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 (Faggiano et al., 1983; Ambrosi et al., 1990). 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 (Heseltine et al., 1989) or reversible
premature ovarian failure in women (Moses et al., 1986; Okuda et al., 1989). Indeed the first such case to be described is a male who maintained testicular volume and fertility in the absence of gonadotrophins (Gromoll et al., 1996). 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 alpha-subunit gene can mimic this situation in some women with the
McCune-Albright syndrome (Malchoff et al., 1994). Lack of LH activity caused by defects in the
LH beta 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
FSH beta 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 (Parma et al., 1993) cause
hyperthyroidism and
TSH beta gene defects (Hayashizaki et al., 1989) and inactivating mutations of the
TSH receptor gene (Sunthornthepvarakul et al., 1995) 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 (Moncayo et al., 1989; Van Weissenbruch et al., 1991; Simoni et al., 1993). 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 (O'Rahilly et al., 1991).
Androgen receptor gene mutations are found in nearly all cases of complete
androgen insensitivity but rarely in partial forms (Patterson et al., 1994). 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.