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A study of prolactin, follicle-stimulating hormone, and luteinizing hormone in puerperium: spontaneous variations and the effect of metergoline
Vol. 37, No.3, March 1982 Printed in U.SA.
FERTILITY AND STERILITY Copyright c 1982 The American Fertility Society
A study of prolactin, follicle-stimulating hormone, and luteinizing hormone in puerperium: spontaneous variations and the effect of metergoline
Leopoldo Falsetti, M.D.* Anna Maria Voltolini, M.D.* Carmen Pollini, B.D.t Antonio Ettore Pontiroli, M.D.:j:§ Universita di Milano, Ospedali Civili, Brescia, ltalia, Ospedale San Raffaele, Milano, and Farmitalia Carlo Erba, Milano, ltalia
In 80 normal puerperae, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), including human chorionic gonadotropin (hCG/LH), and prolactin (PRL) levels were evaluated 6 to 29 hours after vaginal delivery. In these puerperae, PRL levels were higher and FSH levels were lower than in menstruating women; hCG/LH levels were very high, due to persisting hCG levels. The values of the three hormones showed a log-normal distribution, and no relationship was found between the three hormones considered in pairs. Thirty-six puerperae chosen from the above 80 were followed during a 5-day period: 24 were not able to breast-feed their babies and were treated with metergoline, an antiserotoninergic agent able to prevent puerperal lactation, 8 or 12 mg/day; 12 additional puerperae, nursing their babies, were evaluated as controls. In lactating women PRL and FSH levels remained steady during the observation period, while hCG/LH levels progressively decreased. Metergoline lowered PRL levels, when employed at both dosages, and FSH levels only at the higher dosage, without affecting the decline of hCG/LH levels. Since dopaminergic drugs are known to lower serum LH levels and not to affect or to increase FSH levels, our data indicate that metergoline might act through a mechanism of action different from dopaminergic drugs. Fertil Steril 37:397, 1982
The puerperium is characterized by lactation and by high prolactin (PRL) levels as well as by amenorrhea and by low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. 1-a Several studies performed so far, both in experimental animals and in women, have failed to establish whether PRL directly inhibits FSH Received February 5, 1980; revised and accepted October 26,1981. *3rd Cattedra di Ostetricia e Ginecologia, Universita di Milano, Ospedali Civili, Brescia, Italia. tFarmitalia Carlo Erba, Milano, Italia. *8th Cattedra di Clinica Medica, Universita di Milano, Ospedale San RaffaeJe, Milano, Italia. §Reprint requests: Antonio Ettore Pontiroli, M.D., Ospedale San Raffaele, 20132, Milano, Italia. Vol. 37, No.3, March 1982
and LH release or interferes with the ovarian responsiveness to gonadotropins. In fact, some results indicate that PRL lowers LH release4 and the LH response to LH-releasing hormone (LHRH),2,5 while other data indicate that PRL primarily affects ovarian function. 6 However, using similar approaches, other authors have suggested that prolactin inhibits neither pituitary nor ovarian function. a, 7 It was reasonable to conceive that if PRL acts on the hypothalamus or on the pituitary to inhibit FSH and LH levels, then (1) a relationship (inverse) should exist at delivery between PRL levels and FSH and LH levels, and (2) any variation of PRL during the first few days of puerperium should be accompanied by a concordant or by an
FaIsetti et aI. PRL, FSH, and LH in puerperium and metergoline
397
r
inverse trend ofFSH and LH. These relationships were therefore evaluated in our study. Among the various attempts to stop puerperal lactation, two major drugs have been widely accepted: bromocriptine, a dopaminergic drug,3 and metergoline, an antiserotoninergic drug. s Both drugs inhibit PRL release 3, 9 and hence lactation in puerperal women3, 10 and in galactorrheic patients.1l, 12 In our study we have also examined PRL, FSH, and LH levels in puerperal, nonlactating women treated with metergoline. MATERIALS AND METHODS
