Original Paper Gynecol Obstet Invest 1992;33:31-35

Departments of Obstetrics and Gynecology, Universities of Siena and Modena, Italy

KeyWords Growth hormone Growth hormone releasing hormone Somatostatin Dopamine Opioid peptides Postpartum period lactation

Control of Growth Hormone Secretion during the Postpartum Period

Abstract The postpartum period is characterized by high levels of circulating steroids which condition hypothalamo-pituitary activities. In pregnancy growth hor­ mone (GH) levels are greatly increased and lack pulsatility. In order to investi­ gate the behavior of GH during the postpartum period, the GH response to GH-relcasing hormone stimulation (50 and 100 pg), to amphetamine, a dopa­ mine receptor agonist, and to FK 33-824. an opiate receptor agonist, was investigated in women during the first 5 days after delivery. In all groups GH responses were significantly lower (p < 0.01) than in normal women studied during the early follicular phase. FK-33-824-induced GH release was similar in postpartum and control women. These results demonstrate reduced pitu­ itary GH response to GH-releasing hormone and to amphetamine in women during the postpartum period, confirming the peculiarity of the hypothalamopituitary component.

Introduction Synthesis and pulsatile secretion of growth hormone (GH) by pituitary somatotrophes is controlled by the interaction between GH-releasing hormone (GH-RH) and somatostatin, both secreted by the hypothalamus. Neurotransmitters (dopamine) and neuropeptides (opi­ oids) also increase GH release under normal conditions in humans [1], Factors such as nutrition, physical exercise, stress, insomnia, age, and reproductive state can influence the release of GH from the pituitary [2, 3]. Sex steroids are regarded as capable of stimulating GH secretion [4], The postpartum period is important for the induction of lactation. It follows pregnancy with its high levels of

Received: April 22. 1991 Accepted: July 16. 1991

circulating steroids which continue to condition hypo­ thalamo-pituitary activity [5-7], The importance of high prolactin (Prl) levels during this period is well known. Increasing during pregnancy, plasma Prl levels reach a maximum before delivery [8, 9], The best-known action of Prl in humans is the induction and maintenance of lac­ tation [10, 11], Prl secretion is inhibited by dopamine (DA) release by T1DA system neurons. Reduced secretion of DA is considered to be the main factor responsible for pathological and physiological hyperprolactinemia [12], Prl and GH have certain similarities: they originate from a common pituitary precursor [13], The secretion of both hormones is influenced by DA and opioid peptides. GH is stimulated, whereas Prl is inhibited by DA [14], and

Dr. Vincenzo Dc Leo Istituto di Clínica Ostctrica e Ginecológica Univcrsitá di Siena Via P. Mascagni 46.1-53100 Siena (Italy)

© 1992 S. Karger AG. Basel 0378-7346/92/0331-0031 $2.75/0

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Vincenzo De Leoa Danila Lanzettaa Donato D ’Antona* Andrea Maietla Latessab Felice Petragliab

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Fig. 1. GH responses to 50 pg GH-RH in 6 puerperal women and 5 controls.

Fig. 2. GH responses to lOOpg GH-RH in 8 puerperal women and 6 controls.

opioids cause the rapid release of both hormones [ 15]. In pregnancy, plasma concentrations of pituitary GH are difficult to distinguish from GH of placental origin [16, 17] and are characterized by loss of the pulsatile pattern during the 24-hour period [18]. There are no data in the literature on the behavior of GH during the postpartum period. Accordingly, we studied the GH response to GHRH, to amphetamine, a DA receptor agonist, and to FK 33-824, an opiate receptor agonist, in a group of women during the postpartum period.

and 5 controls received a lower dose of GH-RH (50 pg). After two basal blood samples (-15 and 0 min), the tests were performed at 8.30 h by cannulation of a forearm vein and lasted 2 h from the GHRH bolus, with blood sampling every 15 min for the first hour and every 30 min thereafter. Amphetamine (7.5 or 15 mg; Recordati, Milan, Italy) was infused over 1 h. In 6 controls and 6 puerperal women two dose regimens of amphetamine diluted in 100 ml 0.9 N saline solution were used. After two basal blood samples (-30 and 0 min) amphetamine was infused from 0 to 60 min and blood samples were taken at 15-min intervals for 90 min and every 30 min thereaf­ ter. FK 33-824,0.5 mg i.v. (z/-ala 2,McPhc 4,Mct(0)-5-al-cnkcphalin: Sandoz, Basel, Switzerland) was given to 6 puerperal women and 6 controls. After two basal blood samples (-15 and 0 min), the test was performed at 8.30 h after cannulation of a forearm vein and lasted 2 h from the FK 33-824 bolus, with blood sampling every 15 min for the first hour and every 30 min thereafter.

