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Department of Neurobiology and Physiology (P.E.C., J.E.L.), Northwestern University, Evanston, Illinois 60208; and Department of Cell Biology and Center for Comparative Medicine (J.P.L., O.M.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Jon E. Levine, Ph.D., Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208. E-mail: jlevine{at}nwu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The positive feedback actions of E2 are regarded as the key hormonal signals that precipitate preovulatory gonadotropin surges in virtually all female mammals. In rodents (2), and possibly in primates as well (3), progesterone receptor (PR) activation also appears to be important in the generation of spontaneous preovulatory surges. PRs, induced by increasing levels of ovarian E2 (4, 5), are abundant in pituitary and defined regions of the hypothalamus, including the arcuate nucleus, the medial preoptic nucleus, and other periventricular regions (6, 7, 8). In E2-primed ovariectomized rats, activation of these PRs by progesterone on proestrus results in augmented and temporally advanced LH surges, more closely resembling peak LH levels found in intact females (9, 10). It has been suggested that ovarian (10, 11, 12) and/or adrenal (11) progesterone secretions just before the spontaneous preovulatory LH surge may normally exert these actions during the ovulatory cycle. Indeed, blockade of progesterone synthesis on the late morning of proestrus has been shown to attenuate gonadotropin surges (13), and blockade of PR by the type II antagonist RU486 given to intact female rats on the morning of proestrus prevents the LH surge that would normally occur in the afternoon (14, 15, 16).
It is not clear, however, if PRs are important only for mediating progesterone’s amplifying actions or if they are even more critically involved in the central mechanisms that drive the surge-generating process itself. Recent evidence suggests that PRs may subserve cellular regulatory functions in the unliganded state (17, 18, 19), and we have recently proposed that this ligand-independent activation of PR may occur as a critically important step in the initiation of LHRH surges (20, 21). In vivo observations in this laboratory and others have revealed that rats lacking both ovarian and adrenal progesterone exhibit LH surges when primed with E2 alone, whereas rats under the same conditions do not surge when administered RU486 (20, 22). If PR activation is indeed a key step in the initiation of preovulatory surges, then one would predict that in the absence of endogenous PRs animals would not exhibit spontaneous preovulatory gonadotropin surges.
Mice homozygous for PR deletions [PR knockout (PRKO)], developed at Baylor College of Medicine using gene-targeting techniques, have become very useful models for elucidating what role this steroid hormone receptor plays in normal reproductive function (23). This mouse model has already been useful in determining PR involvement in rodent sexual receptivity and behavior (23). It has been recently demonstrated that PRKO female mice exhibit greatly attenuated lordosis quotients in response to sexually active wild-type (WT) male mice, as well as to induction by intracerebroventricular application of dopamine (19). PRKO females are unable to ovulate, and therefore are infertile. Additional studies revealed that, even in the presence of exogenous gonadotropins PMSG and human chorionic gonadotropin (hCG), mature preovulatory follicles present in the ovary failed to rupture. These receptor mutants seem to have no deficiency in follicular development but instead are unable to effectively recognize ovulatory signals. These mice also possess other abnormalities, such as hypersensitive uterine responsiveness to steroids and lack of responsiveness to decidual stimulation. Since hCG shares a high degree of homology with LH, it would seem that PR activation is necessary in the ovary to transduce the ovulatory signal, and that PRKO mice are insensitive to the actions of LH, were that signal present. It is not known whether anovulation in these animals is additionally due to impairment of the neuroendocrine axis and disruption of the PR-mediated processes in brain and pituitary that mediate gonadotropin surge generation.
These experiments were conducted to characterize the endocrine status of PRKO mice, so as to better understand the role(s) that PRs may play in reproductive hormone cycles in female rodents. Hormone levels were measured under basal and presumed stimulated conditions to assess the degree to which PR ablation may impact both the negative and positive feedback regulation of gonadotropin secretions and the spontaneous, ovulatory cyclicity of reproductive hormones.
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Materials and Methods |
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In two groups of mice (10 WT, 10 PRKO) vaginal smears were monitored daily for 12 weeks. Only three of 10 WT mice displayed a relatively consistent 5-day cycle. Remaining WT mice displayed both 4- and 5-day cycles in an unpredictable fashion. Regularly cycling mice were killed on the evening of putative proestrus. None of the PRKO mice displayed regular cycles and instead exhibited smears consisting of an unvarying mixture of leukocytes, nucleated cells, and cornified cells. Three days after exposure to mature male mouse bedding, three WT and seven transgenic mice were killed via cardiac puncture. Animals were killed at 1900 h, coincident with lights out, as this time is typical for observation of LH surge peaks in mice. Previous experiments (24) indicate that the ascending phase of the LH surge in intact, pheremonally induced mice occurs between 1700–1800 h and the LH peak occurs at approximately 1900–2000 h, with levels returning to baseline around 2100–2200 h.
Mice were anesthetized with methoxyflurane (Metofane, Pitman-Moore, Inc., Washington Crossing, NJ), and an incision was made with sharp scissors, exposing the peritoneum just below the xiphoid process. The rib cage was bisected and spread, and the diaphragm cut. A 21 g needle was inserted into the right ventricle of the heart, and blood was withdrawn in quantities ranging from 500 µl to 1 ml. Brains, pituitaries, kidneys, and adrenals were removed from mice and fresh frozen on dry ice. Blood was centrifuged and plasma was assayed for LH, FSH, E2, progesterone, and PRL via RIA.
