Kallmann Syndrome The second most common hypothalamic cause of primary amenorrhea associated with hypogonadotropic hypogonadism is insufficient pulsatile secretion of GnRH (Kallmann syndrome), which has varied modes of genetic transmission. Insufficient pulsatile secretion of GnRH leads to deficiencies in FSH and LH (36). Kallmann syndrome is often associated with anosmia (inability to perceive odors), although a woman may not be aware of her impaired sense of smell. The hypogonadism and anosmia arise because of failure of proper neuronal migration during fetal development.
Other Causes of Gonadotropin-Releasing Hormone Deficiency Deficiencies in GnRH may be caused by developmental or genetic defects, inﬂammatory processes, tumors, vascular lesions, or trauma. Central nervous system tumors that lead to primary amenorrhea, the most common of which is craniopharyngioma, are usually extracellular masses that interfere with the synthesis and secretion of GnRH or stimulation of pituitary gonadotropins.
Virtually all of these patients have disorders in the production of other pituitary hormones and LH and FSH (37,38). Prolactin-secreting pituitary adenomas are rare in childhood and more commonly occur after development of secondary sexual characteristics.
Genetic Disorders 5α-Reductase Deficiency 5α-Reductase deficiency should be considered a cause of amenorrhea (39). Patients with this disorder are genotypically XY, frequently experience virilization at puberty, have testes (because of functioning Y chromosomes), and have no m¨ullerian structures as a result of functioning AMH. 5α-Reductase converts testosterone to its more potent form, dihydrotestosterone. Patients with 5-reductase deficiency differ from patients with androgen insensitivity because they do not develop breasts at puberty (Fig. 30.2). These patients have low gonadotropin levels as a result of testosterone levels that are sufficient to suppress breast development and allow normal feedback mechanisms to remain intact. Normal male differentiation of the urogenital sinus and external genitalia do not occur because dihydrotestosterone is required for this development. Normal internal male genitalia derived from the wolffian ducts are present because this development requires only testosterone. Male pattern hair growth, muscle mass, and voice deepening are testosterone dependent.
Gonadotropin-Releasing Hormone Receptor Mutations Several mutations are identified in the GnRH receptor gene that causes abnormal GnRH function. Most affected patients are compound heterozygotes, but homozygous autosomal recessive mutations are identified. The GnRH receptor is a G-protein–coupled receptor. Functional studies show that the mutations cause marked decrease in binding of GnRH to its receptor or prevent second-messenger signal transduction. Without a functional signal transduction, FSH and LH are not stimulated and are unable to promote follicular growth (40). All patients are normosomic. Receptor mutations in GnRH cause 17% of sporadic cases of idiopathic hypogonadotropic hypogonadism with normal olfaction (41).
Follicle-Stimulating Hormone Deficiency Patients with FSH deficiency usually seek treatment for delayed puberty and primary amenorrhea associated with hypoestrogenism.