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Cocaine Abuse and

Reproductive Function

in Women

Nancy K. Mello, Ph.D.

INTRODUCTION

A number of abused drugs may compromise reproductive function

and disrupt menstrual cycle regularity (Mello et al. 1992, pp. 575-621;

Smith and Smith 1990; Teoh et al. 1994a, pp. 437-473; Mello and

Mendelson 1997). Chronic abuse of alcohol and other drugs is associated with several neuroendocrine disorders that are expressed clinically

as anovulation, luteal phase dysfunction, and amenorrhea. Single

episodes of alcohol or other drug intoxication also may result in hormonal changes that impair menstrual cycle function. In addition

to specific disorders of the menstrual cycle, the effects of such drugs

on neuroendocrine hormones essential for normal reproductive function may compromise other aspects of women’s health, including

immune function, which in turn may enhance the risk for acquired

immunodeficiency syndrome (AIDS).

This chapter summarizes some recent research on the effects of

cocaine on neuroendocrine hormones that are essential for normal

reproductive function. A more extensive review of cocaine’s effects on

anterior pituitary, gonadal, and adrenal hormones has been published

elsewhere (Mello and Mendelson 1997). At present, relatively little is

known about the mechanisms by which cocaine, alcohol, and other

drugs of abuse disrupt the menstrual cycle. Although a number of drugs

disrupt the menstrual cycle in similar ways, this does not mean that all

drugs act through similar mechanisms. Regulation of the reproductive

system is complex and depends on interactions among the hypothalamus, pituitary, ovaries, and adrenal glands. Each component of the

reproductive system has both positive and negative feedback effects on

each other component. An imbalance in any part of the hypothalamicpituitary-ovarian and hypothalamic-pituitary-adrenal system can jeopardize these fragile feedback interrelationships. It seems unlikely that

cocaine acts primarily at a single target site, but it is not yet known how
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drugs of abuse affect the functional integration and regulation of the

neuroendocrine system and how this, in turn, may be related to druginduced disorders of reproductive function (see Mello and Mendelson

1997 for review).

CLINICAL DESCRIPTION OF

MENSTRUAL CYCLE DISORDERS

A menstrual cycle occurs approximately every 28 days in women and

higher primates throughout their reproductive lifespans. The hormonal

changes that define the phases of the menstrual cycle are among the

most fundamental of biological rhythms. The onset of menstruation

defines the beginning of a cycle, the follicular phase, and heralds the

development of the ovarian follicle that culminates in ovulation. Subsequently, the site of the ruptured ovarian follicle becomes the corpus

luteum, and there is a concomitant increase in progesterone during the

luteal phase. This postovulatory rise in progesterone is essential for the

maintenance of the fertilized ovum if conception occurs. In the

nonfertile cycle, the demise of the corpus luteum is followed by menstruation and the beginning of the next menstrual cycle.

The adverse effects of cocaine on reproductive cycle function

include disorders of menstrual cycle duration as well as impairments in

folliculogenesis, ovulation, and luteal phase adequacy. These disruptions

may result in a series of clinical syndromes that include amenorrhea,

anovulation, and luteal phase dysfunction. The complete cessation of

menses for periods of months or years is called amenorrhea; anovulation

is the failure to ovulate; and luteal phase dysfunction is defined either as

a short luteal phase of 8 days or less from ovulation to menses or an

inadequate luteal phase when progesterone levels are abnormally low but

the interval from anovulation to menstruation is of normal length. Both

anovulation and luteal phase dysfunction may occur in women who

continue to menstruate. Cocaine and alcohol abuse also may result in

disorders of prolactin regulation. These disorders may be expressed

clinically as abnormally high prolactin levels, or hyperprolactinemia,

which is sometimes associated with abnormal secretion of breast milk, a

condition called galactorrhea. Cocaine and alcohol abuse both increase

the risk for spontaneous abortion once pregnancy occurs.

