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There is indirect evidence that heightened exposure to early androgen may increase the probability that a girl will develop a homosexual orientation in adulthood. One such putative marker of early androgen exposure is the ratio of the length of the index finger (2D) to the ring finger (4D), which is smaller in male humans than in females, and is smaller in lesbians than in heterosexual women. Yet there is also evidence that women may have different sexual orientations at different times in their lives, which suggests that other influences on female sexual orientation, presumably social, are at work as well. We surveyed individuals from a gay pride street fair and found that lesbians who identified themselves as 'butch' had a significantly smaller 2D:4D than did those who identified themselves as 'femme.' We conclude that increased early androgen exposure plays a role in only some cases of female homosexuality, and that the sexual orientation of 'femme' lesbians is unlikely to have been influenced by early and rogens. KEY WORDS: androgen; sexual orientation; finger length ratios; lesbians.

We argue that within-sex variation resulting from the prenatal organizational and adult activational effects of gonadal steroid hormones has the potential to obscure between sex differences in cognitive performance and functional cerebral asymmetry. Two putative markers for prenatal testosterone, finger ridge count (FRC) asymmetry and the 2D:4D finger length ratio, have been linked to within-sex variation in cognitive performance. In particular, FRC allows the identification of men and women who show a reversal of the typical sex-related pattern of task performance. Three paradigms for the study of activational effects--seasonal, menstrual, and diurnal hormonal cycles--have evaluated changes in task performance and functional cerebral asymmetry. The performance of sex-dimorphic, but not sex-neutral, tasks changes with estrogen across the menstrual cycle and with testosterone across its seasonal and diurnal cycles. Functional cerebral asymmetry also changes systematically across both the menstrual cycle and th e diurnal testosterone cycle in such a way that suggests left hemisphere performance increases as testosterone levels decline whereas right hemisphere performance increases as estrogen levels decline. In studies of sex differences, such correlates of within-sex hormone-related differences are rarely measured or controlled. Whatever the explanation for the associations of putative markers and hormone cycles with differences in cognitive abilities and cerebral asymmetry, it is clear that these relationships have the potential to contribute to the elusive nature of sex differences in cognition and functional brain organization. KEY WORDS: sex differences; cognition; functional cerebral asymmetry; testosterone; estrogen.

The relations between sexual orientation and age of puberty in both men and women were examined in a national probability sample of the United States. The sample was the National Health and Social Life Survey (E. O. Laumann, 1. H. Gagnon, R. T. Michael, & S. Michaels, 1994), which contains 3432 cases. Gay/bisexual men reported an earlier age of puberty (e.g., age of first pubic hair) relative to heterosexual men, but lesbian/bisexual women did not report a different age of puberty (i.e., age of menarche) than heterosexual women. These results confirm findings from prior research examining age of puberty using nonrepresentative samples and add to a body of literature suggesting that gay/bisexual men may score, on average, in the female-typical direction on certain sex-dimorphic physical and developmental characteristics. KEY WORDS: puberty; sexual orientation; hypothalamus; probability sampling; menarche.

Exposure of the female sheep fetus to exogenous testosterone in early pregnancy permanently masculinizes the reproductive neuroendocrine axis. Specifically, in utero androgens given to female lambs from day 30 to 90 of a 147 day pregnancy dramatically altered the response of the gonadotropin releasing hormone (GnRH) neuronal network in the hypothalamus to both estrogen (E) and progesterone (P) feedback. Elevated concentrations of estrogen stimulated a massive release of GnRH in gonadectomized female sheep; however, male and androgenized female lambs were unable to respond to high E concentrations by producing this preovulatory-like 'surge' of GnRH. Further, the inhibitory actions of progesterone (P) were also sexually differentiated and adult males and androgenized females were much less responsive to P-negative feedback than normal ewes. The consequences of these abnormal steroid feedback mechanisms were reflected in the fact that only 72% of ovary-intact androgenized ewes exhibited normal estrous cycles in their first breeding season whereas none had a single estrous cycle during the second breeding season. In contrast, 100% of the control animals exhibited repeated reproductive cycles in both seasons. These data indicate that a relatively short exposure to male hormones during in utero life permanently alters the neural mechanisms that control reproduction and leads progressively to a state of infertility. KEY WORDS: sexual dimorphism; estrogen; progesterone; LHRH; sheep.

