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What Do Sex, Twins, Spotted Hyenas, ADHD, and Sexual Orientation Have in Common? Dennis McFadden Perspectives on Psychological Science 2008 3: 309 DOI: 10.1111/j.1745-6924.2008.00082.x

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Downloaded from pps.sagepub.com at University of Texas Libraries on November 5, 2014 PERSPECTIVES ON PSYCHOLOGICAL SCIENCE

What Do Sex, Twins, Spotted Hyenas, ADHD, and Sexual Orientation Have in Common? Dennis McFadden

Department of Psychology and Center for Perceptual Systems, University of Texas

ABSTRACT—The otoacoustic emissions (OAEs) measured in measures may exist. They are unquestionably imperfect, but we a collection of special populations of humans and certain now have measures that seem to be sensitive to the degree of nonhuman species suggest that OAEs may provide a win- exposure to androgens a developing fetus receives. Some read- dow into some processes of human prenatal development ers surely will find it bizarre that those measures come from the and sexual differentiation. For reasons that are unclear, auditory system. Even more bizarre, some of the measures in- OAEs appear to be highly sensitive to events occurring volve sounds that come out of the ear. during prenatal development that seem to be related to the There are still plenty of dangling threads, but if you like degree of exposure to androgens a fetus receives. The mysteries involving stacks of compelling (if circumstantial) (largely circumstantial) evidence for a relationship be- evidence, pleas for parsimony, and collections of odd and cu- tween androgen exposure and OAE strength comes from a rious facts, you are going to love this story. The tale itself is based series of studies of twins, children with attention-deficit/ on a collection of physiological measures of the auditory system hyperactivity disorder, people of differing sexual orienta- obtained from several special populations. The mystery is tions, and spotted hyenas, among others. Some conclusions whether some or all of those outcomes are attributable to a are bolstered by parallel studies using auditory evoked common cause and, if so, what that cause might be. In the end, potentials (AEPs). OAEs and AEPs are simple, objective, you will find that the scientific jury is still out, but at least you noninvasive measures that appear to have potential as will know the essence of the case as it currently stands, and you tools of value to researchers working on a wide variety of will know something about these measures that may be revealing basic and applied topics beyond audition. about aspects of prenatal development. Plus, you will have an- other example for use in class of how following one’s nose in science can lead into totally unexpected realms. Human prenatal development involves an enormously complex Before examining the details of the mystery, it is necessary to series of processes that culminate in an individual having a body cover some background material, both on prenatal development and brain ready both to experience the rich array of stimuli that and on the auditory system. Then, evidence from such sources as constitute the everyday world and to benefit and mature physi- spotted hyenas, human twins, children with attention-deficit/ ologically and behaviorally in a sex-typical manner in response hyperactivity disorder (ADHD), and people of differing sexual to those stimuli. Much of what happens during human prenatal orientation will be presented for your consideration. The back- development is currently inaccessible to us, so most of what we ground is a bit long, but along the way you are likely to learn a know comes from indirect measures, accidents of nature, and few new facts to spice up those tired old lectures you’ve been observations of other species. Imagine how valuable it would be giving on development and perception. Junkies for more detail to scientists of various stripes to have some simple, noninvasive can read the footnotes. measures that are obtainable from adults and that provide in- formation about one of those otherwise invisible processes op- BACKGROUND ON PRENATAL DEVELOPMENT erating on the brain during early development. Well, such In humans, as in all mammals, the two sexes emerge as follows. All eggs carry one X chromosome, and they are fertilized by Address correspondence to Dennis McFadden, Department of Psy- chology and Center for Perceptual Systems, University of Texas, sperm cells that carry either an X or a Y chromosome. As the Austin, TX 78712-0187; e-mail: [email protected]. fertilized egg divides and becomes an embryo, all subsequent

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daughter cells are either XX or XY depending on which type of dimensional space, and what implications it carries for the lis- sperm cell fertilized the egg. If the developing embryo is XY,it tener’s behavior. To make this transformation, a delicate mem- carries a gene, called SRY,ontheY chromosome that is activated brane inside the cochlea (the basilar membrane) is displaced up early in the first trimester of prenatal development, and that gene and down in accord with the movements at the eardrum, and is responsible for the development of embryonic testes in that XY sensitive cells residing on the basilar membrane (the cochlear embryo. The testes begin to manufacture androgens, including hair cells) sense that movement and initiate neural activity when testosterone, which diffuse throughout the developing embryo and the movement is sufficiently great. begin the process of masculinization of body, brain, and behavior. Besides receiving, transducing, analyzing, and processing in- That is, the normally developing male fetus masculinizes itself via coming sounds, the human cochlea also can make sounds of its its own production of androgens. Embryos lacking the Y chro- own (Kemp, 1978, 1979; Probst, Lonsbury-Martin, & Martin, mosome, and thus the SRY gene, do not develop testes, and those 1991; Shera & Guinan, 1999). These sounds, known as otoacoustic XX embryos develop with female bodies, brains, and behavior. emissions (OAEs), are generated by the mechanisms that evolved Because the absence of the SRY gene leads to a sequence of to give the mammalian inner ear the extremely high sensitivity it events that culminates in a female individual, it is common to see has. (At 1,000 Hz—about two octaves above middle C—the the process summarized as ‘‘in all mammals, including humans, weakest sound that can just be heard by a normal ear displaces the female is the default condition.’’ eardrum about 0.5 nm, or about the diameter of a potassium atom; The production of androgens by the testes of the developing Mead C. Killion, personal communication, February 8, 2007.) human male fetus peaks between Weeks 10 and 22 after con- Because the mechanisms that provide such high sensitivity ac- ception (Smail, Reyes, Winter, & Faiman, 1981), after which the tually increase the magnitude of the displacement of the basilar fetal androgen levels gradually decline so that the hormone membrane for weak sounds, the term cochlear amplifiers is com- levels of male and female infants are essentially identical at monly used to denote those mechanisms. Because each successive birth. Then, beginning at birth and lasting for about 20 weeks, location along the length of the basilar membrane (each adjacent the testes of the male infant produce a ‘‘second surge’’ of an- frequency region) has its own amplification devices, the cochlea drogens (Smail et al., 1981), after which the hormone levels in can be viewed as having a sequence of frequency-specific cochlear male and female children again are essentially identical until amplifiers arrayed along its length. There are several types of puberty (when chaos ensues). Thus, any sex difference in body, OAEs, but I will focus primarily on two of them: spontaneous brain, or behavior present at birth or present between about 6 OAEs (SOAEs) and click-evoked OAEs (CEOAEs). months of age and puberty cannot be attributable to differences To measure SOAEs, all one need do is insert a sensitive mi- in the existing circulating levels of sex hormones. Rather, those crophone into the external ear canal of a subject seated com- sex differences are either aftereffects of the sex differences in fortably in a sound-deadened room, record the sounds present in exposure to androgens experienced during prenatal or early the canal, do some simple processing to exclude the most noisy postnatal development or the result of environmental or so- moments in the recording (breathing, swallowing, movements of cialization processes operating after birth. (After puberty, of the jaw, neck, or head, etc.), and then represent the result as a course, any sex difference may carry a contribution from cur- frequency spectrum (Pasanen & McFadden, 2000). Any SOAEs rently circulating levels of hormones. Eventually some sex emerge as sharp peaks out of the background noise of the re- differences surely will be shown to be attributable to mecha- cording system (see Fig. 1). SOAEs typically have quite narrow nisms other than degree of exposure to hormones—such as ge- bandwidths and can be thought of as pure tones emanating from netic mechanisms; see Arnold, 2002—but I am unaware of the the inner ear. A simple (if not completely accurate) way to think existence of any unequivocal examples in humans.) In summary, about an SOAE is that it results from an individual cochlear normal XX embryos proceed along a default path toward be- amplifier (or a small collection of them) being defective in a way coming female in body, brain, and behavior, whereas normal XY that drives it into positive feedback, causing that location along embryos masculinize themselves by producing androgens both the basilar membrane to ‘‘ring’’ continuously at its characteristic prenatally and then again right after birth (the second surge), frequency. In humans, at least one SOAE can be found in about thereby proceeding along the path to becoming physiologically 75%–85% of female ears and in about 45%–65% of male ears and behaviorally male. (Versions of the second surge exist in (e.g., Bilger, Matthies, Hammel, & Demorest, 1990; McFadden other mammals as well—see Wallen & Baum, 2002.) & Pasanen, 1999; Talmadge, Long, Murphy, & Tubis, 1993).1