Analysis of these disorders is complicated by the fact that each

clinical entity may result from hormonal disruptions that occurred earlier
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in the menstrual cycle. For example, although follicle-stimulating hormone (FSH) is only one determinant of normal folliculogenesis, adequate

FSH levels are necessary for normal follicle development and maturation

(Goodman and Hodgen 1983). Suppression of FSH may delay follicle

maturation and subsequent ovulation or result in luteal phase dysfunction

after timely ovulation. Abnormally high levels of either luteinizing

hormone (LH) or estradiol during the follicular phase may contribute to

FSH abnormalities and anovulation and/or luteal phase dysfunction

(Dierschke et al. 1985, 1987; Zeleznik 1981). High levels of estrogens

during the early luteal phase may shorten the cycle by 5 or 6 days, which

is analogous to a luteal phase defect (Hutchison et al. 1987). Abnormally

high or low prolactin levels also may be associated with luteal phase

dysfunction (McNeely and Soules 1988). Hyperprolactinemia may also

be a concomitant of amenorrhea. The continuing controversies and

unresolved issues concerning the prevalence, differential diagnosis, and

pathogenesis of luteal phase dysfunction have been critically examined by

Stouffer (1990) and McNeely and Soules (1988). However, it appears

that any drug-induced imbalance in anterior pituitary, gonadal, and

adrenal hormones may lead to disruption of the normal menstrual cycle.

IMPLICATIONS OF POLYDRUG ABUSE

Polydrug abuse involving cocaine and other drugs appears to be

increasingly common, so the contribution of a single drug to these reproductive disorders is often difficult to determine in clinical studies. Moreover, concurrent abuse of several drugs may increase the adverse consequences of single drug use (Kreek 1991, pp. 91-112). For these reasons

the author and colleagues have examined the effects of acute and chronic

exposure to cocaine in the female rhesus monkey. Neuroendocrine

control of the menstrual cycle is similar in rhesus females and in women,

so the rhesus monkey is a model of choice in reproductive biology. In

studies of endocrine pharmacology, as well as basic reproductive biology,

this model has led to new approaches to the study of clinical phenomena.

For example, after the discovery of the importance of pulsatile gonadotropin release in neuroendocrine control of the menstrual cycle in rhesus

monkeys (Knobil 1974, 1980), it was found that many infertility disorders

in women are associated with infrequent LH pulses of low amplitude

throughout the menstrual cycle or no LH pulses at all (Crowley et al.
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1985; Santoro et al. 1986). These abnormal LH pulsatile release patterns

are associated with amenorrhea. Administration of synthetic hypothalamic luteinizing hormone-releasing hormone (LHRH) restored normal

LH release patterns and fertility (Crowley et al. 1985; Filicori et al. 1994;

Martin et al. 1993; Santoro et al. 1986). Although malnutrition and a

number of medical disorders, as well as strenuous exercise, may contribute to amenorrhea, these findings suggest the possibility that cocaine and

alcohol also may disrupt the pulsatile release of these essential hormones,

resulting in amenorrhea; studies to evaluate this hypothesis are ongoing.

The primate model of cocaine and other drug self-administration

is especially valuable for studying the effects of chronic drug use on

neuroendocrine hormones. In laboratory studies, rhesus monkeys selfadminister most drugs that are abused by humans, and the neuroendocrine effects of a single drug such as cocaine can be studied without the

confounding influence of polydrug abuse, malnutrition, and concurrent

medical disorders. Rhesus monkeys also can be used to study the effects

of multiple drugs under controlled conditions (Mello et al. 1995a).

EFFECTS OF CHRONIC COCAINE SELFADMINISTRATION ON THE MENSTRUAL CYCLE

The effects of chronic cocaine self-administration on menstrual cycle

duration and anterior pituitary and gonadal hormones have been examined for periods of 2 to 3 years in adult rhesus females (Macaca mulatta)

(Mello et al. 1997). Drug-naive rhesus females were adapted to the

laboratory for several months until stable ovulatory menstrual cycles

occurred. Then the monkeys were implanted with intravenous catheters

under aseptic conditions and trained to self-administer cocaine and

food on a simple operant task. Monkeys were given access to cocaine

in 4 sessions each day and were limited to 20 injections per session to

minimize any possible adverse drug effects. Under these conditions, each

monkey could control the frequency and amount of cocaine injected up

to a limit of 8 mg/kg/day. Food self-administration sessions preceded

each drug self-administration session so that cocaine intoxication would

not compromise food intake. A nutritionally fortified banana pellet diet

also was supplemented with fresh fruits and vegetables, multiple vitamins, and chow. Water was continuously available, and a 12-hour lightdark cycle was in effect. Monkeys remained healthy and active, and
135

food intake and body weight were normal under these limited cocaine

access conditions.

