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Home , Fetus, Puberty

The Hormonal Effects of Use on the and

Kara Gabriel, M.A., Candace Hofmann, M.A., Maria Glavas, B.Sc., and Joanne Weinberg, Ph.D.

During , the hormonal systems of the mother and fetus are intricately interconnected to ensure normal fetal development. Accordingly, maternal alcohol consumption during pregnancy can interfere with fetal development, not only directly, through adverse effects exerted by alcohol that crosses the and enters the fetal bloodstream, but also indirectly, by disturbing the functions and interactions of maternal and fetal . In both the mother and the fetus, alcohol exposure can impair the functioning of the hypothalamic-pituitary-adrenal axis, which regulates the body’s response to ; the hypothalamic-pituitary-gonadal axis, which controls reproductive functions; and the hypothalamic-pituitary- axis, which regulates the metabolism of almost all tissues. In addition, alcohol can interfere with the activities of growth and insulin-like growth factors, which promote body growth and activity. Some of the effects of maternal alcohol consumption on fetal hormone systems may contribute to the adverse effects observed in children with fetal alcohol syndrome and related disorders. KEY WORDS: AODE (alcohol and other drug effects); ; mother; fetus; fetal development; polypeptide hormones; adverse drug effect; prenatal alcohol exposure; fetal alcohol syndrome; placenta; pituitary-adrenal axis; pituitary-thyroid axis; -pituitary axis; somatotropin; growth promoting factors; insulin; congenital anomaly; animal model; literature review

he endocrine (i.e., hormonal) the activities of all components of the the amount of data from subjects system plays a critical role in by acting either continues to grow, research using animal Tmaintaining the body’s internal directly on the endocrine glands and/ models of prenatal alcohol exposure equilibrium (i.e., homeostasis). Through or on the hypothalamus or pituitary. has greatly expanded scientific under- the release of hormones, the endocrine In a pregnant , alcohol- standing of alcohol’s effects on endo- system regulates functions as diverse as induced alterations in endocrine activity crine function. , stress response, meta- may affect not only her health but also bolism, growth, and behavior. Two her ability to maintain a successful structures—(1) a region called pregnancy. Moreover, alcohol consump- The Role of the Placenta the hypothalamus and (2) the pituitary tion during pregnancy can directly affect gland, which is attached to the base of fetal development because alcohol read- During pregnancy, the placenta plays the brain through the pituitary stalk— ily crosses the placenta. Finally, alcohol a pivotal role in maintaining pregnancy work together to control the activity of consumed during pregnancy may alter and affecting fetal development. Until most endocrine glands in the body, includ- fetal development indirectly by disrupt- the fetal endocrine system is func- ing the adrenal glands, (i.e., ing the normal hormonal interactions tional, the placenta acts as a miniature and testes), and thyroid gland. In between the mother and the fetus. This endocrine system, producing hormones turn, each of those glands produces one article reviews the multiple hormonal such as human chorionic , or more hormones (e.g., cortisol, estro- effects of alcohol use during pregnancy chorionic thyrotropin, and chorionic gen, , and thyroid hormone) on the mother and fetus. The article corticotropin. Through its hormone that control various physiological incorporates findings from both human production, the placenta regulates activities in the body. Alcohol can alter and animal studies, because although fetal growth, maturation, and nutrient