In the traditional model for sexual differentiation in mammals, the female phenotype is the default condition. That is, the female-typical pattern will persist unless acted upon by hormones early in development. The frequency of play fighting in rats, as in most other mammals, is sexually differentiated, and conforms to the traditional mode]. Males engage in more play fighting than females, and this can be reduced to female-typical levels by neonatal castration. Furthermore, females can be induced to play fight at male-typical levels if treated with testosterone neonatally. Fractionation of play fighting into its constituent components, attack and defense, reveals that it is the frequency of attack that is sexually differentiated, not the likelihood of defense. However, in males, defensive behavior changes at puberty so that the play becomes 'rougher.' For males to switch to this rougher form of play fighting, they have to be androgenized perinatally. Hence, for males, this second aspect of play fighting that is sexually differentiated also follows the traditional model. In marked contrast, development of the female-typical pattern does not. Neonatal treatment of females with testosterone has no effect; at puberty, they still show the female-typical pattern. On the the other hand, ovariectomy, either at birth or at weaning, leads to females exhibiting the male-typical transition to rougher play fighting at puberty. That is, ovarian hormones appear to actively inhibit the expression of a male-typical trait in females. Play fighting, then, is a mixture of traits, with some features conforming to the traditional model and some not. For some phenotypic features, ovarian hormones appear to exert an active role in their development. KEY WORDS: play; aggression; testosterone; ovarian hormones; rats.

This review discusses the developmental course of gonadal and genital development in males. Data reveal that although in initial stages there are no discernible morphological differences in embryo development, male differentiation is initiated by three testicular hormones, Mullerian-inhibiting substance, testosterone, and insulin-like 3.

Current risk assessment techniques for almost all chemicals involve establishing a threshold dose, or the dose below which no adverse effects are seen. But threshold doses may not apply in situations where the chemical mimics the actions of an endogenous compound - such as a steroid hormone - that is important to development. In such cases, any exposure may exceed the threshold. Recent studies with the red-eared slider turtle have shown that exogenous estradiol - even when applied to eggshell in doses as low 0.4 ng - will affect sex development during embryogenesis. Considering that only 0.2% of the estradiol applied to the eggshell ends up in the embryo, it becomes apparent that even very low dosages of steroid hormones or their mimics can have profound biological effects. We tested this idea using eight compounds identified in the yolk of alligator eggs from Lake Apopka, Fla. Five of the compounds - the PCB mixture Aroclor 1242, trans-Nonachlor, cis-Nonachlor, p,p' -DDE, and chlordane - altered sex ratio outcomes when applied to eggshells during development. Aroclor 1242 produced the most powerful effects, shifting the ratio of females almost twofold, while chlordane had the greatest effect when combined with estradiol. Administration of all eight compounds together also increased the ratio of females to males. However, comparing the single-compound exposures at the same dosages indicate that these compounds behave differently in combination than they do singly, emphasizing the need for further studies using chemical mixtures reflecting proportions found in nature. The effect of chlordane and Aroclor 1242 on aromatase activity levels during embryogenesis in the brain and adrenal-kidney-gonad (AKG) complex was also examined. Chlordane, a suspected anti-androgen in this species, did not affect aromatase activity in either the brain or the AKG. However, Aroclor 1242 significantly altered aromatase activity levels in the red-eared slider turtle brain - but not in the AKG - during a crucial developmental period. After this crucial period, Aroclor 1242 caused an increase in aromatase activity in the AKG of embryos just prior to hatch. Additionally, hatchling males treated during embryogenesis with Aroclor 1242 and chlordane exhibited significantly lower testosterone levels than controls in response to follicle-stimulating hormone administration, while chlordane-treated females had significantly lower progesterone, testosterone, and 5(alpha)-dihydrotestosterone levels relative to controls. These results are similar to those found in juvenile alligators from Lake Apopka. Males treated with Aroclor 1242 and trans-Nonachlor displayed an elevated estradiol response to FSH administration vs. control males. Taken together, these results suggest that EDCs exert effects during embryonic development that extend beyond birth. They also suggest that the alterations in sex steroid hormone levels observed in animals from contaminated areas may result from EDC-induced alterations in the neuroendocrine axis controlling gonadal sex steroid hormone production.

This study examines the affect of steroidal estrogens in determining the sex of red-eared spider turtles. The data suggests that weak environmental estrogens may synergize with stronger natural estrogens.

The findings of this study indicate even very low doses of exogenous estradiol adversely affect the eggs of red-eared slider turtles. No threshold dose was observed because endogenous estrogens were already at a significantly high concentration to affect sex reversal.

