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It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4-6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 +/- 10 to 234 +/- 62 pmol/L, untreated and CC treated; P < 0.05) and estrone (125 +/- 14 to 257 +/- 29 pmol/L; P < 0.05) levels with a significant lowering of IGF-I levels (297 +/- 25 to 230 +/- 17 micrograms/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 +/- 11 to 245 +/- 58 pmol/L; P < 0.05) and estrone (301 +/- 32 to 401 +/- 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 +/- 43 to 214 +/- 27 micrograms/L; P < 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione. The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.

The aetiology of polycystic ovary syndrome (PCOS) is unknown. It is uniquely characterized by oligomenorrhoea or amenorrhoea associated with normal or high oestrogen levels. This prospective clinical study was designed to examine the possible role of the lack of cyclical exposure to progesterone in the development of gonadotrophin and androgen abnormalities in PCOS. Gonadotrophin, androgen and oestrogen levels were measured in 15 PCOS patients and 10 normal subjects untreated and following treatment with the progestogen medroxyprogesterone acetate (MPA). When compared to control subjects, PCOS patients had significantly higher luteinizing hormone (LH) pulse height, pulse amplitude, integrated LH levels, LH response to gonadotrophin-releasing hormone (GnRH) and LH/FSH ratio; LH pulse frequency was similar in the two groups. In addition, the testosterone/sex hormone binding globulin ratio (T/SHBG), androstenedione and oestrone concentrations in the plasma were significantly higher in PCOS than in control subjects. When PCOS patients were treated with MPA for 5 days, there were significant decreases (p < 0.02-0.001) to values no longer different from normal: from 8.7 +/- 1.2 to 5.6 +/- 0.8 IU/l for integrated LH levels (untreated and MPA-treated PCOS); from 31.2 +/- 3.5 to 12.9 +/- 1.5 IU/l for LH response to GnRH; from 2.4 +/- 0.26 to 1.3 +/- 0.2 for LH/FSH ratio; and from 10.4 +/- 0.63 to 8.5 +/- 0.7 nmol/l for androstenedione. Significant decreases (p < 0.05-0.005) to values that still remained significantly higher than in normal subjects occurred for: LH pulse height, 11.05 +/- 1.3 to 6.88 +/- 0.79 IU/l (untreated and MPA-treated PCOS); LH pulse amplitude, 2.8 +/- 0.5 to 1.8 +/- 0.2 IU/l; total testosterone, 2.5 +/- 0.2 to 2.0 +/- 0.2 nmol/l; T/SHBG ratio, 14.1 +/- 1.7 to 11 +/- 1.5; and oestrone, 265 +/- 24 to 208 +/- 29 pmol/l. These results are consistent with the concept that ovulation failure and progesterone deficiency play a facilitatory role in the development of the hypothalamic-pituitary abnormality giving rise to disordered LH secretion in PCOS.