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Neuroendocrine and Reproductive Functions in Male Mice with Targeted Disruption of the Prolactin Gene¹

Department of Physiology, Southern Illinois University School of Medicine (R.W.S., V.C., A.B.), Carbondale, Illinois 62901-6512; and the Department of Physiology and Biology, University of Cincinnati (N.H., W.Z.), Cincinnati, Ohio 45267-0576

Address all correspondence and requests for reprints to: Dr. R. W. Steger, Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois 62901-1625. E-mail: rsteger{at}som.siu.edu

	Abstract

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Mice with a targeted disruption (knock-out) of the PRL gene (PRL-KO) were used to study the physiological role of PRL in the control of male neuroendocrine functions related to reproduction. Compared with normal males, PRL-KO mice had significant reductions in median eminence dopamine content, plasma LH levels, LH and FSH secretion in vitro (per mg pituitary), and weights of seminal vesicles and ventral prostate. PRL was not detectable in incubation medium with pituitaries from PRL-KO mice. No alterations were detected in PRL-KO mice in median eminence norepinephrine, plasma testosterone levels, or testosterone release (per mg testis) in vitro with or without LH. No differences were detected in PRL-KO vs. normal male mice in the interval from housing with normal female mice until conception, rate of pregnancy, or the number of live pups per litter. Pituitary weight in PRL-KO mice was increased (1.78 ± 0.22 vs. 3.35 ± 0.20 mg; P < 0.001), presumably due to reduced feedback inhibition and hypertrophy and/or hyperplasia of nonfunctional lactotrophs. These results indicate that the absence of PRL reduces pituitary LH release, attenuates median eminence dopaminergic activity, and affects the growth of seminal vesicles and ventral prostate. Although it was previously shown that PRL can repair the reproductive defect in male pituitary dwarf mice, our current results imply that the PRL deficiency alone is not sufficient to cause male infertility, although there are obvious alterations in reproductive neuroendocrine function in PRL-KO males.

	Introduction

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THE EFFECTS of pathological elevation of peripheral PRL levels, hyperprolactinemia, on male reproductive function in the human and in several species of experimental animals have been characterized in considerable detail (1, 2, 3, 4). In contrast, the normal role of physiological levels of PRL in the male is much less clearly defined because models of PRL deficiency are limited. In the mouse, congenital PRL deficiency caused by recessive mutations at the pit-1 (Snell dwarf; dw) or prophet of pit-1 (Ames dwarf; df) loci is associated with reduced plasma gonadotropin and testosterone (T) levels, reduced levels of testicular LH and PRL receptors (PRL-R), and severe suppression of fertility (5, 6, 7, 8). These deficits can be partially corrected by PRL replacement therapy (5, 6, 8, 9). Although these findings suggest an important role of PRL in male reproductive development and function, their interpretation is greatly complicated by the combined deficiency of GH and TSH as well as PRL in both Snell and Ames dwarf mice (10, 11).

Targeted gene disruption (knock-out) offers new possibilities for defining the physiological roles of hormones and other chemical messengers. Disruption of PRL signaling by knocking out the PRL-R gene resulted in some delay of male fertility without producing any obvious abnormalities in the male reproductive system (12) (Kelly, P., personal communication). Animals with a targeted disruption of the PRL gene (PRL-KO mice) are viable, and initial studies detected no abnormalities in male reproductive functions of these animals (13, 14). The present studies were undertaken to characterize neuroendocrine functions related to reproduction in PRL-KO mice compared with those in their normal siblings.

