MENSTRUAL IRREGULARITIES ASSOCIATED WITH
THE USE OF CHLORDIAZEPOXIDE (LIBRIUM)
M. James Whitelaw, MD
Department of Surgery,
O'Connor Hospital,
2061 Clarmar Way,
San Jose, California
From: JAMA,
February 4, 1961
During the past four years several reports (1-6) have appeared on the effect of phenothiazine ataraxic drugs on the reproductive functions of animals and the human female. Recently a new non-phenothiazine ataraxic drug, chlordiazepoxide hydrochloride (Librium), has found widespread use in the treatment of mild anxiety states and nervous disorders. There has been no published evidence, experimental or clinical, to suggest that it has any effect on the hypothalamic pituitary ovarian axis.(7) Because of the profoundly disturbing effects on the female reproductive cycle associated with the administration of minimal amounts of this drug, this report is given.
Material
Seventeen normally menstruating women, all infertility patients who had been under observation for a minimum of 5 months and whose basal body temperature patterns were normal, were given chlordiazepoxide hydrochloride because of evidence of tubal spasm or nervous tension. The drug was given 3 times a day for four days, usually starting on day 9 or 10 of a theoretical 28-day cycle. The effects of this drug on the cycles of these 17 patients, their basal body temperatures, vaginal smears, and endometrial patterns, are tabulated in the table.
| Patient Number | Length of Cycle, Days | Basal Body Temperature | Remarks |
|---|---|---|---|
| 1 | 17 | No Rise | -- |
| 2 | 15 | No Rise | -- |
| 3 | 19 | No Rise | -- |
| 4 | 17 | No Rise | -- |
| 5 | 15 | No Rise | -- |
| 6 | 37 | Rose on Day 25 | Delayed Ovulation |
| 7 | 44 | Rose on Day 31 | Delayed Ovulation |
| 8 | 48 | No rise | -- |
| 9 | 47 | Rose on Day 36 | Delayed Ovulation |
| 10 | 28 | Normal Rise | -- |
| 11 | 29 | Normal Rise | -- |
| 12 | 28 | Normal Rise | -- |
| 13 | 30 | Normal Rise | -- |
| 14 | 26 | Normal Rise | -- |
| 15 | 29 | No Rise | Estrogenic Smear, Day 25 |
| 16 | 28 | No Rise | Suction Biopsy, Proliferative Phase, Day 23 |
| 17 | 25 | No Rise | Estrogenic Smear, Day 24 |
Discussion
It has been shown that chlorpromazine and related phenothiazines in large doses may produce amenorrhea of several months' duration.(1-3) It has been noted that small doses of chlorpromazine may delay ovulation and menstruation.(5,6) Chlordiazepoxide, which bears no chemical structural relationship to the phenothiazines, has presumably a greater effect on the hypothalamic pituitary ovarian axis, in minimal amounts, and under these particular conditions, than the phenothiazines. Of the 17 patients taking the drug, it completely interfered with ovulation in nine patients, as shown by early menses and a flat anovulatory basal body temperature pattern, which was further substantiated by an endometrial biopsy showing only a proliferative type of response or an estrogenic type of vaginal smear. In 3 patients, menses were delayed. Only 5 patients showed a normal pituitary ovarian response. It is difficult to explain the mechanism responsible for the premature bleeding in 5 of the 17 patients; it may be due to a partial blocking of the hypothalamic pituitary axis. The results obtained by various investigators with the phenothiazine drugs, as well as the results reported here with chlordiazepoxide, tend to indicate that these drugs should be used with caution in the normally menstruating female. In any differential diagnosis, an iatrogenic cause of menstrual irregularities should always be considered.
Summary
Seventeen female infertility patients with normal cycles were give chlordiazepoxide hydrochloride (Librium) 3 times daily for 4 days starting on day 9 or 10 of a theoretical 28-day cycle. In 5, bleeding started on day 19 or earlier. In 4, bleeding was delayed for 10-22 days with 3 having a corresponding delay in ovulation. Three failed to ovulate with a normal-length cycle as judged by vaginal smears, suction biopsy, and basal body temperatures. Only 5 had normal cycles. It is suggested that ataraxic drugs be used with caution in the menstruating female and that an iatrogenic cause be included in the differential diagnosis of menstrual irregularities. Chlordiazepoxide presumably acts the same as other phenothiazines at the hypothalamic level in inducing menstrual irregularities.
References
Clark, M.L., and Johnson, P.C.: Amenorrhea and Elevated Level of Serum Cholesterol Produced by a Trifluoromethylated Phenothiazine (SKF 5354-A), J Clin Endocr 20:641-646 (April) 1960.
Barraclough, C.A.: Induction of Pseudopregnancy in Rat by Reserpine and Chlorpromazine, Abstracted, Anat Rec 127:262 (Feb.) 1957.
Velardo, J.T.: Induction of Pseudopregnancy in Adult Rats with Trilafon, Highly Potent Tranquilizer of Low Toxicity, Fertil Steril 9:60-66 (Jan-Feb.) 1958.
Suzuki, M., and others: Effect of Chlorpromazine on Function of Endocrine Organs, Endocr Jap 3:67-72 (July) 1956.
Whitelaw, M.J.: Delay in Ovulation and Menstruation Induced by Chlorpromazine, abstracted, J Clin Endocr 16:972 (July) 1956.
Whitelaw, M.J.: Chlorpromazine (Thorazine) in Infertile Female, Int J Fertil 5:175-177 (April-June) 1960.
Personal Communication to the author from Roche Laboratories, May, 1960.
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