A number of commentators agree that the evidence reviewed in the target article supports a previously unrecognized role for ovarian hormones in feminization of the brain. Others question this view, suggesting that the traditional model of sexual differentiation already accounts for ovarian influence. This position is supported by various reinterpretations of the data presented (e.g., ovarian effects are secondary to the presence/absence of androgen, ovarian effects are smaller than testicular effects, ovarian effects are not organizational). We discuss these issues, and reiterate our position that evidence of neurobehavioral ovarian effects is incompatible with the currently accepted model of sexual differentiation. Other points regarding species generalizations, the direct versus indirect action of estrogen, and nonhormonal mechanisms of sexual differentiation are also discussed. Finally, we address the controversial issue of using ratio scores in the assessment of the human corpus callosum (where CC scores are divided by an index of brain size). Future applications to human research are also discussed.

Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization. Keywords: activational effects; androgens; corpus callosum; estrogen; female default hypothesis; feminization; masculinization; organizational effects; sensitive periods; sexual differentiation; testosterone

This study assessed marital conflict behavior and endocrine function in 90 newlywed couples. Blood samples acquired hourly from 8:00 a.m. through 10:00 p.m. were combined to provide composite daytime values for 3 stress hormones - epinephrine (EPI), norepinephrine (NEPI), and cortisol - and 3 related hormones (ACTH, growth hormone, and prolactin). These pooled data provided a window on endocrine function in couples for whom the day included a conflict. For wives, higher probabilities of husband's withdrawal in response to wife's negative behavior were associated with higher NEPI and cortisol levels. In addition, higher frequencies of positive behaviors were associated with lower EPI and higher prolactin levels among wives. Husbands' endocrine data were not associated with behavioral data. These findings are discussed in the context of gender models of marital conflict.

Androgen controls the expression of the laryngeal-specific myosin heavy chain responsible for the fast twitch in the laryngeal muscles (LM) of male Xenopus laevis frogs. Females express LM in a few fast-twitch muscle fibres. The number of muscle fibres expressing LM and the expression of LM increases in juvenile females treated with androgen. In juvenile males all the muscle fibres express LM and the expression increases on treatment with androgen. Castrated males show a decrease in the expression of LM. Androgen probably activates the large number of its receptors present in the larynx.

Sexual differentiation in malacostracan Crustacea is controlled by the androgenic gland hormone (AGH). In males, the primordial androgenic glands (AG) develop and AGH induces male morphogenesis. In females, the primordial AG does not develop and the ovaries differentiate spontaneously. Implantation of the AG into females yields various results, showing that the sensitivity to AGH differs with the species and the receptive organs. Purified AGH of the isopod Armadillidium vulgare consists of at least two molecular forms, which exist as monomeric proteins with molecular weights of 17,000 [+ or -] 800 and 18,300 [+ or -] 1,000 Da and with isoelectric points of about 4.5 and 4.3, respectively. The antiserum raised against purified AGH makes it possible to measure AGH activity by immunoassay. Neurohormones control male and female reproduction. In males, they are involved in the maintenance of the male germinative zone and the control of AG activity. In females, the secondary vitellogenesis is controlled by the vitellogenesis-inhibiting hormone (VIH) and the vitellogenesis-stimulating hormone (VSH). VIH isolated from the lobster Homarus americanus is a peptide with a molecular weight of 9,135 Da and shows homology to the crustacean hyperglycemic hormone and molt-inhibiting hormone. Involvement of the molting hormone and the juvenile hormone-like compound in the secondary vitellogenesis have also been suggested. In the amphipod Orchestia gammarella, the vitellogenesis-stimulating ovarian hormone (VSOH) seems to control vitellogenin synthesis.

Data do exist to support the fact that the corpus callosum is relatively larger in women than in men. The corpus callosum is an integral part of the brain, and contrary to Fitch & Denenberg's examples of 'pseudostatistics,' is not an extrinsic structure when determining its relative size.

Whereas adult sex differences in brain morphology and behavior result from developmental exposure to steroid hormones, the mechanism by which steroids differentiate the brain is unknown. Studies to date have described subtle sex differences in levels of proteins and neurotransmitters during brain development, but these have lacked explanatory power for the profound sex differences induced by steroids. We report here a major divergence in the response to injection of the [Gamma]-aminobutyric acid type A ([GABA.sub.A]) agonist, muscimol, in newborn male and female rats. In females, muscimol treatment primarily decreased the phosphorylation of cAMP response element binding protein (CREB) within the hypothalamus and the CA1 region of the hippocampus. In contrast, muscimol increased the phosphorylation of CREB in males within these same brain regions. Within the arcuate nucleus, muscimol treatment increased the phosphorylation of CREB in both females and males. Thus, the response to GABA can be excitatory or inhibitory on signal-transduction pathways that alter CREB phosphorylation depending on the sex and the region in developing brain. This divergence in response to GABA allows for a previously unknown form of steroid-mediated neuronal plasticity and may be an initial step in establishing sexually dimorphic signal-transduction pathways in developing brain.

