Effects of Drugs on the Male and Female Reproductive Systems

ANNALS O F CLINICAL AND LABORATORY SCIENCE, Vol. 15, No. 6 Copyright © 1985, Institute for Clinical Science, Inc. Effects of Drugs on the Male and Female Reproductive Systems *EDWARD P. FODY, M.D. and fERNEST M. WALKER, M.D., P h.D. *Laboratory Service and f Clinical Laboratories John L. McClellan Veterans Administration Medical Center Little Rock, AR 72205 ABSTRACT Infertility, permanent or temporary, resulting from drug-induced injury is an important clinical problem. Many common used drugs are potentially toxic to gonads. It is well-known that estrogens are toxic to the male genital system, but androgens may also produce infertility. Anovulation may also be a consequence of exposure to sex steroids. Cimetidine regularly pro duces hypospermia in men; phenytoin does so occasionally. Marijuana has been shown to be a gonadal toxin, while the effects of lysergic acid dieth ylamide (LSD) remain controversial. The most significant group of drugs that may injure the gonads is the cancer chemotherapeutic agents, of which the alkylating agents are the worst offenders. Prediction of infertility induced by these agents may be possible based on the duration of therapy and the patient’s age and sex. Introduction injury. Since increasing numbers of patients, especially young persons with Drug-induced gonadal injury is an hemic and lymphoid malignancies, are important cause of infertility. Such injury now experiencing prolonged survival is often unpredictable and, perhaps more after treatment with these agents, it is significantly, may be reversible if the especially important to appreciate their offending agent is discontinued. role as gonadal toxins so that the patient’s Many different types of drugs may be future reproductive potential may be toxic to the gonads. Protein and steroid assessed. hormones, analgesics, histamine antago nists, anesthetics, cardioactive drugs, Physiology and antimicrobials have all been impli cated. Ethanol, heavy metals, and cer In both male and female, the hypo tain solvents are also toxic, but they will thalamus and adenohypophysis play not be covered here. major roles in control of gonadal func The most clinically significant area of tion. Gonadotropin releasing hormone drug-induced gonadal toxicity involves (GNRH - also called LHRH),42 a deca- the anti-neoplastic agents. These drugs peptide, is secreted from the hypothala regularly produce profound gonadal mus and travels via the intervening 451 0091-7370/85/1100-0451 $01.20 © Institute for Clinical Science, Inc. 452 FODY AND WALKER microvasculature to the adenohypo at day 14 of the menstrual cycle. This physis, where it causes the release of causes a marked increase in the release luteinizing hormone (LH) and follicle- of LH and FSH from the adenohypo stimulating hormone (FSH). These travel physis.32 via the general circulation to the gonads, Follicle stimulating hormone, as its where they exert their principal effects.1 name implies, is responsible for the The release of GNRH into the hypophy growth of the ovarian follicle during the seal portal veins is episodic, resulting in first half of the monthly cycle. Luteiniz pulsatile secretion of LH and FSH. ing hormone acts synergistically with In men, the secretion of GNRH is vari FSH to accelerate follicular growth. able and subject to a number of influ Ovulation occurs in response to the mid ences of higher centers upon the hypothal cycle peak of FSH and LH. amus. A negative feedback mechanism Thus FSH and LH cause the ovary to involving the effects of androgens and secrete both estrogen and progesterone. possibly other substances inhibits GNRH Estrogen has a negative feedback effect secretion. on the hypothalamus and adenohypo Luteinizing hormone binds to specific physis, reducing the secretions of GNRH membrane receptors on the Leydig cells and the gonadotropins, respectively. of the testes. This binding causes the Progesterones and androgens may also release of testosterone (and also estra exert a negative feedback effect, but this diol) from the cell. Testosterone is not is less effective than that of estrogen. water-soluble; it is transported in the A positive feedback effect of estrogen plasma primarily bound to albumin and upon the adenohypophysis also exists testosterone-binding globulin. Testoster and is stronger, on a mole per mole basis, one has an inhibitory effect upon the for LH than for FSH. Progesterone also secretion of GNRH by the hypothalamus exerts a positive feedback. and of LH and FSH by the adenohypo physis. This completes the negative feed Methods of Evaluation of Drug Effects back loop. on the Gonads and Fertility Follicle stimulating hormone, after release from the adenohypophysis, binds Drug effects on the gonads and fertility to membrane receptors of the Sertoli may be evaluated by studies of animals cells within the seminiferous tubules. or humans. This binding, like that of LH, causes an Animal studies are usually carried out increase in intracellular cyclic AMR according to the following protocol. The FSH binding is necessary to allow the