasound. This phenomenon was reversible in a small number of women when their medication was changed from valproate to lamotrigine (Lamictal). Researchers still do not know whether infertility and irregular menstrual cycles are due to epilepsy or due to certain common anti-seizure medications, especially those that are processed through the liver, Dr. Spanaki-Varelas says. They can interrupt hormone levels and prevent ovulation. CONTRACEPTIVE CHOICES Women receiving a liver enzyme-enducing anti-epileptic medication have at least a 6% failure rate per year for oral hormonal contraceptive pills. Cytochrome P450-inducing anti-epileptic drugs enhance hepatic metabolism of contraceptive steroids and increase binding of steroids to serum proteins. This reduces the concentration of biologically active steroid hormone. Most commonly used oral contraceptives contain 35 mcg or less of estrogenic compounds and may be ineffective in women who take some anti-epileptic drugs. Subdermal levonorgestrel implants (Norplant) are also less effective in women receiving enzyme-inducing anti-epileptic drugs. Women taking enzyme-inducing anti-epileptic drugs should use non-hormonal methods of contraception or receive contraceptives containing 50 mcg or more of the estrogenic component. Consideration of anti-epileptic drugs that do not induce liver enzymes may also be an option in some patients. (See Table, next page) TABLE 1-- Anti-epileptic Drug Effects on Oral Contraceptives Agents that induce liver enzymes and May compromise OC efficacy are- Carbamazepine (Tegretol), Felbamate (Felbatol), Phenytoin (Dilantin), Phenobarbital, Primidone(Mysoline), Oxcarbazepine (Trileptal), Topiramate (Topamax). Agents that do not compromise OC Efficacy are: Gabapentin (Neurontin), Levetiracetam (Keppra), Lamotrigine (Gabitril), Valproate (Depakote), Zonisamide (Zonegran), OC = oral contraceptive TABLE 2 -- Resources: Epilepsy Foundation The Foundation provides information and referral for women with epilepsy. By contacting the Foundation or local affiliates, physicians and lay persons may obtain a series of fact sheets on issues of concern in women with epilepsy. Telephone: 800-EFA-1000--Web site: www.efa.org North American Pregnancy Registry- Get teratogenic risks of anti-epileptic drugs. Pregnant women should contact the registry before they have a diagnostic ultrasound. Telephone: 888-233-2334 SEXUAL DYSFUNCTION-- A reduction in sexual desire is reported in one fourth to one third of women with epilepsy. As with infertility, the contribution of the social and psychological stresses of living with epilepsy may be an important factor in these higher rates of dysfunction. More than one third of women in an outpatient survey reported difficulty with sexual arousal. Another common complaint was painful intercourse because of vaginal dryness and vaginismus. A study of physiologic responses to erotic stimulation found a reduction in vaginal blood flow in women with epilepsy compared with a control group of women without epilepsy. Dysfunction in sexual arousal can be helped by counseling, enhanced foreplay, and vaginal lubricants. Changing to an alternative anti-epileptic drug also may help. WOMEN VS. THE DOCTORS-- Until recently the management of women with epilepsy took no account of the effects their hormone levels can have on seizure activity. Yet as many as 70% of women with epilepsy notice that their seizures are influenced by ovulation, by menstruation and even by menopause, when menstruation ends and production of the female hormones estrogen and progesterone slow down. In menstruating women, ovulation normally occurs at around the 14th day of a 28-day cycle; menstruation on the 28th day marks the beginning of a new cycle. Women for generations have been trying to convince their doctors that there is some connection between their periods and their seizures. The doctors until recently didn’t believe that there was a major relevance with seizures in women and the women’s hormones. Sadly, for many women who experience menstrual cycle-related epilepsy, the fact is that not many doctors are as educated as they should be about these issues. According to a survey conducted by the Epilepsy Foundation and published on the Journal of Women’s Health & Gender-Based Medicine (Vol.9 No.9, 2000), the groups of physicians who were most likely to be educated about the issues unique to women with epilepsy were neurologists, endocrinologists, and epileptologists (a subgroup of neurologists specializing in epilepsy). OB/GYNs ranked fourth in their knowledge of the effects that seizure disorders in women had on reproductive health and other women’s health issues. The survey included 3335 healthcare professionals, representing a wide range of specialists who were likely to provide care to women with epilepsy. The survey results revealed that: ·Most of the respondents did not understand the specific effects that estrogen and progesterone have on seizure threshold. ·Most were not educated about the menstrual-associated seizure patterns, and were not able to identify which