A search for immunoglobulins inhibiting gonadal cell steroidogenesis in premature ovarian failure

Premature ovarian failure (POF) may be caused by the action of circulating gonadotrophin receptor-blocking antibodies. Luteinizing hormone (LH)-stimulated testosterone production from mouse Leydig cells and follicle stimulating hormone (FSH)-stimulated oestradiol production from immature rat Sertoli cells were therefore studied in the presence of protein-G purified immunoglobulin G (IgG) samples from control subjects (n = 9), infertile women with elevated early follicular phase FSH levels but otherwise normal menstrual cycles (n = 10), and patients with POF (n = 10) or Graves' disease (n = 10). A saturating and subsaturating (78% for LH; 60% for FSH) dose of each hormone was chosen for study. A commercial preparation of human IgG (Sigma IgG, 0.75 mg/ml) employed as negative control had no effect on basal or gonadotrophin-stimulated steroidogenesis. In its presence, saturating doses of LH (2 IU/l) and FSH (20 IU/l) gave rise to 11.2 +/- 0.8 (n = 7) and 25.1 +/- 5.8 (n = 8) fold increases in steroid secretion. IgG (0.75 mg/ml) had no effect in the four groups on LH-stimulated testosterone outputs using a saturating (2 IU/l) or subsaturating (1 IU/l) dose of hormone. For example, LH (2 IU/l)-stimulated testosterone production was 94% (83-96 median; interquartile range) and 88% (81-99) of the Sigma IgG control for control and POF groups respectively. However, four out of nine IgG samples from the normal subjects (mean +/- SEM = 86 +/- 6%), two out of 10 of the high FSH group (77 +/- 4%), five out of 10 with Graves' disease (86 +/- 3%) and six out of 10 with POF (76 +/- 6%) gave rise to LH (2 IU/l)-stimulated testosterone outputs which were lower (P < 0.05) than that of Sigma IgG control. Using the identical set of patients and an IgG concentration of 0.25 mg/ml, the FSH-stimulated oestradiol outputs of the four groups were similar when using either the saturating (20 IU/l) or subsaturating (5 IU/l) dose of the hormone. Thus, the percentage of FSH (20 IU/l)-stimulated oestradiol production of the Sigma IgG control was 81 (66-89 median, interquartile range) and 50 (38-84) for control and POF groups respectively. However, once again individual patients had inhibitory IgGs such that four out of nine (controls), three out of 10 (high FSH group), four out of 10 (Graves' disease) and six out of 10 (POF patients) inhibited (P < 0.05) FSH (20 IU/l)-stimulated oestradiol secretion by 52 +/- 9 (mean +/- SEM), 44 +/- 7, 52 +/- 6 and 41 +/- 6% respectively. Of the patients with inhibitory IgGs the extent of inhibition of gonadotrophin-stimulated steroid secretion was similar between the groups. In conclusion, there is little evidence to suggest that immunoglobulins blocking gonadotrophin receptors are a mechanism for POF in a large proportion of women suffering from this condition.