BACKGROUND ON OTOACOUSTIC EMISSIONS 1SOAEs typically are not heard by their owners. This may be an example of a long-term perceptual adaptation; the SOAEs are continuously present from birth and the nervous system generally is disinterested in steady-state stimu- The function of the human inner ear, or cochlea, is to transform lation. Some people with hearing loss report hearing tonal sounds, especially in airborne pressure changes present at the eardrum into neural quiet environments. This tinnitus (McFadden, 1982) is not a matter of hearing SOAEs. Tinnitus is neural activity that has no acoustical basis, whereas SOAEs activity that is usable by higher brain centers trying to figure out are real sounds present in the ear canal. Also, tinnitus exists in damaged ears, what that sound was, where it was coming from in three- and OAEs require a normal cochlea.

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25 Subject A Subject A

15

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−5

Subject B −15

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Subject B Sound−pressure Level (dB)

15 Sound−pressure Level (dB) 5 0 10203040 Time (ms ) −5 Fig. 2. Click-evoked responses from the same two ears as shown in −15 Figure 1. The echolike responses differ markedly across individual ears, but they are highly constant across time in the same ear. In ears with 04 2.0 4.0 6.0 8.0 10.0 spontaneous otoacoustic emissions (SOAEs), the presentation of the click stimuli can briefly synchronize the SOAEs, hence the tonal-like appear- Frequency (kHz) ance of the click-evoked otoacoustic emission (CEOAE) in the top panel Fig. 1. Spectral representations of the sounds recorded from the and the pseudoperiodic appearance in the bottom panel. ear canals of two people. The top panel is from an ear containing one strong spontaneous otoacoustic emission (SOAE) at approximately 1,700 Hz; the remainder of the curve represents the acoustical and measured in essentially all normal-hearing human ears (e.g., electrical noise floor at each frequency shown. The bottom panel is 2 from an ear having so many SOAEs that they would be difficult to Probst et al., 1991). count reliably, which is why we use an objective algorithm for identifying OAEs exhibit large individual differences, but they are both and counting the number of SOAEs in an ear (Pasanen & McFadden, reasonably constant through life (Burns, Campbell, & Arehart, 2000). 1994; Burns, Campbell, Arehart, & Keefe, 1993; Engdahl, Ar- nesen, & Mair, 1994; Franklin, McCoy, Martin, & Lonsbury- Martin, 1992; Kemp, Bray, Alexander, & Brown, 1986; Prieve CEOAEs are echolike responses produced by the cochlea et al., 1993) and highly heritable (McFadden & Loehlin, 1995; in response to brief sounds (Kemp, 1978, 1979; Probst McFadden, Loehlin, & Pasanen, 1996), so they sometimes have et al., 1991). To measure CEOAEs, one presents the ear been described as a kind of fingerprint of the ear. The compar- with a series of weak clicks not unlike the ‘‘snap’’ one ison is imperfect, however, because even though OAEs can be hears from older wall switches when flipping on an electric quite stable through life, they are not immutable. Any agent that light. Each click produces an echolike response that is produces temporary or permanent hearing loss (such as expo- highly individualistic, but consistent, for that ear. These re- sure to intense sound or ototoxic drugs—e.g., McFadden & sponses can last for 40–60 ms following each click. Because Pasanen, 1994; McFadden & Plattsmier, 1984) also will di- the individual echolike responses are quite weak, they minish the OAEs (because the underlying cochlear amplifiers can be extracted from the background noise of the ear canal are damaged). Accordingly, all our studies include only young only by averaging the responses given to a series of several adults who pass a hearing screening test. hundred click stimuli. The stiffness of the basilar membrane That completes the background information, so now on to the changes continuously along its length, and current thinking is story. that the CEOAE response consists of echoes coming from lo- cations along the basilar membrane containing local inhomo- 2The reason for using the term echolike to describe CEOAE responses is that, geneities in the otherwise-smooth gradient of change in unlike echoes in canyons or stairwells, the different frequency components in stiffness. Examples of CEOAE responses from different ears are the click stimulus emerge from the cochlea with different time delays (see shown in Figure 2. Clearly, CEOAEs can differ greatly in Kemp, 1978). The standard explanation for this is that the high-frequency components are reflected back into the external ear canal from local inhomo- ‘‘shape’’ and in strength. When characterizing CEOAEs, it is geneities located at the basal (eardrum) end of the cochlea and successively common to measure the root-mean-square amplitude of the lower frequency components are reflected back from inhomogeneities located at successively more distant (apical) locations along the cochlea. Because CEOAE echolike waveform and express that value in decibels sound- waveforms consist of a succession of individual echoes, CEOAEs can last many pressure level (dB SPL). Unlike SOAEs, CEOAEs can be tens of milliseconds following a click of 100-ms duration, as is seen in Figure 2.

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Fig. 3. Sex differences in otoacoustic emissions (OAEs). The spontaneous OAEs (SOAEs) and click-evoked OAEs (CEOAEs) from the same subjects are shown on the left and right, respectively. Human females have more SOAEs and stronger CEOAEs than do males, and for both sexes, right ears have more SOAEs and stronger CEOAEs than do left ears. Both these differences are evident in newborns as well as in adults, implying that there is some prenatal mechanism(s) responsible for these sex and ear differences. In these data, the effect sizes for the sex differences in SOAEs and CEOAEs were about 0.98 and 0.76, respectively; traditionally, effect sizes of 0.2, 0.5, and 0.8 are considered small, medium, and large, respectively (Cohen, 1992). In one study, the correlation between SOAE number and CEOAE strength was 0.76 (McFadden & Pasanen, 1999). Error bars designate standard errors.

