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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 1 103-106
Copyright © 1998 by The Endocrine Society

Original Studies

Postpartum Hyperprolactinemia and Hyporesponsiveness of Growth Hormone (GH) to GH-Releasing Peptide

Francis de Zegher1, Bernard Spitz, Greet Van den Berghe1, Danielle Lemmens, Karin Vanweser, Katrien Keppens and Cyril Y. Bowers

Departments of Pediatrics, Obstetrics and Gynecology, and Intensive Care Medicine, University of Leuven (F.d.Z., B.S., G.V.d.B., D.L., K.V., K.K.), Leuven, Belgium; and the Department of Endocrinology, Tulane University (C.Y.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Francis de Zegher, Department of Pediatrics, University Hospital Gasthuisberg, 3000 Leuven, Belgium.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Human PRL and GH as well as their respective receptors have closely related origins. In peripartal women, physiological hyperprolactinemia is associated with a pronounced hyposomatotropism that remains to be fully characterized. Through paracrine mechanisms, PRL-secreting "pregnancy cells" may modulate the secretory function of somatotropes, which are known to express PRL receptors.

Within a randomized, placebo-controlled design, we examined GH responsiveness in 10 nonpregnant women and in 58 mothers either in early (median, 48 h; range, 42–54 h after delivery; all lactating) or late postpartum (median, 10 weeks; range, 3–25 weeks; lactating and nonlactating subgroups), using GH-releasing peptide-1 (GHRP-1; 100-µg iv bolus) as the GH secretagogue.

Baseline serum PRL concentrations were low and similar (median, 5 µg/L) in nonpregnant controls and nonlactating, late postpartum women and were elevated in lactating women, particularly in the early postpartum period (median, 102 µg/L), compared to those in the late postpartum period (median, 27 µg/L).

GHRP-1 elicited GH responses in all study groups; lactation was associated with lower and slower GH responses. Serum GH concentrations (20 min after GHRP-1 treatment) in controls (median, 78 µg/L) were 7- and 5-fold higher than those in lactating women studied, respectively, early or late postpartum. Baseline prolactinemia presented an inverse correlation with GH responsiveness; the higher baseline PRL concentration, the lower and the slower the GH response to GHRP-1.

GH hyporesponsiveness in postpartum women is herewith further characterized to include the GHRP pathway. The inverse relationship between baseline prolactinemia and GH responsiveness is consistent with the concept that pregnancy cells may exert, either directly or indirectly, an inhibitory effect on the secretory capacity of somatotropes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HUMAN PRL and GH have closely related origins (1). Historically, the distinction between PRL and GH was prompted by the study of the PRL-secreting "pregnancy cells," characterizing the pituitary during gestation (2, 3, 4). In the human, there are two phases of PRL hypersecretion, and they both culminate around birth: the fetal-neonatal phase (5, 6, 7) and the pregnant-lactating phase (2, 8). In both the perinatal and peripartal phases, pituitary PRL and GH present opposite secretory patterns. In the fetus, circulating PRL concentrations rise toward the end of gestation, and GH levels fall; immediately after birth, serum PRL levels decrease, and GH secretion is amplified (5, 9). Similarly, maternal prolactinemia increases with advancing gestation while serum levels of pituitary GH fall (and those of placental GH rise); postpartum, hyperprolactinemia gradually decreases in relation to lactation, and GH release recovers (2, 8, 10, 11, 12).

Human PRL and GH receptors belong to the same receptor family (13). PRL does not bind to the GH receptor, but GH binds to both GH and PRL receptors (14, 15). The recent finding that PRL receptors are expressed by normal human somatotropes (16) raised the interesting possibility that PRL may act as a paracrine regulator of GH secretion in the human, a mechanism that has previously been suggested to be operative in the rat (17). We tested this hypothesis in vivo by examining GH responsiveness at different stages of postpartum hyperprolactinemia (2, 8), using GH-releasing peptide-1 (GHRP-1) as a secretagogue. Postpartum prolactinemia is higher in the early than in the late postpartum period and is higher in lactating than in nonlactating mothers (2). GHRP-1 is a potent member of a novel class of synthetic GH secretagogues acting through distinct G protein-coupled receptors (18, 19).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The effects of placebo or GHRP-1 administration on GH and PRL secretion were studied, after informed consent was obtained, in four groups of women of similar age (range, 24–40 yr).