Eighty healthy parturient women aged 18 to 33 years who had recently completed via vaginal delivery a full-term normal pregnancy were evaluated. Following a previous pregnancy, all the puerperae had given proof of adequate mammary activity. A blood sample was obtained 6 to 29 hours after delivery (day 2), all samples being collected at about 9:00 A.M. Thirty-six of the above puerperal women were followed up during a 5-day period (days 2 to 6): 24 of them could not breast-feed,their babies for nonendocrinologic medical reasons or for personal reasons and were treated with metergoline 8 mgl day (12 women) or 12 mg/day (12 women) in divided doses for 5 days; 12 additional puerperae breast-feeding their babies and receiving no treatment were chosen from the remaining 56 and were considered as controls. All these women were subjected to the blood samplings as indicated above and 48 and 96 hours later. Blood samples were taken after an overnight fast and at least 2 hours of bed rest, 3 hours after the last metergoline administration or the last suckling. After centrifugation, sera were stored at - 20° C until assayed by radioimmunoassay (RIA) for PRL,13 FSH,14 and LH 15 content. The antibody used in our radioimmunoassay for LH cross-reacts with ~-human chorionic gonadotropin (~-hCG); therefore, in some cases serum levels of subunit ~-hCG were evaluated by a specific antibody.16 In our hands, the interasSaY variations of RIAs were 7.0%, 6.8%, 8.0%, and 8.6%, for PRL, LH, FSH, and ~-hCG, respectively. The intraassay variations were 4.0%, 5.5%, 5.0%, and 4.4%. Recoveries of added doses were 99.8%,97.5%,98.0%, and 97.5%. In our laboratory the upper PRL level 398
in normally menstruating women is 20 ng/ml; FSH levels vary during the menstrual cycle from 525 to 4200 ng/ml (15 to 20 mIUlml); serum LH levels vary from 100 to 600 ng/ml (20 to 120 mIUI ml). Due to cross-reactivity between ~"hCG and LH, serum hCGILH levels greater than 104 ng/ml (2 x 103 mIU/ml) are easily found during puerperium or following first-trimester abortion. Statistical analysis was performed following logarithmic transformation of the original values, since it was possible to verify (see Results) that the distributions of data of PRL, FSH, and hCGI LH were log-normal. To evaluate the possible relationship existing in basal conditions between serum levels of PRL, FSH, and hCG/LH, pairwise correlations were computed. Next, an analysis of variance was carried out on the data of each group of subjects, in order to examine the linear and the quadratic regression of PRL, FSH, and hCG/LH values on the various 8
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~eUE~n~U Figure 1 Distribution of serum PRL, FSH, and hCG/LH levels in 80 puerperal women 6 to 29 hours following an uneventful vaginal delivery. On the left side, data are indicated in ngl ml as cumulative frequency curves, in probits; on the right side, data are indicated after log-transformation,
FaIsetti et aI. PRL, FSH, and LH in puerperium and metergoline
Fertility and Sterility
!~ \ ~
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no rEg"8S8iOn Y,,1.88-0.059(tOOMfX
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8 mg
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y.3.63..Q.t1(*o.o17)X'
y.~27-QC16(*o.ooerx
y,,18.84-2.16{t0268)x
Figure 2 Pattern of serum PRL, FSH, hCG/LH, and f3-hCG during the 5-day observation period in control subjects, breastfeeding women (e...._e), and in puerperae treated with metergoline, 8 mg/day ( x - x ) and 12 mg/day (0-0). Equations of regression lines of the four hormones are indicated. Standard errors of the regression coefficients are in parentheses. 0 = 0.05 < P < 0.1; 00 = P < 0.01; 000 = P < 0.001.