	Materials and Methods

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The animals were produced by crossing PRL-KO (-/-) males with phenotypically normal (N; +/-) females. The progeny was classified as PRL-KO or N by PCR analysis of DNA extracted from tail clippings (14). Sixteen PRL-KO and nine N animals were studied. All animal protocols were approved by the local committee on animal care. After reaching adulthood (2–3 months of age), each male was placed in a cage with two normal young adult virgin females. The females were checked daily for birth of litters, the numbers of live and dead pups were recorded, and females with litters were removed from the male’s cage. Six weeks after placing the males with the females (i.e. 2.5–3 weeks after most of the females had been removed), the males were moved to a laboratory at 0645 h and, starting 1.5 h later, were anesthetized with ether, bled by cardiac puncture, and killed by decapitation. The blood plasma was saved for measurements of LH and T by RIAs previously validated for the use in mouse plasma (7). At the time of death, the brain was rapidly removed, and the median eminence was dissected free and frozen, as was the remaining brain for subsequent determinations of DA and norepinephrine (NE) content by HPLC with electrochemical detection (15). Before assay, the brains were allowed to thaw partially to allow dissection of the medial basal hypothalamic area. This area consisted of a tissue block 2.0 mm deep extending from the caudal border of the optic chiasm to the rostral margin of the mammillary bodies and laterally to the hypothalamic sulci. The pituitaries were weighed, cut in half, and used for determinations of LH, FSH, and PRL contents or were incubated for 1 h in medium 199 after a 1-h preincubation (16). The levels of LH, FSH, and PRL in the media were measured by RIAs. The testes were weighed, decapsulated, preincubated for 30 min, and incubated for 4 h in 2 ml Krebs-Ringer-bicarbonate buffer containing glucose in an atmosphere of 95% oxygen-5% carbon dioxide in the presence of 0, 2.5, or 12.5 ng ovine LH (oLH NIH-26)/ml, and the levels of T in the media were measured by RIA. The results of RIAs were expressed in terms of NIH standards: LH RP-3 for LH, FSH RP-2 for FSH, and AFP-6476C for PRL. In each study, all samples were processed in the same assay, and the intraassay coefficients of variation were 4.99% for T, 2.84% for plasma LH, and 3.3% for PRL.

The male accessory reproductive glands, seminal vesicles (SV), coagulating glands, and ventral prostate (VP), were removed and weighed (SV and coagulating glands were weighed both with and without their secretions). The epididymides as well as the liver, spleen, and adrenals were also removed and weighed.

The significance of the differences between the values measured in PRL-KO and N mice was calculated using Student’s t test.

	Results

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Fertility
All of the PRL-KO and N males were fertile. Seventeen of 18 females mated to N males delivered litters, with 83% of the litters arriving within 24 days after placing the females with the male. Thirty-one of 32 females mated to PRL-KO males delivered litters, with 88% of the litters arriving within 24 days after mating. The number of live pups per litter did not differ between the 2 groups (9.68 ± 0.39 and 10.06 ± 0.63 for PRL-KO and N males, respectively).

Organ weights
There were no significant differences between PRL-KO and N animals in body weight or in the weights of the testes, epididymides, or coagulating glands. The weights of the SV and VP were significantly reduced in PRL-KO compared with those in N mice. In contrast, the weight of the pituitary was increased by approximately 100% in PRL-KO males. The weight of the liver was significantly reduced in PRL-KO animals, and there were no significant differences in the weights of the spleen, or adrenals (Table 1). The results of histological analysis of multiple organs from PRL-KO animals from this same line of mice have been described previously (14).

View larger version (29K): [in this window] [in a new window]   Figure 1. Median eminence (top panel) and medial basal hypothalamic (bottom panel) NE and DA contents determined in PRL-KO mice and their normal littermates. Values are expressed as the mean ± SEM. Asterisks denote a statistical difference from the respective control value (P < 0.05).

View larger version (35K): [in this window] [in a new window]   Figure 2. Plasma LH and T concentrations in PRL-KO mice and their normal littermates. Values are expressed as the mean ± SEM. Asterisks denote a statistical difference from the respective control value (P < 0.05).

	Discussion

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The reduced DA content in the median eminence of the hypothalamus is compatible with the well documented negative feedback relationship of PRL and tuberoinfundibular DA (TIDA) neurons in which PRL provides a stimulatory input to the function of this neuronal group (17, 18). The median eminence contains terminal fields of TIDA neurons.

Suppression of plasma LH levels in PRL-KO animals is consistent with the reduced LH levels in PRL-deficient dwarf mice (5, 7) and with the ability of PRL treatment or PRL-secreting ectopic pituitary transplants to stimulate LH release in mice (4). This is in contrast to rat and man, where hyperprolactinemia leads to decreases in LH secretion (2). Curiously, treatment of dwarf mice with PRL or pituitary transplants failed to increase plasma LH levels (5, 19).

The reduction in plasma LH levels could be secondary to changes in either pituitary or hypothalamic function. Although in vitro LH secretion was not different between the PRL-KO and control mice, responses to LHRH stimulation were not evaluated. However, previous studies suggest that the effects of hyper- or hypoprolactinemia on gonadotropin release are most likely due to PRL effects on the hypothalamus rather than to effects on the pituitary (2). Hyperprolactinemia may reduce LH secretion in the rat by reducing noradrenergic stimulation of LHRH release while in the mouse, hyperprolactinemia increases NE turnover and LH secretion (20). The hypothalamic NE content was unchanged in the present experiment, but content does not necessarily reflect neuronal activity, and additional studies measuring NE turnover need to be completed to address this question. Alternatively, the LHRH neuron or numerous other neuronal products affecting LHRH release could be affected by PRL.