170 Alcohol Health & Research World Hormonal Effects of Alcohol on the Mother and Fetus

utilization. In addition to its endocrine pregnancy and providing support for activity, the placenta acts as a partial Mechanisms of Alcohol- the fetus. Any disruption of the mater- barrier, or filter, between the maternal nal hormone balance can lead to poor and fetal , allowing the transfer Induced Changes in pregnancy outcome, including fetal birth of some maternal hormones and other Hormone Levels defects. As the following sections de- substances (e.g., alcohol) from the scribe, alcohol can interfere with mater- mother to the fetus while preventing The concentration of a given nal endocrine functions through numer- the transfer of others. As a result of hormone in the blood depends ous mechanisms (also see textbox). these placental functions, the fetus is on many factors, including the exposed to three sets of hormones: (1) rate at which the hormone is Effects on the Hypothalamic- those secreted by the placenta, (2) those produced and secreted, its distri- Pituitary-Adrenal Axis produced by the mother, and (3) the bution in the body, and the rate fetus’s own hormonal secretions. at which it is removed from the The hypothalamic-pituitary-adrenal Alterations in placental functioning, blood. Alcohol can interfere with (HPA) axis is a hormone system that plays including the production and activity of a hormone’s function by altering an essential role in the body’s response placental hormones, may affect fetal each of those factors. In addition, to stressful events (see table, p. 172). growth and development and increase total hormone concentration During periods of stress, the hypothal- the risk of spontaneous . To does not necessarily correspond amus secretes corticotropin-releasing date, little information is available on the to the concentration of active hormone (CRH), which, in turn, stim- direct effects of alcohol on the placental hormone in the blood, because ulates the release of adrenocorticotropic hormones in . Animal models called binding proteins, hormone (ACTH) from the pituitary have extended researchers’ limited under- or globulins, may attach to and gland. ACTH regulates the growth and standing of the placenta’s role in the temporarily inactivate a hormone. activity of the outer layer of the adrenal effects of prenatal alcohol exposure. Alcohol also may alter the levels glands (i.e., the ) and of these proteins, thereby modi- induces the secretion of adrenal hor- fying endocrine activity and, dur- mones called glucocorticoids—cortisol Alcohol’s Impact on ing pregnancy, inducing complex (in humans) and corticosterone (in Endocrine Functioning consequences for both mother rodents). As the glucocorticoid levels in Pregnant Women and fetus. increase in the blood, they act on the pituitary, hypothalamus, and other Historically, alcohol research in humans brain regions to inhibit further activa- has been conducted primarily in men. alcohol’s effects on neuroendocrine tion of the HPA axis. This process of Only during the past two decades have function in women, see Mello et al. inhibiting further hormonal activation researchers begun to analyze alcohol’s 1993). Studies have found that women is called negative feedback. effects on women (for a review of have higher blood alcohol levels (BALs) In the short term, glucocorticoids than men after drinking the same mobilize the body’s energy resources to amount of alcohol per body . In respond to stress. This mobilization KARA GABRIEL, M.A., and CANDACE addition, women show an accelerated occurs at the expense of energy-dependent HOFMANN, M.A., are doctoral students in progression of alcohol-related adverse functions, such as digestion, growth, the Department of Psychology and MARIA consequences, developing alcohol- and reproduction. When the stressful GLAVAS, B.SC., is a doctoral student in the induced disease and brain damage situation is prolonged (i.e., lasts for Graduate Program in , earlier in life and after lower alcohol weeks or months) or occurs frequently, University of British Columbia, Vancouver, intake than men (for a review, see the resulting metabolic effects and redis- British Columbia, . All three stu- Roman 1988). The reasons for the tribution of resources may have patholog- dents are pursuing their dissertation research differential risks associated with alco- ical consequences, including the devel- in the laboratory of Joanne Weinberg, Ph.D. hol consumption for women and men opment of ulcers, growth retardation remain poorly understood, emphasiz- and underdevelopment (i.e., ) JOANNE WEINBERG, PH.D., is a professor ing the importance of further studies in children, and suppression of the in the Department of and an on alcohol’s impact on physiological . Alcohol consumption Honorary Professor in the Department of functioning in women. also activates the HPA axis and stimu- Psychology, University of British Columbia, Even fewer studies have investigated lates glucocorticoid release, similar to Vancouver, British Columbia, Canada. the consequences of alcohol consump- the effects of stress. (For more informa- tion during pregnancy on women’s tion on alcohol’s effects on the HPA This work was supported in part by National physiological (including endocrine) axis, also see the article by Gianoulakis, Institute on and Alcoholism functions. The maternal endocrine pp. 202–210). grants AA–07789 to Joanne Weinberg system undergoes numerous changes The basal or resting activity of the and F31 AA–05499 to Kara Gabriel. that are geared toward maintaining the HPA axis (i.e., the activity in the absence

Vol. 22, No. 3, 1998 171 of stress) increases during pregnancy. or low alcohol concentrations. Because and reproductive functions of the This increase results in higher CRH and the hormones of the HPA axis play gonads and stimulate the production of ACTH levels and, consequently, elevated numerous roles in energy distribution, sex hormones, including and glucocorticoid levels in the blood of preg- metabolism, and immune function, (women also secrete small nant females compared with nonpregnant alcohol-induced HPA activation may amounts of androgens, such as testos- females. Researchers have investigated produce widespread physiological changes terone). Both estrogens and androgens alcohol’s impact on HPA activity in during pregnancy. activate numerous processes in the both pregnant and nonpregnant females. maturing organism, such as the onset of Studies of pregnant rodents found that Effects on the Hypothalamic- , the development of secondary alcohol consumption further stimulated Pituitary-Gonadal Axis sex characteristics, and the behaviors an already activated HPA axis. Thus, associated with reproduction. In the compared with pregnant females on The hormones of the hypothalamic- developing fetus, androgens also have non-alcohol-containing diets, pregnant pituitary-gonadal (HPG) axis control an organizing function, affecting not only females receiving an alcohol-containing reproductive functions and behavior. the testes and ovaries but also the size diet exhibited increases in The HPG axis is activated by the secre- and function of different brain regions. weight, resting glucocorticoid levels, and tion of gonadotropin-releasing hormone Researchers have clearly documented the HPA response to stress (for a review, (GnRH) from the hypothalamus. the adverse effects of chronic alcohol see Weinberg 1993). This alcohol-induced GnRH, in turn, stimulates the release consumption on women’s reproductive activation of the HPA axis occurred early of luteinizing hormone (LH) and follicle- functioning. For example, alcoholic during pregnancy and persisted through- stimulating hormone (FSH) from the women have a higher frequency of out gestation, regardless of whether the pituitary. Both LH and FSH regulate menstrual abnormalities, such as irreg- alcohol-containing diet included high the development, growth, maturation, ular and the cessation of