Thus far, the effects of chronic cocaine self-administration on menstrual cycle duration have been examined in eight rhesus females and

compared with six control females that were occasionally exposed to

single doses of cocaine. Approximately 50 percent of all menstrual cycles

were of abnormal duration in the cocaine self-administration group,

whereas only 6 percent of cycles were abnormal in the control group.

Abnormally short cycles, consistent with luteal phase defects, accounted

for 17 percent of the abnormal menstrual cycles. The rest of the cycles of

abnormal duration were longer than each monkey’s precocaine baseline

cycles by one or more standard deviation from the mean or met criteria

for amenorrhea (60 days with no menses). There were 19 amenorrheic

cycles when no menses occurred for 61 to 190 days. Approximately onethird of the menstrual cycles studied during cocaine self-administration

were anovulatory as defined by midluteal phase progesterone levels below

4.5 ng/mL. These data suggest that chronic cocaine exposure disrupts

menstrual cycle regularity in otherwise healthy monkeys studied under

controlled conditions. The menstrual cycle disruptions observed are

consistent with clinical reports on women who abuse cocaine and who

are also polydrug abusers (Teoh et al. 1992) and with experimental

evidence that 2 or more weeks of cocaine exposure disrupt estrous

cyclicity in the rat (King et al. 1990, 1993).

ACUTE EFFECTS OF COCAINE ON

NEUROENDOCRINE FUNCTION

Alcohol and other drugs may have different effects on neuroendocrine hormones if intoxication occurs occasionally or chronically through

time (Mello et al. 1992, pp. 575-621; Mello and Mendelson 1997).

Interpretation of the effects of chronic cocaine self-administration on the

menstrual cycle is complemented by examination of the acute effects of

single doses of cocaine on the neuroendocrine hormones that are essential for normal reproductive function. Neuroendocrine effects of single

doses of cocaine eventually clarify the ways in which cocaine disrupts

reproductive function.

Recent studies of the acute effects of alcohol as well as those of

cocaine have challenged some common assumptions about how drugs
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disrupt neuroendocrine regulation. Drug-related disorders of reproductive function have traditionally been attributed to a suppression of

pituitary and gonadal hormones (Mello et al. 1992, pp. 575-621). The

basic concept is that drugs disrupt regulation of the reproductive system

by suppressing basal levels of essential hormones. Yet there is accumulating evidence that acute cocaine intoxication, as well as acute alcohol

intoxication, may stimulate rather than suppress the release of LH from

the anterior pituitary (Mello and Mendelson 1997). These data further

complicate the understanding of how cocaine intoxication induces

derangements of the menstrual cycle.

Cocaine’s Effects on Luteinizing Hormone

In the normal menstrual cycle, a midcycle surge in LH stimulates

ovulation, the release of the ovum from the ovary. One recent unexpected finding is that cocaine stimulates LH in female rhesus monkeys

during both the follicular and the midluteal phases of the menstrual cycle

(Mello et al. 1990a, 1993). Cocaine also stimulates LH in male humans

and in male rhesus monkeys (Mello et al. 1993; Mendelson et al. 1992a).

LH stimulation would not have been predicted from the basic pharmacological actions of cocaine. Cocaine inhibits dopamine reuptake and acts

as an indirect dopamine agonist, and clinical studies have shown that

administration of dopamine agonists suppresses rather than increases LH

(see Yen 1986, pp. 178-263). Yet a significant increase in LH after acute

cocaine administration has been a consistent and robust finding across

species and in gonadally intact males and females. Moreover, in rhesus

females, administration of cocaine concurrently with synthetic LHRH,

the hypothalamic hormone that stimulates LH release, resulted in a

significant enhancement of peak LH levels (Mello et al. 1990b).

One exception to this general finding is that cocaine has no effect

on LH or FSH in ovariectomized rhesus monkeys (Mello et al. 1995b).

The same doses of cocaine used in gonadally intact males and females,

studied under the same conditions (Mello et al. 1990a, 1990b, 1993),

did not change gonadotropin hormone levels in ovariectomized females

even though plasma cocaine levels were equivalent (Mello et al. 1995b).

