Potential diagnostic utility of intermittent administration of short-acting gonadotropin-releasing hormone agonist in gonadotropin deficiency

Abstract

Objective: To determine if intermittent, low-dose, short-acting gonadotropin-releasing hormone agonist (GnRH-agonist) administration sufficiently up-regulates pituitary-gonadal function in gonadotropin deficiency to be of diagnostic or therapeutic value.

Design: Case-control study.

Setting: General clinical research center.

Patient(s): Normal adult volunteers and gonadotropin-deficiency patients.

Intervention(s): Low-dose leuprolide acetate administered subcutaneously at 4- to 5-day intervals up to 1 year.

Main outcome measure(s): Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses.

Result(s): In normal men and women, low-dose GnRH-agonist repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally gonadotropin-deficient men (n = 6) and women (n = 1), none of whom had a normal LH response to an initial GnRH-agonist test dose, this regimen consistently stimulated LH to the normal baseline range within 2 weeks. Long-term GnRH-agonist administration to a partially gonadotropin-deficient man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n = 2) responded normally to a single GnRH-agonist injection; however, repeated dosing did not seem to induce the normal priming effect.

Conclusion(s): The subnormal LH response to GnRH-agonist in patients with congenital gonadotropin deficiency normalized in response to repetitive intermittent GnRH-agonist administration but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRH-agonist but otherwise had normal hormonal responses to GnRH-agonist. We conclude that intermittent administration of a short-acting GnRH-agonist is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of gonadotropin deficiency.

Figure 1

Effect of repeatedly administering GnRHag (1.0 μg/kg) in healthy volunteers. GnRHag (arrows) was given at 4 (males, n=5) or 5 (female, n=5) day intervals. Peak gonadotropin responses (shown) occurred on the day of GnRHag administration. Significant differences from day 1 baseline within a group are shown (* p<0.05). Notice scale differences between males and females.

Figure 2

Effect of repeatedly administering GnRHag (1.0 μg/kg) to GnD patients. GnRHag administration was repeated every 5 days (arrows) in both male GnD (n=6) and female GnD (n=3) patients. Testosterone was only sampled at baseline in men, while estradiol was sampled daily, with black bars representing 24 hrs after injection. Baseline and peak responses are indicated by open and closed bars, respectively. The lower limits of baseline (dotted line) and peak levels (solid line) for normal volunteers are shown for comparison. LH and estradiol responses of the congenitally GnD female patient (n=1) were low, but those of the hypothalamic amenorrhea patients (n=2) were normal. Notice scale differences between males and females.

Figure 3

Long term, intermittent GnRH agonist treatment of a partially GnD male. The response to GnRHag dose and interval variation was tested. On days 1–21 the patient was given 1.0 μg/kg GnRHag every 5 days. Between days 22–135 GnRHag dose was increased to 10 μg/kg every 5 days. For days 136–210 the patient was again given 1.0 μg GnRHag every 5 days. On day 211 through the remainder of the evaluation, the GnRHag dose was changed to 10 μg/kg every 4 days. On day 287, depot testosterone (50 mg every 2 weeks, then increased to 100 mg every 2 weeks) was added. The acute hormonal responses to GnRHag administration were tested intermittently as shown; vertical lines connect baseline and peak at each visit (the testosterone response was only evaluated at 24–48 hr on three occasions). There was no obvious effect of the testosterone supplementation on LH and FSH responses. The lower limit of baseline (dotted line) and peak levels (solid line) for normal volunteers at 1.0 μg/kg are shown for comparison.