Materials and Methods Subjects Informed consent of the subjects participating in the study was obtained. The subjects were 26 women in the postpartum period (puerperal subjects; 23-32 years old, body weight 51-56 kg) and 23 normal women with regular menstrual cycles (21-20 years old, weighing 49-56 kg). All of the former group had a normal pregnancy (40 weeks), labor, and delivery. The study was performed during the 1st week after delivery and during the early follicular phase in con­ trols. Experimental Protocol GH-RH (1-44) (100 pg; UCB-Bioproducts, Belgium) was given to 8 puerperal women and 6 controls. A further 6 puerperal women


Radioimmunoassay Plasma GH concentrations were measured by double-antibody radioimmunoassay in all samples. Radim (Rome, Italy) kits were used. The samples were assayed in duplicate at two dilutions. All samples from a given subject were assayed together. Quality control pools at low, normal, and high GH levels were present in each assay. The assay sensitivities were 1.5 ng/ml for GH. Inter- and intra-assay coefficients of variation were 5.0 and 2.5%. Statistical Analysis The results were expressed as absolute values (ng/ml). Statistical analysis of the results was performed using Student’s t test for the comparison of different groups.

Dc Leo/Lanzetta/D’Antona/ Latessa/Petraglia

Growth Hormone during the Postpartum Period

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GH ng/ml 10



0 Fig. 3. GH responses to 7.5 and 15 mg amphetamine in puerperal women and con­ trols.

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180 min

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Results Basal plasma GH levels were similar in controls and puerperal women (2.6 ± 1.2 vs. 2.3 ± 0.9 ng/ml). The pattern of GH after administration of 50 pg GHRH is shown in figure 1. In puerperal women GH-RH stimulation induced an increase which was significantly lower (p < 0.01) than that observed in normal women, with a peak of 18 ± 4 ng/ml at 30 min in controls as com­ pared with 6.5 ± 1.3 ng/ml in puerperal women.


60 Time


120 min

Figure 2 shows the pattern of GH after administration of 100 pg of GH-RH. Again, the stimulus of GH-RH induced a significantly greater increase in controls than in puerperal women (p < 0.01). The maximum increment was reached at 30 min in both groups, with levels of 25 ± 3.2 ng/ml in controls and 7.8 ± 0.5 ng/ml in puerperal women. The patterns of GH after infusion of 7.5 or 15 mg amphetamine did not change in the puerperal women, whereas in the control group they showed a significant


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Fig. 4. GH responses to 0.5 mg FK 33824 in puerperal women and controls.

increase, reaching a peak after 30 min in the women receiving 7.5 mg amphetamine and after 60 min in those who received 15 mg (fig. 3). After FK 33-824. the pattern of GH showed a similar significant increase in puerperal subjects and in controls (fig. 4). The maximum increment was reached at 15 min in the controls with levels of 11.6 ± 1.3 ng/ml and at 30 min in puerperal women with levels of 12 ± 2.3 ng/ml.

Discussion The GH-RH test and amphetamine or FK 33-824 administration provided much information about the functional state of the hypothalamo-pituitary axis during the postpartum period. Our findings showed that there is a smaller GH response to GH-RH or amphetamine in puerperal women than in controls. One of the possible explanations of pituitary somatotroph hyporesponsiveness to GH-RH and amphetamine during the postpartum period is the protraction of the state of pituitary hypofunction present in pregnancy, as shown by the absence of GH response to GH-RH in pregnant women at term [ 19] and after insulin or arginine stimulation [20, 21 ]. There is evidence of an absence of GH pulsatility and the existence of high basal levels of GH during the 3rd trimester of pregnancy, suggesting that the GH present is of placental origin [22], This excessive production of placental GH may inhibit the pituitary function by direct negative feed­ back on pituitary somatotroph cells, at the same time inducing increased production of hypothalamic somato­ statin. Whatever the inhibitory mechanism, it persists during the early postpartum period. Increased production of somatostatin may inhibit the GH response even at the GH-RH dose of maximum stimulation, as in our puer­ peral subjects. The dopaminergic system induces an in­