days. In order to test the significance due to the above sources of variability, the error variances represented respectively by the interaction linear x patients and quadratic x patients were used. RESULTS
Figure 1 shows the cumulative frequency curves of the PRL, FSH, and hCGILH levels observed in 80 puerperal women before starting breast-feeding or metergoline treatment. On the left side, probits are plotted against the values; on the right side, probits are plotted against log values. As one can see, the transformation to logarithms has eliminated the curvature indicating that data appear normalized after log-transformation. For this reason, analyses were carried out after log-transformation. PRL levels were significantly higher than in normally menstruating females; FSH levels were .lower than during the whole menstrual cycle. Serum LH levels varied from 430 to 10,200 ng/ml, represented for the most part by residual ~-hCG. In some cases, serum levels of ~-hCG (specific unit) and hCG/LH were evaluated and were found to vary from 74 to 367 mIU/ml and from 80 to 400 mIU/ml, respectively, indicating that LH levels in our puerperae were very low. No correlation was found between the values of the three hormones, considered in pairs (r always < 0.1, P always> 0.1). Figure 2 shows the pattern of each hormone during the 5-day observation period in 12 breastfeeding women and in 24 women treated with metergoline, either 8 or 12 mg/day. Prior to the start of breast-feeding or metergoline treatment, Vol. 37, No.3, March 1982
PRL and hCG/LH levels were superimposable and FSH levels were not significantly different in the three groups of puerperae. PRL remained steady in lactating women but sharply decreased in metergoline-treated puerperae. FSH remained steady in lactating women and in puerperae treated with 8 mg/day metergoline and showed a trend to decrease in puerperae treated with 12 mg/day metergoline. hCGILH levels promptly decreased in all groups of puerperae, ~-hCG showing a similar pattern. When a decrease of a given hormone was present, the linear regression was statistically significant, indicating a progressive and constant reduction of serum levels. No statistical difference was found between regression coefficients of PRL in metergoline-treated groups (8 versus 12 mg/day) nor ofhCG/LH in control versus treated groups, indicating that PRL was similarly affected by metergoline at the two dosages, while hCG/LH levels were not affected by metergoline. Metergoline fully prevented puerperal lactation in all women, no significant difference being noted between the two dosages employed. Following discontinuation of treatment, no rebound lactation was observed. DISCUSSION
It has been known for a long time that lactation,. whatever its origin, interferes with regular menstrual cycles. However, the exact mechanism through which lactation inhibits ovulation and the menstrual cycle is still a matter of debate; hypothetically, PRL might inhibit the normal activity of the hypothalamic-pituitary-ovarian axis by interfer~ng primarily with the function of the hypothalamus, the pituitary gland, or the ovaries. In agreement with previous reports, l in this study we have found that normal puerperal women exhibit, shortly after vaginal delivery, low serumFSH levels, thus justifying puerperal amenorrhea and infertility; LH levels were also low, hCG levels accounting for most of the hCG/LH levels observed. 1, 17 No significant correlations were found between PRL,FSH, and hCG/LH levels, considered in pairs, in 80 women prior to breast-feeding or to metergoline administration. Also, we found no relationship between the three hormones during the 5-day observation period in 12 lactating women. In fact, PRL and FSH levels remained steady, while hCGILH levels promptly decreased.
Falsetti et aI. PRL, FSH, and LH in puerperium and metergoline
399
This lack of relationship is in keeping with other studies showing that, in hyperprolactinemic states, the FSH and the LH responses to LH-RH can be normal and are not affected by the bromocriptine-induced reduction of PRL levels. 7 , 9 These data suggest that an elevated PRL release is not the cause for the reduced FSH and LH release that is commonly observed in puerperium, but rather suggest another interpretation: lactation, on the one hand, and the reduced release ofFSH and LH, on the other, might be two markers of a common (hypothalamic?) modification. This assumption· is supported by the fact that, in the puerperal rat, the suckling stimulus inhibits LH release, 5 even in the presence of low PRL levels, and by our finding that lactating puerperae show progressively decreasing LH levels, in spite of constant PRL levels. If PRL does not directly affect pituitary function, it is possible that hyperprolactinemia modifies the ovarian function, rendering the ovary less sensitive to exogenous stimulation; this assumption is supported by the fact that doses of gonadotropins greater than usual are required to induce ovarian estrogenic release in patients with elevated serum PRL levels. 