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. Chlorpromazine, opiates, and opi ate antagonists have been reported to Chronic phenytoin therapy has been cause hyperprolactinemia by interfering associated with decreased FSH levels with LH secretion.715’36 and hypospermia. Testosterone levels were unaltered.33 Animal experiments

G o s s y p o l suggested that the metabolism of sex ste roids is increased by phenytoin.24 Gossypol is a yellowish phenolic com Other anticonvulsants have not been pound derived from cotton plants. It is a proven to be toxic to the gonads. Several, promising male antifertility agent. including phénobarbital, phenytoin, and The mechanism by which gossypol acts valproate, have been shown to be terato has not been fully elucidated. Its effect genic in human or animal studies.6 on the structure of Leydig cells is vari

able, although it does suppress Leydig D r u g s o f A b u s e cell testosterone synthesis.31 Many investigators have studied the Infertility, impotence, and sperm effect of gossypol treatment on blood abnormalities have been described in a hormone levels (testosterone, FSH, and group of previously fertile men receiving LH) in experimental animals and man. methadone. Heroin users remained fer The results have been inconsistent.31 tile.6 Gossypol does regularly suppress Two studies have described the sperm counts in men. Azoospermia gonadal effects of chronic marijuana use results if therapy is continued and is in men.16,18 Both describe hypospermia reversible if the drug is stopped. Side and sperm structural abnormalities. effects have generally limited the clinical These may be reversible if marijuana use utilization of gossypol. is discontinued. There have been no reports of abnormal offspring of male

C l M E T I D I N E users. A single study of chronic female marijuana smokers demonstrated irreg Cimetidine is one of the most com ular menstrual cycles, anovulation, and monly prescribed drugs in the United decreased prolactin levels.4 There have States. Although its primary pharmaco been no long-term studies of fertility logic function is as a histamine H2 recep rates, libido, or sexual function among tor antagonist, cimetidine also is an chronic marijuana users. androgen antagonist at Leydig cell bind A number of studies have looked at the ing sites.7,15 toxic effects of lysergic acid diethylamide Hypospermia regularly has been doc (LSD). These studies have been exam umented in groups of men receiving ined for the effect of LSD on chromo cimetidine therapy. Testosterone levels somes, usually in the peripheral blood. were also reduced. Cimetidine appar Different results have been reported; ently blunted the peak response to some studies have described chromo gonadotropin secretion, since overall somal gaps and breakage as a result of EFFECTS OF DRUGS ON REPRODUCTIVE SYSTEMS 455

LSD exposure, while others have found ervation of reproductive function is no such changes. Studies of the terato obviously of great concern. genicity of LSD in animals have shown Alkylating agents (chlorambucil, cyclo inconsistent results. A study of preg phosphamide, nitrogen mustard, etc.) nancies in women who had taken LSD bind to desoxyribonucleic acid (DNA). did not reveal an increase in abortions Rapidly dividing cells, such as germinal or birth defects compared to con epithelium, are especially sensitive to trols 9.10.14.19.20,21,25,28 their effects.8,35 Antimetabolites such as methotrexate

I nsecticides and 5-fluorouracil appear to have less gonadal toxicity. Organophosphate and carbamate in The vinca alkaloids, vincristine and secticides are generally not toxic to the vinblastine, and antibiotics such as bleo gonads. Chlorinated hydrocarbons, how mycin and adriamycin have little direct ever, have been shown to affect the gonadal toxicity. testes in an adverse manner. One of the problems in assessing the Dibromodichloropropane (DBCP), in effects of anticancer drugs in humans is one study, was shown to cause azoosper that the drugs are almost always used in mia, with loss of germ cells on testicular combination. This makes assessment of biopsies, in men chronically exposed for the toxicity of a single agent quite diffi more than ten years. Men with two to cult. ten years exposure to DBCP showed There is little doubt that significant variable degrees of oligospermia and testicular injury can occur in males being hypospermatogenesis. Those with less treated with alkylating agents. It appears than two years exposure showed no that the prepubertal testis is more resis changes.5,35 Polychlorinated biphenyl tant to such damage than the postpuber- (PCB) and dimethyl-2-dichlororinyl tal one. phosphate (DDVP) have been shown to Ten of 63 boys treated with cyclophos produce marked testicular toxicity in ani phamide developed gonadal toxicity. By m als.12,22 contrast, 10 of 15 postpubertal boys The prototype halogenated organic treated with the same drug showed evi insecticide, DDT, may have an estro dence of gonadal injury.8 genic effect, but no gonadal toxicity has Sherins et al demonstrated that mech- been reported. lorethamine hydrochloride (MOPP) ther apy for Hodgkin’s disease was signifi

