Three Facets of Sexual Differentiation, NEJM
Muggle
Volume 350:323-324, Number 4
January 22, 2004
Three Facets of Sexual Differentiation
Daniel D. Federman, M.D.
Sexual reproduction requires three types of differentiation: gonadal
for the production of gametes, genital for the conveyance of gametes
to a point of fertilization, and behavioral for the urge to behave
sexually. Two articles in this issue of the Journal illuminate several
of these steps.
MacLaughlin and Donahoe (pages 367-378) provide a current view of the
genetics of gonadal development, describing genes that are responsible
for the formation of the urogenital ridge and the migration of germ
cells to it, resulting in the formation of a bipotential gonad (see
Figure). Defects in the genes that are involved in this process cause
infertility and diverse renal and genital anomalies. The best-defined
gene involved in gonadal differentiation, SRY, is found on the short
arm of the Y chromosome and (with a lot of help) induces the
bipotential gonad to differentiate into a testis. SRY and the SOX9
gene that it induces have major roles in this process, with support
from steroidogenic factor 1 (SF-1) and opposition from DAX1. Smaller
parts are played by WT1 and other genes. Defects in these genes cause
the gonadal dysgenesis syndromes, in which a failure of gonadal
differentiation is combined with female genital development.
Overexpression of DAX induces what is called XY sex reversal, but this
term is misleading. Testicular differentiation is prevented, but there
is no true ovarian differentiation either. To date, there is no
convincing evidence that an ovarian differentiation factor exists.
Figure. Factors Involved in the Determination of Male Sex.
A complex series of steps must occur in gonadal differentiation. A
number of genes are critical to appropriate male genital development.
SRY (sex-determining region of the Y chromosome), a gene on the short
arm of the Y chromosome, is a testis-determining factor. The SOX9 gene
is also important in male sexual differentiation. DAX1, an orphan
member of a nuclear hormone receptor family located on the X
chromosome, interacts with steroidogenic factor 1 (SF-1). Other genes
involved in male gonadal differentiation include the tumor-suppressor
gene WT1 (Wilms' tumor 1), and the müllerian inhibiting substance gene
(MIS) and its receptor, MIS-R.
The second phase of preparation for sexual reproduction, genital
differentiation, is hormonally mediated. Working through an X-linked
androgen receptor, testosterone mediates the positive development of
the wolffian ducts into the vas deferens, epididymis, and seminal
vesicles. Dihydrotestosterone, which is primarily produced from
testosterone in target tissues by the action of 5 reductase, induces
the differentiation of the penis and scrotal sacs. It uses the same
androgen receptor as testosterone does and binds to it with 10 times
the affinity of testosterone. The androgen receptor is a site of
enormous mutability; there have been several hundred reported cases of
complete or incomplete androgen insensitivity. Patients with such
insensitivity have no müllerian ducts (and antimüllerian hormone is
intact), but the degree of masculinization varies widely among such
patients: they may have none at all, if androgen insensitivity is
complete, or may be normal except for gynecomastia. In striking
contrast, there has been only one reported case of an estrogen-
receptor defect, suggesting that this receptor has a strategic role in
fetal survival.
Behavioral differentiation has proved to be the most enigmatic of the
three steps. The first component, the sense of oneself as male or
female -- which Reiner and Gearhart (pages 333341) refer to as sexual
identity -- is established in most children by two and a half years of
age and in essentially all children by three years. At this age,
sexual identity is separated from sexuality -- that comes later. Sexual
identity was long thought to be psychologically derived through the
internalization of social cues given to the infant on the basis of the
appearance of the external genitalia. But this view has had to be
modified. In two disorders, 5-reductase deficiency and 17-
hydroxysteroid dehydrogenase deficiency, newborns look predominantly
female and are raised as girls but then have dramatic virilization at
puberty. Many such persons gradually assume a male sexual identity and
sex role. Similarly, there are isolated cases in which male children
who had been raised as female because of a traumatic amputation of the
penis insisted on assuming a male sexual identity and sex role when
they were teenagers or adults. The report by Reiner and Gearhart
describes 8 of 14 genetically male children with severe cloacal
exstrophy who, after being raised as female, later chose a male sexual
identity. Taken together, such evidence points strongly to a hormonal
role in the sexualization of the brain.
The remaining components of human sexuality are incompletely
understood. Erotic responsiveness and sexual drive or libido in boys
and men are, at least in part, dependent on testosterone. Whether
estrogen plays a part, as it does in some crucial effects of
testosterone, is not clear. But sexual behavior in girls and women is
not similarly dependent on estrogen. Indeed, testosterone -- again,
perhaps along with estrogen -- may be an important factor in arousal
and drive in women. But intimacy, tenderness, and relationship appear
to be important contributors to female sexuality. The final aspect of
sexuality, the choice of partners, is virtually terra incognita. For
the specific purpose of preserving the race, sexual activity must be
heterosexual. But for the manifold goals of love, warmth, and
mutuality, other choices are satisfactory.
Another important outcome of evolution is that so-called sex hormones
have major roles in somatic tissues as well as in reproduction.
Testosterone affects height, body mass, hair growth, muscle strength,
bone mass, and lipid metabolism and is probably involved in
aggression. Estradiol influences the pubertal growth spurt and growth
arrest, bone density, and cardiovascular metabolism and also plays a
part in the development of breast and prostate cancer, as well as
other conditions. Almost every specialty of medicine recognizes sex
differences in the epidemiology, clinical manifestations, course, and
treatment of disease. Thus, everyone in medicine should be interested
in the effects of sex differences in the earliest stages of
development and in the entire course of patients' lives.
Source Information
From Harvard Medical School, Boston.