THE STORY OAEs (see Fig. 4).3 (A less specific explanation would simply posit a contribution from some aspect of the normal processes of Human Studies masculinization, without mentioning hormones explicitly.) The first fact of interest is that, in humans, OAEs exhibit sex How might one test this prenatal-androgen-exposure expla- differences (McFadden, 1998). SOAEs are more numerous and nation for the sex differences in OAEs? Direct experimental CEOAEs are stronger in females than they are in males (Bilger et manipulations of androgen levels in developing humans clearly al., 1990; McFadden, 1993a; McFadden & Loehlin, 1995; are not ethical or desirable. One alternative would be to study McFadden et al., 1996; McFadden & Pasanen, 1998, 1999; people who were exposed to atypical hormone levels during McFadden & Shubel, 2003; Talmadge et al., 1993; also see Fig. prenatal development because of some malfunction of the or- 3). The second fact is that this is true in newborns as well as in dinary developmental processes. Examples include congenital young adults (e.g., Burns, Arehart, & Campbell, 1992; Burns et adrenal hyperplasia (CAH) and androgen-insensitivity syn- al., 1994; Morlet et al., 1995, 1996; Strickland, Burns, & Tubis, drome. These special populations have been studied by others to 1985). As noted above, whenever sex differences exist at birth, they cannot be attributable to then-current differences in levels 3As the data of Figure 3 reveal, the right ears of humans show more SOAEs of sex hormones, so it is common to assume that these differ- and stronger CEOAEs than do the left ears, a mean laterality difference that exists in newborns as well as in young adults. These mean differences arise ences are aftereffects of earlier differences in development because about two thirds of us have more or stronger emissions in the right ear. (Nelson, 2005). In that spirit, the best-documented sex difference Average hearing sensitivity also is slightly better in right ears than in left (and slightly better in females than in males; see McFadden & Mishra, 1993), which during prenatal development is the differential exposure to an- is in accord with OAEs and hearing sensitivity both being results of a common drogens in male and female fetuses, so it is not unreasonable to cause: the cochlear amplifiers (see Fig. 4). Neither of these laterality effects wonder if the sex differences in the OAEs of newborns are at- appears to be related to handedness. Suggestions about the origins of these ear differences include possible lateral asymmetries in the strength of the efferent tributable, at least in part, to the normal hormonal processes of system (McFadden, 1993b). Almost nothing is known about ear differences in masculinization that occur prenatally. To be specific, one rea- OAEs or hearing sensitivity in other species, but in small samples of both rhesus monkeys and spotted hyenas, at least, there was no consistent laterality sonable explanation is that prenatal androgen exposure acts to in OAEs (McFadden, Pasanen, Raper, et al. 2006; McFadden, Pasanen, Wel- weaken the cochlear amplifiers in males and thus to weaken their dele, et al., 2006).

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That prediction was confirmed when we measured OAEs in spotted hyenas (McFadden, Pasanen, Weldele, Glickman, & Place, 2006). If anything, the CEOAEs of female spotted hyenas were slightly weaker than those of males, not stronger (far left in Fig. 5). That is, we have evidence that OAEs (and, by implica- tion, the cochlear amplifiers) are, in fact, weakened by exposure to high levels of androgens prenatally, just as the prenatal- androgen-exposure explanation suggests. Additional corroboration comes from measurements of OAEs obtained from a small number of spotted hyenas who had been treated with antiandrogenic drugs during gestation. Those drugs partially blocked the normal actions of androgens in the bodies and brains of the developing fetuses, and the prenatal-androgen- exposure explanation predicts that the OAEs in those treated hyenas should be stronger than those in hyenas allowed to develop normally, which is exactly what we observed (center of Fig. 5). As the data at the right in Figure 5 show, spotted hyenas Fig. 4. A boxology illustrating that the strength of the otoacoustic ovariectomized or castrated at various times after birth had emissions and hearing sensitivity are both thought to be results of a OAEs that were indistinguishable from those of untreated hye- common cause (the strength of the cochlear amplifiers), and the cochlear nas. This suggests that the current (in these cases, low) levels of amplifiers are thought to be weakened by prenatal exposure to androgens. It is believable that other auditory characteristics or abilities also may be sex hormones in adult animals affect OAEs much less than do affected by prenatal androgen exposure; as always, further research is necessary. Based on Figure 1 in McFadden (2002) and reproduced with kind permission of Springer Science and Business Media. Two−Ear Averages Spotted Hyena 25 Female test other hypotheses (e.g., Collaer & Hines, 1995; Wisniewski Male et al., 2000), but unfortunately, my attempted collaborations have failed so far, and I have no evidence to report from those tantalizing natural experiments. Another possibility is to relate 20 OAEs to other measures known or suspected to be affected by prenatal androgen exposure, such as auditory evoked potentials and finger-length ratios, and this approach is discussed below. A 15 final alternative to direct experimental manipulations in humans from 1 − 5 kHz (dB SPL) is the use of animal models, and, fortunately, there is something N = 9 3 2 Mean rms Amplitude of CEOAE relevant to report from that quarter. 10

Animal Studies Prenatal Untreated Antiandrogen Ovx / Castr The spotted hyena (Crocuta crocuta) is a fascinating species, in general as well as in this context. The females are larger than the Treatment Group males, they dominate the males, and they have evolved an Fig. 5. Click-evoked otoacoustic emission (CEOAE) strength for un- elaborated clitoris that looks very much like a penis (at least to treated and treated spotted hyenas. Unlike humans, female spotted hy- human observers). The clitoris is erectile and is traversed by a enas do not have stronger CEOAEs than do males (untreated data on far left—two-ear averages; the dotted line permits easy comparison among single canal that serves for mating, birth, and urination. Female groups). The effect size for the sex difference in untreated animals was – spotted hyenas are masculinized in these ways in part by being 0.36. This suggests that the high levels of androgens to which female exposed to high levels of androgens during prenatal and early spotted hyenas are exposed weaken their cochlear amplifiers, in accord with our prediction. Spotted hyenas of both sexes that were treated with postnatal development (Frank, Glickman, & Licht, 1991; antiandrogen agents (flutamide and finasteride) during prenatal devel- Glickman, Frank, Pavgi, & Licht, 1992). Accordingly, this spe- opment exhibited stronger CEOAEs than did untreated hyenas, which is cies represents an excellent test of the prenatal-androgen-ex- also in accord with the prenatal-androgen-exposure explanation (data in center). Finally, animals that were either ovariectomized (Ovx) or cas- posure explanation for the sex differences in (human) OAEs. trated (Castr) after birth had CEOAEs that were not statistically different Specifically, if that explanation is correct, the cochlear amplifiers from those of untreated hyenas of the same sex (data on right), revealing of female spotted hyenas should be weakened by their exposure that current, circulating levels of hormones have much less effect on the cochlear amplifiers than do prenatal exposures. Error bars designate to high levels of androgens prenatally, and the OAEs of females of standard errors. Based on Figure 3 in McFadden, Pasanen, Weldele, this species thus should not be stronger than those of males. et al. (2006) and reproduced with kind permission of Elsevier Limited.