Hormone Systems Affected by Maternal Alcohol Consumption and Their Components

Hormone System or Hormone Abbreviation Site of Production

Hypothalamic-pituitary-adrenal axis (involved in the stress response) Corticotropin-releasing hormone CRH Hypothalamus Adrenocorticotropic hormone ACTH Glucocorticoids Adrenal glands Cortisol (humans) Corticosterone (rats) Hypothalamic-pituitary-gonadal axis (controls reproductive functions and behavior) Gonadotropin-releasing hormone GnRH Hypothalamus Luteinizing hormone LH Pituitary gland Follicle-stimulating hormone FSH Pituitary gland Estrogens Primarily ovaries Androgens (e.g., testosterone) Primarily testes Hypothalamic-pituitary-thyroid axis (controls overall metabolic rate in almost all tissues and organs) Thyrotropin-releasing hormone TRH Hypothalamus Thyroid-stimulating hormone TSH Pituitary gland Thyroxine T4 Thyroid gland Triiodothyronine T3 Thyroid gland system (promotes body growth and activity as well as energy storage in tissues) Growth hormone-releasing hormone GHRH Hypothalamus Somatostatin SS Hypothalamus Growth hormone GH Pituitary gland Insulin-like growth factors 1 and 2 IGF-1, IGF-2 Primarily liver