7 Although our data indicate that PRL does not directly affect pituitary function, further studies are required. to clarify the nature of the PRL-gonadotropin relationship in lactation. Metergoline, probably through its antiserotonin activity,8 has already been shown to inhibit basal as well as stimulated PRL release,9 thus accounting for the inhibitory effect ofthe drug on puerperal lo and on pathologic l2 lactation. In our study we have confirmed the inhibitory effect of metergoline, at either 8 or 12 mg/day, on PRL release in· puerperal women, this effect being dramatically quick. Serum FSH levels tended to decrease in women treated with metergoline, at the higher dosage but not at the lower dosage. So far, no clear evidence of a serotonin-mediated modification of FSH release has been observed either in the experimental animal or in the human being. Therefore, it is possible that the removal ofthe suckling stimulus by itself is responsible for the declining ofFSH levels; however, the fact that the higher dosage of metergoline lowered FSH levels might be interpreted as evidence of a metergoline-mediated decrease of FSH release. Recently, some authors have suggested that metergoline inhibits PRL release through a dopaminergic, and not an antiserotoninergic mech400
anism, basing their conclusion on the similarity of action of metergoline and bromocriptine in acromegalic patients. l8 However, at variance :with metergoline, both ergotamine in the puerperal rat 5 and bromocriptine in puerperal women l9 elicit FSH release. In addition, in our subjects, metergoline did not affect hCG/LH release. Similarly, in a group of normal women many dopaminergic agents, but not metergoline, lowered serum LH levels. 20 Taken together, these data indicate that metergoline inhibits PRL release, probably through an antiserotoninergic, and probably not through a dopaminergic activity, and support the concept of a serotonin-mediated release of PRL in puerperal women. REFERENCES 1. Jaffe RB, Lee PA, Midgley AR Jr: Serum gonadotropins before, at the inception of, and following human pregnancy. J Clin Endocrinol Metab 28:1281, 1969 2. Miyake A, Tanizawa 0, Aono T, Kurachi K: Pituitary LH response to LH-RH during puerperium. Obstet Gynecol 51:37,1978 3. Del Pozo E, Varga L, Schults KD: Pituitary and ovarian response patterns to stimulation in the postpartum and in galactorrhea-amenorrhea. Obstet Gynecol 46:539, 1975 4. Grandison L, Hoson G, Chen HT, Advis J, Simpkins J, Meites J: Inhibition by prolactin of post-castration rise in LH. Neuroendocrinology 23:312, 1977 5. Lu KH, Chen HT, Huang HH, Grandison L, Marshall S, Meites J: Relation between prolactin and gonadotropin secretion in postpartum lactating rats. J Endocrinol 68:241, 1976 6. McNattyKP, Sawers RS, McNeilly AS: A possible role for prolactin in the control of steroid secretion by the human Graafian follicle. Nature (London) 250:653, 1974 7. Archer DF, Josimovich JB: Ovarian response to exogenous gonadotropins in women with elevated serum prolactin. Obstet Gynecol 48:155, 1976 8. Beretta G, Ferrini R, Glasser AH: 1,6-dimethyl-8-betacarbo benzil-oxy-aminomethy1-1 O-a-ergoline, a potent long-lasting 5-hydroxy-tryptamine antagonist. Nature (London) 207:421, 1965 9. Pontiroli AE, Castegnaro E, Vettaro MP, Viberti GC, Pozza G: Stimulatory effect of the dopa-decarboxylase inhibitor Ro 44602 on prolactin release: inhibition by L-dopa, metergoline, methysergide, and 2-br-alpha ergocriptine. Acta Endocrinol (Copenh) 84:36, 1977 10. Delitala G, Masala A, Alagna S, Devilla L, Lodico G, Lotti G: Metergoline in the inhibition of puerperal lactation. Br Med J 1:744, 1977 11. Del Pozo E, Varga L, Wyss H, Tolis G, Friesen H, Wenner R, Vetter L, Vettwiller A: Clinical and hormonal response to bromocriptine (CB-154) in the galactorrhea syndromes. J Clin Endocrinol Metab 39:18, 1974 12. Crosignani PG, Peracchi M, D'Alberton A, Lombroso GC, Trojsi L, Cammaneri G, Caccamo A, Attanasio AA, Reschini E: Different approaches to the treatment of hyperprolactinemic states. In Prolactin and Human Reproduction, Edited by PG Crosignani, C Robin. London, Academic Press, 1977, p 273
FaIsetti et aI. PRL, FSH, and LH in puerperium and metergoline
Fertility and Sterility
13. Sinha YN, Selby FW, Lewis UJ, Vanderlaan WP: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509, 1973 14. Midgley AR Jr:Radioimmunoassay: a method for human chorionic gonadotropin and human luteinizing hormone. Endocrinology 79:10,1966 15. Midgley AR Jr: Radioimmunoassay for human folliclestimulating hormone. J Clin Endocrinol Metab 27:295, 1967 16. Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet GynecoI132:113, 1972 17. Lahteenmii.ki P: The disappearance of HCG and return of pituitary function after abortion. Clin Endocrinol (Ox£) 9:101,' 1978
