Clinical manifestations of genetic defects affecting gonadotrophins and their receptors

Raised activity of the LH axis caused by activating mutations of LH receptor gene presents with precocious puberty in boys, analogous to the presentation of LH secreting pituitary adenomas. LH 'hyperactivity' in females appears to have no effect. Hyperactivity of the FSH axis caused by activating mutations of the FSH receptor gene might parallel the presentation of FSH secreting pituitary adenomas with Sertoli cell hypertrophy in men or reversible premature ovarian failure in women. Indeed the first such case to be described is a male who maintained testicular volume and fertility in the absence of gonadotrophins. Female precocious puberty may require hyperactivity of both gonadotrophin axes because of the 'two-cell' arrangement required for ovarian oestrogen production. Mutations of the Gs α-subunit gene can mimic this situation in some women with the McCune-Albright syndrome. Lack of LH activity caused by defects in the LHβ molecule causes infertility in men and that resulting from inactivating mutations of the LH receptor gene causes Leydig cell agenesis in men while ovarian development in females is relatively normal. Lack of FSH activity caused by defects in the FSHβ caused infertility in a female, and that caused by inactivating mutations of the FSH receptor gene causes ovarian dysgenesis in women but only variable depression of spermatogenesis in men. Incidentally, this categorization of reproductive disorders may also be applied to the TSH axis. Pituitary adenomas and activating mutations of the TSH receptor gene cause hyperthyroidism and TSHβ gene defects and inactivating mutations of the TSH receptor gene cause hypothyroidism. To complete the analogy with thyroid disorders, it is curious that despite structural similarities with the TSH receptor, neither LH nor FSH receptor autoantibodies have a prominent role in ovarian pathophysiology. Complete gonadotrophin resistance is likely to be very rare, however, so what are we likely to find in partial gonadotrophin resistance? Might the 'resistant ovary syndrome' come right in the end, with corresponding minor FSH receptor mutations? Experience with insulin and androgen resistance syndromes suggests that such a scenario is unlikely. Insulin receptor gene mutations are found in extreme Type A insulin resistance but not in moderate forms of insulin resistance. Androgen receptor gene mutations are found in nearly all cases of complete androgen insensitivity but rarely in partial forms. Mild resistance to hormone action is rarely detectable in relatives who are heterozygous for receptor mutations which are inherited in a recessive pattern. It seems unlikely therefore, that individuals heterozygous for inactivating receptor mutations will manifest symptoms of reproductive disorders and account for common conditions. Thus, while mutation analysis provides new insights into the gender specific role of the gonadotrophins the cause of early gonadal failure in the majority of individuals remains a mystery.