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, than do nonalcoholic women function becomes impaired. In , produced primarily in the liver. These (Mello et al. 1993). Those menstrual hypothyroidism is marked by reductions growth factors, whose production is abnormalities may be mediated, at least in metabolic rate and energy expendi- induced by growth hormone, act on in part, by alcohol-induced elevations ture, resulting in widespread changes various tissues to mediate the effects in another pituitary hormone— in tissue function as well as in drowsi- of growth hormone. In addition, —that suppresses ovulation ness and listlessness. IGFs are thought to play an impor- (Mello et al. 1993). In , nonpregnant humans, tant role in the regulation of fetal Studies of alcohol’s effects on HPG chronic alcohol abuse has long been asso- growth and development. activity in pregnant women found that ciated with thyroid dysfunctions (Israel Studies in human alcoholics have alcohol use altered the levels of sex et al. 1979). Dysfunction of the thyroid not yet identified characteristic alcohol- hormone-binding globulin (SHBG), a most often results from alcohol-induced induced alterations in growth hormone that binds to and temporarily liver damage, which interferes with the secretion and activity, at least in part inactivates androgens, thereby regulating conversion of T4 to T3. Research in because confounding factors (e.g., the the balance between biologically active pregnant animals has shown that alcohol duration of alcohol use and the presence and inactive androgens (Ylikorkala et consumption may reduce the levels of of alcohol-associated illnesses) also influ- al. 1988). During a normal pregnancy, TSH in the blood but not in the pitu- ence growth hormone secretion. Animal SHBG levels increase with advancing itary, suggesting that alcohol alters research has shown that pregnant . Ylikorkala and colleagues maternal HPT activity (for a review, see alcohol-consuming rats exhibit reduced (1988) demonstrated that in heavy- Hannigan 1993). The functional signif- growth hormone levels (for a review, drinking women whose alcohol abuse icance of such alterations for both the see Weinberg 1993). In addition, several resulted in fetal damage, SHBG levels pregnant female and the fetus, however, animal studies have indicated that alco- increased less than in nondrinking is still unknown. hol consumption may alter IGF levels women. Perhaps as a result of this in pregnant females. For example, Breese reduction in binding protein levels, the Effects on Growth Hormone and and Sonntag (1995) reported that IGF-1 heavy-drinking women exhibited ele- Insulin-Like Growth Factors levels in the blood were reduced and vated levels of active testosterone between IGF-2 levels in the blood were increased weeks 16 and 22 of gestation. These As the name implies, growth hormone in alcohol-consuming pregnant rats findings indicate that alcohol may affect promotes the body’s growth and activity compared with non-alcohol-consuming levels most strongly during as well as the storage of energy in vari- pregnant rats. Moreover, the researchers the first half of pregnancy. ous tissues, including fat (i.e., adipose), noted significant reductions in a com- liver, muscle, , , and . In ponent of IGF-binding protein, indicat- Effects on the Hypothalamic- the absence of growth hormone, both ing that alcohol may alter the regulation Pituitary-Thyroid Axis animals and humans show stunted of maternal IGF function. These altera- growth. Conversely, the hormone’s pre- tions may contribute to overall changes The hypothalamic-pituitary-thyroid sence results in increased growth as well in metabolism and other effects on both (HPT) axis regulates the rate of meta- as enhanced organ size and function. maternal and fetal systems. bolism in the body and is essential for Growth hormone is produced in the the normal growth and development pituitary gland. Secretion of the hormone of almost every organ system. The HPT is stimulated primarily by growth Alcohol’s Impact on axis is activated by the secretion of hormone-releasing hormone (GHRH), Endocrine Functioning thyrotropin-releasing hormone (TRH) which is released from the hypothal- in the Fetus and from the hypothalamus, which stimu- amus. An inhibiting hormone that is lates the release of thyroid-stimulating also secreted by the hypothalamus— Maternal alcohol consumption during hormone (TSH) from the pituitary. somatostatin—cooperates with GHRH pregnancy can produce devastating effects TSH, in turn, regulates the growth to regulate growth hormone secretion. on the fetus. The most severe conse- and activity of the thyroid gland and In addition, estrogens and androgens quence is fetal alcohol syndrome (FAS), the secretion of two structurally related promote and glucocorticoids inhibit which is associated with characteristic thyroid hormones—thyroxine (T4) growth hormone release, demon- patterns of abnormal facial structures, and triiodothyronine (T3). Of those two strating the interactive nature of the growth retardation, and developmental hormones, T3 is substantially more endocrine system. abnormalities of the central nervous sys- active, and much of the body’s T4 is Although growth hormone exerts tem (CNS). FAS was first associated converted into T3 in the liver and other some of its effects by acting directly with maternal alcohol consumption more tissues. Reductions in thyroid hormone on its target tissues, small proteins than 25 years ago (Lemoine et al. 1968; levels, a condition called hypothyroid- called insulin-like growth factors (IGFs), Jones and Smith 1973). More recently, ism, can result in serious consequences, or somatomedins, mediate other researchers have adopted three terms to the extent of which depends on the time effects. In adults, two forms of IGFs characterize children who were affected during the person’s life when thyroid exist—IGF-1 and IGF-2—which are by alcohol prenatally but do not meet

