Reproductive dysfunction and endocrine disorders are fairly common among women with epilepsy.63 Fertility is reduced by 20% to 30% of the expected number of offspring among married epileptic women, although the reduction may affect only women whose seizures began before the age of 10.64 Of women with partial seizures of temporal lobe focus (TLE), 35% have anovulatory cycles.65
Hyposexuality is seen more often in women with epilepsy than in the general population; 25% to 65% of women with TLE are estimated to be affected.66 It is seen much more often in those with TLE than in those with primary generalized epilepsy.
Hyposexuality is characterized by lack of libido and difficulty in achieving orgasm. The disorder may be due to a number of factors, including
Hyposexuality occurs more commonly with right-sided TLE, in which it is associated with hypothalamic hypogonadism (HH) and low serum LH level.63 Women with left-sided TLE, on the other hand, are rarely hyposexual.
About 60% of women with TLE have menstrual cycle abnormalities, such as amenorrhea, oligomenorrhea, or abnormally long (> 32 days) or short (< 26 days) menstrual cycle intervals.63 These menstrual cycle abnormalities are often associated with distinct reproductive endocrine disorders.63 Two of these disorders are polycystic ovary syndrome (PCOS) and hypothalamic hypogonadism (HH). Other possible causes of menstrual cycle abnormalities are premature menopause and functional hyperprolactinemia. Both are more common in women with epilepsy than in women in the general population.
According to NIH criteria, PCOS is characterized by the presence of ovulatory dysfunction; polymenorrhea, oligomenorrhea, or amenorrhea; clinical evidence of hyperandrogenism or hyperandrogenemia, such as hirsutism and acne; and exclusion of other endocrinopathies (e.g., Cushing syndrome, hypothyroidism, late-onset congenital adrenal hyperplasia). Polycystic-appearing ovaries (PCAOs) may be part of PCOS but are not part of the necessary criteria to make the diagnosis. Conversely, women with PCAOs may ovulate normally and do not necessarily have PCOS.
Although the occurrence of PCOS and PCAOs in women with epilepsy continues to be a topic of research and controversy, especially regarding the influence of valproate use on their occurrence, both PCOS and PCAOs are overrepresented in women with epilepsy. In a recent study of endocrine function in women with epilepsy, 26% of women with localization-related epilepsy and 41% of women with idiopathic generalized epilepsy had PCAOs, which was significantly more than in the control group, of which only 16% had PCAOs.67
The pathogenic mechanism of these disorders has not been established. It may relate to the effect of temporal lobe seizures and/or interictal epileptiform discharges upon the functioning of the hypothalamo-pituitary-gonadal hormonal axis.
Ovulation is controlled by luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are regulated by luteinizing hormone-releasing hormone (LHRH) secreted by hypothalamic LHRH-containing neurons.68 The LHRH neurons release LHRH into the portal hypophyseal circulation, which carries it to the anterior pituitary. There, LHRH stimulates the release of LH, FSH, or both into the systemic circulation.
FSH acts on the ovary to stimulate the maturation of the follicle. This process is associated with production by the ovary of estrogen during the follicular phase of the menstrual cycle. When the follicle is mature, a surge of estrogen production stimulates a surge in LH secretion from the pituitary by a positive feedback. This is followed by ovulation, the release of the ovum from the follicle.
The remaining follicle now becomes transformed into corpus luteum, which secretes progesterone and estrogen during the luteal half of the menstrual cycle. At the end of this phase, production of both estrogen and progesterone falls, leading to menstruation.69
LHRH, LH, and FSH are secreted in a pulsatile manner. LH pulses in the peripheral blood are controlled by LHRH pulses.69 Alteration in the normal pulsatile pattern of LHRH and LH secretion may be important in the pathophysiology of reproductive disorders with abnormal ovulation, including PCOS and HH.
