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To elucidate the mechanisms of action of GnRH agonists on uterine leiomyomas, morphometric and ultrastructural studies have been carried out on leiomyomas from patients treated with goserelin, and comparisons made with untreated tumors. The treated cases showed a variable degree of reduction of uterine size associated with leiomyoma shrinkage, and there was a correlation between the volume loss and the original size of the uterus. The morphological features of the treated lesions were very variable, with some showing evidence of marked cellular shrinkage and ultrastructural cytoplasmic changes, some having a lymphoid cell infiltrate, and others being indistinguishable from untreated control cases apart from having an increased number of compound lysosomes in the myoma cell cytoplasm. The degree of cellular shrinkage, measured by nuclear crowding, showed an inverse relationship to the proportion of collagen in the sections but none of the histological variables measured correlated with the degree of uterine shrinkage. It is concluded that the proportion of collagen in the lesions and other factors such as density of estrogen receptors, vascularity, cell proliferation rates, and degree of inflammatory cell infiltration affect the response to GnRH agonist therapy.

The effects of estrogen upon gonadoptropin release in vivo in the human female were studied by testing the pipuitarys response to a standard dose of synthetic luteinizing hormone-releasing hormone (LH-RH) in differing steroid environments and by injecting estrogens upon spontaneous LH and follicle stimulating hormone (FSH) release in various clinical states. 100 mcg LH-RH was administered iv on Days 4 9 14 and 22 of the same cycle. LH response was greatest on Day 14 and was greater on Day 22 than on Day 4 or 9. .5-2.5 mg estradiol benzoate was administered im during the follicular phase of normal cycles to measure the effects of LH-RH before and 48 hours after estrogen injection. An increase in LH and FSH release was observed. Levels of estradiol peaked 8-24 hours after the im injection of 2 mg estradiol benzoate in 6 normal women but returned to near basal levels after 56-72 hours. When 14 patients with amenorrhoea of hypothalamic origin received 1 mg estradiol benzoate im 6 patients were capable of producing positive feedback release of LH but only 3 showed accompanying FSH surges. These 6 patients ovulated but the other 8 did not although given doses of clomiphene up to 200 mg daily for 5 days. Changing estrogen levels modulated LH and FSH secretion by means of negative and positive feedback and increased estrogen levels appeared to modify pituitary responsiveness to LH-RH.