Vol. 22, No. 3, 1998 173 all the criteria for FAS (Stratton et al. 1996). alcohol exposure (i.e., whether the fetus and ensures homeostasis in response The term “partial FAS” refers to chil- is exposed to alcohol during the critical to stress. In the fetus, the first cells to dren with confirmed prenatal alcohol period of development of a particular become functional in the pituitary are exposure and evidence of some com- organ system). The is the those that release ACTH. By 9 weeks ponents of the characteristic facial time during which an organ system is of gestation, the human fetal pituitary anomalies but without full FAS. The undergoing crucial steps in development gland contains measurable ACTH term “alcohol-related birth defects” and/or maturation and consequently levels. Because maternal ACTH cannot (ARBDs) is used for children who have is most vulnerable to the disruptive cross the placenta into the fetal circula- primarily physical malformations or effects of any agent that causes abnormal tion, the fetal HPA system is controlled physiological abnormalities. Last, the fetal development or birth defects. For by a placental hormone called human term “alcohol-related neurodevelopmen- example, because the development of chorionic corticotropin until the fetal tal disorder” (ARND) describes children the facial and skull occurs during hypothalamus and pituitary have fully with either physical CNS abnormali- the first 3 months of gestation in matured. Maternal glucocorticoids (e.g., ties (e.g., smaller head size or structural humans, alcohol exposure during the cortisol), however, can cross the placenta brain abnormalities) or with behavioral first trimester can affect those structures and enter the . and/or cognitive abnormalities, such as and result in the characteristic facial As noted previously, alcohol con- deficits in memory, skills, or abnormalities observed in children with sumption activates the HPA axis and learning ability. FAS. Conversely, alcohol exposure dur- stimulates glucocorticoid release. The type and extent of the alcohol- ing the second or third trimester is more Therefore, alcohol consumed during induced fetal damage is partly related often associated with growth retardation pregnancy will activate the maternal to the level and pattern of fetal alco- and neurological defects, because fetal HPA axis and result in increased glu- hol exposure. For example, lower levels growth and brain development happen cocorticoid levels. Those glucocorticoids of prenatal alcohol exposure are required more rapidly during those gestational can cross the placenta, resulting in to induce neurodevelopmental effects stages. If maternal alcohol consumption elevated glucocorticoid levels in the than to induce physical or growth effects occurs during all three trimesters, the fetal blood, thereby signaling the fetal (Streissguth et al. 1989). Research in fetus is exposed to alcohol during the HPA axis to decrease its activity. At the nonhuman has shown that critical periods for the development of same time, however, alcohol in the behavioral deficits may occur without facial characteristics, growth patterns, maternal blood also crosses the placenta accompanying physical abnormalities and CNS function and thus may and directly activates the fetal HPA axis. (Clarren et al. 1990). Moreover, those develop full FAS. Such conflicting messages may alter studies found that effects of prenatal Prenatal alcohol exposure may adver- the development of the fetal HPA axis alcohol exposure are clearly observable sely affect the fetal endocrine system by disrupting communication among after once-per-week alcohol consump- and, consequently, the functioning of the CNS, hypothalamus, pituitary, and tion resulting in BALs above 140 mil- numerous organ systems. The endocrine adrenal glands. ligrams per deciliter (mg/dL) (i.e., the activities of both mother and fetus To investigate alcohol’s effects on the equivalent of four to six standard drinks1 change throughout gestation. For exam- fetal HPA axis, researchers have com- consumed by an average-sized woman). ple, whereas the transfer of maternal pared HPA activity in newborn rodents Indeed, maternal binge drinking (i.e., hormones across the placenta and/or that were prenatally exposed to alcohol consumption of five or more standard placental hormone production is essen- with newborn control animals that were drinks per occasion) during pregnancy is tial during early pregnancy, the activity not exposed to alcohol. In those stud- one of the strongest predictors of later of the fetal endocrine system becomes ies, alcohol-exposed neonates showed neurodevelopmental deficits in children more pronounced and important later evidence of prenatal HPA activation, with alcohol-induced damage (Streissguth in gestation. Consequently, alcohol’s such as elevated corticosterone levels in et al. 1989). Possibly, the effects of binge impact on fetal endocrine activity may the blood and brain for several days after drinking are particularly severe because occur through different avenues at dif- birth (see Weinberg 1993). Thereafter this drinking pattern results in high ferent time periods. Because of their and up to approximately 3 weeks of age, BALs in both mother and fetus, followed numerous effects on physiological the alcohol-exposed animals exhibited by repeated withdrawal episodes. More- processes, alcohol-induced alterations in a reduced HPA response to various kinds over, the fetus cannot metabolize alcohol hormone levels likely mediate some of of stress (e.g., exposure to a novel envi- effectively, because its immature liver does the effects of prenatal alcohol exposure. ronment, cold, or ether), as indicated not produce the necessary enzymes. by reduced levels of corticosterone and β 2 The type of fetal damage that results Effects on the HPA Axis -endorphin (see Weinberg 1993). may also be related to the timing of Those findings suggest that prenatal The HPA axis is essential for life alcohol exposure may delay the matura- 1One standard drink is defined as one 12-ounce because it affects the metabolism and tion of the HPA axis or of the pathways can of beer or wine cooler, one 5-ounce glass of activity of numerous systems (e.g., the in the brain that activate the hypotha- wine, or 1.5 ounces of distilled spirits. nervous system and the immune system) lamus in response to stress.