Synthetic LHRH stimulated LH release in these ovariectomized females

even though cocaine did not (Mello et al. 1995b). The reason for

this difference between the acute effects of cocaine in intact and

ovariectomized monkeys has not yet been determined, but one obvious
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possibility is that ovariectomized monkeys have only trace amounts of

estradiol, the ovarian hormone that is necessary for the LH periovulatory

surge in a normal menstrual cycle. The role of estradiol in cocaine’s

stimulation of LH is undetermined, and the effects of cocaine on ovarian

steroid hormones are unknown.

The implications of a cocaine-induced increase in LH for the

biologic and reinforcing properties of cocaine are unclear, but it is

interesting to speculate that if cocaine increases LH near midcycle,

this increase in turn could trigger ovulation and result in an increased

risk for pregnancy. Moreover, clinical studies suggest that sexual arousal

is associated with increased LH levels (LaFerla et al. 1978), and the

cocaine-induced increase in LH could be associated with the enhanced

sexuality reported by some cocaine abusers (see Mello et al. 1990a for

discussion).

Cocaine’s Effects on Adrenocorticotropic Hormone

Cocaine also stimulates adrenocorticotropic hormone (ACTH)

release from the anterior pituitary. Corticotropin-releasing hormone

(CRH) cannot be measured directly in peripheral blood, but by implication, cocaine also stimulates CRH release because CRH stimulates

ACTH release. These stimulatory effects of cocaine appear to be

centrally mediated because administration of CRH antagonists prevents

the cocaine-induced increase in ACTH (Rivier and Vale 1987).

Cocaine administration is followed by a rapid increase in ACTH

in women (J.H. Mendelson, personal communication, November 1996),

men, and rhesus males (Mendelson et al. 1992b, 1992c, pp. 131-155;

Sarnyai et al. 1996; Teoh et al. 1994b). It is possible that these stimulatory effects of cocaine on ACTH and CRH may contribute to the

menstrual cycle disorders observed in chronic cocaine abusers. It is well

established that synthetic CRH administration has a direct suppressive

effect on release of LH and FSH, and this in turn may result in

anovulation and amenorrhea (Olster and Ferin 1987; Xiao and Ferin

1988). Yet cocaine stimulates both LH and ACTH after acute administration, and it is possible that chronic cocaine exposure may lead to

disregulation of these feedback systems. The significance of rapid

changes in ACTH for cocaine’s reinforcing effects is unclear, but the

time course parallels the time course of increases in plasma cocaine and
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reports of positive changes in mood (Mendelson et al. 1992b, 1992c,

pp. 131-155; Mello and Mendelson 1997).

In contrast to cocaine’s stimulatory effects in men and women,

cocaine had no effect on ACTH in ovariectomized monkeys even

though synthetic CRH stimulated ACTH in the same animals (Sarnyai

et al. 1995). The basis for the lack of cocaine stimulation of both

ACTH and LH in ovariectomized females is unclear (Mello et al. 1995b;

Sarnyai et al. 1995). However, as noted above, one possible explanation

is the low levels of gonadal steroid hormones in ovariectomized monkeys

compared with gonadally intact males and females. Studies are in

progress to examine anterior pituitary responsivity to cocaine in

ovariectomized females during ovarian steroid hormone replacement

regimens.

Cocaine’s Effects on Prolactin

Hyperprolactinemia is another endocrine abnormality sometimes

associated with chronic cocaine abuse and with cocaine abstinence

syndrome (Cocores et al. 1986; Dackis and Gold 1985; Mendelson et al.

1989). Analysis of the pulsatile release characteristics of prolactin in

hyperprolactinemic male cocaine abusers revealed an increased peak

amplitude but no change in pulse frequency (Mendelson et al. 1989).

These data were interpreted to indicate that cocaine changed the

dopaminergic inhibition of basal prolactin secretion.

The ways in which cocaine abuse may disrupt prolactin regulation

are very complex (Mello and Mendelson 1997). Prolactin is a hormone

that is under inhibitory dopaminergic control. Cocaine acts

as an indirect dopamine agonist because it binds to the dopamine

transporter and blocks the reuptake of dopamine. A single acute dose

of cocaine decreases prolactin in rhesus males and females, presumably

as a result of increasing dopamine levels (Mello et al. 1990a, 1993).

