Byne et al 2001 Los Núcleos Intersticiales del Hipotálamo Anterior Humano

Hormones and Behavior 40, 86–92 (2001)

Los Núcleos Instersticiales del Hipotálamo Anterior Humano: una Investigación de la Variación en relación con el Sexo, la Orientación Sexual y el Estatus VIH

William Byne,*,†,1[1] Stuart Tobet,‡ Linda A. Mattiace,*,† Mitchell S. Lasco,§ Eileen Kemether,* Mark A. Edgar,\ Susan Morgello,¶ Monte S. Buchsbaum,* and Liesl B. Jones*,**

*Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029; Veterans Affairs Medical Center, Bronx, New York 10468; The Shriver Center, Department of Biomedical Sciences, 200 Trapelo Road, Waltham, Massachusetts 02452; §Department of Applied Psychology, New York University, New York, New York 10009; \Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021; and Department of Pathology, Mount Sinai School of Medicine, New York, New York 10029; **Department of Biology, Lehman College, Bronx, New York

Received August 9, 2000; accepted March 1, 2001


Los núcleos intersticiales del hipotálamo anterior humano [interstitial nuclei of the human anterior hypothalamus] (INAH1–4) han sido considerado candidatos para la homología con el núcleo sexualmente dimórfico del área preóptica de la rata. Se ha descrito dimorfismo volumétrico sexual en tres de estos núcleos (INAH1–3), y del INAH3 se ha informado que es más pequeño en los hombres homosexuales que en los heterosexuales. El estudio presente midió el INAH en secciones coronales manchadas con Nissls [Nisslstained coronal sections] en material de autopsia proveniente de 34 hombres presuntamente heterosexuales (24 HIV2 and 10 HIV1), 34 mujeres presuntamente heterosexuales (25 HIV2 and 9 HIV1), y 14 hombres homosexuales HIV1. El estatus de VIH influyó significativamente en el volumen del INAH1 (8% más grande en hombres y mujeres heterosexuales HIV1, en relación con los individuos HIV2 individuals), pero no influyó en ningún otro INAH. El INAH3 en hombres presuntamente heterosexuales contenía significativamente más neuronas y ocupaba un volumen mayor que en las mujeres presuntamente heterosexuales. No se detectó diferencia sexual en volumen para cualquier otro INAH. No se observó variación sexual en tamaño o densidad neuronal en ningún INAH. Aunque hubo una tendencia en el sentido de que el INAH3 ocupara un volumen menor en hombres homosexuales comparados con los heterosexuales, no hubo diferencia basada en la orientación sexual en el número de neuronas dentro del núcleo.


Key Words: hypothalamus; preoptic area; sex difference; human; homosexuality; sexual orientation; AIDS; HIV.

Examination of the human hypothalamus for morphological sex differences comparable to those described in animals (Bleier et al., 1982; Commins and Yahr, 1984; Gorski et al., 1978; Hines et al., 1985; Tobet et al., 1986) has produced discrepant results. Swaab and Fliers (1985) examined a hypothalamic cell group previously designated as the intermediate nucleus (Brockhaus, 1942) and found it to be larger in males than in females. They suggested that the nucleus may correspond to the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the rat (Gorski et al., 1978). Consequently, they redesignated it as the SDNPOA or, more simply, the sexually dimorphic nucleus (SDN) (Swaab and Hoffman, 1988, 1995). Allen et al. (1989) were unable to verify a sex difference in that nucleus; however, they identified two other nuclei which they called the second and third interstitial nuclei of the anterior hypothalamus (INAH2 and INAH3), both of which they found to be larger in males. They designated the SDN of Swaab and Fliers as the first interstitial nucleus of the anterior hypothalamus (INAH1). Thus, the terms intermediate nucleus, SDN-POA, SDN, and INAH1 correspond to a single cell group in the human. Allen et al. (1989) also described a nucleus which they called INAH4 for which they found no sexual dimorphism. Like Allen et al. (1989), LeVay (1991) found INAH3 to be larger in males than in females and found no sex difference in INAH1 or INAH4. LeVay (1991), however, found no sex difference in the volume of INAH2.