Knoferl, Markus W., Doraid Jarrar, Martin G. Schwacha, Martin K. Angele, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry. Severe hypoxemia in the absence of blood loss causes a gender dimorphic immune response. Am J Physiol Cell Physiol 279: C2004-C2010, 2000.--A gender dimorphic immune response has been observed after trauma and severe hemorrhage, a condition believed to be associated with tissue hypoxia. Although studies have shown that hypoxemia per se in males causes a systemic inflammatory response, it is unclear if the inflammatory response to hypoxemia exhibits gender dimorphic characteristics. To study this, male and female C3H/HeN mice in the proestrus state of the estrous cycle were subjected to hypoxemia (95% [N.sub.2]-5% [O.sup.2]) or sham hypoxemia (room air) for 60 min. Later (2 h), plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-[Alpha] levels were determined along with splenic immune responses. Plasma IL-6 and TNF-[Alpha] concentrations after hypoxemia were significantly increased in males but not in females. Splenocyte proliferation was depressed in males after hypoxemia but not in females. A shift toward an immunosuppressive Th-2 cytokine profile was observed in males after hypoxemia [decreased interferon-[Gamma] (Th-1) and increased IL-10 (Th-2)], whereas no such shift was observed in females. Splenic macrophage IL-6, IL-10, and IL-12 production were suppressed in males after hypoxemia; however, such suppression was not observed in females. These findings therefore indicate that a gender dimorphic immune response also exists after hypoxemia in the absence of blood loss and tissue trauma, similar to trauma-hemorrhage. Furthermore, because no systemic inflammatory response or alterations in T lymphocyte or macrophage functions are observed in proestrus females but such parameters are markedly altered after severe hypoxemia in males, these studies indicate that proestrus females can tolerate hypoxemia better than males. rodent; inflammation; cytokines; sex steroids; proestrus

Male sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3). Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum. In mouse, prenatal exposure to 17[Beta]-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism). In the current study, we show that maternal exposure to estrogens, including 17[Alpha]- and [Beta]-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism. These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment. [C] 2000 Academic Press Key Words: Insl3; RLF; Ley I-L; cryptorchidism; estradiol; Estriol; DES; gubernaculum.

Many agricultural chemicals are known to impact wildlife populations by disrupting endocrine pathways. We recently found a population of bullfrogs in a fish hatchery with a female-biased sex ratio. Furthermore, some animals in this population undergo premature sex differentiation. In comparison, bullfrog sex ratios in a wildlife refuge were not skewed and differentiation occurred at the normal developmental stage, suggesting that endocrine disruption may be occurring at the hatchery. Our laboratory studies focus on endosulfan, a common pesticide used worldwide. Low dose (ppb) endosulfan treatment affects mortality in R. catesbeiana, pheromone production in the red-spotted newt and development of secondary sexual characteristics in the mosquitofish. Although some endocrine disrupting compounds act directly at the level of a specific steroid receptor, others appear not to have high affinity binding for these receptors, yet have endocrine disrupting affects We hypothesize that some endocrine disrupting chemicals may be affecting either the expression or function of steroidogenic factor 1, a nuclear receptor known to be a critical regulator of steroidogenesis. Supported by Council for Tobacco Research Grant #4661R1.

My laboratory focuses on the role of steroids on development in anuran amphibians. We have explored the role of thyroid hormones, corticoids, and sex steroids on sex differentiation and metamorphosis in multiple species. Recently, we have developed a number of bioassays for detecting steroid and thyroid hormone agonism and antagonism by xenobiotics. One assay, the Hyperolius argus endocrine screen (HAES[TM] test) is promising as a laboratory screen because it simultaneously tests for androgenic, estrogenic, and thyroid hormone-like activity. Also, the specificity parallels results in mammals: for example, estrogens that are not carcinogenic in mammals are not detected in the HAES[TM] test. Examinations in other amphibians, using a vitellogenin assay and sex reversal of gonads in Xenopus laevis, suggest that effects in H. argus cannot be extrapolated to other amphibian species, however. We feel that using the two assays combined, we can accurately identify hormone agonists / antagonists that would effect amphibians. Supported by NSF grants IBN-9513362 and IBN-9508996.