This acute suppression of prolactin appears inconsistent with the

hyperprolactinemia seen clinically. However, it is thought that chronic

cocaine abuse may lead to a downregulation of dopamine receptors,

sometimes referred to as “dopamine depletion,” that is, decreased

dopamine synthesis and secretion (Dackis and Gold 1985). Prolactin is

secreted from the anterior pituitary by the lactotrophs. The dopaminesensitive lactotrophs, which have primarily D2

 dopamine receptors,
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secrete significantly more prolactin than thyrotropin-releasing-hormonesensitive lactotrophs (Yen 1991, pp. 357-388). It is possible that chronic

cocaine exposure may impair the sensitive regulatory feedback relationship between hypothalamic dopamine and prolactin to result in

hyperprolactinemia seen clinically.

One way to study changes in prolactin regulation as a function of

chronic cocaine exposure is to give infusions of exogenous dopamine

and measure the degree to which prolactin is suppressed and the level

to which prolactin increases after the dopamine infusion is stopped

(Mello et al. 1994). Although exogenously administered dopamine does

not cross the blood-brain barrier, it does act at the median eminence and

the anterior pituitary (Yen 1979, pp. 387-416). This approach was used

to determine whether there were progressive changes in the prolactin

response to dopamine in rhesus females studied before cocaine exposure

and after several months of cocaine self-administration (Mello et al.

1994).

The top panel of figure 1 shows the effects of dopamine infusions

and interruptions on prolactin in four normal rhesus females studied

before chronic cocaine exposure. These monkeys had low baseline

prolactin levels (6.2 ng/mL) that significantly decreased to below

2 ng/mL during dopamine infusions. Prolactin returned to baseline

levels after each dopamine infusion ended.

The bottom panel of figure 1 shows the effects of dopamine infusions

in the same group of rhesus females after they had self-administered

cocaine for an average of 74 days. These monkeys took an average of

4.78 mg/kg/day of cocaine during the 30 days before this study. Baseline

levels of prolactin were significantly higher than before cocaine and

now averaged 20 ng/mL. Dopamine infusions continued to suppress

prolactin significantly, but after each dopamine infusion stopped,

prolactin increased to about the same or higher levels than before

cocaine exposure. There was a significant and progressive increase in

prolactin levels after each dopamine infusion, and peak prolactin levels

reached hyperprolactinemic levels of 60 ng/mL. Hyperprolactinemia is

defined clinically by daytime prolactin levels above 25 ng/mL. These

data suggest that dopamine probes can be used to unmask cocainerelated changes in prolactin regulation before the development of

hyperprolactinemia (Mello et al. 1994).
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FIGURE 1. Effects of dopamine infusions (10 μg/kg/min) and

interruptions on prolactin (ng/mL) before and after

chronic cocaine self-administration. A continuous infusion

of dopamine (10 μg/kg/min) was started immediately

after collection of samples 2, 13, and 24. Each dopamine

infusion (shown as a shaded area) continued for

80 minutes and stopped abruptly after collection of

samples 10, 21, and 32. Bolus samples for prolactin

analysis were collected at 10-minute intervals except

during the first two interruptions of the dopamine

infusion when the first two samples were collected at

5-minute intervals. Prolactin levels (ng/mL) are shown

on the left ordinate, and consecutive samples are

shown on the abscissa. Each data point represents the

mean× (±SE) of four monkeys. The top panel shows the

effects of dopamine infusions and interruptions on

prolactin in drug-naive monkeys. The bottom panel shows

the effects of dopamine infusions and interruptions on

prolactin in the same monkeys after an average of

74 (±19) days of cocaine exposure. These monkeys had

self-administered an average of 4.78 (±0.67) mg/kg/day

of cocaine for the past 30 days.

KEY: × = mean; SE = standard error

SOURCE: Mello et al. 1994. Copyright 1994 by the American Society for Pharmacology

and Experimental Therapeutics (Bethesda, MD).
141

Evidence consistent with this notion comes from another monkey

that had been exposed to cocaine for a total of 571 days at the time of an

acute dopamine probe (figure 2). This monkey had taken the maximum

amount of cocaine available, 8 mg/kg/day, for the past month. During a

dopamine probe study, prolactin increased from a baseline of 28 ng/mL

to a peak of 141 ng/mL after the first dopamine infusion stopped. This

postdopamine increase in prolactin was more than five times higher than

normoprolactinemic levels. Subsequently, this monkey lost her catheter

and became markedly hyperprolactinemic during cocaine abstinence.