To address the discrepancies in the literature regarding sexual dimorphism of the INAH, we assessed the volume of each of the INAH in serial sections from postmortem specimens obtained at autopsy and also examined each nucleus for sex differences in neuronal density, total neuronal number, and mean neuronal size. In agreement with two prior studies (Allen et al., 1989; LeVay, 1991), we found INAH3 to be sexually dimorphic, occupying a significantly greater volume in males than females. In addition, we determined that the sex difference in volume was attributable to a sex difference in neuronal number and not in neuronal size or density (Byne et al., 2000). We found no evidence for sexual dimorphism of any other INAH.

LeVay (1991) examined the volumes of the INAH for variation with sexual orientation in men. He found the volume of INAH3 in homosexual men to be smaller than that of presumed heterosexual men and comparable in size to that of presumed heterosexual women. On the basis of that result, he hypothesized that INAH3 is dimorphic, not only with sex, but also with sexual orientation, at least in men (LeVay, 1991). LeVay’s characterization was done only for volume and not for cell number.

We now report our examination of the INAH for possible variation with sexual orientation in men. Sexual orientation was determined from a review of medical records available at autopsy. No information regarding sexual orientation was available for subjects that died from causes unrelated to HIV infection. Inthe absence of such information, all individuals who were not known to be HIV positive (HIV1) at the time of death were classified as heterosexual because of the low rate of homosexuality in the population (Hamer et al., 1993; Michael et al., 1994). Specimens were obtained from HIV1 men only if the autopsy record listed a single HIV risk factor (i.e., intravenous drug use or homosexual behavior). Those for whom intravenous drug use was the only known risk factor were presumed to be heterosexual. Those for whom homosexual behavior was listed as the risk factor were presumed to be homosexual. Thus, as in the study of LeVay (1991), all specimens from homosexual men came from individuals who died from opportunistic infections associated with HIV infection. It has, therefore, been necessary to examine possible effects of HIV infection on the INAH. To date, we have examined all four INAH for volumetric variation with sexual orientation and HIV status. In addition, we have examined INAH3 for such variation in neuronal number, size, and packing density. In the absence of a source of brains from women of known sexual orientation, it has not been feasible to address the possibility that one or more of the INAH exhibit variation with sexual orientation in women.

The present sample includes the specimens from HIV-negative (HIV-) individuals who were included in our earlier study (Byne et al., 2000) in which all of the morphometric methods were fully described. Throughout the text, data are presented as mean 6 standard error of the mean (SEM). The mean age of subjects did not differ significantly across groups: HIV1 presumed heterosexual males 47.1 6 10, n 5

10; HIV2 presumed heterosexual males 49.5 6 2.9, n 5 24; HIV1 presumed heterosexual females 40.6 6

3.2, n 5 9; HIV2 presumed heterosexual females 49.9 6 2.5, n 5 25; and HIV1 homosexual males 41.8 6 2.5, n 5 14.

HIV Influence on INAH1 and Sexual Influence on INAH3


Volumes (in Cubic Millimeters) of the INAHa
Heterosexual males Heterosexual females Homosexual males, HIV+
INAH 1 .364 6 .017 (n 5 21) .424 6 .033 (n 5 9) .372 6 .018 (n 5 20) .409 6 .003 (n 5 8) .379 6 .026 (n 5 12)
INAH 2 .059 6 .004 (n 5 23) .058 6 .010 (n 5 10) .055 6 .002 (n 5 24) .058 6 .013 (n 5 8) .059 6 .005 (n 5 13)
INAH 3 .123 6 .009 (n 5 22) .108 6 .009 (n 5 9) .077 6 .006 (n 5 25) .067 6 .012 (n 5 9) .096 6 .007 (n 5 14)
INAH 4 .101 6 .010 (n 5 22) .103 6 .011 (n 5 8) .091 6 .010 (n 5 25) .083 6 .013 (n 5 9) .085 6 .012 (n 5 14)
a Some INAH were incomplete in some specimens precluding volume determination. The number of specimens for which volumes could be determined, therefore, varied among the nuclei as indicated. An ANOVA (excluding the homosexual males) revealed a significant main effect of HIV status only for INAH1 [F(1, 55) 5 4.02, P , 0.05] and a significant main effect of sex only for INAH3 [F(1, 61) 5 20.7, P , 0.0001]. There was no significant sex 3 HIV interaction for any nucleus.