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After the first few weeks of life, the exposed animals may show deficits in (i.e., ) and decreas- pattern of reduced responsiveness to their ability to use or respond to cues ed testosterone levels in the blood stress is reversed. In fact, adolescent and in their environment. compared with control animals. adult animals prenatally exposed to Similar to the findings in animals, alcohol typically display increased HPA a recent study in human whose • Adult male animals prenatally activation in response to various types drank heavily at conception exposed to alcohol exhibit lower of stress as indicated by the following found greater increases in cortisol levels testis and prostate as well observations (see Weinberg 1993). in response to stress (e.g., having blood as decreased levels of testosterone drawn) compared with control infants and LH (which is released from • In response to stress such as immobil- (Jacobson et al. in press). Furthermore, the pituitary to stimulate testos- ization, ether, or cold, alcohol-exposed children prenatally exposed to alcohol are terone formation in the testes). animals show elevated corticosterone, known to be hyperactive, uninhibited, ACTH, and/or β-endorphin levels and impulsive in behavior, particularly Alcohol-induced reductions in testos- compared with control animals. in challenging or stressful situations. terone levels may alter testosterone’s Because the hormones of the HPA axis effects on brain organization during • Animals prenatally exposed to alcohol act on the CNS to alter behavior and gestation and may explain the differences show increased ACTH and corticos- performance in stressful situations, in brain structure and sex-typical terone levels following one-time (i.e., altered HPA activity may underlie some behavior seen between animals prena- acute) exposure to drugs such as alco- of the behavioral problems seen in chil- tally exposed to alcohol and control hol and morphine compared with dren prenatally exposed to alcohol. animals. For example, the SDN–POA control animals. in the hypothalamus is smaller in males Effects on the HPG Axis prenatally exposed to alcohol than in • Stress-induced elevations in ACTH control males (Barron et al. 1988). and corticosterone levels appear to During gestation, the HPG axis influ- These alcohol-induced structural alter- be prolonged in alcohol-exposed ences not only the development of the ations may contribute to the changes animals following immobilization but also the organi- in sex-typical behaviors observed after stress, suggesting that those animals zation of the CNS.3 Under the influence prenatal alcohol exposure. For example, may be less able to inhibit HPA of testosterone (and, possibly, ), compared with control animals, male activity or recover from stress than certain brain areas (i.e., sexually dimor- rats prenatally exposed to alcohol take control animals. phic areas) develop differently in males longer to mount females during copula- and females. For example, several areas tion and show a decreased frequency of Excessive HPA activity may have in the brain differ in size between males intromission (i.e., penetration) (Udani profound consequences throughout the and females. In particular, the preoptic et al. 1985). Another sex-typical behav- animal’s life, including possible impair- area of the hypothalamus contains a ior is found in the navigation of a ments in growth or immunity resulting region—the sexually dimorphic nucleus complex, spatial maze (i.e., the Lashley from a redistribution of energy resources. of the preoptic area (SDN–POA)— III maze), which male rats typically learn Interestingly, the effects of prenatal alco- that is considerably larger in males than faster than do female rats. Male rats hol exposure may differ between male in females and plays an important role prenatally exposed to alcohol, however, and female offspring and may also in sexual and maternal behaviors in rats require more trials to learn the maze depend on the nature and intensity of (Arnold and Gorski 1984). than do control males, whereas female the stressor applied, the hormone ana- Research conducted in animal models rats prenatally exposed to alcohol require lyzed (e.g., corticosterone, ACTH, or has shown that prenatal alcohol exposure fewer trials to learn the maze than do β-endorphin), and the time course of adversely affects male offspring by alter- control females (McGivern and Riley hormone measurement. For example, ing the structure and function of the fetal 1993). These data suggest that at least when animals were exposed to repeated testes as well as other components of the in rats, prenatal alcohol exposure may immobilization stress, males prenatally urogenital tract (see Weinberg 1993; result in the “” of behavior exposed to alcohol showed increases McGivern and Riley 1993). For example: in β-endorphin levels, whereas females showed increases in ACTH levels. In • In the fetus, alcohol decreases the 2β-Endorphin is a similar to morphine contrast, control males and females number of testosterone-producing that is produced in the brain and other organs. It showed habituation (i.e., lower hormone cells in the testes and reduces testos- is released by the pituitary in response to stress. levels) in their HPA responses to this terone production by inhibiting 3In humans, the external genitalia of both sexes repeated, predictable stressor (Weinberg certain enzymes. begin to develop at 9 to 10 weeks after concep- et al. 1996). This example emphasizes tion, and the -specific differentiation of the brain occurs throughout gestation. In rodents, the not only that alcohol-exposed males • At birth, animals prenatally exposed process of occurs in the last and females may respond differently to alcohol exhibit decreased brain lev- week of pregnancy and continues during the first to stress but also highlights that alcohol- els of the active form of testosterone 2 weeks after birth.

