The influence of gonadal steroids on the dopamine inhibitory effect on gonadotropin release in men

FERTILITY AND STERILITY Copyright © 1984 The American Fertility Society

Vol. 42, No.6, December 1984 Printed in U.S A.

The influence of gonadal steroids on the dopamine inhibitory effect on gonadotropin release in men

Carlo Foresta, M.D. * Giovanni Scanelli, M.D. Sergio Marra, M.D. Cesare Scandellari, M.D. Istituto di Semeiotica Medica, Cattedra di Patologia Medica III, University of Padua, Medical School, Padua, Italy

Many authors! have clearly demonstrated in man that dopamine or dopaminergic drugs induce a significant fall in circulating luteinizing hormone (LH), but others2 have not demonstrated that dopamine affects gonadotropin secretion. Furthermore, experimental data support the hypothesis that the tuberoinfundibular dopaminergic system inhibits LH-releasing hormone (LHRH) neuronal activity in the lateral palisade zone of the median eminence. 3 Gonadal steroids, estrogens in particular, influence the dopamine turnover at a hypothalamic level 4 ; this has been evidenced in rats by cyclic changes in the hypothalamic dopamine turnover during the estrous cycle. 5 It therefore seems probable that gonadal steroids exert a feedback control of gonadotropin secretion at the hypothalamic-hypophyseal level involving the dopaminergic system. To ascertain whether there is a relationship between the gonadal steroid environment and the inhibition of gonadotropin secretion by dopamine in men, the effect of dopamine infusion on gonadotropin plasma levels was evaluated in castrated subjects, with no gonadal steroids, and in normal subjects, before and after treatment with clomi-

Received January 24, 1984; revised and accepted July 27, 1984. *Reprint requests: Carlo Foresta, M.D., Istituto di Semeiotica Medica, via Ospedale Civile, 105, 1-35100 Padua, Italy.

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phene citrate (CC), a specific nonsteroidal estrogen receptor antagonist. MATERIALS AND METHODS

The study was carried out on four castrated men, 18 to 23 years orage, and four age-matched normal men. Castration was due to a trauma that occurred at least 6 months before the patients were examined by us; none were under gonadal steroid replacement therapy. Informed consent was obtained from all subjects. After an overnight fast and 1 hour of bed rest, an intravenous catheter was inserted in each arm; one was used for the infusion of dopamine-HCI (Dopamina Simes, "Revivan," Simes S.p.a., Milan, Italy) dissolved in normal saline at a constant rate of 4 I-lg/kg/ minute over a period of 4 hours, and the other was used for basal blood sampling, both done at 30minute intervals during the infusion. In normal men, dopamine infusion was also administered on the sixth day after receiving 200 mg CC/day for 5 days. Sera were immediately frozen and stored at - 20°C until the assays were performed. LH and follicle-stimulating hormone (FSH) were measured by specific antibody radioimmunoassay using reagents supplied by Biodata (Milan, Italy); each hormone was measured in duplicate in the same assay. The intraassay and interassay variation coefficients were 4% and 7%, respectively. Results are reported as the mean ± Fertility and Sterility

Table 1. Mean and Standard Deviation ofUI Responses to Dopamine Infusion inNormal Men, Castrated Men, and Normal Men After Treatment with CC Minutes after dopamine infusion -60

-30

0

30

60

90

120

150

180

210

240

mIUlml

Normal Mean SD Castrated Mean SD Normal after CC Mean SD

10.0 1.3

9.8 1.1

10.1 1.1

9.3 1.2

8.5 0.8

8.3 0.9

7.5 0.7

6.8 1.0

6.5 0.5

6.7 0.7

7.1 7.1

70.2 9.7

71.3 10.5

70.7 10.3

61.8 7.3

54.7 7.1

46.9 8.0

51.4 3.9

39.6 4.3

39.3 4.8

40.6 4.9

41.3 6.2

30.8 5.9

30.4 6.0

30.4 6.2

26.0 3.8

23.4 3.4

21.3 3.8

18.3 2.5

16.9 2.8

17.3 3.8

18:0 3.1

19.6 3.6

standard deviation. The data were analyzed statistically with Student's t-test for paired and unpaired data. RESULTS

Our findings are summarized in Table 1. Dopamine infusion caused a progressive and significant fall in circulating LH levels in normal, castrated, and CC-treated normal subjects (P < 0.05, P < 0.005, and P < 0.001, respectively, versus baseline values). LH plasma levels in normal subjects receiving CC had a net decrease significantly greater (P < 0.012) than that before CC treatment (Fig.!). The maximum decrease percentage in LH plasma levels in normal subjects (35.6 ± 3.6) was significantly lower than that of normal men after receiving CC (44.6 ± 2.4; P < 0.005) and that of castrated subjects (44.4 ± 2.7; P < 0.005) (Table 2).

FSH levels. In men, therefore, the dopaminergic system does not appear to greatly influence FSH secretion. The gonadal steroid environment appears to influence significantly the sensitivity of LH inhibition by dopamine infusion. In castrated and in normal men after CC treatment there is in fact an enhanced LH sensitivity to dopamine inhibition. On the other hand, it has been demonstrated that there is a greater dopamine inhibition of LH se-

I DO~AM~NE

.4pg/Kg/min·1

o JLH mUI/ml 10

20

DISCUSSION

Our study has considered three kinds of clinicoexperimental models: (1) normal subjects, with regular levels of estrogens and androgens; (2) normal CC-treated subjects, with normal androgen levels but with blocked estrogen effects; and (3) castrated men with very low levels of both estrogens and androgens. Our findings demonstrate that dopamine infusion induces a significant reduction in circulating LH levels in normal men, castrated men, and normal men after CC administration. In agreement with most other authors, l we observed that FSH levels are not inhibited by dopamine infusion; however, some authors 6 report that dopamine causes a significant but small decrease in Vol. 42, No.6, December 1984

30

40

50+--r----.----.---- r 2 1 -1 o

.

