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 andro- genic 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.