Vol. 22, No. 3, 1998 175 in males and in the “masculinization” results in growth retardation (i.e., short of human gestation. Therefore, effects of of behavior in females. stature) and mental retardation. During prenatal alcohol exposure on HPT func- Changes in HPG activity and in the first weeks of gestation, the transfer tion that are detectable after birth in behaviors controlled by the HPG axis of maternal thyroid hormones to the rodents may occur during the last also have been noted in female rodents fetus may play an important role in trimester of gestation in humans and prenatally exposed to alcohol, includ- fetal development. By 11 to 12 weeks may have already recovered before the ing the following (see Weinberg 1993; of gestation, however, the thyroid of infants are assessed after birth. In addi- McGivern and Riley 1993): the human fetus can produce and secrete tion, the alcohol-induced changes in its own hormones. Maternal alcohol the regulatory and/or growth-promoting • Increased levels of the pituitary consumption may reduce the availability roles of thyroid hormones during fetal hormone prolactin and decreased of thyroid hormones to the fetus either development may be more subtle in levels of LH in the blood from indirectly, by inhibiting the transport human newborns than in rats. Never- approximately 22 to 35 days of age of maternal hormone across the placenta, theless, it is possible that even mild (the elevated prolactin levels may or directly, by interfering with the func- alcohol-induced prenatal alterations in persist into adulthood) tion of the fetal thyroid once it is active. HPT activity could have lasting effects Studies in animal models have dem- on the function of many body systems • Delays in puberty and in displaying onstrated that following prenatal alcohol and might contribute to the adverse sexually receptive behavior, possibly exposure, the growth of the thyroid gland effects of fetal alcohol exposure. resulting from the hormonal changes is retarded (for a review, see Hannigan 1993). For example, in rodents prena- Effects on Growth Hormone and IGFs • Impaired maternal behavior (e.g., tally exposed to alcohol, reduced thyroid nest building and pup retrieval) hormone levels were observed during the Growth hormone and IGFs play a cen- first 2 to 4 weeks of postnatal life. tral role in promoting body growth and • Deficits in sexual behavior and earlier Researchers also have noted that numer- development. Accordingly, alcohol- cessation of estrus cycling (i.e., the ous parallels exist between the effects of induced impairment of this hormone equivalent to in humans), prenatal alcohol exposure and hypothy- system during fetal development could indicating that prenatal alcohol roidism. For example, in both conditions have severe consequences. Animal studies exposure may accelerate the aging the cell numbers in certain brain regions have shown that newborn animals process of the female reproductive that are important for memory (i.e., the prenatally exposed to alcohol had reduced system (McGivern et al. 1995). hippocampus) and motor control (i.e., growth hormone levels compared with the cerebellum) are reduced. Further- control animals (Thadani and Schanberg Limited data are available on the more, both conditions result in fetal 1979). More recently, researchers have association between prenatal alcohol growth retardation; delayed skeletal mat- shown that the activity of IGFs, which exposure and HPG activity in humans. uration; and behavioral problems, such play an essential role in fetal develop- The available information indicates as hyperactivity and learning disabilities. ment, may be affected by prenatal alco- that prenatal alcohol exposure may Finally, researchers have found that treat- hol exposure. Compared with control slightly delay puberty in males, ment with thyroid hormone soon after animals, young animals that had been although the time of onset of puberty birth reversed some of the developmen- prenatally exposed to alcohol exhibited still is generally within normal limits tal delays observed in animals prenatally lower IGF-1 levels in the blood and in those adolescents (Streissguth et al. exposed to alcohol (Gottesfeld and brain as well as reduced expression of 1991). More extensive investigations Silverman 1990), further supporting the the responsible for the production regarding the effects of prenatal alcohol association between prenatal alcohol of both IGF-1 and IGF-2 in the liver exposure on HPG activity and sexual exposure and hypothyroidism. (Singh et al. 1996; Mauceri et al. 1996). development and behavior in humans An analysis of numerous studies on Both the diminished fetal brain con- are needed. children prenatally exposed to alcohol, centrations of IGF-1 and the decreased however, showed no long-term changes expression of the IGF genes may con- Effects on the HPT Axis in thyroid function or thyroid hormone tribute substantially to the retardation levels (Hannigan et al. 1995). The of brain growth associated with FAS. Normal functioning of the HPT axis discrepancy between the findings in Interestingly, prenatal alcohol exposure is critical for growth and development humans and those in animals may be appears to result in increased expression as well as for regulation of the body’s partially attributable to differences of the for IGF-binding protein overall metabolic rate. Reductions in thy- between humans and animals in the in the fetal and placenta (Fatayerji roid hormones during the first 2 years critical periods during which alcohol et al. 1996). Increased levels of IGF- of life may be particularly devastating, exposure occurs. For example, rodents binding protein may decrease the because those hormones play a crucial typically are tested for HPT function levels of active IGFs in those tissues, role in CNS development. Accordingly, soon after birth, a time that is develop- thereby contributing to general fetal untreated hypothyroidism in infancy mentally equivalent to the third trimester growth retardation.