oral contraceptives interfered with anti-epileptic drugs. ·The majority of respondents did not know that women with epilepsy have significantly more infertility, reproductive endocrine disorders, and sexual dysfunction. CATAMENIAL EPILEPSY-- This is where epilepsy is linked directly to menstruation. Tests have shown that seizures can be directly linked to a woman’s menstrual cycle. In these tests seizures usually increase during the first two to three days of the cycle, and then again during days 8-14 of the cycle.3 Dr. Nancy Nolde, Ph.D. explains that this type of epilepsy can be treated by the removal of both ovaries, hormone therapy, and the use of adjunctive anti-epileptic medication. All of these can be effective treatments. This is very interesting to me personally because I have for many years tried to convince my doctor to give me a hysterectomy, but to no avail. I could never get the neurologists and the gynecologists to speak with one another about the issue. This went on for years and years before I finally got the hysterectomy that I wanted, but only because I was diagnosed with ovarian cysts. The gynecologist asked me whether I wanted them to remove my ovaries or leave them. I said REMOVE THEM! I finally got my wish and after the surgery I had fewer seizures. They diminished dramatically. Then I came across a drug study that I qualified for and started that last February. As of today I have only had 2 partial complex seizures where I lose consciousness and fall, and I have had about 5 simple partial seizures where I remain conscious but am in a “frozen” state. I would probably not have had some of the seizures that I did if I had not been taken off of the study early. They had to take me off of the double-blind part of the study early because the drug level was too high in my blood. They took me completely off of the drug before restarting me into the open label phase of the study and taking a lower mg pill. Within that time period I had about 4 of the seizures I mentioned. Before the hysterectomy and the Talampanel drug study I was having as many as 3-5 seizures every month. Even before the new medication I was having only about 1 or 2 seizures every other month. This is a lot less than when I was in my 20’s and 30’s when I was having an average of 5-10 seizures every month. What an improvement! I told my neurologist that if I get much better after the hysterectomy I was going to sue every doctor in this town who wouldn’t hear me when I said I wanted a hysterectomy. I just wish that the doctors would listen to their patients more. I am also glad that more women are getting into the neurology field. I know that they tend to understand a woman’s body much better than a man can. All the doctors I went to said that I could only have a hysterectomy if there was something wrong with my reproductive organs. Luckily 2 years ago something went wrong that didn’t cause me to lose my life, but allowed me to regain it. MENOPAUSE-- Women who have had seizures all their lives tend to stop menstruating earlier than women in general. If seizures worsen in some women with ovulation and menstruation, it would seem logical to think they would ease with the onset of menopause, but this isn’t always the case.2 A 1999 study showed that 67% of epileptic women noted changes in their seizure frequency with menopause. For 27%, seizures lessened or improved, but in 41%, they became worse. Another 20% of women actually began having seizures for the first time after menopause. There is the possibility that women taking hormone replacements constitute some of the problems for women in their menopausal years. OSTEOPOROSIS-- Certain older anti-seizure medications described as liver inducers can put women at greater risk of osteoporosis, even at a young age. One of these drugs in particular is Dilantin. Many who have taken this drug have had problems with calcium degeneration in the teeth as well as other bones of the body. Women on these drugs can help to prevent osteoporosis by taking vitamin D and calcium supplements. Newer medications don’t have this effect.4 It is important to understand that approximately 65% of patients never discover the cause of their epilepsy. The connection between hormones and epilepsy was first mentioned in medical literature in 1855. However, awareness of the effects that female hormone levels have on epileptic episodes is slowly improving. Many doctors who were surveyed in 1988 by the Epilepsy Foundation and only 5% of the doctors correctly answered most questions about the interaction between epilepsy and pregnancy, oral contraceptives, and low fertility. Campaigns were started to raise awareness among medical colleges and community health care professionals who treat women with epilepsy about the hormone-epilepsy connection. There is a need for more than 5% of the research money to be invested in the area of “women and epilepsy” since 50% of the individuals affected are women with more chronic problems of controlling their seizures than men due to their female hormones. college term paper by oller