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the levels experienced prenatally (e.g., center of Fig. 5). Some recent OAE measurements in ovariectomized and castrated sheep (Ovis aries) confirmed this finding (McFadden, Pasanen, Valero, Roberts, & Lee, 2008). Two important caveats are attached to these potentially in- formative outcomes: (a) the Ns were small (although it was a census of all spotted hyenas available to us), and (b) no one yet knows if humanlike sex differences exist in the OAEs of the other three species of hyenas (none of which has highly masculin- ized females). In science, few stories are ever complete. Meshing nicely with these outcomes from spotted hyenas are some outcomes from rhesus monkeys (Macaca mulatta). Both males and females who were administered additional androgens late in prenatal development (when cochlear receptor cells are developing) exhibited weakened (masculinized) CEOAEs, which is in accord with the prediction of the prenatal-androgen-exposure explanation. The pattern of results for rhesus monkeys treated with androgens or antiandrogens early in prenatal development did not conform that well with prediction (see McFadden, Pasanen, Raper, Lange, & Wallen, 2006, Fig. 4), perhaps because the dose levels were smaller than in the hyenas and/or the treatments occurred too early in gestation to affect the developing cochlea. In science, few stories are ever simple either. An encouraging recent finding is that female sheep that had been treated with additional androgens during prenatal development did have CEOAEs that were weaker Fig. 6. Spontaneous otoacoustic emissions (SOAEs; top panel) and (masculinized) than those in untreated females (McFadden et al., click-evoked otoacoustic emissions (CEOAEs; bottom panel) for nontwins and twins of different types (two-ear averages throughout). Of special 2008), which is in accord with our prediction (see Fig. 4). interest here is the fact that females with male cotwins (opposite-sex dizygotic females) had otoacoustic emissions (OAEs) that were more like those of males than those of females from any other group. The most More Evidence appropriate comparison is opposite-sex dizygotic females with same-sex dizygotic females because both shared their intrauterine and postbirth Before the reader reaches a final decision about OAEs and the environments with a twin. In these data, the effect sizes for the difference prenatal-androgen-exposure explanation, there are some addi- between opposite-sex and same-sex dizygotic females for SOAEs and tional findings from certain special populations that appear to be CEOAEs were 0.49 and 0.43, respectively. The reason for the smaller average numbers of SOAEs here as compared with those in Figure 3 is relevant. Even if future research proves them not to be relevant, that the latter data were obtained after our measurement techniques had they are interesting in their own right. improved (see Pasanen & McFadden, 2000). Error bars designate stan- dard errors. Based on Figure 2 in McFadden (2002) and reproduced with kind permission of Springer Science and Business Media. OAEs in Twins OAEs exhibit large individual differences. In an attempt to es- timate how much of that individual variability is attributable to more like the OAEs measured in males. The effect was present genes and how much is attributable to environmental influences, for both SOAEs and CEOAEs, although it was more pronounced we measured OAEs in twin pairs. The outcome was that identical for the former (see Fig. 6). There are a number of possible ex- (monozygotic) twin pairs were substantially more similar in their planations for this fascinating outcome, and later in this article expression of OAEs than were fraternal (dizygotic) twin pairs I discuss some of the precautions we took to rule out some of and the estimates of heritability hovered around 0.75 (McFad- those possibilities. For the moment, I would like to suggest that den & Loehlin, 1995; McFadden, Loehlin, & Pasanen, 1996). the explanation for the differences in the OAEs of OSDZ females Although this outcome is not uninteresting for the story being already may be before us. told here, it is overshadowed by another outcome from the same Perhaps the cochleas of our OSDZ females were masculinized study. during early development by virtue of their having been exposed In addition to the same-sex dizygotic twins, we also measured to high levels of androgens prenatally. That is obviously the same the OAEs in a sample of opposite-sex (OSDZ) twin pairs. To our explanation I offered to explain the sex difference in human surprise, the OAEs of the females with male cotwins were much OAEs, which makes it appealingly parsimonious, but what weaker than were the OAEs of any other group of females tested would be the origin of those androgens? Perhaps the answer is (McFadden, 1993a; McFadden et al., 1996), which made them the male cotwin developing in that same uterus. That is, might

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some of the androgens being produced by the normally devel- oping male cotwin somehow be affecting the prenatal cochlear development of the female cotwin? This suggestion is not com- pletely preposterous because an effect of this sort (the intra- uterine position phenomenon) has been documented in other mammals (e.g., Clark & Galef, 1998; vom Saal, 1989). Namely, female fetuses developing between two male fetuses can be masculinized on several dozen physiological and behavioral measures (vom Saal, 1989), and the reason for this is that some androgens diffuse out of the male fetuses and pass to the female fetus via the intrauterine fluid. Perhaps a similar process can occur in humans. Note that OSDZ females also have been reported to have masculinized dentition (Boklage, 1985; Dempsey, Townsend, & Richards, 1999), greater (masculinized) birth weight (Glinianaia, Magnus, Harris, & Tambs, 1998), and reduced lifetime reproductive success (Lummaa, Pettay, & Fig. 7. Click-evoked otoacoustic emission (CEOAE) strength for left Russell, 2007).4 If degree of androgen exposure is not the source and right ears in boys diagnosed with attention-deficit/hyperactivity disorder (ADHD) and in controls (all aged 7–12 years). In both ears, the of these differences, then other explanations must be found. CEOAEs of the ADHD/Inattentive boys were weaker than those of the ADHD/Combined boys or the control boys, who did not differ statisti- cally. One interpretation is that the cochlear amplifiers of the ADHD/ Children With ADHD Inattentive boys were weakened early in development by exposure to higher-than-normal levels of androgens. The effect sizes for the differ- A study on children with ADHD provides another source of ences between the ADHD/Inattentive boys and the control boys were circumstantial evidence for the prenatal-androgen-exposure about 0.97 and 0.95 for the left and right ears, respectively. The Ns explanation. ADHD is at least twice as common in males as in differed in the two ears because of very weak responses in some ears. Error bars designate standard errors. rms 5 root mean square. Based on females, and precursors to the diagnostic symptoms character- Figure 1 in McFadden, Westhafer, et al. (2005) and reproduced with kind istic of the disorder often are evident early in life (American permission of Elsevier Limited. Psychiatric Association, 2000). From the arguments made above, both this early emergence and the sex imbalance suggest that perhaps the degree of prenatal exposure to androgens might appeared to exist for girls, but our sample size was too small to be a contributing factor to the expression of ADHD. permit conclusive decisions. Currently, multiple subtypes of ADHD are recognized. For the There are many possible explanations for ADHD/Inattentive purposes of this article, the most important subtypes are ADHD/ boys having weak OAEs, but among them is the now-familiar Inattentive, in which the person has only the inattention prenatal-androgen-exposure explanation. The implication is symptoms with no hyperactivity/impulsivity, and ADHD/Com- that the ADHD/Inattentive boys may have been exposed to bined, in which the person has both the inattention and hyper- higher-than-normal levels of androgens at some point in early activity/impulsivity symptoms. (Some investigators have development, perhaps during prenatal development. This ex- suggested, on the basis of clinical measures alone, that these two planation has appeal in part because it is parsimonious and in groups should be characterized as different disorders, not part because of the large sex imbalance in the prevalence of different subtypes of the same disorder; e.g., Milich, Balentine, ADHD. If more boys than girls are born predisposed to ADHD, & Lynam, 2001.) We measured OAEs in boys diagnosed as ei- might not prenatal androgen exposure have contributed in some ther ADHD/Inattentive or ADHD/Combined as well as some way? Actually, the latter reasoning is undercut by the fact that non-ADHD boys. We found no difference between the OAEs of more boys than girls are diagnosed in both the ADHD/Combined ADHD/Combined boys and controls, but the OAEs of the and ADHD/Inattentive categories/subtypes (Willcutt & Carl- ADHD/Inattentive boys were much weaker than the OAEs of son, 2005), yet the OAEs of the ADHD/Combined boys were not either of the other groups (McFadden, Westhafer, Pasanen, hypermasculinized. I have no explanation for this dissociation of Carlson, & Tucker, 2005); that is, their OAEs were hyper- the two ADHD categories, but if the ADHD/Inattentive and masculinized. The results are shown in Figure 7. Similar effects ADHD/Combined categories do eventually prove to be better conceptualized as different disorders rather than as subtypes of 4 Both Van Anders, Vernon, and Wilbur (2006) and Voracek and Dressler the same disorder (e.g., Milich et al., 2001), then perhaps this (2007) also reported masculinized finger-length ratios in OSDZ females, but Medland, Loehlin, and Martin (2008) measured a much larger sample and dissociation will become more understandable. There is one failed to confirm that outcome. As the name suggests, finger-length ratios are more piece of evidence: We found another physiological mea- calculated by dividing the length of one finger by that of another on the same hand (see Manning, 2002). The sex difference in finger-length ratios emerges sure (finger-length ratios—see Footnote 4) that also was hyper- early in prenatal life (Malas, Dogan, Evcil, & Desidicioglu, 2006). masculinized in those same ADHD/Inattentive boys showing