experimental species, often a mouse, rat, Sertoli cell to promote spermatogenesis. or rabbit, is given the drug or chemical Androgens are also required. It has been of interest over a period of time. Often suggested that the Sertoli cell secretes a rather large doses are used. Exposure to substance known as inhibin in response fecund controls of the opposite sex may to FSH stimulation. It is postulated that sometimes be allowed to study repro inhibin has a negative effect upon GNRH ductive ability. After a predetermined released from the hypothalamus and interval, sacrifice occurs, and the gonads FSH released from the adenohypo are examined histologically. physis.23 Animal experiments have several In the female, the hypothalamic-ade- obvious advantages. Experimental vari nohypophyseal axis operates similarly to ables can be controlled, large doses may the male. Gonadotropin releasing hor be administered, and the entire gonad mone is secreted from the hypothalamus may be examined at any desired interval. EFFECTS OF DRUGS ON REPRODUCTIVE SYSTEMS 453 The principle disadvantage is that of the testis following estrogen adminis extrapolation of data from animal to man tration is similar to that seen after is often not valid. hypophysectomy.26 Azoospermia, gyne In men, assessment of reproductive comastia, and loss of libido also occur.13 function is simplified by the fact that Progesterone has much less effect on germ cells (spermatozoa) may be col the testis than estrogens, perhaps in part lected and studied. Thus, seminal fluid because it can serve as a substrate for analysis provides the basis for fertility testosterone synthesis.30 Its effect on tes studies. If hypospermia or azoospermia ticular function and histology is highly is found, additional tests, such as testic variable.13 ular biopsy or hormonal studies, may be The action of androgens is more sub performed. tle. Testosterone is normally produced In women, evaluation of reproductive by the Leydig cells under the influence function is more difficult, since germ ofLH. Testosterone, accompanied by cells are not readily accessible. A woman FSH, is necessary for spermatogenesis to is assumed to be infertile if she desires occur in the seminiferous tubules. Supra- to be pregnant and is not successful after physiologic doses of testosterone result two years. Infertility of her male partner in accentuated feedback inhibition upon must be excluded, as must mechanical the hypothalamus and adenohypophysis, factors, such as obstruction of the fallo suppressing the release of FSH and LH. pian tubes, if gonadal factors are to be The loss of LH matters little, since its implicated. Amenorrhea or decreased primary purpose is to stimulate testos levels of gonadotropins or estrogens in terone production by Leydig cells. How the blood or urine strongly suggest that ever, FSH is required for spermatogen a woman is subfertile. Demonstration esis. Therefore, men receiving large that such changes occur after exposure to doses of androgens may develop oligo a drug or chemical and, even more spermia. 1 importantly, disappear following with In women, estrogens and progester- drawal of the offending agent, often is ones are not directly toxic to the ovaries. used to implicate the particular sub However, administration of these agents stance as a gonadal toxin. may cause anovulation by suppression of However, in all human studies, con gonadotropin secretion through negative founding variables exist. For example, a feedback. patient with a suspected drug-induced Experimental evidence exists that pro gonadal lesion may be receiving other lactin is essential for normal gonadal drugs as well, or may be incidentally function in males. Barthe has demon exposed to other gonadal toxins such as strated that treatment with prolactin nor ethanol, heavy metals, radiation or malizes reproductive function in a strain industrial chemicals. Therefore, impli of mouse with a congenital deficiency of cation of a particular agent as a gonadal the hormone.3 Prolactin probably acts by toxin is almost always based on popula potentiating the effects of LH on Leydig tion studies. cells,1 which have been shown to have prolactin receptors.211 S e x S t e r o i d s In female rodents, prolactin is known to be important as a leukotropic agent, Estrogens have a pan-toxic effect on but its role in women is unsettled. Pro the male genitalia. They are inhibitors of lactin levels vary little with the men gonadotropin release and have a direct strual cycle.32 toxic effect on the testes. The histology Hyperprolactinemia causes impotence 454 FODY AND WALKER in men and amenorrhea and galactorrhea basal gonadotropin levels did not in women.2,32 Although most often decrease. Decreased prostate and sem hyperprolactinemia results from a pitu inal vesicle weights have been reported itary tumor, a number of drug effects in experimental animals treated with exist. A reciprocal relationship exists cim etidine.35,38’40 between prolactin and LH, i.e., drugs that elevate one tend to depress the A nticonvulsants other.

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