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

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

View larger version (14K): [in this window] [in a new window]   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.

View larger version (24K): [in this window] [in a new window]   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.

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

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. 2).

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. 1). 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.

Received August 13, 1997.

Revised September 17, 1997.

Accepted September 23, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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