Amy B. Wisniewski

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement. Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex. Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ). Three traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

Auditory scene analysis by songbirds: stream segregation of birdsong by European starlings (Sturnus vulgaris).

Three experiments examined the capacity of European starlings to segregate perceptually 2 superimposed, intermixed auditory stimuli. The stimuli were 10-s song samples from 2 of 4 songbird species: European starling, brown thrasher, mockingbird, and nightingale. The birds first learned a discrimination between the intermixed song pairs. Then, they maintained the discrimination with novel song exemplars in the mixtures and when song stimuli for each species were presented alone. Performance fell, but remained above chance, when song pairs were mixed with the dawn chorus of bird song. The results show that starlings were identifying the songs of individual species within the baseline superimposed song pairs, a process of auditory stream segregation and scene analysis (A. S. Bregman, 1990).

Gender in childhood obesity: Family environment, hormones, and genes

BACKGROUND The prevalence of obesity among children in the United States represents a pool of latent morbidity. Though the prevalence of obesity has increased in both boys and girls, the causes and consequences differ between the sexes. Thus, interventions proposed to treat and prevent childhood obesity will need to account for these differences. OBJECTIVE This review examines gender differences in the presentation of obesity in children and describes environmental, hormonal, and genetic factors that contribute to observed gender differences. METHODS A search of peer-reviewed, published literature was performed with PubMed for articles published from January 1974 through October 2008. Search terms used were obesity, sex, gender, hormones, family environment, body composition, adiposity, and genes. Studies of children aged 0 to 18 years were included, and only articles published in English were reviewed for consideration. Articles that illustrated gender differences in either the presentation or underlying mechanisms of obesity in children were reviewed for content, and their bibliographies were used to identify other relevant literature. RESULTS Gender differences in childhood obesity have been understudied partially because of how we define the categories of overweight and obesity. Close examination of studies revealed that gender differences were common, both before and during puberty. Boys and girls differ in body composition, patterns of weight gain, hormone biology, and the susceptibility to certain social, ethnic, genetic, and environmental factors. CONCLUSION Our understanding of how gender differences in pediatric populations relate to the pathogenesis of obesity and the subsequent development of associated comorbid states is critical to developing and implementing both therapeutic and preventive interventions.

Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats

Background Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders. Objective We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs). Methods and Results The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [3H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity. Conclusions Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.

Perinatal exposure to genistein alters reproductive development and aggressive behavior in male mice

Exposure to endocrine disrupting chemicals adversely affects reproductive development and behavior in males. The goal of this study was to determine if exposure to genistein, an isoflavone found in soy, during early periods of sex differentiation alters reproductive development and behavior in male mice. Female C57BL/6 mice were fed a phytoestrogen-free diet supplemented with 0, 5 or 300 mg/kg of genistein throughout gestation and lactation. Anogenital distance (AGD) and body mass of male offspring was measured weekly from postnatal days 2-21, timing of preputial separation was assessed at puberty, and in adulthood, reproductive organ masses, sperm and testosterone production, and reproductive and aggressive behaviors were assessed. Exposure to genistein resulted in smaller AGD are reduced body mass, with the low-dose diet exerting a greater effect. Timing of preputial separation, adult reproductive behavior, sperm concentrations and testosterone production were not influenced by genistein treatment at either dose. Aggressive behaviors were decreased, whereas defensive behaviors were increased, in males that received the low-dose genistein diet. Exposure to genistein during critical periods of sex differentiation results in concurrent and persistent demasculinization in male mice. Phenotypic and behavioral abnormalities induced by genistein showed a non-monotonic response, where treatment with a low dose exerted a greater effect than treatment with a high dose of genistein. Given the popularity of soy infant formulas, the influence isoflavone exposure on reproductive and behavioral health in boys and men should be considered.

Congenital micropenis: Long-term medical, surgical and psychosexual follow-up of individuals raised male or female

Objectives: to document long-term medical, surgical and psychosexual outcome of individuals with congenital micropenis (13 males, 5 females). Methods: Physical measurements from childhood were collected retrospectively from medical records and at adulthood by physical examination. An adult psychosexual assessment was conducted with a written questionnaire and oral discussion. Results: Adult penile length was below the normal mean in all men. Three women had vaginoplasty resulting in normal length. All men reported good or fair erections but 50% were dissatisfied with their genitalia. Dissatisfaction with body image resulted from having a small penis (66%), inadequate body hair (50%), gynecomastia (33%) and youthful appearance (33%). Ten men were heterosexual, 1 homosexual and 2 bisexual. Among women, 4 (80%) were dissatisfied with their genitalia. Three women reported average libido with orgasm and were also heterosexual. Two women had no sexual interest or experience. Finally, males were masculine and females feminine in their gender-role identity, and both groups were satisfied with their sex of rearing. Conclusions: Regarding choice of gender, male sex of rearing can result in satisfactory genito-sexual function. Female gender can also result in success, however it requires extensive feminizing surgery.

Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women

Context: Recent interventional studies indicate that post-menopausal hormone replacement therapy is associated with an increased risk of cardiovascular mortality and breast cancer. Isoflavones, a class of plant estrogens, have structural similarities to estradiol. Hence, isoflavones may exert beneficial estrogenic health effects in postmenopausal women with fewer adverse effects. Objective: To evaluate the effect of high-dose isoflavones on self-reported quality of life (QOL), cognition, lipoproteins and androgen status in post-menopausal women. Design and subjects: Double-blind, randomized, placebo-controlled, 12-week trial of 93 healthy, ambulatory, post-menopausal women (mean age 56 yr). The study was conducted at a tertiary care center in the United States. Intervention: Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). Both soy and the placebo were provided in the form of a powder to be mixed with beverages. Main outcome measures: QOL was judged by the Menopause-specific Quality of Life (MENQOL) questionnaire while cognitive function was assessed with standard instruments. Total, free, and bioavailable testosterone, gonadotropins, SHBG, and fasting lipids were measured. Results: Eighty-four women (90%) completed the study (active=38, placebo=46). There was a significant improvement in all 4 QOL subscales (vasomotor, psychosexual, physical, and sexual) among the women taking isoflavones, while no changes were seen in the placebo group. No significant changes in cognition, serum androgens or plasma lipids were seen within any of the groups. However, at the end of the study, a group-by-time interaction was observed such that total testosterone and HDL levels were significantly lower in the isoflavones compared to placebo groups. Conclusion: High-dose isoflavones is associated with improved QOL among women who have become menopausal recently. Hence, the timing of isoflavone supplementation with regards to the onset of menopause appears to be important. The use of isoflavones, as an alternative to estrogen therapy, may be potentially useful and seemingly safe in this group of women who are looking for relief from menopausal symptoms.

46,XY DSD with Female or Ambiguous External Genitalia at Birth due to Androgen Insensitivity Syndrome, 5 -Reductase-2 Deficiency, or 17 -Hydroxysteroid Dehydrogenase Deficiency: A Review of Quality of Life Outcomes

Disorders of sex development refer to a collection of congenital conditions in which atypical development of chromosomal, gonadal, or anatomic sex occurs. Studies of 46,XY DSD have focused largely on gender identity, gender role, and sexual orientation. Few studies have focused on other domains, such as physical and mental health, that may contribute to a persons quality of life. The current review focuses on information published since 1955 pertaining to psychological well-being, cognition, general health, fertility, and sexual function in people affected by androgen insensitivity syndromes, 5- reductase-2 deficiency, or 17-hydroxysteroid dehydrogenase-3 deficiency—reared male or female. The complete form of androgen insensitivity syndrome has been the focus of the largest number of investigations in domains other than gender. Despite this, all of the conditions included in the current review are under-studied. Realms identified for further study include psychological well-being, cognitive abilities, general health, fertility, and sexual function. Such investigations would not only improve the quality of life for those affected by DSD but may also provide information for improving physical and mental health in the general population.

Sexual Differentiation: From Genes to Gender

A person’s sex can be considered across various levels. To illustrate, genes, hormones, and genitalia can all be considered physical markers of a person’s sex. In addition to physical markers, behaviors such as gender role, gender identity and sexual orientation can be perceived as stereotypically male or female. The purpose of this review is to summarize current knowledge of sexual differentiation which emphasizes genetic and hormonal mechanisms that result in male and female development of gonads and genitalia. Finally, consideration is given to associations between genetic sex, gonadal sex, and hormonal sex with gender.

Depressive symptoms, quality of life, and neuropsychological performance in HIV/AIDS: the impact of gender and injection drug use.

Limited attention has been paid to the potential impact of gender and injection drug use (IDU) on mood, quality of life, and neuropsychological performance in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Several studies that describe the natural history of HIV/AIDS in terms of mental health and neuropsychological ability have focused solely on men or have excluded injection drug users. Women and injection drug users are two groups for whom the incidence of HIV infection is increasing. Additionally, the National Academy of Sciences recently recommended that studies concerned with health-related research include males and females, and that researchers analyze their data for gender differences. The goals of the current study were to investigate possible relationships between HIV and IDU status and depressive symptoms, quality of life, and neuropsychological performance in women and men matched for age, race, and education. Overall, women reported more depressive symptoms than men, and this gender difference was most evident in women who were both infected with HIV and who were also injection drug users. Women and HIV-infected individuals reported the poorest quality of life scores. Women outperformed men on a measure of verbal memory and HIV− participants outperformed HIV+ participants on a measure of perceptual speed. Finally, gender and HIV status interacted such that uninfected women performed the best, and infected men performed the worst, on a test of verbal memory. A better understanding of how men and women with different drug use profiles respond to HIV/AIDS may substantially improve survival, as well as aspects of daily functioning, of affected individuals. Thus, further study and development of treatment protocols targeted at including women and IDU are needed.