Bart C.J.M. Fauser

Effect of lower versus higher doses of tamoxifen on pituitary-gonadal function and sperm indices in oligozoospermic men

Summary:  Administration of the antiestrogen tamoxifen for one month to 12 patients with idiopathic oligozoospermia significantly increased the mean basal testosterone (T) level and the responses of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to constant luteinizing hormone releasing hormone (LHRH) infusion but did not significantly influence the mean oestradiol (E2) levels or the E2 over testosterone ratio. Mean sperm concentration and total sperm output increased by about 70% after a mean treatment period of 5.5 ± 0.4 months. No statistically significant difference was found between the two subgroups of patients treated with either the lower (5 or 10 mg once daily) or higher dose of tamoxifen (10 mg twice daily) with respect to basal or LHRH stimulated gonadotropin and testosterone response or the E2/T ratio and the effect on sperm density and total sperm output. In both subgrounps the sperm motility and morphology remained unchanged.

Differential effect of luteinizing hormone-releasing hormone infusion on testicular steroids in normal men and patients with idiopathic oligospermia

Basal serum gonadotropin levels in 11 oligospermic men were significantly higher than in 9 euspermic control subjects, although most were still in the normal range. Basal serum testosterone (T), 17-hydroxyprogesterone (17-OHP), and estradiol levels and their ratios did not differ significantly. Continuous luteinizing hormone-releasing hormone (LH-RH) infusion (1 microgram/minute for 180 minutes) during integrated blood sampling evoked similar gonadotropin responses in both groups but had a differential effect on T: in the control subjects T increased (P less than 0.01) within 15 minutes to 1.5 times baseline, whereas in the oligospermic men T decreased (P less than 0.01). From 60 minutes on, however, T also significantly rose in the oligospermic men, but the maximum increment was about half lower (P less than 0.01) than in the euspermic men, despite virtually similar rises in 17-OHP. Only in the oligospermic men did the 17-OHP/T ratio increase (P less than 0.02) during LH-RH, which is compatible with the occurrence of a 17,20-lyase block. Serum estradiol did not increase in either group. In conclusion, continuous LH-RH infusion uncovers an intrinsic difference in acute Leydig cell stimulation between euspermic and oligospermic men.

Long-Term, Pulsatile, Low Dose, Subcutaneous Luteinizing Hormone-Releasing Hormone Administration in Men with Idiopathic Oligozoospermia Failure of Therapeutic and Hormonal Response

Summary:  In four normal men with a history of long standing infertility, severely disturbed sperm qualities (determined in at least three spermiograms), normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels (measured over a time period of 90 minutes), and lack of evidence of further andrological or other obvious endocrine disorders the effectiveness of luteinizing hormone‐releasing hormone (LH‐RH) treatment was investigated. LH‐RH was administered subcutaneously with a portable, comterized infusion pump (Zyclomat) for 3 months, with administration intervals of 90 minutes and bolus dosages of 5 μg (three patients) and 20 μg (one patient).

The effect of pulsatile and continuous intravenous luteinizing hormone-releasing hormone administration on pituitary luteinizing hormone and follicle-stimulating hormone release in normal men

In 14 healthy, potentially fertile men, pituitary gonadotropin responses were studied under standardized conditions. Luteinizing hormone-releasing hormone (LH-RH) was given as a continuous infusion of 1 microgram/minute for 4 hours or in a pulsatile fashion with 20 micrograms as an intravenous bolus at intervals of 20 minutes for 4 hours. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration showed an oscillating pattern around a plateau level reached within 45 minutes during continuous LH-RH administration. During pulsatile infusion, an identical pattern for the first 45 minutes was observed with, thereafter, a continuous increase from 105 minutes until the end of the infusion. The mean increase in the serum LH level during pulsatile administration was significantly higher (P = 0.00001) than the mean increase seen during continuous infusion. The follicle-stimulating hormone concentration revealed a gradual progressive increase after both methods of stimulation, without a significant difference in the mean increase between the two types of administration. This study demonstrates the existence of a self-priming effect of LH after pulsatile LH-RH administration in the man like that in the woman.

Pharmacokinetics of intravenous luteinizing hormone-releasing hormone administration in men: effects of various dosages.

Exogenous luteinizing hormone-releasing hormone (LH-RH) was intravenously administered as a single-bolus injection to 26 healthy normal men. LH-RH doses were selected at 1, 2.5, 5, and 20 micrograms for exploration of the optimum LH-RH dose to obtain adequate pituitary stimulation. Blood samples (for LH-RH and LH determinations) were collected at frequent intervals from 10 minutes before to 60 or 90 minutes after injection. LH-RH peak levels varied, in a dose-dependent way, between 119 +/- 16 and 517 +/- 70 ng/l. Peak values were all reached between 1 and 3 minutes after injection, and elimination occurred rapidly, with half-lives between 2.6 +/- 0.4 and 5.2 +/- 1.0 minutes. The area under the curves increased significantly (P less than 0.01) if the doses of LH-RH had been augmented from 1 to 20 micrograms. Maximum LH values were reached more rapidly in the low-dose (1 and 2.5 micrograms) experiments (between 13.5 and 16.3 minutes), with an obvious decline afterwards. The area under the LH curves increased (P less than 0.01) if the doses of LH-RH had been elevated from 1 to 2.5 micrograms, but no further increase of LH release occurred (P greater than or equal to 0.21) if LH-RH doses were further elevated from 2.5 to 20 micrograms. The current study demonstrates that a 2.5-micrograms intravenous LH-RH dose is best suited for an adequate pituitary stimulation in normal men.