Vol. 37, No.3, March 1982
18. Chiodini PG, Liuzzi A, Muller EE, Botalla L, Cremascoli G, Oppizzi G, Verde G, Silvestrini F: Inhibitory effect of an ergoline derivative, metergoline, on GH and prolactin levels in acromegalic patients. J Clin Endocrinol Metab 43:356, 1976 19. Nader S, KjeldJM, Blair CM, Tooley P, Gordon H,'Fraser TR: A study of the effect ofbromocriptine on serum estradiol, prolactin and follicle-stimulating hormone levels in puerperal women. Br J Obstet Gynaecol 82:570, 1975 20. Pontiroli AE, Pellicciotta G, De Castro e Silva E, De Pasqua A, Girardi AM, Alberetto M, Pozza G: Interaction of dopaminergicand antiserotoninergic drugs in the control of prolactin and LH release in normal women. Acta Endocrinol (Copenh) 93:271, 1980
Falsetti et al. PRL, FSH, and LH in puerperium and metergoline
401
FERTILITY AND STERILITY Copyright c 1982 The American Fertility Society
A study of prolactin, follicle-stimulating hormone, and luteinizing hormone in puerperium: spontaneous variations and the effect of metergoline
Leopoldo Falsetti, M.D.* Anna Maria Voltolini, M.D.* Carmen Pollini, B.D.t Antonio Ettore Pontiroli, M.D.:j:§ Universita di Milano, Ospedali Civili, Brescia, ltalia, Ospedale San Raffaele, Milano, and Farmitalia Carlo Erba, Milano, ltalia
In 80 normal puerperae, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), including human chorionic gonadotropin (hCG/LH), and prolactin (PRL) levels were evaluated 6 to 29 hours after vaginal delivery. In these puerperae, PRL levels were higher and FSH levels were lower than in menstruating women; hCG/LH levels were very high, due to persisting hCG levels. The values of the three hormones showed a log-normal distribution, and no relationship was found between the three hormones considered in pairs. Thirty-six puerperae chosen from the above 80 were followed during a 5-day period: 24 were not able to breast-feed their babies and were treated with metergoline, an antiserotoninergic agent able to prevent puerperal lactation, 8 or 12 mg/day; 12 additional puerperae, nursing their babies, were evaluated as controls. In lactating women PRL and FSH levels remained steady during the observation period, while hCG/LH levels progressively decreased. Metergoline lowered PRL levels, when employed at both dosages, and FSH levels only at the higher dosage, without affecting the decline of hCG/LH levels. Since dopaminergic drugs are known to lower serum LH levels and not to affect or to increase FSH levels, our data indicate that metergoline might act through a mechanism of action different from dopaminergic drugs. Fertil Steril 37:397, 1982
The puerperium is characterized by lactation and by high prolactin (PRL) levels as well as by amenorrhea and by low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. 1-a Several studies performed so far, both in experimental animals and in women, have failed to establish whether PRL directly inhibits FSH Received February 5, 1980; revised and accepted October 26,1981. *3rd Cattedra di Ostetricia e Ginecologia, Universita di Milano, Ospedali Civili, Brescia, Italia. tFarmitalia Carlo Erba, Milano, Italia. *8th Cattedra di Clinica Medica, Universita di Milano, Ospedale San RaffaeJe, Milano, Italia. §Reprint requests: Antonio Ettore Pontiroli, M.D., Ospedale San Raffaele, 20132, Milano, Italia. Vol. 37, No.3, March 1982
and LH release or interferes with the ovarian responsiveness to gonadotropins. In fact, some results indicate that PRL lowers LH release4 and the LH response to LH-releasing hormone (LHRH),2,5 while other data indicate that PRL primarily affects ovarian function. 6 However, using similar approaches, other authors have suggested that prolactin inhibits neither pituitary nor ovarian function. a, 7 It was reasonable to conceive that if PRL acts on the hypothalamus or on the pituitary to inhibit FSH and LH levels, then (1) a relationship (inverse) should exist at delivery between PRL levels and FSH and LH levels, and (2) any variation of PRL during the first few days of puerperium should be accompanied by a concordant or by an
FaIsetti et aI. PRL, FSH, and LH in puerperium and metergoline
397
r
inverse trend ofFSH and LH. These relationships were therefore evaluated in our study. Among the various attempts to stop puerperal lactation, two major drugs have been widely accepted: bromocriptine, a dopaminergic drug,3 and metergoline, an antiserotoninergic drug. s Both drugs inhibit PRL release 3, 9 and hence lactation in puerperal women3, 10 and in galactorrheic patients.1l, 12 In our study we have also examined PRL, FSH, and LH levels in puerperal, nonlactating women treated with metergoline. MATERIALS AND METHODS