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hypermasculinized OAEs (McFadden, Westhafer, et al., 2005). Just a coincidence?

Sexual Orientation A final source of circumstantial evidence about the effects of prenatal androgen exposure on OAEs comes from studies of people of differing sexual orientations. We used the answers to a number of standard questionnaire items to categorize subjects as heterosexual, homosexual, or bisexual. The outcome was that homosexual and bisexual women had OAEs that were weaker than those of heterosexual women (i.e., their means shifted in the direction of the males; McFadden & Pasanen, 1998, 1999). By contrast, the OAEs of homosexual males appeared to be no different from those of heterosexual males. The results for both SOAEs and CEOAEs are shown in Figure 8. (The data are not shown, but the finger-length ratios in these nonheterosexual women also were masculinized—see McFadden & Shubel, 2002—although that is not a universal finding—see McFadden, Loehlin, et al., 2005.) These outcomes for nonheterosexual women carry an inter- esting implication. If female is the default condition in all mammals, including humans, then the default choice for sex partner is male; the typical female chooses a male for a sex Fig. 8. Number of spontaneous otoacoustic emissions (SOAEs; top pa- nel) and strength of click-evoked otoacoustic emissions (CEOAEs; bottom partner. This default characteristic clearly is changed in de- panel) for people of differing sexual orientations. The data for hetero- veloping males; the typical male chooses a female for a sex sexual females and heterosexual males are shown at the far left and far partner. It appears that this change from default to nondefault right, respectively; substantial sex differences are evident. The data for homosexual and bisexual women are shifted in the direction of the het- state is made early in male development, perhaps during pre- erosexual males (i.e., they are masculinized). The data for heterosexual natal development, so it is not unreasonable to presume that and nonheterosexual males were not different (the Ns for bisexual males exposure to androgens somehow contributes to this change to the were too small to permit credible conclusions). The effect sizes for the sex differences in the heterosexuals were approximately 0.98 and 0.76 for nondefault choice for sex partner. That is, one simple inter- SOAEs and CEOAEs, respectively. The effect sizes for the differences pretation about how typical males and females acquire their between the heterosexual and nonheterosexual females were approxi- 5 opposite choices in sex partner is that prenatal androgen ex- mately 0.57 and 0.41 for SOAEs and CEOAEs, respectively. rms root mean square; peSPL 5 peak-equivalent sound-pressure level. Error posure somehow produces a masculinization of the brain re- bars designate standard errors. Based on Figure 3 in McFadden (2002) gion(s) responsible for choice of sex partner in humans. By and reproduced with kind permission of Springer Science and Business logical extension, then, the fact that nonheterosexual women Media. exhibit the male-typical choice for sex partner frequently has been explained in terms of a masculinization of those regions of the brain responsible for choice of sex partner in humans. That tials (AEPs), and they are obtained by attaching electrodes to the is, a plausible physiological explanation for nonheterosexuality scalp and recording the sequence of brain-wave peaks that re- in women is that some (possibly highly localized) regions of sult when clicks are presented to the ears. AEPs are commonly the brain were shifted from their default state by some sort of measured to obtain information about the integrity of the pe- masculinizing process at some point in development, perhaps ripheral auditory system in people who cannot be tested during prenatal development. Our finding of masculinized behaviorally (e.g., infants, people with brain damage), and, like OAEs in nonheterosexual women is in accord with that type of OAEs, AEPs exhibit sex differences that are present in new- explanation; both the masculinized OAEs and the homosexu- borns as well as in adults (Chiarenza, D’Ambrosio, & Cazzullo, ality could be aftereffects of exposure to higher-than-normal 1988; Hall, 1992). Standard procedure involves measuring the levels of androgens in some localized regions of the brain during timing (latency) and/or size (amplitude) of the various peaks in some localized period(s) of time in development (McFadden, these brain waves. (The direction of the sex difference in latency 2002). or amplitude depends on the particular peak—see McFadden & The OAE results for nonheterosexual women were corrobo- Champlin, 2000.) We found that several measures in nonhet- rated in a follow-up study that measured auditory brain waves in erosexual women were shifted in the direction of the males, just people of differing sexual orientations (McFadden & Champlin, as was true of the OAEs (McFadden & Champlin, 2000). This 2000). These measurements are called auditory-evoked poten- reveals that both the cochlea and the auditory brain (and per-