The control group consisted of healthy nonpregnant women (n = 10), including three mothers who were studied more than 6 months after last delivery. According to a randomized cross-over design, each woman of this group was studied twice (placebo and GHRP-1), with an interval of 1 month. At the time of study, women were either in the late follicular stage of a spontaneous cycle or between days 11–21 of a cycle timed by low dose estrogen/progestogen contraceptive medication.

In the three other groups, each woman was studied once (randomization for placebo or GHRP-1) after delivery of a healthy singleton infant. One group consisted of lactating women (n = 20) in the early postpartum phase (median, 48 h after delivery; range, 42–54 h). The two remaining groups consisted of lactating (n = 19) and nonlactating (n = 19) women in the late postpartum phase (range, 3–25 weeks after delivery; median, 9 and 11 weeks, respectively).

An indwelling venous catheter was placed approximately 20 min before the start of the study. Blood was sampled every 20 min, from 20 min before until 100 min after administration of the study compound. Placebo (5 mL saline) or GHRP-1 (100 µg GHRP-1 in 5 mL saline) was administered as iv bolus over approximately 2 min. All studies were started between 0800–1000 h, at least 2 h after a light breakfast. In the groups of lactating mothers, the last breastfeeding before the study was initiated approximately 90 min (±30 min) before bolus injection.

GHRP-1 (Ala-His-Dß-Nal-Ala-D-Trp-Phe-Lys-NH2) was provided by Dr. C. Y. Bowers. Serum GH concentrations were measured by RIA using a polyclonal antibody (20), and serum PRL was determined by immunoradiometric assay (Medgenix, Fleurus, Belgium). Student’s t test was used for statistical analysis; results were log transformed before analysis when appropriate. Bonferroni corrections were applied when multiple comparisons were performed. Statistical significance was considered to be reached at P < 0.05. Results are expressed as the mean ± SEM unless indicated otherwise.

The study protocol was approved by the ethical committee of the University of Leuven Medical School.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go depicts serum PRL and GH responses to placebo or GHRP-1 administration in the four study groups. Figure 2Go summarizes baseline PRL levels and displays a synopsis of GH responsiveness, as judged by serum GH concentrations 20 min after GHRP-1 injection.



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  		Figure 1. PRL (upper panels) and GH (lower panels) responses to placebo or GHRP-1 administration in nonpregnant women, early postpartum women, and lactating or nonlactating, late postpartum women (from left to right). Median serum concentrations are depicted with respective 25th percentile (P 25) and 75th percentile (P 75) values.

 



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  		Figure 2. Baseline prolactinemia (left panel) and serum GH concentrations 20 min after GHRP-1 administration (right panel) in nonpregnant women, early postpartum women, and lactating or nonlactating, late postpartum women. PP, Postpartum. *, P < 0.01.

 
As anticipated, lactation was associated with increased prolactinemia. Baseline serum PRL concentrations were similar in control women (5.1 ± 0.6 µg/L; median, 4.6 µg/L) and nonlactating, late postpartum women (6.3 ± 1.4 µg/L; median, 5.0 µg/L); both were lower (P < 0.005) than those in early postpartum women (140 ± 38 µg/L; median, 102 µg/L) and lactating, late postpartum women (26.5 ± 6.1 µg/L; median, 22.6 µg/L). Relatively small, but significant, PRL responses were detected 20 min after GHRP-1 administration in control, early postpartum, and nonlactating, late postpartum women (Fig. 1Go).

Significant GH responses to GHRP-1 were observed in all study groups (Fig. 1Go).

Lactation was associated with lower GH responses. Twenty minutes after GHRP-1 administration, GH concentrations in control women (75.9 ± 8.0 µg/L; median, 78.1 µg/L) were higher (P < 0.01) than those in early postpartum women (13.8 ± 3.2 µg/L; median, 11.2 µg/L) and lactating, late postpartum women (33.6 ± 9.9 µg/L; median, 15.3 µg/L; Fig. 2Go).