Eighty healthy parturient women aged 18 to 33 years who had recently completed via vaginal delivery a full-term normal pregnancy were evaluated. Following a previous pregnancy, all the puerperae had given proof of adequate mammary activity. A blood sample was obtained 6 to 29 hours after delivery (day 2), all samples being collected at about 9:00 A.M. Thirty-six of the above puerperal women were followed up during a 5-day period (days 2 to 6): 24 of them could not breast-feed,their babies for nonendocrinologic medical reasons or for personal reasons and were treated with metergoline 8 mgl day (12 women) or 12 mg/day (12 women) in divided doses for 5 days; 12 additional puerperae breast-feeding their babies and receiving no treatment were chosen from the remaining 56 and were considered as controls. All these women were subjected to the blood samplings as indicated above and 48 and 96 hours later. Blood samples were taken after an overnight fast and at least 2 hours of bed rest, 3 hours after the last metergoline administration or the last suckling. After centrifugation, sera were stored at - 20° C until assayed by radioimmunoassay (RIA) for PRL,13 FSH,14 and LH 15 content. The antibody used in our radioimmunoassay for LH cross-reacts with ~-human chorionic gonadotropin (~-hCG); therefore, in some cases serum levels of subunit ~-hCG were evaluated by a specific antibody.16 In our hands, the interasSaY variations of RIAs were 7.0%, 6.8%, 8.0%, and 8.6%, for PRL, LH, FSH, and ~-hCG, respectively. The intraassay variations were 4.0%, 5.5%, 5.0%, and 4.4%. Recoveries of added doses were 99.8%,97.5%,98.0%, and 97.5%. In our laboratory the upper PRL level 398
in normally menstruating women is 20 ng/ml; FSH levels vary during the menstrual cycle from 525 to 4200 ng/ml (15 to 20 mIUlml); serum LH levels vary from 100 to 600 ng/ml (20 to 120 mIUI ml). Due to cross-reactivity between ~"hCG and LH, serum hCGILH levels greater than 104 ng/ml (2 x 103 mIU/ml) are easily found during puerperium or following first-trimester abortion. Statistical analysis was performed following logarithmic transformation of the original values, since it was possible to verify (see Results) that the distributions of data of PRL, FSH, and hCGI LH were log-normal. To evaluate the possible relationship existing in basal conditions between serum levels of PRL, FSH, and hCG/LH, pairwise correlations were computed. Next, an analysis of variance was carried out on the data of each group of subjects, in order to examine the linear and the quadratic regression of PRL, FSH, and hCG/LH values on the various 8
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~eUE~n~U Figure 1 Distribution of serum PRL, FSH, and hCG/LH levels in 80 puerperal women 6 to 29 hours following an uneventful vaginal delivery. On the left side, data are indicated in ngl ml as cumulative frequency curves, in probits; on the right side, data are indicated after log-transformation,
FaIsetti et aI. PRL, FSH, and LH in puerperium and metergoline
Fertility and Sterility
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y.~27-QC16(*o.ooerx
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Figure 2 Pattern of serum PRL, FSH, hCG/LH, and f3-hCG during the 5-day observation period in control subjects, breastfeeding women (e...._e), and in puerperae treated with metergoline, 8 mg/day ( x - x ) and 12 mg/day (0-0). Equations of regression lines of the four hormones are indicated. Standard errors of the regression coefficients are in parentheses. 0 = 0.05 < P < 0.1; 00 = P < 0.01; 000 = P < 0.001.
days. In order to test the significance due to the above sources of variability, the error variances represented respectively by the interaction linear x patients and quadratic x patients were used. RESULTS
Figure 1 shows the cumulative frequency curves of the PRL, FSH, and hCGILH levels observed in 80 puerperal women before starting breast-feeding or metergoline treatment. On the left side, probits are plotted against the values; on the right side, probits are plotted against log values. As one can see, the transformation to logarithms has eliminated the curvature indicating that data appear normalized after log-transformation. For this reason, analyses were carried out after log-transformation. PRL levels were significantly higher than in normally menstruating females; FSH levels were .lower than during the whole menstrual cycle. Serum LH levels varied from 430 to 10,200 ng/ml, represented for the most part by residual ~-hCG. In some cases, serum levels of ~-hCG (specific unit) and hCG/LH were evaluated and were found to vary from 74 to 367 mIU/ml and from 80 to 400 mIU/ml, respectively, indicating that LH levels in our puerperae were very low. No correlation was found between the values of the three hormones, considered in pairs (r always < 0.1, P always> 0.1). Figure 2 shows the pattern of each hormone during the 5-day observation period in 12 breastfeeding women and in 24 women treated with metergoline, either 8 or 12 mg/day. Prior to the start of breast-feeding or metergoline treatment, Vol. 37, No.3, March 1982