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haps the finger-length ratios) show subtle masculinization ef- fects in the nonheterosexual women we tested. Finding addi- tional physiological evidence consistent with the OAE results encourages us that our initial findings and our interpretations are on the right track, and it may help some uncertain readers reach a verdict on the prenatal-androgen-exposure explanation. However, it must be emphasized that no one yet knows for cer- tain when in life the changes in the nonheterosexual brain occur, nor how or where. So far in this discussion of sexual orientation, nothing has been said about physiological concomitants of homosexuality in males, in part because their OAEs were similar to those of heterosexual males (see Fig. 8). However, some AEPs of non- heterosexual males did show differences from those of hetero- sexual males, and the direction of effect was interesting indeed. Several AEP measures obtained from nonheterosexual males Fig. 9. Amplitude of Wave 5 of the auditory evoked-potential (AEP) for were even more different from those of the heterosexual females people of differing sexual orientations. The data for heterosexual females than were those of the heterosexual males—they were hyper- and males (far left and far right, respectively) exhibited a significant sex difference; that effect size was approximately 0.51 for this measure. The masculinized. Although this result runs counter to the stereo- data for homosexual and bisexual women were shifted in the direction of type of nonheterosexual males being effeminate, that stereotype heterosexual males (masculinized), just as was true for otoacoustic is undeniably flawed, and there are other examples of apparent emissions (OAEs; see Fig. 8). In addition, the amplitude for nonhetero- sexual males was even smaller than in heterosexual males (hyper- hypermasculinizations in nonheterosexual males (e.g., Bogaert masculinized). Other AEP measures showed similar shifts for both sexes. & Hershberger, 1999; Lalumiere, Blanchard, & Zucker, 2000). For this measure, the effect sizes for the difference between the hetero- Furthermore, research on nonhuman species in which addi- sexual and nonheterosexual females was approximately 0.24, and the effect size for the differences between the heterosexual and nonhetero- tional androgens were given early in life has regularly revealed sexual males was approximately 0.54. Data from women using oral con- instances of some traits being hypermasculinized, some being traceptives were excluded here (see McFadden, 2000). hypomasculinized, and some being no different from controls, either within treated groups or within individual animals (see McFadden, 2002, for a discussion). Apparently, different lo- calized structures of the body and brain can be affected differ- of androgens is only one possible mechanism for obtaining ently by masculinizing mechanisms such as degree of androgen masculinization in parts of the brain or body. Globally, the exposure. Examples of a masculinization in the AEPs of non- hormone levels actually could be the same in two individual heterosexual females and a hypermasculinization in the AEPs of fetuses, but if the cells in some brain region(s) in one of the nonheterosexual males are shown in Figure 9. fetuses had more active receptors for the hormone of interest, These auditory concomitants to homosexuality are interesting there could be more hormone uptake and thus a stronger ma- in part because there is no obvious way that people could con- sculinization of that brain structure(s). Also, in the mammalian sciously change their OAEs or AEPs the way they might change brain, circulating testosterone can be converted (aromatized) their gestures, walk, speech, dress, appearance, etc. That is, into estradiol when the enzyme aromatase is present (Nelson, these physiological concomitants suggest that some fundamen- 2005). Although estradiol is a form of estrogen and is nominally tal biological processes contribute to the existence of homo- a ‘‘female hormone,’’ in some mammals, estradiol can be a strong sexuality, and the evidence that these auditory measures are masculinizing agent (although estradiol seems not to be neces- relatively constant through life further suggests that some of sary for establishing gender identity or sexual orientation in those processes were operating early in development, perhaps humans; see Wallen & Baum, 2002). Thus, if the cochlea and during prenatal development. The possibility of biological auditory system in some species were responsive to exposure to contributions to homosexuality is not a new idea, of course (e.g., estradiol, two individuals having different rates of aromatization Ellis & Ebertz, 1997; Rahman & Wilson, 2003); this is just of testosterone to estradiol could end up with differentially additional evidence supporting that plausible idea. masculinized auditory systems. Also note that the difference in androgen concentration, receptor density, and/or the rate of aromatization might exist only in certain isolated brain regions Fessing Up and/or only for short time periods during development (‘‘local- It’s time to come clean and admit to having been overly sim- ized effects’’—see McFadden, 2002); they need not be different plistic in regard to underlying mechanisms. Logically, globally. Finally, these different mechanisms are not mutually masculinization can occur numerous ways; globally high levels exclusive, so the potential for complexity clearly is high.

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Thus, it is possible that sometime during the development of change in the cochlea that would diminish the strength of the females who later become nonheterosexual, the levels of an- cochlear amplifiers? That question is addressed in the Summary drogens might be elevated either globally or locally in the brain, section. causing a localized masculinization. Alternatively, the levels of androgens might be the same in nonheterosexual females (or in OSDZ females or in ADHD/Inattentive boys), but the receptor Alternative Explanations density for androgens is atypically high in some brain regions The bow to parsimony having been made, it still is reasonable to during some, perhaps limited, time periods during development. ask if other factors known to affect the cochlear amplifiers and Whatever the exact mechanism, however, the end result would OAEs might be responsible for some or all of the differences in be a masculinization of the affected brain regions (plus the au- OAEs that we have seen in our special populations. Those fac- ditory system), and it is that masculinization event that is crucial tors include exposure to intense sound and/or exposure to oto- to this explanation of the atypical choice of sex partner in toxic drugs because both can affect the cochlear amplifiers and nonheterosexual women. It must be emphasized that any com- induce hearing loss. That is, might OSDZ females have been plex human behavior such as sexual behavior is bound to be exposed to high noise levels early in life because they were influenced both by physiological and environmental factors. So raised with a (noisy) male cotwin and that is the origin of their the above account needs to be read in terms of predisposing weakened OAEs, rather than prenatal hormonal events? Or physiological substrates being acted upon by biology, experi- perhaps females raised with male cotwins take to (ototoxic) ence, and environment. The term prenatal androgen exposure drugs later in life as a way of forgetting their (male-besmirched) has been used throughout this article to encompass all of these childhood. Similarly, perhaps there is something in the lifestyles various possible mechanisms of masculinization, not just glob- of nonheterosexual women that leads them to be exposed to ally different levels of androgens across individuals. higher noise levels and/or to certain drugs that affect their co- The complexity of the situation is highlighted by the fact that chlear amplifiers and OAEs? females with CAH are exposed to such globally high levels of Clearly, there are many specific forms these general questions androgens prenatally that their genitalia are masculinized at could take, meaning that it is impossible to test them all. Our birth and their interests in toys, playmates, and clothing tend to screening procedures did include questions about exposures to be more male-like (Collaer & Hines, 1995), but their sexual intense sounds and drug use in the past 24–48 hr, and potential behavior apparently is less affected. In one study, CAH women subjects often were asked to reschedule their test session on the did not have more sexual experiences with females than did non- basis of their answers to those questions. Furthermore, all of the CAH women, but they did exhibit more nonheterosexual ten- subjects in all of our studies passed a hearing screening test just dencies on several measures of psychosexual differentiation prior to OAE or AEP testing. Accordingly, all had ‘‘normal’’ than did non-CAH women (Zucker et al., 1996). hearing sensitivity in the quiet. Unfortunately, this is an im- perfect control because, at each test frequency, ‘‘normal hear- ing’’ is a range, not a single value. This means that an individual, Parsimony or group, might have a small amount of hearing loss induced by As mentioned earlier and as further discussed later in this ar- noise exposure or drug use that is not sufficient for exclusion ticle, there are alternative explanations possible for each of the from the study but still does involve a weakening of the cochlear individual findings reported above. Indeed, it is logically pos- amplifiers and OAEs from some preexposure level. This creates sible that, when all the truths are known, each of our various a difficult experimental problem, but we have implemented two outcomes will have a unique explanation, with no threads actual tests to determine whether subclinical hearing loss was binding them together. Until then, however, science dictates that responsible for any of the group differences we have measured. one tries to find the simplest possible explanation for as many Nearly every form of hearing loss known proceeds from the facts as possible, and the prenatal-androgen-exposure expla- basal end of the cochlea toward the apical end, which means that nation appears to do the job. It directly explains the sex differ- it affects high-frequency sounds before it affects lower fre- ences seen in the OAEs and AEPs of newborns and adults, the quency sounds. If nonheterosexual females (or opposite-sex various results observed for spotted hyenas, and the weak OAEs female twins or ADHD/Inattentive boys) were the victims of a in opposite-sex dizygotic females. With a few extra assumptions, slight, but relevant, hearing loss that was responsible for the it also fits with the results observed in ADHD children and group differences in OAEs, then the primary difference between nonheterosexual females and males. This explanation now ap- the two groups ought to be in the high-frequency regions of the pears to be solid enough for all of us to become serious about cochlea (where the nonheterosexuals presumably have more devising tests to disprove it. Of particular interest to me are tests hearing loss than do the heterosexuals). Accordingly, were we to or measurements aimed at understanding the specific cochlear eliminate the contribution of the high-frequency regions of the mechanisms or processes underlying the sex differences in cochlea to our data, then the difference between the groups OAEs. Concretely, exactly what might prenatal androgens should diminish or disappear. Our way of eliminating the