For the initial analysis (Table 1), HIV1 and HIV2 heterosexual males and females were analyzed in a two-way ANOVA for the volumes of INAH1–4. Only INAH3 revealed a significant influence of sex. There was a highly significant effect of sex (P , 0.0001), with no influence of HIV status [F(1, 61) 5 1.61, P . 0.20]. Only INAH1 revealed a significant influence of HIV status, as there was a statistically significant effect on volume (P 5 .047). Volume was increased in HIV1 males and HIV1 females by about 8% (0.369 6 0.012 vs 0.401 6 0.017). Since there was no significant influence of HIV status on INAH3, the influence of sexual orientation was analyzed by a one-way ANOVA collapsing across HIV status to yield three groups: male heterosexual, female heterosexual, and male homosexual subjects. This analysis yielded a significant effect of group: F(2, 76) 5 13.95, P , 0.0001, with the majority of the effect due to the male–female difference. The size of INAH3 in homosexual males (0.096 6 0.007, n 5 14) was intermediate between the heterosexual males (0.121 6 0.007, n 5 31) and females (0.073 6 0.005, n 5 34), but the differences did not reach statistical significance relative to either group (P . 0.05, post hoc Tukey–Kramer HSD) (Fig. 1).


FIG. 1. Eighty-micron-thick coronal sections from specimen ms-136 (69-year-old presumed heterosexual male) illustrating the INAH, which are indicated by the corresponding numbers. INAH1 and INAH2 are seen clearly in level a, in which INAH3 begins to emerge as an area of increased density within MP-AHN. Level b is 880 mm posterior to level a. INAH3 and INAH4 are prominent.

INAH3 is in close proximity to a cell group designated by Bleier as AH-ST (see Byne, 1998, for discussion). Abbreviations: AH-ST, confluence of the anterior hypothalamic nucleus (AH) with the bed nucleus of the stria terminalis (ST); MP-AHN, medial preopticanterior hypothalamic nucleus; PVN, paraventricular nucleus; oc, optic chiasm; SON, supraoptic nucleus; v, third ventricle.


Influences on Brain Weight

Excluding the homosexual male group, there were significant sex (P , 0.001) and HIV (P , 0.05) influences on brain weight with males (1347.3 g) having greater brain weights than females (1187.3 g) and HIV2 individuals (1299.1 g) having greater brain weights than HIV1 individuals (1235.5 g). Although the interaction of sex and HIV status was not significant (P 5 0.11), the bulk of the HIV influence was due to larger brain weights in HIV2 heterosexual males (1409.6 6 22.9) vs HIV1 heterosexual males (1291.0 6 41.1). This may not be due to the HIV infection itself, as the average brain weight for the HIV1 homosexual males (1409.3 6 31.5) did not differ from that of the HIV2 heterosexual males (Table 2); however, in the absence of an HIV2 homosexual group, the main and interactive effects of sexual orientation and HIV status cannot be completely analyzed. None of the dependent variables examined exhibited significant covariance with brain weight. Similarly, no variables covaried with age, and mean ages did not differ across groups.

Brain Weights (Grams)a
HIV status Male heterosexual Female Male homosexual
Positive 1291.0 6 41.1 (n 5 10) 1180.0 6 30.1 (n 5 9) 1409.3 6 31.5 (n 5 14)
Negative 1409.6 6 22.9 (n 5 24) 1194.6 6 22.6 (n 5 25)
a An ANOVA, excluding the homosexual males, revealed a main effect of sex [F(1, 65) 5 27.3, P , 0.0001] a main effect of HIV status

[F(1, 65) 5 4.3, P 5 0.04] and no sex 3 HIV interaction (P 5 0.114). The bulk of the HIV effect is accounted for by the reduction of brain weight in the HIV1 heterosexual males relative to the HIV2 heterosexual males.