Effect of aromatase inhibition by Δ1-testolactone on basal and luteinizing hormone-releasing hormone-stimulated pituitary and gonadal hormonal function in oligospermic men

Aromatase inhibition by delta 1-testolactone (TL), 500 mg twice daily for 4 weeks, in nine patients with idiopathic oligospermia lowered circulating estradiol (E2) levels by about 30%, enhanced the secretion of follicle-stimulating hormone (+ 30%), 17-hydroxyprogesterone (17-OHP) (+ 40%), and testosterone (T) (+ 30%), but did not affect serum luteinizing hormone levels. Despite E2 lowering, there was an accumulation of 17-OHP over T, suggesting 17, 20-lyase inhibition. Unexpectedly, administration of TL almost completely deleted the T response to continuous luteinizing hormone-releasing hormone infusion present before TL therapy, despite similar gonadotropin release. Because the 17-OHP response to the luteinizing hormone-releasing hormone infusion was even higher during therapy, the 17,20-lyase lesion seemed aggravated despite substantial reduction of E2 levels. Although the present data suggest that estrogens play a less dominant role in the origin of the late steroidogenetic lesion than previously assumed, the suggestion also arises that TL per se, in addition to its antiestrogenic action, exerts an inhibiting effect on the 17,20-lyase locus, which may obscure the beneficial effect of reducing E2.

Serum luteinizing hormone-releasing hormone (LH-RH) and gonadotropic hormones in men after a bolus dose of LH-RH: comparison of different doses and routes of administration

Serum levels of luteinizing hormone-releasing hormone (LH-RH), LH, and follicle-stimulating hormone (FSH) were measured for 60 minutes after 5- and 20-micrograms bolus doses of LH-RH given either intravenously or subcutaneously to 20 healthy men, for the study of LH-RH pharmacokinetics and the corresponding pituitary gonadotropin release. Intravenous (5- and 20-micrograms) LH-RH administration revealed much sharper LH-RH pulses, with significantly higher levels between 1 and 5 minutes (P less than 0.001) but lower levels between 30 and 60 minutes (P less than 0.05), compared with the subcutaneous route. No statistically significant differences were observed in the magnitude and time occurrence of maximum LH release or in the area under the LH response curves between intravenous and subcutaneous LH-RH administration, either in the 5-micrograms or in the 20-micrograms group. FSH responses were small and insignificant in all the performed tests. The intravenous route of administration seems preferential in therapeutic regimens that use pulsatile exogenous LH-RH, because the conditions of intermittent pituitary stimulation are more adequately fulfilled and the risk of dose accumulation is reduced. Furthermore, LH-RH doses of 5 micrograms are capable of producing adequate pituitary LH release, whereas increases in the pulse dose up to 20 micrograms seem to have no additional effects.

Pituitary gonadotropin responses to different modes and doses of intravenous luteinizing hormone-releasing hormone administration in normal men *

In 22 potentially fertile men, pituitary gonadotropin secretion was investigated by intravenous luteinizing hormone-releasing hormone (LH-RH) administration. LH-RH was administered continuously (1 microgram/minute) and in a pulsatile fashion (20 micrograms at 20-minute intervals, 20 micrograms at 60-minute intervals, and 60 micrograms at 60-minute intervals), for 3 hours, under standardized conditions. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration after any type of pulsatile administration rose significantly more than after continuous LH-RH administration. The mean increase in LH after pulsatile LH-RH administration with a 60-micrograms dose and 60-minute intervals was significantly greater than after pulsatile administration with a 20-micrograms dose and 20- or 60-minute intervals. No differences were observed in follicle-stimulating hormone responses after any type of LH-RH administration. These data confirm the existence of a self-priming effect for LH in the men; and maximum pituitary stimulation, within the dosage range tested, is reached after pulsatile LH-RH stimulation with an interval of 60 minutes.

Testicular Steroid Response to Continuous and Pulsatile Intravenous Luteinizing Hormone‐Releasing Hormone Administration in Normal Men

Summary:  In 18 healthy normal men Leydig cell response was examined following intravenous luteinizing hormone‐releasing hormone (LH‐RH) administration under standardized conditions. The same total amount of LH‐RH was administered for 3 hours both in a continuous (1 μg/min; C (1, 1)) and in a pulsatile fashion, by giving a 20μg dose at 20 minutes intervals, P (20,20), and a 60 μg dose at 60 minutes intervals, P (60,60).

Short‐ and Long‐Term Hormonal Effects of a Single Dose of 50 mg Tamoxifen Administered to Normal Males

Summary:  To five potentially fertile males, a single dose of 50 mg tamoxifen was administered orally to explore the short‐ and long‐term hormonal effects on the hypothalamic‐pituitary‐gonadal axis. Blood specimens were obtained through an integrated sampling technique for the first two hours after the intake of the drug. Then, samples were taken daily throughout one week, and twice weekly for the next two weeks. Hormone measurements of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and oestradiol were obtained by specific RIA. All the subjects showed different response patterns. No general characteristic of the hormonal changes in the investigated group could be given. A consistent correlation between the within‐individual levels of gonadotrophin and sex steroid changes could not be observed. It is concluded, within the limits of the used experimental design, that in healthy males a single administration of tamoxifen does not result in consistent changes in serum levels of either gonadotrophins or sex steroid hormones.