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contributions from the high-frequency regions of the cochlea sheep who were exposed to androgens during prenatal devel- was to reanalyze the SOAE data after deleting all SOAEs above 3 opment have weaker OAEs than do untreated female sheep. The kHz. That is, only data from the region of the cochlea less likely more circumstantial evidence is that human females having to have hearing loss were included. The result was that the male cotwins have weak OAEs, that children diagnosed as SOAEs of the nonheterosexual females still were masculinized, ADHD/Inattentive subtype have weak OAEs, that homosexual as compared with those of the heterosexual females (see Fig. 8), and bisexual females have weak OAEs and masculinized AEPs, and if anything, the effect sizes were greater than before and that homosexual males have hypermasculinized AEPs. (McFadden & Pasanen, 1999). That is, an incipient hearing loss Parsimony argues that if a single explanation appears to cover a appears not to be responsible for the difference in OAEs in set of facts (and the prenatal-androgen-exposure explanation women of different sexual orientations. appears to fill that bill), then it should be tentatively accepted After seeing that the OAEs and AEPs of nonheterosexual while additional tests are devised and implemented. Direct women were weaker than those of heterosexual women, I won- experimental manipulations on humans always will be prohib- dered if the use of oral contraceptives might affect those auditory ited on this topic, but additional natural experiments do exist measures. If so, and if the direction of effect was to strengthen and can be exploited. For example, the explanation predicts that the OAEs and AEPs, then the partial masculinization seen in the women with congenital adrenal hyperplasia should have weak nonheterosexual women as a group might be solely attributable (masculinized) OAEs and AEPs and that XY people with an- to the greater prevalence of oral-contraceptive use in the het- drogen-insensitivity syndrome should have female-typical erosexual women (and all my talk and thinking about prenatal OAEs and AEPs. Tests in additional species also may be in- masculinization effects has been a waste of everyone’s time). formative; for example, marmosets typically give birth to twins, Because we had items about drug use in our questionnaires, we some of which are same-sex pairs and some of which are were able to reanalyze the data to determine if use of oral con- opposite-sex pairs. traception contributed to our outcomes. The result was that use One feature regrettably missing from this story is an expla- of oral contraception does alter OAEs and AEPs (McFadden, nation for what strong (or weak) cochlear amplifiers and OAEs 2000), but the direction of effect is opposite to the group mean for everyday hearing. Are there certain auditory abilities differences we had seen. Use of oral contraception masculinized that are closely tied to the strength of the cochlear amplifiers and OAEs (slightly) and AEPs (more severely). That is, by including others not tied to it at all? We do know that hearing sensitivity is users of oral contraception in our OAE studies, we were un- positively correlated with OAE strength (e.g., McFadden & derestimating the actual differences between heterosexual and Mishra, 1993), but beyond that, little is known about the rela- nonheterosexual women, not exaggerating them. As a result of tionships between auditory ability and OAE strength (or AEP this discovery, our published report on AEPs (and Fig. 9) ex- strength). My lab now is working on this topic, but it is too early cluded the data from all users of oral contraception. Women to comment publicly. reading this should be pleased to know that there is no reason to Another feature regrettably missing from this story is any believe that the masculinizing effects of oral contraceptives on information about the actual cochlear mechanisms that are the auditory system are anything but temporary. susceptible to being masculinized early in development. Real- istically, this information can come only from animal research, SUMMARY and that research has yet to be done. Indeed, currently very little is known even about the basic sex difference in OAEs in species So, that is my story. As promised, the reader has seen a number of other than humans. The issue of sex differences has not been a pieces of evidence that individually are rather interesting and hot topic for the physiologists and biochemists who study the collectively seem to point to the conclusion that the human auditory system, and as a consequence, we still know very little auditory system can be affected early in development, perhaps about hormonal effects in the species commonly used for audi- by the androgenic hormones that control the processes of tory research: gerbils, chinchillas, guinea pigs, and cats. Un- masculinization of body, brain, and behavior. Regrettably, spec- fortunately, these species do not have SOAEs, and technical ulation and inference play more central roles in the story than difficulties preclude the measurement of CEOAEs from small I wish, but we continue to work to reduce them both. The big mammals. Furthermore, the form of OAE that can be obtained question is whether all these facts have a common mechanistic from small mammals (called distortion-product OAEs or origin or are just a farrago of marginally related findings. DPOAEs) exhibits only small sex differences in humans (Bow- The facts most compellingly linked to the prenatal-androgen- man, Brown, & Kimberley, 2000; Cacace, McClelland, Weiner, exposure explanation are that both OAEs and AEPs show sex & McFarland, 1996; Gaskill & Brown, 1990; Moulin, Collet, differences in newborn humans, that spotted hyenas do not ex- Veuillet, & Morgon, 1993) and rhesus monkeys (McFadden, hibit a sex difference in OAEs, that spotted hyenas who were Pasanen, Raper, et al., 2006), suggesting that the cochlear exposed to antiandrogenic drugs during prenatal development mechanisms underlying DPOAEs may be less susceptible have stronger OAEs than do untreated hyenas, and that female to masculinizing agents than are the cochlear mechanisms