C y t o t o x i c A g e n t s cantly more toxic to the prepubertal than the postpubertal testis.34 With the recent advances that have Maguire et al performed testicular been made in the chemotherapy of can cer, the effects that these compounds T A B L E I may have on the gonads has become of Effects of Cytotoxic Therapy in Males with great concern. Many of the malignancies, Acute Myeloblastic Leukemia Apparently Correlates such as acute lymphoblastic leukemia, w ith D uration as w ell as Type o f Therapy* Hodgkin’s disease, Wilms’ tumor and 1. Less than 30 days - normal testes neuroblastoma, that are treated with 2. Five days to 40 months - m aturation arrest aggressive chemotherapy regimens occur 3. Seventeen days to 84 months - hypospermatogenesis primarily in young people. Prolonged 4. Three to 63 months - Sertoli cells only remissions and cures of these conditions *Maguire, L.C., Dick, F. R., and Sherman, B. M.: are now considered possible, and pres Cancer 48:1967-1971, 1981. 456 FODY AND WALKER biopsies on 29 adult males with acute TABLE I I I leukemia who received cytotoxic che Conclusion Regarding Gonadotoxicity of Cytotoxic Agents motherapy. The results are summarized 1. Alkylating agents are principal offenders. in table I.27 2. Drugs act synergistically. Hensle et al, in a study of testicular 3. Other agents (e.g., vincristine, bleomycin) may be cytotoxic for gonads. biopsies of young men receiving cytoxic 4. Combination chemotherapy makes it difficu lt to implicate single agents. therapy for acute lymphoblastic leuke 5. Likelihood of permanent gonadal injury is related to mia, found that all patients had some his dose and duration of therapy. 6. Whether or not the prepubertal gonad is less sensi tologic abnormality. The results are tive to cytotoxicity than the postpubertal remains controversial. shown in table II.17 7. In adult males, age is unrelated to toxicity. Recovery of reproductive function in In adult females, age is an important determinant of t o x i c i t y . men is highly variable and depends in 8. In both males and females, germinal epithelium is the principle target of cytotoxic drugs. Leydig part on duration of therapy. Maguire et cell damage may also be important. al found that irreversible injury occurred 9. Treatment with estrogen and progesterone may reduce toxicity in females. after 3 to 84 months of therapy for acute leukemia. Azoospermia is a bad prognos tic sign as it is usually permanent. The assessment of infertility in women needed to produce irreversible ovarian uses different systematic criteria and failure ranges from 12 to 27 g in women methods. Failure to re-establish a normal less than 29 years to three g or less in menstrual cycle is almost always indica one third of women over 30. Toxicity tive of loss of reproductive potential. appears to be enhanced when multiple Direct assessment of germ cells, how chemotherapeutic agents are used.37,39 ever, as is done with sperm analysis in The current state of knowledge con men, is usually not possible. cerning the effects of cytotoxic chemo In men, the critical period for therapy in men and women is summa increased gonadal sensitivity appears to rized in table III. be puberty. After this time, age is not a determinant of toxicity. Older women, Conclusion however, have been shown clearly to be at increased risk for ovarian toxicity as Toxicity to the gonads is a common compared to younger counterparts. The effect of certain commonly used drugs. critical age is not known; however, 85 For most of these, the toxicity is revers percent of women over 25 treated with ible with cessation of therapy. The most MOPP for Hodgkin’s disease developed toxic drugs are those used in cancer che permanent ovarian failure.8 The alkylat motherapy, especially the alkylating ing agents appear to be the worst offend agents. Injury produced by these drugs ers, and the dose of cyclophosphamide is often irreversible.

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