Because ANOVA revealed a significant group effect on brain weight, an additional ANOVA was run for INAH3 volume/brain weight. The results were the same as for the raw volumes of INAH3. There was a significant main effect of sex [F(1, 61) 5 12.07, P 5 0.009], but no effect of HIV [F(1, 65) 5 .416, P 5 0.5213]. Post hoc Tukey–Kramer HSD failed to demonstrate a significant difference between homosexual men (0.069 6 0.006) and either heterosexual men (0.087 6 0.005) or women (0.061 6 0.004) (P . 0.05, each test), although there was a trend for INAH3/brain weight to be reduced in the homosexual relative to heterosexual men (P , 0.10, two-tailed) (Table 3).


La cantidad de neuronas del INAH 3 varía con el sexo pero no con la orientación sexual

En nuestros estudios previos, el hallazgo cellular más robusto fue una cantidad incrementada de neuronas en el INAH 3 de los varones, comparados con las mujeres (Byne et al., 2000). El presente conjunto de datos acuerda con aquellos resultados en los individuos presumiblemente heterosexuales, ya que el INAH 3 del varón contiene en promedio aproximadamente el 60% más de neuronas que en la mujer. La cantidad de neuronas en INAH 3 de varones homosexuales no difirió de los varones heterosexuales. En cuantgo a la cantidad neuronal, un ANOVA de dirección única reveló un efecto grupal significativo [F(2, 53) 5 7.21, P , 0.01] que fue atribuible al hecho de que ambos grupos de varones tenían más neuronas en el INAH 4 que los grupos de mujeres. La tendencia hacia un volumen decrecido de INAH 3 en el grupo de homosexuales varones en ausencia de diferencia en el número total neuronal, sugirió la importancia potencial de estudiar la densidad neuronal. Hubo una fuerte tendencia en pro de una influencia de la orientación sexual en la densidad neuronal en el INAH 3 [F(2, 53) 5 3.03, P 5 0.057], íntegramente atribuible a una densidad neuronal más alta en el INAH 3 de los homosexuales varones, versus heterosexuales varones y mujeres (Tabla 3). No hubo efecto de grupo en el area transeccional (mm2) de neuronas dentro del INAH 3 (varones héterosexuales 120.7 6 3.4, n 5 21; mujeres 118.4 6 3.1, n 5 21; varones homosexuales 121.9 6 3.8, n 5 14).


TABLE 3      
INAH3 Dataa      
  Heterosexual male Female Homosexual male
Volume (mm3)      
HIV2 .123 6 .009 (22) .077 6 .006 (25)  
HIV1 .108 6 .009 (9) .067 6 .012 (9) .096 6 .007 (14)
All .121 6 .007 (31) .073 6 .005 (34)**  
Volume/brain wt (mm3/g)      
HIV2 .088 6 .006 (22) .064 6 .005 (25)  
HIV1 .086 6 .007 (9) .058 6 .011 (9) .069 6 .006 (14)
All .087 6 .005 (31) .061 6 .004 (34)**  
Neurons per mm3      
HIV2 14484 6 1179 (13) 15912 6 1113 (12)  
HIV1 17755 6 1447 (8) 16167 6 1224 (9) 18792 6 881 (14)††
All 15730 6 960 (21) 16021 6 804 (21)  
Neuronal number      
HIV2 1737 6 179 (13) 1123 6 156 (12)  
HIV1 1887 6 275 (8) 1122 6 249 (9) 1831 6 184 (14)
Total 1794 6 149 (21) 1123 6 135 (21)**†  
a Cellular parameters were assessed only if INAH3 was completely intact. These parameters were assessed in either all intact specimens

per group or a randomly selected subset of intact specimens. ANOVAs are described in text.