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underlying CEOAEs. In spite of these difficulties, Guimaraes, the mechanisms that mammals have evolved to acquire the ex- Zhu, Cannon, Kim, and Frisina (2004) did report stronger cellent hearing sensitivity we have? Or might there possibly be DPOAEs in female CBA mice than in males. (Because this sex some small evolutionary advantage to having an auditory system difference was evident in middle-aged mice but not in young that is responsive to prenatal androgen levels or to whatever the mice, this may prove to be an example of a differential, age- relevant factor(s) are? Regrettably, but realistically, the answers related hearing loss rather than a sex difference associated with to these questions are likely to be slow to emerge. early sexual differentiation.) However, S.L. McFadden, Hens- In the spirit of full disclosure, I must emphasize that OAEs do elman, and Zheng (1999) found no sex differences in the have limitations as measures of developmental processes. Any DPOAEs of chinchillas. In rhesus monkeys (McFadden, Pa- event or agent that weakens the cochlear amplifiers will produce sanen, Raper, et al., 2006) and sheep (McFadden et al., 2008), both a loss of hearing sensitivity and a weakening of the OAEs. CEOAEs are stronger in females than in males, just as in hu- These include exposure to intense sounds (either chronically or mans, suggesting that ultimately our knowledge about which acutely), various ototoxic drugs, aging, and the menstrual cycle. cochlear mechanisms are susceptible to being masculinized The cochlear amplifiers do have a limited capacity to recover may have to come from one of the larger mammalian species. from exposure to adverse events, so some instances of weakened Although the research literature currently is silent about OAEs will be temporary, but when the cochlear amplifiers are which specific elements in the cochlea are masculinized and not able to recover fully, the weakening of the OAEs will be how it happens, speculation is always possible. The cochlear permanent. The hearing loss that is correlated with aging is receptor cells known as the outer hair cells (OHCs) are known to probably the most obvious subject variable for investigators to be crucial to some forms of OAE (Davis, 1983). The OHCs avoid. In our studies, we typically limit our samples to young elongate and contract as their stereocilia are sheared and as the adults (college age through the mid-30s). Because people are cells undergo depolarization and hyperpolarization (Brownell, exposed to such high noise levels in modern society and because Bader, Bertrand, & de Ribaupierre, 1985). The molecule prestin there are large individual differences in susceptibility to noise- (Liberman et al., 2002) in the cell wall of OHCs is responsible induced hearing loss, it is wise for investigators to screen for for this electromotility, and the electromotility appears neces- normal hearing levels even when using young subject pools. sary for good hearing sensitivity. Thus, it is logically possible Another limitation is that the OAE differences we have mea- that masculinization of the cochlea might involve fewer prestin sured for our special populations are not large enough to allow molecules being present in the OHCs and/or less regular, co- OAEs to be used diagnostically for individuals. These are group linear alignment of the prestin molecules that are present. Either effects that eventually may be accepted as informative about way, electromotility ought to be reduced. An active mechanism early developmental processes, as suggested above, but it is also exists in the stereocilia of the hair cells, at least in lizards highly unlikely that OAEs alone ever could be used to determine (Manley, 2006), so masculinization of the cochlea also might the group membership of individual people. involve some differences in the stereocilia or their cross-links. When summarizing this story, it is easy to get caught up in the Neurophysiological evidence reveals that the OHCs are under accumulating evidence and lose track of what may be its most the influence of efferent fibers that arise from the hindbrain fascinating aspect. What these various findings reveal, quite (Brown, Nuttall, & Masta, 1983), and efferent activity also is unexpectedly, is that the auditory system apparently is highly known to reduce OAEs (e.g., McFadden, 1993b; Moulin, Collet, sensitive to certain (as yet unknown, but possibly hormonal) & Duclaux, 1993). Thus, masculinization of the cochlea might influences operating early in development and some aftereffects involve alterations in the degree of control the efferent fibers of that apparent sensitivity persist into adulthood. As a conse- have over OHC electromotility. In the cochlea, a small differ- quence, the auditory system apparently has the capacity to serve ence in electrical potential exists between the canal filled with as a window onto certain processes of prenatal development and endolymph and the two canals filled with perilymph, and the sexual differentiation. Exactly why the cochlea and auditory existence of that potential difference means that the shearing of system have this sensitivity is still a mystery, but because they the stereocilia modulates a potential difference that is larger do, investigators interested in developmental phenomena other than the one across the membranes of the individual hair cells. than auditory perception itself have some additional, noninva- Accordingly, masculinization of the cochlea might involve a sive (if unlikely) tools at their disposal. The relative constancy of reduction in this endocochlear potential. OAEs through life suggests that these tools can be used across a Perhaps the most puzzling aspect of this story for many wide age range (as long as the cochlear amplifiers remain un- readers will be the question: Why is the peripheral auditory damaged). Much more needs to be learned before these tools can system apparently so sensitive to whatever mechanisms are be used with confidence, but I am hopeful that at least some operating during early development to produce the OAE and readers have been convinced that additional work is worthwhile. AEP differences seen both between the sexes and in the special The prenatal-androgen-exposure hypothesis of interest here populations discussed? Is this susceptibility simply an epi- is like many in physiological psychology in that it is inherently phenomenon, just as OAEs themselves are epiphenomenal to impossible to test directly in humans, and the investigator is

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forced to resort to trying to acquire additional evidence from Brownell, W.E., Bader, C.R., Bertrand, D., & de Ribaupierre, Y. special populations (which may not have differed developmen- (1985). Evoked mechanical responses of isolated cochlear outer tally in the exact manner presumed) and/or from measurements hair-cells. Science, 227, 194–196. Burns, E.M., Arehart, K.H., & Campbell, S.L. (1992). Prevalence of in other species (which may differ from humans in unknown spontaneous otoacoustic emissions in neonates. Journal of the ways that make the comparison inappropriate). This can make it Acoustical Society of America, 91, 1571–1575. difficult for folks accustomed to resolving scientific questions Burns, E.M., Campbell, S.L., & Arehart, K.H. (1994). Longitudinal with direct experimental manipulations to reach a verdict on a measurements of spontaneous otoacoustic emissions in infants. proposed explanation. Much of the evidence is necessarily cir- Journal of the Acoustical Society of America, 95, 385–394. cumstantial, and there are numerous implicit assumptions un- Burns, E.M., Campbell, S.L., Arehart, K.H., & Keefe, D.H. (1993). Long-term stability of spontaneous otoacoustic emissions [Ab- derlying the arguments. Said simply, ‘‘Wedon’t know whodunit.’’ stract]. Association for Research in Otolaryngology, 16, 98. The best I can hope for here is that I have presented the case in a Cacace, A.T., McClelland, W.A., Weiner, J., & McFarland, D.J. (1996). way that has made the facts and the arguments clear. This being Individual differences and the reliability of 2F1-F2 distortion- science, our verdict now actually does not matter much because product otoacoustic emissions: Effects of time-of-day, stimulus ultimately time and new facts will resolve the uncertainties and variables, and gender. Journal of Speech and Hearing Research, a jury will be unnecessary. But it sure would be nice to know if 39, 1138–1148. Chiarenza, G.A., D’Ambrosio, G.M., & Cazzullo, A.G. (1988). Sex and I have been on the right track. ear differences of brain-stem acoustic evoked potentials in a sample of normal full-term newborns: Normative study. Acknowledgments—The research reported here was sup- Electroencephalography, 71, 357–366. Clark, M.M., & Galef, B.G., Jr. (1998). Effects of intrauterine position ported by an ongoing grant from the National Institute on on the behavior and genital morphology of litter-bearing rodents. Deafness and other Communication Disorders (DC 00153). The Developmental Neuropsychology, 14, 197–211. studies on rhesus monkeys, spotted hyenas, and ADHD children Cohen, J. (1992). A power primer. Psychological Bulletin, 112, 155– were realized only because of the generous cooperation of our 159. Collaer, M.L., & Hines, M. (1995). Human behavioral sex differences: splendid collaborators. E.G. 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