crease in GH secretion by inhibition of the activity of somatostatin. The reduced dopaminergic tonus in puer­ peral women is evident from the high Prl levels and their significant reduction after administration of direct and indirect dopamine agonists [23-25]. The GH hyporesponsiveness to the stimulation tests observed in our sub­ jects may depend on the presence of many secretory peaks of GH which occur during suckling. These may act by a short feedback on GH release and by stimulating the release of somatostatin [15], Much evidence suggests that the neuroendocrine mechanism responsible for GH and Prl release during suckling depends mainly on increased opioid tonus [26, 27], The stimulatory action of the opioid system on GH is further confirmed by the increase in GH observed by us after administration of FK 33-824 in puerperal women and controls. The opioid system seems to be able to evoke a greater release of GH in puerperal women than can GHRH and amphetamine. This suggests that the stimulatory action of the opioid system on GH levels undergoes a fur­ ther reduction by the dopaminergic system rather than being controlled by GH-RH. The concomitant Prl peak evoked by suckling confirms the further reduction in dopaminergic tonus [28, 29], The present results confirm the peculiarity of the post­ partum period as far as pituitary' function is concerned, including the component of the somatotroph cells. This period is characterized by a reduced GH response to GHRH, as in growth deficit and other pathologies associated with impaired GH secretion [30], It is also possible that GH plays an important role in the induction and maintenance of lactation. The GH stimulatory tests, especially the GH-RH test, might help to clarify this role if performed in puerperal women before lactation begins and in women with inadequate milk production.



5 De Leo V, Celia SG, Camanni E, Genazzani AR. Muller EE: Prolactin lowering effect of amphetamine in normoprolactinemic subjects and in physiological and pathological hyper­ prolactinemia. Horm Mctab Res 1983:15:439. 6 Petraglia F, De Leo V. Sardelli S. Mazzullo G. Gioffrè WR. Genzzani AR. D'Antona N: Pro­ lactin changes after administration of agonist and antagonist dopaminergic drugs in puer­ peral women. Gynecol Obsiet Invest 1987:23: 103.

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7 Muller EE, Cavagnini F. Martinez-Campos A, Maraschini C, Giovannini P, Novclli A. De Leo V: Dynamic testing of prolactin and growth hormone secretion in patients with neu­ roendocrine disorders. Acta Endocrinol (Copenh) 1984:107:155. 8 Tyson JE, Hwang P. Guyda H. Friesen HG: Studies of prolactin secretion in human preg­ nancy. Am J Obstet Gynecol 1972; 113:14. 9 Rigg LA, Yen SSC: The pattern of increase in circulating prolactin levels during human ges­ tation. Am J Obstet Gynecol 1977; 129:454.

Growth Hormone during the Postpartum Period

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1 Muller EE: Neural control of somatotrope function. Physiol Rev 1987:67:962. 2 Gelato MC. Merriam GR: Growth hormone releasing hormone. Annu Rev Physiol 1986:48: 569. 3 Frohman LA. Jansson JO: Growth hormone releasing hormone. EndocrRev I986;7:223. 4 Ho K.Y, Evans WS. Blizzard RM, Veldhuis JD. Merriam GR. Samojlik E, Furlanetto R. Rogol AD, Kaiser DL. Thorner MO: Effects of sex and age on the 24 h profile of GH secretion in man: Importance of endogenous estradiol con­ centrations. J Clin Endocrinol Metab 1987:64: 51.

