Monogenic Disorders of Puberty

Normal puberty is associated with the onset and progressive activation of the hypothalamic-pituitary-gonadal (HPG) axis and the resultant development of secondary sexual characteristics. Puberty begins with increasing nocturnal pulsatile hypothalamic GnRH secretion, which gradually occurs throughout the 24-h day. Pulsatile GnRH stimulates pituitary FSH and LH secretion, ultimately stimulating gonadal steroid production and gametogenesis in females and males. In the ovary, FSH stimulates follicular maturation and estrogen production through aromatization of androgens, whereas LH stimulates androgen production by theca cells, triggers ovulation, and maintains progesterone production by the corpus luteum. In the testis, FSH acts on Sertoli cells to initiate spermatogenesis and LH acts on Leydig cells to stimulate testosterone production. The hypothalamic-pituitary-adrenal (HPA) axis also has some minor input into the physiological process of puberty, through the secretion of adrenal androgens. However, the major involvement of the HPA axis in puberty is in its potential pathological influence, primarily in accelerating its onset and/or progress. Traditionally, the onset of adrenal androgen secretion in childhood has been termed “adrenarche,” whereas the onset of gonadal steroid secretion has been called “gonadarche.” Delayed puberty describes the clinical condition in which the pubertal events start late or are attenuated or arrested. In contrast, precocious puberty describes the clinical condition in which the pubertal events start early. Mutations have been identified in an increasing number of genes that influence the onset and progression of puberty. These discoveries have provided new insights into the physiology and pathophysiology of this important life transition and have greatly influenced the practice of reproductive medicine. For instance, the concept of two gonadotropins acting on two separate cell types in the gonad has been the cornerstone of reproductive endocrinology, while it has been traditionally believed that both FSH and LH are required for fertility in females and males. However, studies of mutant gonadotropin receptors indicate that female reproductive capacity depends primarily on FSH, whereas male reproductive capacity depends primarily on LH. We summarize the molecular defects that influence gonadal and/or adrenal function and cause delayed (Table 1) or precocious puberty (Table 2). Here, we present genes whose alterations result in abnormal puberty in girls and boys.