Both diminished and excessive LH pulsatile secretion can lead to loss of ovulation. Ovulation starts only after the LH pulsatile pattern becomes established during puberty69 and is lost when LH pulsatility is lost (e.g., in secondary amenorrhea due to anorexia nervosa) or becomes excessive.69 Women with PCOS may have increased LH pulse frequency.69 Women with hypothalamic hypogonadism have decreased LH pulse frequency.70
The control of the pulsatile release of LHRH by LHRH cells is subject to modulatory influences from different parts of the brain,71 including the amygdala, a structure in the temporal lobe often involved in TLE. There are direct anatomic and physiologic connections between the amygdala and the preoptic area and the mediobasal hypothalamus, the sites of the LHRH-containing neurons.72,73
The amygdala can be divided, anatomically and functionally, into two distinct parts:74
LH pulsatile secretion is altered in women with epilepsy. Women with untreated epilepsy have higher LH pulse frequency than normal controls.75
More particularly, epileptiform discharges involving the left amygdala may lead to increased secretory activity of the hypothalamic LHRH neurons and/or their terminals, resulting in increased LH pulse frequency and PCOS.70,76
In contrast, epileptiform discharges involving the right amygdala may lead to reduced activity of the LHRH neurons, reduced LH pulse frequency, and hypothalamic hypogonadism.70
A positive feedback cycle (see Figure 2) may be envisaged whereby TLE leads to endocrine reproductive disorders with failure of ovulation, which in turn further exacerbates the seizure disorder.
Fig. 2: A cross-section of the anterior temporal lobe and diencephalon, depicting direct projections from the two anatomically distinct functional divisions of the amygdala to the same ventromedial hypothalamic neurons. The different influences of these projections on hypothalamic neurosecretory cells modulate pulsatile gonadotropin-releasing hormone (GnRH) secretion. Releasing hormones enter the pituitary portal system and regulate the pattern of luteinizing hormone and follicle-stimulating hormone secretion by the pituitary. These gonadotropins induce ovulation and stimulate estradiol and progesterone production. Gonadal steroids, in turn, bind to specific amygdaloid hormone receptors and influence neural activity, including epileptiform discharges.
Ovulatory dysfunction is not confined to women with epilepsy of temporal lobe origin, however. In a recent study of the predictors of ovulatory failure in women with epilepsy,64 women with idiopathic generalized epilepsy had anovulatory cycles 37% of the time, which was significantly more than the 11% anovulatory cycles among the control group. Women with localization-related epilepsy, with 14% anovulatory cycles, did not differ from the controls.
Reviewed and revised May 2004 by Cynthia Harden, MD, Weill Cornell Medical College.
Women with partial epilepsy often complain of an irregular menstrual cycle-usually prolonged but sometimes shortened (or both). These irregularities may be related to several reproductive endocrine disorders, especially polycystic ovary syndrome (PCOS) and hypothalamic hypogonadism (HH). Of course, if a woman complains of secondary amenorrhea, pregnancy or menopause should not be forgotten as a possible cause.
Here is a suggested approach to the evaluation of a woman with epilepsy and reproductive dysfunction:
In PCOS, one or more of the androgens (FT, A, or DHEAS) are elevated, the usual LH/FSH ratio of 1 is increased to > 2.5, and prolactin may be increased (in about 25%). Both total testosterone and free testosterone and should be checked because total testosterone may be affected by several antiepileptic drugs and free testosterone is the functionally relevant parameter.
In HH, LH, FSH, and estradiol are all low.
In hyperprolactinemia, remember that psychotropic medications (including benzodiazepines when used as AEDs [e.g., clonazepam]) and temporal lobe epilepsy are possible causes.
Hypothyroidism is a common cause of menstrual irregularities.
During the midluteal phase (e.g., menstrual cycle day 22), test:
In inadequate luteal phase syndrome (regardless of cause), the progesterone level is less than the normal 5 ng/mL. In PCOS, estradiol is normal.
In HH, both estradiol and progesterone are low.
Adapted from: Klein P and Herzog AG. Endocrine aspects of partial seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 207-232.
With permission from Elsevier (www.elsevier.com).
Reviewed and revised May 2004 by Cynthia Harden, MD, Weill Cornell Medical College.
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