The bottom panel of figure 2 shows dramatically hyperprolactinemic

baseline prolactin levels of 326 ng/mL. A prolactin level above

300 ng/mL exceeds levels measured in human females during suckling

(Yen 1991, pp. 357-388). Prolactin was suppressed to 154 ng/mL during

dopamine infusion and then increased to 270 and 174 ng/mL after the

dopamine infusion stopped (Mello et al. 1994).

The mechanisms underlying cocaine’s effects on prolactin regulation

and the clinical significance of cocaine-related hyperprolactinemia are

poorly understood (Mello and Mendelson 1997). Hyperprolactinemia

may contribute to menstrual cycle abnormalities and amenorrhea

associated with chronic cocaine exposure. Moreover, from the broader

perspective of women’s health, prolactin abnormalities may compromise

immune function (Reichlin 1993) and increase vulnerability to human

immunodeficiency virus (HIV) infection. Clinical studies of chronic

cocaine abusers have shown an increase in the size of the pituitary gland,

or pituitary volume, which could reflect hyperplasia of the lactotrophs,

the cells that release prolactin (Teoh et al. 1993). There is recent

evidence that hyperprolactinemia may be associated with increased risk

for relapse to cocaine abuse (Teoh et al. 1990; Weiss et al. 1994). These

clinical findings suggest that hyperprolactinemia is a biological index of

the severity of cocaine dependence that may predict relapse to cocaine

abuse.

NEUROENDOCRINE HORMONES AND GENDER

DIFFERENCES IN COCAINE’S EFFECTS

Cocaine, as well as other abused drugs, may disrupt the menstrual

cycle by altering basal levels of critical neuroendocrine hormones.

Moreover, recent evidence suggests possible hormonally mediated

differences in cocaine’s effects. Recall that cocaine stimulated LH
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FIGURE 2. Effects of dopamine infusions (10 μg/kg/min) and

interruptions on prolactin (ng/mL) levels in one monkey

during cocaine self-administration and after cocaine

withdrawal. Dopamine infusion and sample collection

procedures were the same as described for figure 1.

The top panel shows the effects of dopamine infusions

and interruptions on prolactin after a total of 571 days of

cocaine exposure. At the time of the study, this monkey

had self-administered cocaine for 215 consecutive days

and had self-administered an average dose of 8 mg/kg/

day of cocaine for the past 30 days. The blood exfusion

catheter clogged at sample 26, and the study was

terminated. The bottom panel shows changes in

prolactin in response to dopamine 89 days after abrupt

withdrawal from a total of 989 days of cocaine selfadministration.

SOURCE: Mello et al. 1994. Copyright 1994 by the American Society for Pharmacology

and Experimental Therapeutics (Bethesda, MD).
143

and ACTH release in normally cycling rhesus females and in human

and rhesus males, but cocaine had no effect on these hormones in

ovariectomized rhesus females (Mello and Mendelson 1997).

Moreover, cocaine did not suppress prolactin in ovariectomized females

as it did in intact males and females (Mello et al. 1995b). Because very

low levels of ovarian steroid hormones are found in ovariectomized

females, this suggests that estradiol may be important for the effects of

cocaine on anterior pituitary hormones in normal females. It is reasonable to assume that female gonadal steroid hormones may confer health

benefits as well as risks (Jaffe 1991, pp. 389-408), and the ways in which

these hormones are modulated by cocaine, alcohol, and other abused

drugs are an emerging area of inquiry.

In one instance, women were somewhat less vulnerable than men

to an adverse consequence of cocaine (Levin et al. 1994). Cocaine

abuse has been associated with a number of cerebrovascular disorders,

including ischemic stroke and intracerebral and subarachnoid hemorrhage. The effects of cocaine on the brain can be measured with an

imaging procedure called single photon emission computed tomography

(SPECT). The author’s group has reported that cerebral perfusion

abnormalities in cocaine abusers are often indistinguishable from those

in early AIDS dementia complex (Holman et al. 1992). SPECT analysis

subsequently showed that cocaine abusers had more focal cerebral

perfusion defects than normal controls (Levin et al. 1994). However,

an unanticipated finding was that the nine female cocaine abusers had

fewer cerebral perfusion defects in the frontal, temporal, and parietal

lobes and in the basal ganglia than the nine men who were matched

in terms of age. Moreover, these women reported having used more

cocaine for a longer time than the men, an average of 15.3 years as

opposed to 8.2 years (Levin et al. 1994).