** Different from heterosexual males, P , .001.    
† Different from both heterosexual and homosexual males, P , .001.  
†† Trend toward increased density in homosexual compared with heterosexual males, P 5 .057.



El estudio aquí presentado prove todavía más evidencia de que el INAH3 ocupa un volumen más grande (Allen et al., 1989; LeVay, 1991) y de que contiene más neuronas (Byne et al., 2000) en los hombres presuntamente heterosexuales que en las mujeres. La característica cellular primaria sexualmente dimórfica del INAH3, la cantidad neuronal, no varió en función de la orientación sexual. El estudio actual no pudo proveer evidencia de dimorfismo sexual en INAH1 (Swaab y Fliers, 1985; Swaab y Hoffman, 1995) o INAH2 (Allen et al., 1989).

Se ha propuesto que las hormonas ejercen una influencia organizacional global en el cerebro en desarrollo, influyendo en el desarrollo de regiones y circuitos cerebrales dentro y fuera del hipotálamo, tales como la comisura anterior (e.g., Allen and Gorski, 1992). También medimos la comisura anterior en los mismos bloques de tejido usados para el estudio hipotalámico aquí presentado (los datos no se muestran) y no pudiemos replicar el informe de que su área transeccional es mayor en las mujeres que en los hombres (Allen y Gorski, 1992). De este modo, en tanto que para el cerebro humano se han descrito una variedad de otras diferencias sexuales estructurales, que incluyen diferencias en el cuerpo calloso, la comisura anterior y porciones del núcleo lecho de la estría terminalis (reseñado en Byne, 1993; Fox et al., 1999), el dimorfismo sexual del INAH3 es por tanto hasta ahota el único que ha sido sujeto a repetidos y exitosos intentos de replicación por parte de laboratorios independientes, con ausencia de fracasos significativos en la replicación.



FIG. 2. Three-dimensional reconstructions of the medial preoptic-anterior hypothalamic continuum of the human (A) and rat (B). INAH3 in the human, like the SDN-POA of the rat, is a component of the MP-AHN. In contrast, the other INAH are situated outside the MP-AHN. In the rat, an expansion of the ventricle (V) is seen behind the anterior commissure (ac). In the human, the region of the reconstruction did not extend through ac posteriorly. Reconstructions were prepared from thionin-stained serial sections with the assistance of Application Visualization System software (Advanced Visual Systems, Inc., Waltham, MA). Abbreviations: ac, anterior commissure; INAH, interstitial nucleus of the anterior hypothalamus; MP-AHN, medial preoptic-anterior hypothalamic nucleus; oc, optic chiasm; SDN-POA, sexually dimorphic nucleus of the preoptic area; SON, supraoptic nucleus.

INAH1 and INAH3 have each been considered as candidates for homology with the much-studied SDNPOA of the rat. We believe that, in addition to its sexual dimorphism, INAH3 more closely resembles the SDN-POA of the rat in a variety of ways, including its positional and cytoarchitectonic characteristics (Byne, 1998; Byne et al., 2000). For example, like the SDN-POA, INAH3 is a component of the medial preoptic-anterior hypothalamic nucleus (MP-AHN) (Fig. 2). In contrast, INAH1 is situated completely outside and lateral to the MP-AHN. While it might be helpful to bring chemoarchitecture to bear on the issue of homology, little is known about specific markers in the human INAH. Moreover, homologous nuclei do not necessarily express the same peptides in all species. For example, the large cholinergic neurons of nucleus basalis of Meynert express galanin in baboons but not in humans (Walker et al., 1991). Inferences regarding homology should, therefore, be based on a consideration of a wide variety of markers. The connections and functions of the nuclei in question are also relevant to the issue of homology, but again, little is known with regard to the INAH.