PRL and hCG/LH levels were superimposable and FSH levels were not significantly different in the three groups of puerperae. PRL remained steady in lactating women but sharply decreased in metergoline-treated puerperae. FSH remained steady in lactating women and in puerperae treated with 8 mg/day metergoline and showed a trend to decrease in puerperae treated with 12 mg/day metergoline. hCGILH levels promptly decreased in all groups of puerperae, ~-hCG showing a similar pattern. When a decrease of a given hormone was present, the linear regression was statistically significant, indicating a progressive and constant reduction of serum levels. No statistical difference was found between regression coefficients of PRL in metergoline-treated groups (8 versus 12 mg/day) nor ofhCG/LH in control versus treated groups, indicating that PRL was similarly affected by metergoline at the two dosages, while hCG/LH levels were not affected by metergoline. Metergoline fully prevented puerperal lactation in all women, no significant difference being noted between the two dosages employed. Following discontinuation of treatment, no rebound lactation was observed. DISCUSSION
It has been known for a long time that lactation,. whatever its origin, interferes with regular menstrual cycles. However, the exact mechanism through which lactation inhibits ovulation and the menstrual cycle is still a matter of debate; hypothetically, PRL might inhibit the normal activity of the hypothalamic-pituitary-ovarian axis by interfer~ng primarily with the function of the hypothalamus, the pituitary gland, or the ovaries. In agreement with previous reports, l in this study we have found that normal puerperal women exhibit, shortly after vaginal delivery, low serumFSH levels, thus justifying puerperal amenorrhea and infertility; LH levels were also low, hCG levels accounting for most of the hCG/LH levels observed. 1, 17 No significant correlations were found between PRL,FSH, and hCG/LH levels, considered in pairs, in 80 women prior to breast-feeding or to metergoline administration. Also, we found no relationship between the three hormones during the 5-day observation period in 12 lactating women. In fact, PRL and FSH levels remained steady, while hCGILH levels promptly decreased.
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This lack of relationship is in keeping with other studies showing that, in hyperprolactinemic states, the FSH and the LH responses to LH-RH can be normal and are not affected by the bromocriptine-induced reduction of PRL levels. 7 , 9 These data suggest that an elevated PRL release is not the cause for the reduced FSH and LH release that is commonly observed in puerperium, but rather suggest another interpretation: lactation, on the one hand, and the reduced release ofFSH and LH, on the other, might be two markers of a common (hypothalamic?) modification. This assumption· is supported by the fact that, in the puerperal rat, the suckling stimulus inhibits LH release, 5 even in the presence of low PRL levels, and by our finding that lactating puerperae show progressively decreasing LH levels, in spite of constant PRL levels. If PRL does not directly affect pituitary function, it is possible that hyperprolactinemia modifies the ovarian function, rendering the ovary less sensitive to exogenous stimulation; this assumption is supported by the fact that doses of gonadotropins greater than usual are required to induce ovarian estrogenic release in patients with elevated serum PRL levels. 7 Although our data indicate that PRL does not directly affect pituitary function, further studies are required. to clarify the nature of the PRL-gonadotropin relationship in lactation. Metergoline, probably through its antiserotonin activity,8 has already been shown to inhibit basal as well as stimulated PRL release,9 thus accounting for the inhibitory effect ofthe drug on puerperal lo and on pathologic l2 lactation. In our study we have confirmed the inhibitory effect of metergoline, at either 8 or 12 mg/day, on PRL release in· puerperal women, this effect being dramatically quick. Serum FSH levels tended to decrease in women treated with metergoline, at the higher dosage but not at the lower dosage. So far, no clear evidence of a serotonin-mediated modification of FSH release has been observed either in the experimental animal or in the human being. Therefore, it is possible that the removal ofthe suckling stimulus by itself is responsible for the declining ofFSH levels; however, the fact that the higher dosage of metergoline lowered FSH levels might be interpreted as evidence of a metergoline-mediated decrease of FSH release. Recently, some authors have suggested that metergoline inhibits PRL release through a dopaminergic, and not an antiserotoninergic mech400
