Exploring the Biological Contributions to Human Health Does Sex Matter? (2001) / Chapter Skim
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3 Sex Begins in the Womb
3 Sex Begins in the Womb
Pages 45-78
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From page 45... ...
In the prenatal period, sex determination and differentiation occur in a series of sequential processes governed by genetic and environmental factors. During the pubertal period, behavioral and hormonal changes manifest the secondary sexual characteristics that reinforce the sexual identity of the individual through adolescence and into adulthood.
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From page 46... ...
of the brain and genitalia. In contrast to the role of the fetal testis in differentiation of a male genital tract and external genitalia in utero, fetal ovarian secretions are not required for female sex differentiation.
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From page 47... ...
Larger fish are more likely to play the male role more often. In contrast, mammalian sex determination is more directly under the
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From page 48... ...
These studies suggest that, as in rodent models, testosterone transferred to human female fetuses can have masculinizing effects on anatomical, physiological, and behavioral traits. In humans, the metabolic stress of pregnancy increases the incidence of gestational diabetes in susceptible women.
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From page 49... ...
Low birth weight or small body size at birth as a result of reduced intrauterine growth are associated with increased rates of coronary heart disease and non-insulin-dependent diabetes in adult life (reviewed by Barker [2000~. The "fetal origins hypothesis" proposes that undernutrition during critical periods of fetal growth can force the fetus to adapt by altering cardiovascular, metabolic, or endocrine functions to survive.
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From page 50... ...
These advances, considered together, illustrate that a failure in any of the sequential stages of sexual development, whether the cause is genetic or environmental, can have a profound effect on the sex phenotype of the individual and can lead to complete sex reversal, various degrees of ambisexual development, or less overt abnormalities in sexual function that first become apparent after sexual maturity (Grumbach and Conte, 1998; Wilson, 1999~. Sex Determination Sex determination and sex differentiation are sequential processes that involve successive establishment of chromosomal sex in the zygote at the moment of conception, determination of gonadal (primary)
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From page 51... ...
The genetic sex of the zygote is established by fertilization of a normal ovum by an X-chromosome- or Ychromosome-bearing sperm. Genes Contributing to Sex Determination Apart from SRY, a number of autosomal and X-chromosome-linked genes have been identified and have a critical role in male or female sex determination, the testis- and ovary-determining cascades (Roberts et al., 1999)
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From page 52... ...
52 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Permission was not granted to electronically reproduce figure 3-1 from /n:Wi//iams Textbook of En docrino/ogy, 9th eel.
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From page 54... ...
WT1 and SF-1 are expressed when the indifferent gonadal ridge first differentiates at 32 days postovulation in both female and male embryos (Hanley et al., 1999~. XY gonadal dysgenesis with resulting female differentiation has occurred in 46,XY individuals with intact SRY function but with duplication of Xp21, leading to a double dose of the DAX-1 (dosage-sensitive sex reversal congenital adrenal hypoplasia congenital-critical region on the X chromosome, gene 1)
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From page 55... ...
Germ cells are not essential for differentiation of the testes (Grumbach and Conte, 1998~. There is a striking sexual dimorphism in the timing of gonadal differentiation under the influence of SRY and other testis-determining genes (Figures 3-2 and 3-3~.
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From page 56... ...
Leydig cells are first found at about 60 days of gestation. Leydig cells secrete testosterone, the regulator of male differentiation of the wolffian ducts, urogenital sinus, and external genitalia.
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From page 57... ...
SEX BEGINS IN THE WOMB 57 Permission was not granted to electronically reproduce figure 3-3 from In:Williams Textbook of Endocrinology, 9th ed.
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From page 58... ...
concentrations during gestation with the histological changes in the fetal testis. In sum, organogenesis of the testis involves successive differentiation of the Sertoli cell and the seminiferous tubules with envelopment of the extragonadally derived germ cells by Sertoli cells, development of the tunica albicans, appearance of Leydig cells, and differentiation of the mesonephric tubules into ductule efferentes, which connect the seminiferous tubules and network with the epididymis to provide the pathway for sperm transport at the ejaculatory duct system (Grumbach and Conte, 1998~.
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From page 59... ...
At about the 11th to 12th week of gestation, long after differentiation of the testis in the male fetus, germ cells in the ovary begin to enter the meiotic prophase, which characterizes the transition of oogonia to oocytes and marks the onset of ovarian differentiation. The Wnt-4 gene, at least in the mouse, acts as a suppressor of the differentiation of steroidogenic cells in the fetal ovary.
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From page 60... ...
The regression of the mullerian ducts and the stabilization and differentiation of wolffian ducts are mediated by different secretions by the fetal testis: a glycoprotein, AMH, secreted by the fetal Sertoli cells and a sex steroid, testosterone, synthesized by fetal Leydig cells. Female development is not contingent on the presence of an ovary because development of the uterus and tubes occurs if no gonad is present.
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From page 61... ...
There is disagreement about the relative contribution of the mullerian ducts and the urogenital sinus to the vagina, but the contact and interaction of the fused mullerian ducts with the urogenital sinus are essential for normal development of the vagina. In female development, proliferation of the vesicovaginal septum pushes the vaginal orifice posteriorally so that it acquires a separate external opening; thus, no urogeni
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From page 62... ...
Table 3-2 provides some examples of variations in sexual differentiation. PUBERTY Puberty is the transitional period between the juvenile state and adulthood during which the adolescent growth spurt occurs, secondary sexual characteristics appear (resulting in the striking sexual dimorphism of mature individuals)
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From page 63... ...
63 to ~ ~ ~ ~m ~ =~ td ·_1 ~ ~ X .= 5x cry V)
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From page 64... ...