By analogy to hypothalamic sex differences in animals (e.g., Byne et al., 1987; Gorski et al., 1978; Tobet et al., 1986) the sex difference in the human INAH3 may depend at least in part on sex differences in developmental exposure to gonadal hormones. The prevailing hypothesis concerning the development of the SDNPOA in rats is that gonadal steroids cause more neurons to survive in males than females (Davis et al., 1996). As the sex difference in INAH3 is in the number of neurons, differences in neuronal survival between

males and females may also contribute to the sexual dimorphism of INAH3. In addition, sex related differences may also emerge later in development as the neurons that survive become part of functional circuits (Hutton et al., 1998). The current results may provide a suggestion of such a later emerging influence. Thus, while the difference in volume between the sexes was accounted for by an increased number of neurons in men, the trend toward a difference between homosexual and heterosexual men was accounted for by a difference in volume without a difference in neuron number (i.e., increased neuronal density). Such a difference in volume could be accounted for in at least two ways. First, it might simply reflect shrinkage during tissue fixation. While that possibility cannot be ruled out, it seems unlikely since no other INAH was similarly affected and there is no evidence of neuronal shrinkage in the homosexual specimens (i.e., neuronal size did not vary between homosexual and heterosexual men). Alternatively, if validated by independent replication, the present findings could reflect a reduction of neuropil within INAH3 in the homosexual group. Work in animals suggests that the elaboration of synaptic connections continues after cytoarchitectonic patterns (i.e., the positioning of neurons) are determined (Byne et al., 1987; Hutton et al., 1998). It is known that postnatal experience in animals can influence the elaboration of neuropil in some brain regions (e.g., Bhide and Bedi, 1984; Turner and Greenough, 1985). In humans, the major expansion of the brain occurs postnatally while the individual is in constant interaction with the environment (for references see Byne and Parsons, 1993). Thus, the elaboration of neuropil may be influenced by postnatal experience in humans. At present, however, nothing is known about the potential importance of either hormonal exposure or postnatal experience on neuropil development in INAH3.

Ha habido una especulación considerable dirigida a las posibles funciones del INAH 3, en particular en relación con un rol potencial en la regulación de los comportamiento sexuales típicos del macho (Allen et al., 1989; LeVay, 1991). Sin embargo, hasta el momento presente no podemos ni adscribir una función cualquiera al INAH 3, ni tampoco podemos interpretar la significación funcional de su dimorfismo sexual. Si el INAH 3 es un sitio relacionado con el tendido de circuitos functional de la orientación sexual, entonces los datos actuales sugieren que las se necesitan otras mediciones que no sean el volumen nuclar simple para discernir cuál es la relación. Tomando como base los resultados del presente estudio, así como los de LeVay (1991), no se puede predecir confiablemente la orientación sexual partiendo sólo del volumen del INAH 3.

El hallazgo de un aumento en el volumen de INAH 1 asociado con la infección de VIH en los grupos heterosexuales no fue anticipado, y debe ser considerado cautelosamente hasta su replicación. Si el aumento en volumen está relacionado con un cambio en el tamaño o la cantidad de las neuronas en los especimenes presentes sigue sin haber sido determinado. Como todos los varones heterosexuales HIV+, así como algunas de las mujeres VIH+, tenían historias de abuso de droga intravenosa, el aumento en el volumen del INAH 1 puede estar relacionado más estrechamente con el uso de droga que con la infección de VIH. Como el INAH 1 es rico en mensaje para la preproencefalina, puede concebibmenete jugar un rol en los sistemas de recompensa del cerebro que está disregulados en la adicción de drogas. En contraste con el INAH 1, no encontramos evidencia de una influencia de VIH en el INAH 3, lo que da credibilidad a la afirmacióin de  LeVay (1991) de que la infección de VIH no explicaba la disparidad del volumen en INAH3 que observó entre hombres homosexuales y heterosexuales.



We acknowledge Noreen Mall for expert technical assistance, and Drs. Harry Vintners, Carol Petito, Mahlor Johnson and Charles Moser for assistance with the procurement of tissues. Tissues were also provided by the Manhattan HIV Brain Bank supported by R24MH59724 to S.M. This work was supported by MH54748 to W.B., MH61376 to S.A.T., and the VISN 3 Mental Illness Research Education and Clinical Center.



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