3

4

HOURS

Figure 1 Net decrease (d) in plasma LH levels during dopamine infusion in normal men (_ _e), normal men after CC treatment (x ...... x ...... x), and castrated subjects (0- - -0- - -0). Foresta et ai. Communications-in-brief

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· Table 2. Maximum Percent Decrease in LH and FSH Plasma Levels in Normal Men, Castrated Men, and Normal Men After CC Administration

gonadal steroid deficiency may be associated with a lower endogenous dopaminergic influence on LH secretion.

Maximum % decrease Subjects

Normal (n = 4) Castrated (n = 4) Normal after CC (n

= 4)

LH

FSH

mlUlml

mlUlml

35.6 ± 3.6 44.4 ± 2.7a 44.6 ± 2.4a

7.5 ± 3.8 9.8 ± 2.5 6.1 ± 2.5

ap < 0.005 versus normal men.

cretion in women with ovarian failure, l as in agonadal women, than in normal women on the second day of their menstrual cycle. 6 In castrated men, estrogen and androgen plasma levels are extremely low; and in normal CCtreated men, the effects of estrogens are blocked, although androgens and their receptors are unchanged. Therefore, the likewise enhanced LH sensitivity to dopamine inhibition in castrated and normal men after CC treatment suggests that especially estrogens or aromatizable androgens play an important role in the dopaminergic system regulating LH secretion. The mechanism by which dopamine exerts its inhibitory effect on LH secretion is not entirely clear. Because dopamine cannot cross the blood-brain barrier, it exerts this effect either on the median eminence, by suppressing LH-RH secretion, or on the pituitary gland, by modifying gonadotropin sensitivity to LH-RH, or in both these ways. Gonadal steroids influence dopamine turnover at the hypothalamic level 4 and it is known that estrogen treatment in ovariectomized rats causes a dose-dependent increase in dopamine turnover in the median eminence 4 ; it has also been observed that the synthesis of dopamine in the median eminence of female rats is five times that of male rats. 7 Estrogen deficiency may therefore determine a reduced endogenous dopamine inhibition of LH secretion, which explains the greater reduction in LH secretion under dopamine infusion. In conclusion, our study shows that dopamine infusion induces a significant decrease in circulating LH levels in normal men, castrated men, and normal men after CC administration. FSH levels are not inhibited by dopamine infusion. In cases of gonadal steroid deficiency, especially estrogen or aromatizable androgen deficiency, dopamine infusion causes an increased sensitivity of LH inhibition. These findings suggest that a 944

Foresta et al. Communications-in-brief

SUMMARY

The aim of this study was to ascertain whether an interrelationship exists between gonadal steroids and the inhibition of gonadotropin secretion by dopamine. The effect of dopamine infusion (4 fLg/kg/minute intravenously) on gonadotropin plasma levels in four castrated men (18 to 23 years of age) and in four age-matched normal men was studied. Normal subjects were studied before and after treatment with a specific nonsteroidal estrogen receptor antagonist, CC. LH plasma levels in normal subjects receiving CC had a maximum decrease percentage and a net deerease significantly greater (P < 0.005 and P < 0.012, respectively) than those before CC treatment. In castrated subjects the maximum decrease percentage was significantly greater (P < 0.005) than in control subjects, but it did not show any difference from that of normal subjects receiving CC. In none of the group were significant changes in FSH concentration observed. The findings suggest that whenever there is a gonadal steroid deficiency, dopamine infusion causes an increased sensitivity to LH inhibition. This may be due to a lower endogenous dopaminergic influence on LH secretion. Acknowledgment. We are grateful to Ms. Mariangela Indino for her careful technical help.

REFERENCES 1. Ferrari C, Rampini P, Malinverni A, Scarduelli C, Benco

R, Caldara R, Barbieri C, Testori G, Crosignani PG: Inhibition of luteinizing hormone release by dopamine infusion in healthy women and in various pathophysiological conditions. Acta Endocrinol (Copenh) 97:438, 1981 2. Leebaw WF, Lee LA, WoolfPD: Dopamine effect on basal and augmented pituitary hormone secretion. J Clin Endocrinol Metab 47:480, 1978 3. Fuxe K, Hokfelt T, Lofstrom A, Johansson 0, Agnati L, Everitt B, Goldstein M, Jeffcoate S, White M, Eneroth P, Gustafsson JA, Sket P: On the role of neurotransmitters and hypothalamic hormones and their interaction in hypothalamic and extrahypothalamic control of pituitary function and sexual behaviour. In Subcellular Mechanisms in Reproductive Neuroendocrinology, Edited by F Naftolin, KJ Ryan, IJ Davies. Amsterdam, ElsevierNorth Holland, 1976, p 193

Fertility and Sterility

4. Fuxe K, Hokfelt T, Nilsson 0: Castration, sex hormones and tubero-infundibular dopamine neurons. Neuroendocrinology 5:107, 1969 5. Lofstrom A: Catecholamine turnover alterations in discrete areas of the median eminence of the 4- and 5-day cYcling rat. Brain Res 120:113, 1977

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6. Judd SJ, Rigg LA, Yen SSC: The effects of ovariectomy and estrogen treatment on the dopamine inhibition of gonadotropin ~nd prolactin release. J Clin Endocrinol Metab 49:182,1979 7. Gudelsky GA, Porter JC: Sex-related differences in the release of dopamine into hypophyseal portal blood. Endocrinology 109:1394, 1981

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