Contraception With an LHRH Agonist: Effect on Gonadotrophin and Steroid Secretion Patterns

Abstract

Chronic treatment with the LHRH agonist D-Ser(TBU)6-LHRH (1-9)-EA (buserelin) has been suggested as a contraceptive method since it has been shown to inhibit ovulation. To elucidate the mechanism of this paradoxical action, we investigated the pattern of gonadotrophin and steroid secretion after the daily intranasal application of 300 micrograms of the agonist. Ten volunteers with ovulatory cycles received the analogue from Day 1 to Day 22 and 5 mg norethisterone acetate from Day 16 to Day 22. Blood samples were taken on Day 1, 15, and 21 every 15 min for 6 h after the application of the agonist. LH secretion was increased nine-fold on the first treatment day as compared to Day 2 of the preceding control cycle. Thereafter, it decreased slowly but was still elevated five-fold on Day 21 of treatment. FSH release increased three-fold on Day 1 but decreased thereafter to values similar to those of the controls. During treatment with the analogue, the LH/FSH ratio changed from 1.3 (controls) to 3.8 on Day 1 and to 5.5 on Day 15 and 21 of treatment. Although the ovary retained follicular activity, ovulation was inhibited in every treatment cycle. This seemed to be due to an impairment of follicular steroid synthesis as indicated by a significant increase of 17 alpha-hydroxyprogesterone and testosterone levels for several hours after the application of the analogue. It appears that at least during the first treatment cycle of daily administration of buserelin the abolishment of pulsatile gonadotrophin release, and the abnormally increased ratio of LH/FSH secretion may possibly impair follicular maturation and thus contribute to the inhibition of ovulation.

Clinical aspects of LHRH analogues in gynaecology: a review

“…3), a pattern similar to that seen with continuous infusion of native LHRH (Belchetz et al 1978). A range of perturbations of gonadotrophin secretion has been described with chronic LHRH agonist therapy including lower gonadotrophin release, attenuation of pulsatile LH secretion (Chang et al 1983;Kuhl et al 1984), increased LH to FSH ratio (Baumann et al 1980Kuhl et al 1984), diminished bioactive to immunoactive LH (Meldrum etal. The importance to the pituitary of pulsatile LHRH exposure is underlined by the successful restoration of gonadotrophin levels in isolated gonadotrophin deficiency (Valk et al 1980), or the restoration of fertility in hypothalamic amenorrhoea (Hurley et al 1984 istered LHRH could disturb folliculogenesis and ovulation by inhibiting the normal pulsatile mode of gonadotrophin release.…”

“…This occurs in non-human primates (Fraser et al 1980) and in the vast majority of treatment cycles in women (Nillius et al 1978(Nillius et al , 1980Bergquist etal. , 1984Baumann et al 1980;Schmidt-Gollwitzer et al 1981a, 19816;Kuhl et al 1984). , 19796,1982aBergquist etal.…”

“…Ovulation either did not occur (Hardt & Schmidt-Gollwitzer 1983;Kuhl et al 1984) or was rare occurring in 3 of 628 treatment cycles and attributed to early technical problems with the nasal spray application (Bergquist. et al 1984).…”

Long-Term Use of the Low Dose LHRH Analogue Combined With Monthly Medroxy-Progesterone Administration

“…has previously been reported [1], It is also well documented that a single intranasal dose of 300 or 400 pg once daily inhibits ovulation [12,13]. In long term contraceptive studies with buserelin.…”

“…In long term contraceptive studies with buserelin. a progressive decrease in circulating levels of E2 has been reported, with an increasing incidence of oligomenorrhoea and amenorrhoea [13,14]. To avoid constant down regula tion.…”