INTERSEX: FEMALE PSEUDOHERMAPHRODITISM
A female
pseudohermaphrodite is an individual with ovaries but whose external genitalia
have a male appearance. This disorder of sexual development usually results
from hormonal disturbances. The maternal use of androgens or high doses of
certain weakly androgenic synthetic progestogens (progestins) can masculinize
or virilize the fetal female external genitalia during susceptible times in
pregnancy. An example of a weakly androgenic substance is the sex steroid
danazol, a derivative of ethisterone (17α-ethinyl-testosterone)
that is used to treat severe endometriosis. Progestogens currently used for
luteal support of pregnancy in in vitro fertilization (IVF) protocols or for
prevention of preterm birth are progesterone, 17α-hydroxyprogesterone
caproate, and dydrogesterone. Along with clitoral enlargement (clitoromegaly),
some degree of fusion of the urogenital folds can occur with exposure from the
8th through the 12th week of gestation. This can present as ambiguous genitalia
at birth. If exposure occurs after the 12th gestational week, then only
clitoral enlargement occurs. Females with clitoral enlargement mature normally
and have normal fertility, as there is almost total regression of the genital
anomaly. Surgical correction of labioscrotal fusion is also a relatively simple
procedure if needed. A much rarer cause of clitoromegaly is Fraser syndrome,
characterized by defects including underdevelopment of the eyes (cryptophthalmos)
and linked to the gene FRAS1, which may be involved in skin epithelial
morphogenesis.
Müllerian
agenesis (Mayer–Rokitansky–Küster–Hauser [MRKH] syndrome) is a congenital
malformation characterized by a failure of the müllerian ducts to develop,
resulting in a missing uterus and variable malformations of the vagina. Unlike
other intersex conditions, MRKH is not associated with virilization but only
absence of internal female genitalia. A female with this condition is
hormonally normal, enters puberty, and develops secondary sexual
characteristics. Typically, the vagina is shortened and intercourse may be
difficult and painful. Medical examination demonstrates complete or partial absence
of the cervix, uterus, and vagina. It is possible for these women to have
genetic offspring by IVF and surrogacy. Women with MRKH typically discover the
condition when the menstrual cycle does not start, as it is the second most
common cause of primary amenorrhea.
The most
common cause of female sexual ambiguity is congenital adrenal hyperplasia
(CAH), an endocrine disorder in which the adrenal glands produce abnormally
high levels of virilizing hormones. In genetic females, this leads to an
appearance that may be slightly masculinized (clitoromegaly) to very masculine.
CAH refers to a constellation of autosomal recessive diseases that result from
mutations in enzymes that mediate cortisol production from cholesterol
(steroidogenesis). Most of these conditions involve excessive or deficient
production of sex steroids, with 95% due to 21-hydroxylase deficiency. In
addition to ambiguous genitalia, there can be vomiting due to salt-wasting,
early pubic hair and rapid growth in childhood, precocious puberty or failure
of puberty, virilization or menstrual irregularity in adolescence, infertility
due to anovulation, and hypertension.
In its
most common form, the vagina terminates in the posterior urethra; more rarely,
it may open into the perineum, with the urethral orifice terminating in the
anterior vaginal wall. The well-developed clitorisresembles a hypospadiac penis
with chordee, and the urethra is usually located in the penile base between two
prominent labia majora, resembling a bifid scrotum. Palpation may reveal a small
(hypoplastic) uterus and adnexa that result from androgenization.
In
addition, there can be various secondary sex characteristics such as marked
muscular growth, resulting in a short, stocky, or square body, and the general
appearance of a well-developed male. Growth in stature is accelerated early,
and the epiphyses close prematurely, resulting in an advanced bone age and a
lower than average adult height. Other virilizing stigmata, such as marked
hirsutism of the face, torso, and extremities, are present. The voice becomes
deep, with the
thyroid
cartilage conspicuous. Breast development and menstruation are lacking. The
signs of virilism are manifest usually at age 2 years and are
characteristically progressive. The urine contains an abnormally large amount
of 17-ketosteroids. Adrenal cortical tumors may also produce virilism, but they
occur after birth when it is too late to cause ambiguous genitalia. Cortisol
administration will suppress pituitary secretion of ACTH and reduce the
activity of the hyperplastic adrenal cortex. This decrease fails to occur in
patients with adrenocortical neoplasm and, thus, aids in the differential
diagnosis. Treatment involves lifelong use of cortisol-like medications and
gender-aligning surgery in some cases. Fertility is possible when the disease
is well controlled.
