We have previously demonstrated that thyroid hormone synergizes with follicle-stimulating hormone (FSH) to exert stimulatory effects on granulosa cell differentiation and function, suggesting that it plays a physiological role in amplifying FSH-mediated differentiation of granulosa cells. The adequate differentiation of these cells, followed by normal follicle development, is indispensable for ovulation and subsequent corpus luteum formation. Thus, in the present studies, the clinical implications of thyroid hormone in the induction of ovulation and corpus luteum function were investigated. Serum levels of total 3,5,3'-triiodothyronine (T3) and total thyroxine (T4) as well as free T3 and T4 were significantly lower in patients with weight loss amenorrhea compared to normal cycling women. Although no ovulation was induced by clomiphene therapy when the serum T3 levels were less than 80 ng/dl, the rate of ovulation induced by clomiphene increased in parallel with the augmentation of serum T3 levels. This suggests that an adequate circulating level of thyroid hormone is one of the factors responsible for successful induction of ovulation by clomiphene citrate. Furthermore, the short luteal phase and insufficient progesterone secretion observed in patients with subclinical hypothyroxinemia were not improved by clomiphene therapy alone, but were improved markedly by combined treatment with thyroid hormone replacement and clomiphene citrate. These data imply that concomitant clomiphene treatment with thyroid hormone replacement therapy is of a great value not only for ovulation induction, but also for the treatment of luteal-phase defect in patients with subclinical hypothyroxinemia.