Variation in clitoral length in rhesus macaques (Macaca mulatta).

Normal pregnancy is associated with high circulating levels of total testosterone due to synthesis of testosterone–estradiol-binding globulin as well as free testosterone and androstenedione in plasma. Protective mechanisms against maternal and fetal virilization counterbalance this biologic hyperandrogenism. An important concern is to evaluate the risk of virilization of a female fetus: the earlier the hyperandrogenism occurs during pregnancy, the higher the risk of fetal virilization.33 During normal pregnancy, high circulating levels of androgens do not lead to fetal virilization. This phenomenon has been attributed to the high levels of estrogen, progesterone, and sex-hormone–binding globulin during pregnancy, which interfere with the biologic activity of androgens,6,10,18 and to placental aromatase, which rapidly converts androstenedione to estrone and 16-hydroxytestosterone to estriol.31 Unless compromised (for example, due to aromatase deficiency), the primate placenta is highly robust at inactivating and conjugating androgens, much more so that are nonprimate placentae.1,30 Therefore, virilization of female offspring in primates due to excess maternal androgen is rare. Sexual differentiation is a sequential and regulated process. Sex chromosomes, established at the moment of fertilization, determines the gonadal sex, which in turn, leads to development of the phenotypic sex, when the masculine or feminine urogenital system is formed. Alterations in any phase of this developmental process during embryogenesis could result in uncontrolled sexual differentiation. Known causes of abnormality in sexual development are environmental (such as the ingestion of virilizing medication during gestation), abnormal sex chromosomes, development of neonatal defects of multifactorial etiology (such as in most cases of hypospadias), and isolated mutation of genes. In general, a specific diagnosis can be established after genetic, endocrine, clinical, and chromosomal evaluations.17 Clitoral hypertrophy has many causes, and androgen is closely associated with clitoral formation. Androgen-induced clitoral hypertrophy is divided into fetal and maternal sources. In regard to fetal sources, congenital adrenal hyperplasia (a well-known cause of clitoral hypertrophy) and deficiencies in cytochromes P450 C21 and C11 are predominantly virilizing disorders. Maternal sources include iatrogenic causes (testosterone and its related steroids, oral progestogens, and diethylstilbestrol), virilizing ovarian or adrenal tumor, luteoma of pregnancy, and congenital hyperplasia.16 An observation that the clitoris appears overly prominent may lead unnecessary diagnostic investigation. In contrast, misdiagnosis can result when clitoromegaly is interpreted as normal for age and species. The current study was undertaken to establish normal standards for the clitoral length of female rhesus monkeys and factors that might influence this parameter.