A sex difference in plasma FSA and LH values is also present in anorchid boys and agonadal girls less than three years old. The high gonadotropin concentrations in infancy are associated with a transient second wave of differentiation of fetal-type Leydig cells and increased serum testosterone levels in male infants for the first 6 months or so and with elevated estradiol levels intermittently in the first 1 to 2 years of life in females.
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From page 65... ...
In addition, striking sex differences exist in the gonadally synthesized glycoprotein hormone inhibins throughout development in boys and girls (Andersson et al., 1997; Sehested et al., 2000~. Inhibin B concentrations are strikingly elevated in males for the first 2 years of life and show a striking increase from childhood levels to adult levels at the onset of puberty, whereas levels of inhibin B are low or undetectable in prepubertal girls, followed by a sharp increase through midpuberty and then a decline.
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From page 66... ...
The actual dimorphic physical changes of puberty are primarily the consequence of testosterone secretion by the Leydig cells in boys and of estrogen secretion by the granulosa cells in girls (Grumbach and Styne, 1998~. Leptin Leptin, a hormone produced by adipose tissue, appears to have an important permissive action in the progression into puberty and the maintenance of normal secondary sex characteristics through its effect on hypothalamic-pituitary-gonadotropin-gonadal function (Clement et al., 1998; Farooqi et al., 1999; Strobel et al., 1998~.
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From page 67... ...
Growth hormone, insulin-like growth factor 1, and triiodothyronine are the principal regulators of prepubertal growth and regulate about 50 percent of the growth during the pubertal period; superimposed on this growth is the linear growth induced by estradiol in both boys and girls. Although the role of estradiol in the pubertal growth spurt in girls has been appreciated for more than 20 years, only now do new observations indicate that estradiol is the major sex steroid responsible for the pubertal
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From page 68... ...
In boys, the estradiol is derived mainly from the extragonadal conversion of testosterone to estradiol in a wide variety of tissues, but there is also a small testicular contribution (Siiteri and MacDonald, 1973~. Furthermore, estradiol, but not testosterone, appears to be the critical mediator of skeletal maturation and epiphyseal fusion and the major sex steroid in bone mineral accrual in boys as well as girls (Grumbach, 2000; and Grumbach and Auchus, 1999~.
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From page 69... ...
The mechanism of activation of adrenal androgen secretion or adrenarche is independent of the mechanisms that regulate the onset of sex steroid secretion by the gonads, which is called "gonadarche" (Grumbach and Styne, 1998~. Premature adrenarche, which is more common in girls than in boys, is characterized by the precocious appearance of pubic hair or axillary hair, less commonly an apocrine odor, and comedones and acne without other signs of puberty or virilization (Grumbach and Styne, 1998~.
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From page 70... ...
In sum, the evidence suggests a link between intrauterine growth retardation and the increased risk of exaggerated adrenarche followed by PCOS, including hyperandrogenism, insulin resistance, dyslipidemia (with or without obesity) , and cardiovascular disease (Barker, 1995, 1997; Cresswell et al., 1997~.
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From page 71... ...
For example, the development of secondary sex characteristics in girls creates social signals that result in different responses from peers, parents, and teachers. There is a substantial literature showing that girls who mature earlier than their peers are at greater risk than girls who mature on time or later than their peers for problems during the pubertal transition and continuing into adulthood.
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From page 72... ...
ADULTHOOD During the long period of about 40 years of fertile adulthood, an individual's occupations, social roles, and lifestyle change episodically and develop slowly as experiences accumulate. Although societal norms are rapidly changing, in general it remains the case that women still predominate as caregivers and organizers with wide-ranging obligations and duties spanning the family, workplace, and leisure realms, whereas men still predominate in more focused aggressive and physically demanding activities with a relatively narrower range of social obligations.
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From page 73... ...
Much of the evidence to support the finding of a cardioprotective effect for estrogen has come from observational studies of women on estrogen replacement therapy, which has shown that estrogen users experience half as many cardiovascular events as nonusers, but numerous questions remain (also discussed in Chapter 5~. An adverse influence of hormone therapy on cardiovascular risk in women with coronary heart disease has been shown during the initial year of use; however, few data are available on the effects of long-term hormone therapy (Grodstein et al., 2000~.
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From page 74... ...
Some reduction in the rate of occurrence of major cardiovascular events was also seen in ASA-treated older patients, but the reduction was not statistically significant. From 1900 through about 1940, Americans who lived to age 65 had a life expectancy of another 11 or 12 years, regardless of sex.
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From page 75... ...
Currently, life expectancy at birth is greater for females than males by ~6 years, but once old age has been attained, it becomes 2 to 3 years (Table 3-3~. The actual life expectancy differs among ethnic groups and is, for example, notably shorter among African American than Caucasian Americans, but the consistency in the observation of an advantage for females across ethnic groups is striking (Figure 3-6~.
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From page 76... ...
FIGURE 3-6 Life expectancy at birth for males and females in several U.S. ethnic groups (data are from 1989 to 1994~.
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From page 77... ...
FINDINGS AND RECOMMENDATIONS Findings Sex differences occur throughout the life span, although their specific expression varies at different at stages of life. · Intrauterine environment: Some sex differences originate in events that begin in the womb, where developmental processes differentially organize tissues for later activation..
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From page 78... ...
Continued development of appropriate animal models, including those involving nonhuman primates, should be encouraged and supported under existing regulations and guidelines (see the Guide for the Care and Use of Laboratory Animals [National Research Council, 19961~. · Researchers should be alert to unexpected phenotypic sex differences resulting from the production of genetically modified animals.
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