By: Ayesha Tufail
Fertility Complications and Epilepsy
What are fertility complications?
Fertility complications refer to physical, hormonal or genetic barriers that prevent conception.
In women ovulation disorders like PCOS, endometriosis or uterine fibroids are the most common cause of infertility. In men the most common cause involves problems with the shape, movement (motility) or amount (low sperm count) of sperm. Other major contributing factors include age, smoking, untreated sexually transmitted infections (STIs) and having obesity or being underweight. These complications usually lead to infertility where you can’t get pregnant for one year of trying to conceive.
(Cleveland Clinic 2023)
Fertility complications in epilepsy itself
Fertility is usually lower in men and women with epilepsy than in the general population. Epilepsy, particularly temporal lobe epilepsy (TLE), is associated with reproductive endocrine disorders in both men and women. Approximately 60% of women with TLE, not using anti-seizure drugs (ASDs), suffer comorbidities such as menstrual disorders and polycystic ovary syndrome. In men, semen abnormalities and low serum testosterone levels are common. Vulnerability to comorbid disturbances is influenced by the location of the epileptic focus and seizure localization. Significantly, the relationship between epileptic activity and reproductive endocrine dysfunction is bidirectional. The seizure activity can induce dysfunction of the hypothalamic–pituitary–gonadal (HPG) axis, altering serum levels of gonadal hormones, which can further aggravate seizure activity. Therefore the development and impact of reproductive endocrine disorders in epilepsy is significantly impacted by biological sex.
The menstrual cycle, or the equivalent rodent estrous cycle, is controlled by the hypothalamic regulation of gonadotropin secretion from the pituitary gland by gonadotropin-releasing hormone (GNRH) neurons. Gonadotropin-releasing hormone neurons are the central output pathway in the neural control of the HPG axis and are likely mediators of epilepsy-associated reproductive dysfunction.
(Jenna C. Carpenter et al 2022 para 1 and 2)
Fertility complications due to Anti-epileptic drugs (AEDs)
Fertility disorders have been attributed both to epilepsy itself and to AEDs. The use of the liver enzyme inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time the increase in serum SHBG levels leads to reduced bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, thus reduced fertility. Valproate (VPA) medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of the VPA related reproductive endocrine changes in men is unknown. On the other hand, in women the use of VPA is associated with a frequent occurrence of reproductive endocrine disorders characterized by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. Young women with epilepsy seem to be especially vulnerable to the effects of VPA on serum androgen levels.
(Jouko Isojärvi 2009 para 1)
Treatment options
Switching from enzyme-inducing AEDs to oxcarbazepine (OXC)
In men, when carbamazepine was replaced with oxcarbazepine, the liver enzyme induction and associated endocrine/metabolic changes normalized. This makes OXC as a treatment substitution option specifically for men who develop reproductive endocrine problems due to CBZ.
Switching from Valproate (VPA) to Lamotrigine (LTG)
This treatment was made specific to women. A study was done where 12 women with an identified VPA related endocrine disorder (polycystic ovaries, hyperandrogenism, or both). switched from VPA to LTG normalized endocrine function over a 1-year follow-up. Serum insulin and testosterone levels returned to normal within 2 months of stopping VPA, and stayed normal afterward. A major treatment finding was that switching between VPA to LTG before adulthood produces better reversal outcomes than continuing into adulthood.
Discontinuation as a general treatment principle (both sexes)
Beyond the specific drug-switch studies, the excerpt states more broadly that AED-related reproductive effects may be reversible upon discontinuation. A separate study on CBZ withdrawal specifically found that stopping the drug led to significant increases in testosterone and free androgen index in both men and women, supporting discontinuation (not just switching) as a viable treatment path when clinically appropriate.
(Jouko Isojärvi 2009)
Citation
Infertility: Types, causes, symptoms, diagnosis & treatment. (2023, April 19). https://my.clevelandclinic.org/health/diseases/16083-infertility
Carpenter, J. c, & Lignani, G. (n.d.). Sex on the brain: Reproductive comorbidities in temporal lobe epilepsy – PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC10009125/
Isojärvi, J. (n.d.-a). Disorders of reproduction in patients with epilepsy: Antiepileptic Drug Related Mechanisms – pubmed. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. https://pubmed.ncbi.nlm.nih.gov/18164216/
