Endocrine and clinical effects of estradiol and testosterone pellets used in long-term replacement therapy

Ten women with estrogen deficiency symptoms because of premature menopause [3], gonadal dysgenesis [3], or surgical menopause [4] received subcutaneous implants consisting of 25--75 mg estradiol (E2) with or without 75 mg testosterone (T). All had elevated plasma FSH, and LH, and low E2 prior to treatment. Plasma levels of FSH, LH, E2, T and estrone (E1) were measured by specific radioimmunoassay techniques prior to treatment, three times a week for the first week and once a week for up to 76 weeks after implantation. Mean plasma E2 levels rose abruptly and reached a maximum of 190 +/- 35 pg/ml within 2 weeks. They fluctuated around 150 pg/ml for 46 weeks, then gradually declined, but remained above pretreatment values for more than 68 weeks. Plasma E1 increased to a lesser extent resulting in E2:E1 ratio between 1 and 5. Elevated FSH and LH titers became suppressed within 4--6 weeks. The lowest average E2 increased occurred after 25 mg implant and was associated with incomplete FSH and LH suppression. There were no differences in maximal E2 levels reached after 50 mg or 75 mg implant, however, after 75 mg implant, E2 levels appeared less variable and were sustained for a longer period of time, averaging 125 pg/ml for 70 weeks. Plasma FSH and LH concentrations were suppressed below pretreatment levels in all patients. The degree of suppression was related to the dose of E2 implanted and, therefore, to plasma E2 levels. The FSH and LH suppression appeared more complete in women with gonadal dysgenesis than in those with premature or natural menopause. Plasma T rose abruptly to a peak mean level of 2.5 +/- 1.6 ng/ml within 2 weeks of implantation. A precipitous and steady decline with return to preimplantation titers between 17th and 18th week were then observed. The E2:E1 ratio during the first 18 weeks after implantation was significantly higher in women who received E2 implant alone than in those who received E2 + T implant. Clinically, all patients had symptomatic improvement within 24--48 hours. Regular withdrawal bleeding followed administration of oral progestogen for up to 76 weeks after implantation in six patients with intact uterus.