Female masculinization under natural environmental and laboratory conditions has been documented for the mosquitofish, G. affinis, exposed to androgenic compounds. In order to determine whether two commonly used agricultural chemicals, endosulfan and zineb, are androgenic, we exposed female mosquitofish to varying low doses (ppb) of either compound for five weeks. Following exposure, we determined for each fish the condition factor, gonosomatic index (GSI), and anal fin length/body length ratio. In the endosulfan study, there was no statistical differences among treatment groups in conditioning factor or GSI. However, the group treated with 0.5 ug/l endosulfan had a significantly higher anal fin length/body length ratio (p=0.006) when compared to the other treatments (0.1 ug/l and 1.0 ug/l). Zineb treatment had no affect on any of the measured parameters. These results suggest that exposure to endosulfan can have masculinizing affects in G. affinis, and that this species may have potential as an indicator species for detection of masculinizing endocrine disrupting compounds in the environment. C.R.

Indirect routes by which gonadal hormones influence sexual differentiation are considered. In rats, differentiation may depend on the way in which the mother responds to the hormonal condition of her pups, and this has implications for the interpretation of the data for humans. Interaction between gonadal hormones and light experience in chicks is compared with the mammalian systems covered in Fitch & Denenberg's review.

We argue that estrogen feminization of the brain is the result of a series of events initiated by differential androgen exposure. There is no need to postulate a feminizing process parallel to androgen-induced masculinization to explain the findings.

There is some very limited evidence for a role of estrogens in human psychosexual masculinization; its interpretation is uncertain. Fitch & Denenberg's demonstration of a role for estrogens in the behavioral feminization of nonhuman mammals implicitly suggests an answer to a riddle posed by the syndrome of congenital adrenal hyperplasia in women.

The Fitch & Denenberg target article focuses almost exclusively on short gestation mammals, which differ substantially from long-gestation mammals in the timing and type of hormonal contribution to their sexual differentiation. Conclusions regarding the role of ovaries in female sexual differentiation may accordingly apply to only a limited number of species. Specific criticisms of the organizational effects of hormones stem from an incomplete reading of the original literature. The mechanisms proposed in this target article reflect an extension of the principle of hormonal organization, not a revolutionary restructuring.

Fitch & Denenberg have shown that manipulations of ovarian and testicular hormones early in development can influence the adult size of the corpus callosum in the rat. The human corpus callosum is highly variable in size and shape, but data are only now beginning to emerge on whether sex steroids influence callosal differentiation in humans. I describe recent data from our own laboratory and suggest avenues for future research.

The activational and organizational hormone effects as originally defined do not conflict with activational influences on brain structure. Ovarian hormonal influences on the rodent corpus callosum could be activational rather than organizational. The masculinization/feminization distinction in brain structure and the timing of sex differences in visuo-spatial abilities need to be clarified.

Evidence accumulates that pre- and postnatally circulating estrogens play an active role in the differentiation of the female brain: the susceptible period for feminization of the brain seems to extend far beyond the period during which masculinization of the brain occurs. Thus, there is a need to reevaluate the widely accepted 'concept of basic femaleness' in sexual brain differentiation.

Developmental counts of axons in the splenium of the rat corpus callosum are compatible with the hypothesis that estrogen may be acting late in development to sculpt the female nervous system.

I discuss Fitch & Denenberg's argument that no correction for brain size is needed when assessing callosal size. Morphometric criteria may not be sufficient to determine whether corrections are needed. Functional studies of callosal transfer will ultimately specify whether corrections for size are necessary in each case.

New knowledge about the sexual differentiation of the brain profoundly changes our understanding of basic topics in brain development such as the false dichotomy between long-lasting and transient effects of hormones on neural activity, the importance of ovarian hormones in brain development, the plasticity of neural structures throughout the life span, and the way measurement issues affect research conclusions.

Fitch & Denenberg provide excellent evidence for the existence of dynamically complex interactions between the structural and functional development of the nervous system. They are to be congratulated for showing how subtle social variables (e.g., handling) may not only influence hormonal 'cascade effects' on the developing nervous system, but may also alter the structure of brain tissue, such as the corpus callosum.

The fact that the female mammalian brain remains responsive to estrogens throughout life may open the way for other instigators of neuronal plasticity, making the female brain different from that of the male in its response to the actions of a number of hormones, to injury and to aging.

Studies of callosal sexual differentiation have concentrated on global measures of callosal size, using the rat as a model for studies of potential hormonal mechanisms. It is time to shift the study of callosal sexual differentiation to a more cellular level. Finally, there are potential problems with using the female rat as the primary model for understanding hormonal mechanisms during postnatal life.

The precise relationship between callosal morphology and specific connectivity is not yet known. Callosal axons are often presumed to be arranged according to their origin. In humans, this is true for the genu and the splenium, which convey axons from the prefrontal and occipital cortices, respectively, but not for the body, where axons from wide parts of the cortex are intermingled.