Lactation was also associated with slower GH responses, as detected by relatively high GH levels 40 min after GHRP-1 compared to 20 min after GHRP-1 administration; relative GH concentrations after 40 min in control women (69 ± 4% of the GH concentration after 20 min) and nonlactating, late postpartum women (76 ± 14%) were lower (P < 0.05) than those in early postpartum (106 ± 16%) and lactating, late postpartum women (107 ± 11%; Fig. 1Go). Baseline PRL concentrations correlated inversely with the amplitude and the swiftness of the GH responses; the higher the baseline PRL level, the lower the GH response (GH level 20 min after GHRP-1; r = 0.54; P < 0.0005) and the slower the GH response (GH levels 20 min vs. 40 min after GHRP-1; r = 0.36; P < 0.025) across the different study groups (n = 39).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Over the past quarter of a century, successive endocrine advances have lead to the delineation of the peripartal phase as a unique episode of pituitary hyposomatotropism in women. More than 2 decades ago, it was the distinction between human GH and PRL that lead to recognition of the puerperal hyposecretion of pituitary GH during lactation (8). A decade ago, the differentiation between pituitary and placental GH contributed to disclosure of the gradual disappearance of pituitary GH from the maternal circulation during the second half of gestation (11, 12). After the discovery of GHRH, the maternal somatotrope was found to be hyporesponsive to this endogenous GH secretagogue both at the end of gestation (21) and in the early postpartum period (22), when circulating insulin-like growth factor I concentrations are not elevated (23). More recently, GH-immunoreactive cells within the adenohypophysis of pregnant women were shown to be reduced in number and to contain a low amount of GH messenger ribonucleic acid, indicating that pituitary GH synthesis is inhibited during gestation (24). The present in vivo study further delineates somatotrope hyporesponsiveness to include the GHRP pathway, the association with lactation, and the correlation with prolactinemia.

The physiological postpartum phase and the pathological condition of microprolactinoma are both characterized by pronounced intrapituitary PRL secretion and are both associated with hypogonadotropic hypogonadism, which may be partially attributable to direct PRL actions, particularly as PRL receptors are known to be abundantly expressed by gonadotropes (16). The low PRL and GH responses elicited through the GHRP pathway in the postpartum phase are also comparable to those evoked in patients with microprolactinoma (25), suggesting that PRL may also have a suppressive effect on the secretory activity of somatotropes. It is plausible that PRL exerts its putative inhibitory effects, either directly or indirectly, on postpartum gonadotrope and somatotrope function through paracrine, rather than endocrine, pathways, as experimental hyperprolactinemia of extrapituitary origin does not appear to affect either LH or GH release (26).

In conclusion, the spectrum of GH secretagogues to which somatotropes of puerperal women appear to be hyporesponsive is herewith extended to GHRP. There appears to be an inverse relationship between postpartum prolactinemia and somatotrope responsiveness. It remains to be established whether this relationship is based on paracrine actions of PRL and, if so, by which direct or indirect mechanisms they are subserved.


   Acknowledgments
 
The authors thank the women who participated in this study, and the nursing staff of the Maternity and Infant Units for their cooperation. Prof. R. Bouillon, Mrs. Viviane Celis, and Mrs. Myriam Smets are acknowledged for PRL and GH measurements, and Prof. K. T. Kovacs (Toronto, Canada) for critical manuscript review.


   Footnotes
 
1 Clinical Research Investigators with the Fund for Scientific Research, Flanders, Belgium. Back

Received August 13, 1997.

Revised September 17, 1997.

