Serotonin-reinstatement of luteinizing hormone surges after loss of positive feedback in ovariectomized rats bearing subcutaneous capsules containing oestrogen

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Abstract
In ovariectomized rats treated chronically with oestrogen there is a loss of positive feedback effects on LH secretion. This was not due to depletion of pituitary LH since injection of LH releasing hormone (LH-RH; 50 ng/100 g body wt) caused a significant (P < 0·01) rise in serum LH even after the loss of spontaneous LH surges. However, the magnitude of the increase in serum LH in response to LH-RH was greater (412 ± 41 μg/l) before than after (291 ± 29 μg/l) loss of the LH surges. Excessive blood sampling was also not responsible, since positive feedback responses declined comparably in rats bled daily or once every 3–4 days. Progesterone (0·5 mg s.c.), administered for 5 consecutive days, failed to restore LH surges indicating that deficiency of this steroid after ovariectomy does not cause positive feedback responses to disappear in rats exposed chronically to oestrogen. Moreover regular daily fluctuations in serum progesterone, probably of adrenal origin, occurred before as well as after daily LH surges were lost. Serotonin content and turnover were depressed (P < 0·05) when ovariectomized rats first received the subcutaneous capsules containing oestrogen. This change correlated temporally with the onset of daily LH surges and was eventually lost. After 30 days exposure to oestrogen, serotonin turnover increased (P < 0·01) and positive feedback responses were absent. Catecholamine levels and turnover did not show differential responses to oestrogen and were depressed after acute as well as chronic steroid treatment. p-Chlorophenylalanine (pCPA; 250 mg/kg)+ l-dihydroxyphenylalanine (l-DOPA; 200 mg/kg), which depress serotonin and enhance catecholamine synthesis respectively, failed to reinstate LH surges, but these were restored in 22% of the rats receiving l-DOPA alone. pCPA, followed 2 days later by 5-hydroxytryptophan (5-HTP) at 11.00 h, reinstated LH surges in 88% of rats, and a dose–response curve showed that as little as 4 mg 5-HTP/kg stimulated repetitive LH surges when given with pCPA according to this schedule. However, the administration of α-methyl-p-tyrosine + l-DOPA, an analogous treatment involving catecholamines, was only marginally effective (15%). These findings suggest that perturbations of monoamine metabolism occurring in ovariectomized rats exposed to oestrogen for several weeks contribute to loss of daily LH surges. Since pCPA + 5-HTP restored LH surges most effectively, then positive feedback may disappear as the facilitatory effect of serotonin is lost after chronic oestrogen administration.