176 Alcohol Health & Research World Hormonal Effects of Alcohol on the Mother and Fetus

MAUCERI, H.J.; BECKER, K.B.; AND CONWAY, S. The Growth hormone normally is released increased understanding of endocrine influence of ethanol exposure on insulin-like growth from the pituitary periodically through- function during pregnancy; of the devel- factor (IGF) type II receptors in fetal rat tissues. Life out the day. Growth hormone release opment of the fetal endocrine system; Sciences 59(1):51–60, 1996. increases in response to various factors, and of the processes influenced by mater- MCGIVERN, R.F., AND RILEY, E.P. Influence of peri- such as changes in blood sugar or insulin nal, placental, and fetal hormones may natal alcohol exposure on sexual differentiation. In: Zakhari, S., ed. Alcohol and the Endocrine System. levels, fasting, or exercise. In children offer new insights into the adverse effects National Institute on Alcohol Abuse and Alcoholism with FAS, growth hormone responses of prenatal alcohol exposure and possible Research Monograph No. 23. Bethesda, MD: the to stimulation by such factors were methods of attenuating those effects. Institute, 1993. pp. 223–248. normal, as were growth hormone levels MCGIVERN, R.F.; MCGEARY, J.; ROBECK, S.; COHEN, S.; AND HANDA, R.J. Loss of reproductive compe- during sleep (for a review, see Rudeen References tence at an earlier age in female rats exposed prenatally and Taylor 1992). In contrast to those to ethanol. Alcoholism: Clinical & Experimental Research 19(2):427–433, 1995. results from growth hormone stimulation ARNOLD, A.P., AND GORSKI, R.A. Gonadal tests, the estimated rate of spontaneous induction of structural sex differences in the central MELLO, N.K.; MENDELSON, J.H.; AND TEOH, S.K. nervous system. Annual Review of Neuroscience An overview of the effects of alcohol on neuroendocrine 24-hour growth hormone secretion in 7:413–442, 1984. function in women. In: Zakhari, S., ed. Alcohol and children with FAS was lower than in BARRON, S.; TIEMAN, S.B.; AND RILEY, E.P. Effects the Endocrine System. National Institute on Alcohol children of normal stature and similar of prenatal alcohol exposure on the sexually dimorphic Abuse and Alcoholism Research Monograph No. 23. Bethesda, MD: the Institute, 1993. pp. 139–169. to that of children who were born small nucleus of the preoptic area of the hypothalamus in male and female rats. Alcoholism: Clinical & ROMAN, P.M. Biological features of women’s alcohol for their gestational age (Hellstrom et Experimental Research 12(1):59–64, 1988. use: A review. Public Health Reports 103(6):628– al. 1996). In addition, the concentra- BREESE, C.R., AND SONNTAG, W.E. Effect of ethanol 637, 1988. tions of IGF-1 and of one component on plasma and hepatic insulin-like growth factor RUDEEN, P.K., AND TAYLOR, J.A. Fetal alcohol neuro of IGF-binding protein in the blood of regulation in pregnant rats. Alcoholism: Clinical & endocrinopathies. In: Watson, R.R., ed. 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In utero exposure to ethanol alters mRNA Alcohol Syndrome: Diagnosis, , Prevention for insulin-like growth factors and insulin-like growth and Treatment. Washington, DC: National Academy factor-binding proteins in placenta and lung of fetal Press, 1996. Conclusions rats. Alcoholism: Clinical & Experimental Research 20(1):94–100, 1996. STREISSGUTH, A.P.; SAMPSON, P.D.; AND BARR, H.M. Neurobehavioral dose-response effects of Alcohol consumption during pregnancy GOTTESFELD, Z., AND SILVERMAN, P.B. Develop- prenatal alcohol exposure in humans in infancy to disrupts the normal functioning of both mental delays associated with prenatal alcohol adulthood. In.: Hutchings, D.E., ed. Prenatal Abuse exposure are reversed by thyroid hormone treatment. of Licit and Illicit Drugs. New York: New York the maternal and the fetal endocrine Neuroscience Letters 109:42–47, 1990. Academy of Science, 1989. pp. 145–158. systems and may disturb the normal HANNIGAN, J.H. Alcohol exposure and maternal-fetal STREISSGUTH, A.P.; AASE, J.M.; CLARREN, S.K.; maternal-fetal endocrine balance. Those thyroid function: Impact on biobehavioral maturation. RANDELS, S.P.; LADUE, R.A.; AND SMITH, D.F. alterations may adversely affect the devel- In: Zakhari, S., ed. Alcohol and the Endocrine System. Fetal alcohol syndrome in adolescents and adults. National Institute on Alcohol Abuse and Alcoholism Journal of the American Medical Association opment and organization of multiple Research Monograph No. 23. Bethesda, MD: the 265(15):1961–1967, 1991. systems in the fetus and likely mediate Institute, 1993. pp. 313–338. THADANI, P.V., AND SCHANBERG, S.M. Effect of some commonly observed effects of pre- HANNIGAN, J.H.; MARTIER, S.S.; AND NABER, J.M. maternal ethanol ingestion on serum growth natal alcohol exposure. The exact mech- Independent associations among maternal alcohol hormone in the developing rat. 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