Perturbations of Negative Feedback Sensitivity in Agonadal Patients Undergoing Estrogen Replacement Therapy*

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Abstract
Urinary gonadotropin excretion was measured in 30 patients with gonadal dysgenesis, aged 2 months to 17 yr. Between bone ages 3–8 yr, mean FSH excretion (575 mlU/h) was elevated 8-fold in agonadal individuals compared to levels in intact prepubertal girls; mean urinary LH (49 mlU/h) in agonadal patients during this time period was increased nearly 2-fold over results from normal prepubertal females. Nine of 10 patients given 0.3 to 0.6 mg conjugated estrogen (Premarin) daily to initiate puberty exhibited prompt suppression of urinary gonadotropin levels from markedly elevated levels to within or very close to the normal prepubertal range. Such a response was found in only two of seven patients given 0.15 mg of the same drug. All instances of suppression were followed by escape from low levels of gonadotropin excretion as treatment was continued. Prior exposure to exogenous or endogenous estrogen markedly reduced the suppressive potential of treatment with 0.3 or 0.6 mg Premarin. A favorable advance of bone maturation in relation to chronological age was achieved by the administration of 0.15 mg Premarin daily, a dose which caused a satisfactory onset of secondary sex characteristics. In conclusion: 1) a component of gonadotropin restraint in midchildhood is supplied by the ovary; 2) adult castrate levels of gonadotropins are achieved in the agonadal patient of peripubertal age in the presence of a highly sensitive negative feedback axis between sex hormones and gonadotropins; 3) sex steroids themselves may modify the gonadotropin-gonadal negative feedback axis in patients with gonadal dysgenesis; and 4) puberty may be initiated favorably with conjugated estrogens in an oral dose of 0.15 mg daily.