Levin and coworkers (1994) concluded that these gender differences

in cerebral perfusion defects could not be explained by differences in

age, race, body mass index, alcohol use, cocaine use, or route of drug

administration. Rather, it was postulated that estrogens and progestins

may protect women from cocaine-associated cerebral vasospasm. This

speculation is consistent with evidence that, before menopause, women

have less atherosclerotic disease and less cerebrovascular disease than

men. These clinical findings suggest that estrogen may protect women
144

from mild atherosclerosis. After menopause, estrogen replacement

therapy reduces risk for premature cardiac disease and osteoporosis

(Jaffe 1991, pp. 389-408).

It is increasingly recognized that changes in hormonal levels

across the menstrual cycle may influence the pharmacokinetics and

pharmacodynamics of treatment medications (Merkatz et al. 1993).

Possible gender differences in drug efficacy or drug toxicity have led to

changes in Food and Drug Administration policy and the development

of clinical guidelines for inclusion of women in clinical trials (Merkatz

et al. 1993). The extent to which gender differences in the biologic

effects of drugs may reflect the differences in hormonal milieu between

men and women is poorly understood. There is a recent report that peak

plasma cocaine levels after intranasal administration were greater during

the follicular phase than during the luteal phase of the menstrual cycle,

but subjective reports of cocaine’s effects were equivalent (Lukas et al.

1996). Men had higher peak plasma cocaine levels and appeared to

have greater subjective responses to intranasal cocaine than women

(Lukas et al. 1996).

COCAINE-NEUROENDOCRINE

INTERACTIONS

One challenge for future research is to clarify the ways in which

cocaine interacts with reproductive hormones to cause disorders of

reproductive function. It is increasingly apparent that analysis of the

effects of cocaine and other drugs on neuroendocrine function requires

integrative physiological studies in women and in whole animal models

because of the complex interrelationships among all the components

of the hypothalamic-pituitary-gonadal and the hypothalamic-pituitaryadrenal axes. However, beyond these issues are many unanswered

questions about how the hormonal milieu may modulate the vulnerability of the brain and the immune system to cocaine’s toxic effects.

Finally, the role of neuroendocrine hormones in cocaine reinforcement

is unclear, but cocaine’s rapid stimulation of LH and ACTH is consistent

with the notion that these hormonal changes may contribute to the

reinforcing properties of cocaine and other abused drugs (see Mendelson

et al. 1992c, pp. 131-155) as well as to adverse drug effects on reproductive function.
145

In conclusion, either the acute stimulatory effect of cocaine intoxication on gonadotropins, estradiol, or ACTH or the suppressive effects

of chronic intoxication may disrupt the functional integration of the

endocrine system and lead to infertility disorders and menstrual cycle

disruptions. In those instances where acute cocaine intoxication may

facilitate premature ovulation and lead to enhanced fertility, disruption

of maternal reproductive hormones may compromise pregnancy outcome (see Hutchings 1989). Whatever the relationship of alcoholand other drug-related disruptions of maternal hormones to fetal growth

and development, it is important to recognize that abused drugs have

similar effects on the neuroendocrine system. Because the combined

effects of several drugs may have more adverse medical consequences

than the use of a single drug (Kreek 1991, pp. 91-112), polydrug abuse

may increase risk for fetal developmental impairments. Unraveling the

relative contributions of poor prenatal care, marginal medical status,

and chronic drug abuse to fetal developmental abnormalities presents

a formidable challenge (Hutchings 1989; Mayes et al. 1992). Drug

avoidance is probably the best recommendation for a successful pregnancy and a healthy baby.

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ACKNOWLEDGMENT

This chapter was prepared with support from National Institute on

Drug Abuse grants DA-00101 and DA-04059.
150

AUTHOR

Nancy K. Mello, Ph.D.

Professor of Psychology (Neuroscience)

Harvard Medical School

Co-Director, Alcohol and Drug Abuse Research Center

McLean Hospital

115 Mill Street

Belmont, MA 02178

(617) 855-2746 (Tel)

(617) 855-2519 (Fax)

mello@mclean.org (E-mail)