The lack of changes in either plasma T levels or responsiveness of testicular T production to LH in vitro was unexpected. PRL was reported to increase the number of testicular LH receptors and testicular responsiveness to LH in several rodent species, including mice (1, 2, 6, 21, 22). Suppression of testicular LH binding in DBA/2 male mice with experimentally induced hyperprolactinemia was believed to be due to down-regulation by chronically elevated LH levels in these animals (4). Perhaps the suppression of LH levels in PRL-KO mice leads to an increase in testicular LH receptors. This could explain the normal plasma T levels despite reduced LH. However, the testicular T response to LH in vitro was not augmented in PRL-KO animals. The maintenance of normal plasma T levels in PRL-KO males in which LH is reduced could also reflect redundancy of stimulatory inputs to the Leydig cells. Conceivably, one of the factors involved, such as insulin-like growth factor I, GH, FSH, or testicular nerves, can substitute for the functions normally served by PRL (7, 23, 24, 25). Coexistence of normal plasma T and suppressed LH levels could also be due to an increased sensitivity of the hypothalamus or pituitary to negative T feedback. Although not tested in the present study, this possibility is consistent with the results obtained in Syrian hamsters (26, 27). In this species, similarly to the mouse, PRL enhances gonadotropin release (26, 27, 28), and there is evidence that this effect of PRL may involve reducing the sensitivity to T feedback (26, 27).

The normal testicular weight and breeding performance of the PRL-KO males suggest that these animals have no major deficits in spermatogenesis or in copulatory behavior. This interpretation is consistent with normal T levels in PRL-KO mice. Previous studies of PRL-KO animals from the same line revealed normal testicular histology (14).

The striking increase in pituitary weight in PRL-KO mice probably results from hypertrophy and/or hyperplasia of nonfunctional lactotrophs in the absence of normal inhibitory input from TIDA neurons. Although further studies will be required to test the validity of this hypothesis and to characterize the cellular composition of the enlarged pituitaries of PRL-KO mice, the data on gonadotropin release in vitro suggest that the number and/or size of the gonadotrophs were probably not affected. The release of LH and FSH per mg pituitary tissue was greatly reduced, but this was an artifact of increased pituitary weight, as the release of these hormones per pituitary was not altered.

A reduction in the weights of the SV and VP is consistent with the ability of PRL to potentiate the effects of androgens on the male accessory reproductive glands in various species, including mice (29, 30, 31, 32). Treatment with PRL or ectopic pituitary transplants increases SV weight in hypophysectomized mice treated with T (30), in dwarf mice (31), and in normal, intact mice (32). Hypertrophy of different lobes of the prostate, including VP, was recently described in transgenic mice overexpressing rat PRL (33).

Thus, the present results suggest that in the male mouse PRL has a physiological role in the control of LH release and in the regulation of growth of the accessory reproductive glands, but is not required for the maintenance of normal plasma T levels or fertility.

Some differences appear to exist between the reproductive consequences of disrupting the PRL gene and the PRL-R gene (12). Male PRL-KO mice are fully fertile (Refs. 13, 14 and the present study). Male PRL-R-KO mice were initially reported to have a high incidence of infertility (12), but were subsequently shown to exhibit a delay, rather than an inhibition, of fertility (Kelly, P., personal communication). PRL-R messenger RNA and PRL binding can be detected in many organs of fetal mice (34, 35), whereas pituitary PRL secretion starts postnatally (36, 37). This raises an intriguing possibility that signaling through PRL-R may be necessary for some early developmental events that are required for normal male sexual maturation. Perhaps PRL-R-mediated actions of placental lactogens and/or maternal PRL delivered via the fetal circulation or the milk are involved in the development of the male reproductive system, its hormonal regulation, or hypothalamic centers that control sexual behavior.

	Acknowledgments

 
The authors thank Clare Fadden for the excellent technical assistance. We also thank the Hormone Distribution Branch, NIDDK, NIH, and Dr. A. F. Parlow for supplying the materials used in the RIAs.

	Footnotes

 
¹ This work was supported by NIH Grants HD-20001 and DK-49895.

Received February 20, 1998.

	References

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