Table 3.

Reproductive hormone levels in men with epilepsy or bipolar disorder exposed and unexposed to valproate

Outcome	Cohort	Patient count before matching	Patient count after matching	Patients with sex hormone results	Mean ±  SD	p-value
Total testosterone (ng/dL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	2716	365 ± 272	0.002**
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	2747	387 ± 252
	Epilepsy exposed to valproate	60,860	50,102	1499	338 ± 260	0.000**
	Epilepsy not exposed to valproate	399,984	50,102	1433	385 ± 262
	Bipolar disorder exposed to valproate	33,450	22,826	890	386 ± 278	0.109
	Bipolar disorder not exposed to valproate	123,881	22,826	1064	405 ± 258
Free testosterone (pg/mL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	1532	93 ± 357	0.046**
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	1530	74 ± 87
	Epilepsy exposed to valproate	60,860	50,102	786	93 ± 433	0.070
	Epilepsy not exposed to valproate	399,984	50,102	774	64 ± 55
	Bipolar disorder exposed to valproate	33,450	22,826	550	92 ± 283	0.799
	Bipolar disorder not exposed to valproate	123,881	22,826	675	88 ± 183
Luteinizing hormone (mIU/mL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	1198	5 ± 5	0.160
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	998	5 ± 6
	Epilepsy exposed to valproate	60,860	50,102	804	5 ± 5	0.615
	Epilepsy not exposed to valproate	399,984	50,102	632	5 ± 5
	Bipolar disorder exposed to valproate	33,450	22,826	274	5 ± 6	0.825
	Bipolar disorder not exposed to valproate	123,881	22,826	287	5 ± 4
Follicle-stimulating hormone (mIU/mL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	1182	6 ± 9	0.320
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	952	7 ± 10
	Epilepsy exposed to valproate	60,860	50,102	809	7 ± 10	0.314
	Epilepsy not exposed to valproate	399,984	50,102	618	6 ± 9
	Bipolar disorder exposed to valproate	33,450	22,826	262	6 ± 8	0.696
	Bipolar disorder not exposed to valproate	123,881	22,826	262	6 ± 7
Prolactin (ng/mL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	3034	25 ± 194	0.118
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	2266	19 ± 30
	Epilepsy exposed to valproate	60,860	50,102	1853	28 ± 248	0.151
	Epilepsy not exposed to valproate	399,984	50,102	1356	19 ± 22
	Bipolar disorder exposed to valproate	33,450	22,826	922	26 ± 118	0.073
	Bipolar disorder not exposed to valproate	123,881	22,826	777	18 ± 20
Estradiol (pg/mL)	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	361	65 ± 152	0.258
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	379	86 ± 319
	Epilepsy exposed to valproate	60,860	50,102	180	57 ± 149	0.505
	Epilepsy not exposed to valproate	399,984	50,102	203	66 ± 126
	Epilepsy exposed to valproate	33,450	22,826	142	63 ± 100	0.300
	Epilepsy not exposed to valproate	123,881	22,826	184	75 ± 112

Legend: ** = Statistically significant result between valproate-exposed and unexposed men (p < 0.05) using two-sided t-test statistics. P-values are unadjusted for multiple comparisons. However, with Bonferroni correction applied across 18 comparisons, only p-values < 0.0028 would be considered statistically significant. SD = Standard deviation.

N.B: An expected mismatch is noted between the total number of patients with epilepsy and/or bipolar disorder and the sum of the number of patients in each subgroup. Since cohorts were not designed to be mutually exclusive, this mismatch is due to the ability for patients to have a record of one or both diagnoses (epilepsy and bipolar disorder) in their electronic health record.