18 Eriksson L, Frankenne F. Eden S. Hcnnen G. Von Schoultz B: Growth hormone 24-h serum profiles during pregnancy. Lack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol 1989:96:949. 19 De Zegher F. Vanderschucren-Lodeweyckx M. Spitz B. Faijerson Y. Blomberg F. Beckers A. Hcnnen G, Frankenne F: Perinatal growth hor­ mone (GH) physiology: Effect of GH-releasing factor on maternal and fetal secretion of pitu­ itary and placental GH. J Clin Endocrinol Metab 1990:77:520. 20 Artenisio AC. Volpe A, Ragonese F. Maccarone G. Forte F, Consolo F: Behaviour of hPé and GH plasmatic rate in pregnant women at different times of pregnancy during dymanic tests. Horm Metab Res 1980:12:205. 21 Yen SSC. Vale P. Tsai CC: Impairment of growth hormone secretion in response to hypoglvcemia during early and late pregnancy. J Clin Endocrinol Metab 1970:31:29. 22 Henne G. Frankenne F. Closset J. Gomez F. PircnsG, El Khayat N: A human placental GH: Increasing levels during second half of preg­ nancy with pituitary GH suppression as re­ vealed by monoclonal antibody radioimmu­ noassays. Int J Fertil. 1985:30:27. 23 Sakar DK, Gottschall PE. Meitcs J: Decline of tuberoinfundibular dopaminergic function resuiting from chronic hyperprolactinemia in rats. Endocrinologyy 1984:115:1269.

24 Camanni F, Gcnazzani AR. Massara F, De Leo V. Molinatti GM. Muller EE: Prolactin respon­ siveness to nomifensine in patients with hyper­ prolactinemia of tumorous or uncertain etiolo­ gy. J Clin Endocrinol 1980:51:65. 25 Camanni F. Gcnazzani AR, Massara F, l a Rosa R. Cocchi D, Muller EE: Prolactin releas­ ing effect of domperidonc in normoprolactincmic and hyperprolactinemic subjets. Neurocndocrinology 1980:30:2. 26 Miki N. Sonntag WE. Forman LJ, Meitcs J: Suppression by naloxone of rise in plasma growth hormone and prolactin induced by suckling. Proc Soc Exp Biol Med 1981:168: 330. 27 Shaar CJ. Clemens JA: The effects of opiate agonists on growth hormone and prolactin re­ lease in rats. Fed Proc 1980:39:2539. 28 Casanueva F. Spampinato S. Locatelli V, Betti R, Cocchi D. Ferri S, Muller EE: Prolactin and growth-hormone releasing effect of enkepha­ lins. Adv Physiol Sci 1981:14:303. 29 Casanueva F, Betti R, Cocchi D. Chieli T, Mantegazza P. Muller EE: Proof for histaminergic but not for adrenergic involvement in the growth-hormone releasing effect of an enkeph­ alin analog in the dog. Endocrinology 1981; 108:157. 30 Tadano K. Hizuka N, Shizume K Asakawa K, Myakawa M. Hirosen N. Shibasalit K. Ling NC: Plasma growth hormone (GH) response to GH.releasing factor in normal children with short stature and patients with pituitary dwarf­ ism. J Clin Endocrinol Metab 1984:58:236.


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10 Martin RH: The place of PRL in human lacta­ tion. Clin Endocrinol (0 x 0 1983:18:295. 1 1 Howie PW, McNelly AS. McArdlc T. Smart L. Houston M: The relationship between suck­ ling-induced prolactin response and lactogenesis. J Clin Endocrinol Mctab 1980:50:670. 12 Crosignani PG. Robin B: Endocrinology of Human Infertility: New Aspects. London. Aca­ demic Press, 1981. 13 Saunders A. Terry LC, Aude! J. Brazeau P. Martin JB: Dynamic studies of growth hor­ mone and prolactin secretion in the female rat. Neuroendocrinology 1976:21:193. 14 Boyd AE. Lebovitz HE. Pfeiffer JB: Stimula­ tion of human growth hormone secretion by L dopa. N Engl J Med 1970:283:1425. 15 Wehrenberg WB. Gaillard RC: Neuroendo­ crine mechanisms regulating growth hormone and prolactin secretion during lactation. Endo­ crinology 1989:124:464. 16 Hennen G. Frankennc F. Closset J: Mono­ clonal antibody to growth hormone: The dis­ covery of a new variant, human placental growth hormone. Serono Symp Publ Raven Press 1985:30:29. 17 Frankenne F. Closset J. Gomez F. Scippo ML. Smal J. Hennen G: The physiology of growth hormones (GHs) in pregnant women and par­ tial characterization of the placental GH vari­ ant. J Clin Endocrinol Metab 1988:66:1171.

Control of growth hormone secretion during the postpartum period.

The postpartum period is characterized by high levels of circulating steroids which condition hypothalamo-pituitary activities. In pregnancy growth ho...
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