Aromatase Deficiency This very rare autosomal recessive abnormality prevents the affected individual from aromatizing androgens to estrogen (28). This syndrome may be suspected even before birth because most mothers of affected children become virilized during pregnancy. This occurs because the placenta cannot convert the fetal androgens to estrogen and they diffuse into the maternal circulation. At birth, a female child has clitoromegaly and posterior labioscrotal fusion (ambiguous genitalia). At puberty, there is no breast development, primary amenorrhea, worsening virilization, absent growth spurt, delayed bone age, and multicystic ovaries. The diagnostic hormonal pattern consists of an elevation of FSH, LH, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels, and undetectable levels of estradiol. Estrogen therapy improves the ovarian and skeletal abnormalities but must be titrated to mimic normal estrogen levels. Estrogen administration should be minimal during childhood and increased at puberty (29,30).
Galactosemia In girls, galactosemia often is associated with ovarian failure, but this condition usually is detected by newborn screening programs. A galactose-1 phosphate uridyl transferase level can be measured to assess the patient for galactosemia or carrier status.
Luteinizing Hormone Receptor Mutation Inactivation of LH receptors is identified in XY pseudohermaphrodites with primary amenorrhea in the absence of secondary sexual characteristics caused by homozygous premature stop codon, deletions, and missense mutations in the LHR gene located on chromosome 2. The Leydig cells in these individuals are unable to respond to LH, causing Leydig cell hypoplasia. This leads to early testicular failure and prevents masculinization. XX siblings with the same mutations develop normal secondary sexual characteristics but are amenorrheic with elevated LH levels, normal FSH levels, and cystic ovaries (31,32).
Follicle-Stimulating Hormone Receptor Mutation An autosomal recessive single amino acid substitution in the extracellular domain of the FSH receptor, which prevents FSH binding, was identified in six families in Finland. This condition leads to primary or early secondary amenorrhea, variable development of secondary sexual characteristics, and high levels of FSH and LH (33).
Other Causes of Primary Ovarian Failure without Secondary Sexual Characteristics
Severe damage to the ovaries before the onset of puberty can lead to ovarian insufficiency and failure to develop secondary sexual characteristics. Ovarian dysfunction can occur in association with irradiation of the ovaries, chemotherapy with alkylating agents (e.g., cyclophosphamide), or combinations of radiation and other chemotherapeutic agents (34,35). Other causes of premature ovarian failure (also known as primary ovarian insufficiency) are more commonly associated with amenorrhea after the development of secondary sexual characteristics, as described below.
Hypogonadotropic Hypogonadism Associated with the Absence of Secondary Sex Characteristics
Primary amenorrhea resulting from hypogonadotropic hypogonadism occurs when the hypothalamus fails to secrete adequate amounts of GnRH or when a pituitary disorder associated with inadequate production or release of pituitary gonadotropins is present.
Physiologic Delay Physiologic or constitutional delay of puberty is the most common manifestation of hypogonadotropic hypogonadism. Amenorrhea may result from the lack of physical development caused by delayed reactivation of the GnRH pulse generator.
Levels of GnRH are functionally deficient in relation to chronologic age but normal in terms of physiologic development.