anism, basing their conclusion on the similarity of action of metergoline and bromocriptine in acromegalic patients. l8 However, at variance :with metergoline, both ergotamine in the puerperal rat 5 and bromocriptine in puerperal women l9 elicit FSH release. In addition, in our subjects, metergoline did not affect hCG/LH release. Similarly, in a group of normal women many dopaminergic agents, but not metergoline, lowered serum LH levels. 20 Taken together, these data indicate that metergoline inhibits PRL release, probably through an antiserotoninergic, and probably not through a dopaminergic activity, and support the concept of a serotonin-mediated release of PRL in puerperal women. REFERENCES 1. Jaffe RB, Lee PA, Midgley AR Jr: Serum gonadotropins before, at the inception of, and following human pregnancy. J Clin Endocrinol Metab 28:1281, 1969 2. Miyake A, Tanizawa 0, Aono T, Kurachi K: Pituitary LH response to LH-RH during puerperium. Obstet Gynecol 51:37,1978 3. Del Pozo E, Varga L, Schults KD: Pituitary and ovarian response patterns to stimulation in the postpartum and in galactorrhea-amenorrhea. Obstet Gynecol 46:539, 1975 4. Grandison L, Hoson G, Chen HT, Advis J, Simpkins J, Meites J: Inhibition by prolactin of post-castration rise in LH. Neuroendocrinology 23:312, 1977 5. Lu KH, Chen HT, Huang HH, Grandison L, Marshall S, Meites J: Relation between prolactin and gonadotropin secretion in postpartum lactating rats. J Endocrinol 68:241, 1976 6. McNattyKP, Sawers RS, McNeilly AS: A possible role for prolactin in the control of steroid secretion by the human Graafian follicle. Nature (London) 250:653, 1974 7. Archer DF, Josimovich JB: Ovarian response to exogenous gonadotropins in women with elevated serum prolactin. Obstet Gynecol 48:155, 1976 8. Beretta G, Ferrini R, Glasser AH: 1,6-dimethyl-8-betacarbo benzil-oxy-aminomethy1-1 O-a-ergoline, a potent long-lasting 5-hydroxy-tryptamine antagonist. Nature (London) 207:421, 1965 9. Pontiroli AE, Castegnaro E, Vettaro MP, Viberti GC, Pozza G: Stimulatory effect of the dopa-decarboxylase inhibitor Ro 44602 on prolactin release: inhibition by L-dopa, metergoline, methysergide, and 2-br-alpha ergocriptine. Acta Endocrinol (Copenh) 84:36, 1977 10. Delitala G, Masala A, Alagna S, Devilla L, Lodico G, Lotti G: Metergoline in the inhibition of puerperal lactation. Br Med J 1:744, 1977 11. Del Pozo E, Varga L, Wyss H, Tolis G, Friesen H, Wenner R, Vetter L, Vettwiller A: Clinical and hormonal response to bromocriptine (CB-154) in the galactorrhea syndromes. J Clin Endocrinol Metab 39:18, 1974 12. Crosignani PG, Peracchi M, D'Alberton A, Lombroso GC, Trojsi L, Cammaneri G, Caccamo A, Attanasio AA, Reschini E: Different approaches to the treatment of hyperprolactinemic states. In Prolactin and Human Reproduction, Edited by PG Crosignani, C Robin. London, Academic Press, 1977, p 273
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13. Sinha YN, Selby FW, Lewis UJ, Vanderlaan WP: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509, 1973 14. Midgley AR Jr:Radioimmunoassay: a method for human chorionic gonadotropin and human luteinizing hormone. Endocrinology 79:10,1966 15. Midgley AR Jr: Radioimmunoassay for human folliclestimulating hormone. J Clin Endocrinol Metab 27:295, 1967 16. Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet GynecoI132:113, 1972 17. Lahteenmii.ki P: The disappearance of HCG and return of pituitary function after abortion. Clin Endocrinol (Ox£) 9:101,' 1978
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18. Chiodini PG, Liuzzi A, Muller EE, Botalla L, Cremascoli G, Oppizzi G, Verde G, Silvestrini F: Inhibitory effect of an ergoline derivative, metergoline, on GH and prolactin levels in acromegalic patients. J Clin Endocrinol Metab 43:356, 1976 19. Nader S, KjeldJM, Blair CM, Tooley P, Gordon H,'Fraser TR: A study of the effect ofbromocriptine on serum estradiol, prolactin and follicle-stimulating hormone levels in puerperal women. Br J Obstet Gynaecol 82:570, 1975 20. Pontiroli AE, Pellicciotta G, De Castro e Silva E, De Pasqua A, Girardi AM, Alberetto M, Pozza G: Interaction of dopaminergicand antiserotoninergic drugs in the control of prolactin and LH release in normal women. Acta Endocrinol (Copenh) 93:271, 1980
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