Clin Endocrinol (Oxf). 1998 Aug;49(2):203-7.
L-5-hydroxytryptophan does not stimulate LH secretion directly from the pituitary in patients with gonadotrophin releasing hormone deficiency.
Lado-Abeal J, Grana M, Rey C, Cabezas-Cerrato J.
Endocrinology and Nutrition Service, Galician General Hospital, Spain. [email protected]
OBJECTIVE: There is abundant histological and physiological evidence that serotonin plays a role in the regulation of LH secretion in rats. Studies in human subjects have been few, but their results include the finding that pulsatile administration of L-5-hydroxytryptophan (5-HTP, the immediate precursor of serotonin) amplifies LH secretion in women in the medium-late follicular phase, and that this effect is not due to 5-HTP directly inducing LH secretion by the pituitary. We have investigated whether 5-HTP amplifies LH secretion by enhancing the response of the pituitary to GnRH. PATIENTS: Seven patients aged 20-40 years with hypogonadotrophic hypogonadism (HH) of hypothalamic origin (3 men with Kallmann's syndrome, 2 women without anosmia and with GH deficiency, and 2 women with anorexia nervosa).
DESIGN: To prime the pituitary, subcutaneous pulsatile GnRH was administered for 7 days at the rate of one 5-20 micrograms pulse every 90 min. The day before the investigation, this regimen was replaced by 1.5-3 micrograms intravenous pulses at the same frequency. On the day of the investigation, 3 ml blood samples were taken every 10 min from 0850 to 19:00 hours. After the first two samples, the intravenous GnRH pulse frequency was increased to one per hour and was maintained at this level throughout the rest of the study. The first 4 h of the study acted as a control phase allowing determination of the pituitary response to GnRH. At 1300 h, 75 mg of the aromatic-L-amino-acid decarboxylase inhibitor carbidopa was administered orally; carbidopa does not cross the blood-brain barrier, and prevents peripheral conversion of 5-HTP to serotonin. At 1600 h, another 75 mg dose of carbidopa was administered, and administration of 8-20 mg pulses of 5-HTP at a rate of one pulse per hour was begun.
MEASUREMENTS: LH was determined in triplicate by an immunoradiometric assay (IRMA), and LH pulses identified by means of a program developed in our laboratory.
RESULTS: When pulsatile administration of GnRH was accompanied by administration of carbidopa and 5-HTP, LH pulse amplitude (2.32 +/- 0.71 IU/I) did not differ significantly from its value in either the GnRH+ carbidopa phase (2.58 +/- 1.12 IU/I) or the unaccompanied GnRH phase (2.77 +/- 1.76 IU/I).
CONCLUSIONS: L-5-hydroxytryptophan-induced amplification of LH secretion in humans is not due to enhancement of the pituitary response to GnRH. The effect of L-5-hydroxytryptophan must therefore be due to its action on the hypothalamus, where it may be hypothesized that it increases GnRH release.
-Unlike many other neurotransmitters, serotonin has been the subject of relatively little research in connection with the regulation of LH secretion in humans, although its involvement in LH regulation in rats is supported by considerable histological and physiological evidence. However, we recently found that ulsatile administration of L-5-hydroxytryptophan (5-HTP) amplifies LH secretion in women in the follicular phase so long as they have an active GnRH pulse generator. Neither the frequency nor the duration of LH pulses are affected, and the effect on pulse amplitude is not due to 5-HTP directly inducing LH secretion by the pituitary.
-7 patients with hypogonadotropic hypogonadism of hypothalamic origin; 3 men and 4 women. IV 5-HTP, 8-20 mg.
-It is well established that serotonin is involved in the regulation of LH secretion in rats, its effects depending on sex and steroid hormone status; whereas in male rats it appears to have merely a permissive role, in females it seems to stimulate LH secretion by acting on the hypothalamus as a neurotransmitter.
-Although our previous study showed that the amplification of LH secretion by 5-HTP was not due to direct induction of LH release by the pituitary, it did not allow determination of whether 5-HTP was acting on the hypothalamus or was enhancing the pituitary response to GnRH.... In the present study, the LH follicular phase pattern secretion (high frequency and low amplitude pulses) has been reproduced in patients with hypogonadotrophic hypogonadism. The results now presented show that 5-HTP does not enhance the effectiveness of GnRH at the pituitary. It may be pointed out that although the dose of 5-HTP used in this work was less than in other studies in order to minimize side effects, the absence of any effect on LH secretion is unlikely to have been due to dose insufficiency, because the obserbed increase in serum cortisol concentrations shows that the quantity of 5-HTP reaching the brain was sufficient to stimulate the hypothalamic-pituitary-adrenal axis.
-In conclusion, the results presented here, together with our earlier findings, show that the stimulation of LH secretion in humans by pulsatile administration of 5-HTP is not due to any effect of 5-HTP on the pituitary. 5-HTP must therefore be assumed to act on the hypothalamus, probably by stimulating GnRH secretion.