Accepted September 23, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Miller WL, Eberhardt NL. 1983 Structure and evolution of the growth hormone gene family. Endocr Rev. 4:97.[CrossRef][Medline]
  2. Friesen HG. 1978 Human prolactin. Ann R Coll Physicians Surg Can. 11:275–281.
  3. Scheithauer BW, Sano T, Kovacs KT, Young Jr WF, Ryan N, Randall RV. 1990 The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc. 65:461–474.[Medline]
  4. Friesen HG. 1995 The discovery of human prolactin: a very personal account. Clin Invest Med. 18:66–72.[Medline]
  5. Kaplan SL, Grumbach MM, Aubert ML. 1976 The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent Prog Horm Res. 32:101.
  6. Gluckman PD, Grumbach MM, Kaplan SL. 1981 The neuroendocrine regulation and function of growth hormone and prolactin in the mammalian fetus. Endocr Rev. 2:363.[CrossRef][Medline]
  7. Mulchahey JJ, Di Blasio AM, Martin MC, Blumenfeld Z, Jaffe RB. 1987 Hormone production and peptide regulation of the human fetal pituitary gland. Endocr Rev. 8:406.[CrossRef][Medline]
  8. Noel GL, Suh HK, Frantz AG. 1974 Prolactin release during nursing and breast stimulation in postpartum and nonpostpartum subjects. J Clin Endocrinol Metab. 38:413–423.[Medline]
  9. de Zegher F, Devlieger H, Veldhuis JD. 1993 Properties of growth hormone and prolactin hypersecretion by the human newborn on the day of birth. J Clin Endocrinol Metab. 76:1177–1181.[Abstract]
  10. Spellacy WN, Buhi WC. 1969 Pituitary GH and PL levels measured in normal term pregnancy and at the early and late postpartum periods. Am J Obstet Gynecol. 15:888–896.
  11. Hennen G, Frankenne F, Closset J, Gomez F, Pirens G. 1985 A human placental GH: increasing levels during second half of pregnancy and pituitary GH suppression as revealed by monoclonal antibody radioimmunoassay. Int J Fertil. 30:27.[Medline]
  12. Frankenne F, Closset J, Gomez F, Scippo ML, Smal J, Hennen G. 1988 The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab. 66:1171.[Abstract]
  13. Kelly PA, Djiane J, Postel-Vinay MC, Edery M. 1991 The prolactin/growth hormone receptor family. Endocr Rev. 12:235–251.[CrossRef][Medline]
  14. Leung DW, Spencer SA, Cachianes G, et al. 1987 Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 330:537.[CrossRef][Medline]
  15. Somers W, Ultsch M, De Vos AM, Kossiakoff AA. 1994 The x-ray structure of a growth hormone-prolactin receptor complex. Nature. 372:409–410.[CrossRef][Medline]
  16. Jin L, Qian X, Kulig E, et al. 1997 Prolactin receptor messenger ribonucleic acid in normal and neoplastic human pituitary tissues. J Clin Endocrinol Metab. 82:963–968.[Abstract/Free Full Text]
  17. Morel G, Ouhtit A, Kely PA. 1994 Prolactin receptor immunoreactivity in rat anterior pituitary. Neuroendocrinology. 59:78–84.[Medline]
  18. Bowers CY. 1994 On a peptidomimetic growth hormone-releasing peptide. J Clin Endocrinol Metab. 79:943–949.[Abstract]
  19. Howard AD, Feighner SD, Cully DF, et al. 1996 A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 273:974–977.[Abstract]
  20. Bouillon R, De Moor P. 1974 Heterogeneity of human growth hormone in serum. Ann Endocrinol (Paris). 35:606–613.[Medline]
  21. de Zegher F, Vanderschueren-Lodeweyckx M, Spitz B, et al. 1990 Perinatal growth hormone (GH) physiology: effect of GH-releasing factor on maternal and fetal secretion of pituitary and placental GH. J Clin Endocrinol Metab. 77:520–522.
  22. de Leo V, Lanzetta D, d’Antona D, Latessa AM, Petraglia F. 1992 Control of growth hormone secretion during the postpartum period. Gynecol Obstet Invest. 33:31–35.[CrossRef][Medline]
  23. Breier BH, Milsom SR, Blum WF, Schwander J, Gallaher BW, Gluckman PD. 1993 Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women. Acta Endocrinol (Copenh). 129:427–435.[Medline]
  24. Stefaneanu L, Kovacs K, Lloyd RV, et al. 1992 Pituitary lactotrophs and somatotrophs in pregnancy: a correlative in situ hybridization and immunocytochemical study. Virchows Arch [Zellpathol]. 62:291–296.
  25. Ciccarelli E, Grottoli S, Razzore P, et al. 1996 Hexarelin, a synthetic growth hormone releasing peptide, stimulates prolactin secretion in acromegalic but not in hyperprolactinaemic patients. Clin Endocrinol (Oxf). 44:67–71.[CrossRef][Medline]
  26. Adler RA, Krieg RJ, Farrell ME, Deiss WP, MacLeod RM. 1991 Characterization of a new animal model of chronic hyperprolactinemia. Metabolism. 40:286–291.[CrossRef][Medline]



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