Remaining intact mice (wild-type, n = 66; PRKO, n = 57) were killed between 1000 h-1400 h to determine basal levels of the above hormones. All mice were killed via cardiac puncture, and organs were harvested as described.
Effects of ovariectomy (OVX)
Ten WT and 10 PRKO mice were ovariectomized under Metofane
anesthesia. Five days post-OVX, five mice in each genotype were killed
via cardiac puncture. The same sacrifice procedure was repeated at 10
days post-OVX for the remaining mice.
Hypothalamic LHRH content
Ten WT and 10 PRKO mice were killed at 1200 h on metestrus,
and their brains were fresh frozen on dry ice. Other WT (n = 10)
and PRKO (n = 8) mice were killed at 5 and 10 days after OVX, and
their brains were also fresh frozen. Mediobasal hypothalami were
dissected, weighed, and homogenized in 0.1 N HCl. After
centrifugation, supernatants were extracted with 3 vol methanol,
lyophilized, and stored for LHRH RIA.
RIA
LH and FSH standards, RP-3 and RP-2, respectively, were
generously provided by NIDDK. Intraassay coefficient of variance (CV)
of LH was 8.5%. Assay CV of FSH was 4.1%. PRL standards and
antibodies were generously provided by Dr. A. F. Parlow at the
Pituitary Hormones and Antisera Center. Assay CV for PRL was 23%.
Progesterone was assayed with the Immuchem Prog 125I kit
(ICN Pharmaceuticals, Costa Mesa, CA). The Intraassay CV for
progesterone was 3.5%. E2 was assayed using the KE2D1 kit
(Diagnostic Products Corp., Los Angeles, CA), and the intraassay CV for
E2 was 9.8%.
Statistical analysis
LH, FSH, E2, progesterone, and PRL means and
SEs were calculated within each genotypic group and
compared by Student’s t test to determine significant
differences in all experiments. Two-way ANOVA was used to assess the
effect of OVX and duration post-OVX upon both genotypic groups. Mean
LHRH content levels were calculated and normalized to wet weight of
mediobasal hypothalami, and genotypic groups were compared using
Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, PRKO mice
exhibited significantly elevated (P < 0.05) basal LH
levels (0.97 ± 0.19 ng/ml; n = 44) in comparison to their WT
counterparts (0.46 ± 0.10 ng/ml; n = 52). Basal FSH levels,
however, as shown in Fig. 1B, were unchanged in PRKO mice (6.13 ±
0.89 ng/ml; n = 42) as compared with WT (5.98 ± 0.26 ng/ml;
n = 54). PRL levels (Fig. 1C) were slightly elevated
(P < 0.05) in PRKOs (69.59 ± 7.27 ng/ml; n
= 22) as compared with WT (45.45 ± 6.94 ng/ml; n = 30).
Comparison of E2 levels between WT mice and PRKOs (Fig. 2A) showed no significant difference (WT:
45.0 ± 30.58 pg/ml, n = 16; PRKO: 67.1 ± 32.52 pg/ml,
n = 21), possibly due to a high degree of variability in both
groups. Progesterone levels (Fig. 2B) did not differ significantly
between the two groups (WT: 46.97 ± 7.34 ng/ml, n = 21;
PRKO: 39.52 ± 5.88 ng/ml, n = 27).
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PRKO mice killed 10 days post-OVX, however, exhibited a further and
significant elevation in basal LH (4.49 ± 1.14 ng/ml;
P < 0.0001), in comparison to 10 day post-OVX WT mice
(2.48 ± 0.43 ng/ml; P < 0.05). FSH levels (Fig. 3B) in both 5 day and 10 day OVX mice were elevated in comparison to
those measured in intact mice (P < 0.01) and
significantly different between genotypic groups at 5 days but not at
10 days: 5 day OVX PRKO (41.56 ± 7.15 ng/ml);, 10 day OVX PRKO
(31.05 ± 1.25 ng/ml); 5 day OVX WT (25.96 ± 1.07 ng/ml);
and 10 day OVX WT (31.38 ± 1.13 ng/ml).
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). Mean FSH levels of WT mice under surging conditions
(8.73 ± 1.852; n = 3) were significantly higher than those
of both WT and PRKO mice under basal conditions, as well as PRKO mice
under surging conditions (4.66 ± 0.53 ng/ml; n = 8) (Fig. 1B).
Hypothalamic LHRH content
When hypothalamic homogenates were assayed and normalized to wet
weight, there was no significant difference in hypothalamic LHRH
content between metestrus WT (83.49 ± 19.12 pg/mg; n = 10)
and PRKO (107.50 ± 27.24 pg/mg; n = 10) mice. There was also
no significant difference in hypothalamic LHRH content between
metestrus mice of either genotype and OVX WT mice at 5 days (65.13
± 14.89 pg/mg; n = 5) or 10 days (88.80 ± 14.53 pg/mg;
n = 5) and PRKO mice at 5 days (74.13 ± 22.99 pg/mg; n
= 3) or 10 days (87.13 ± 12.23 pg/mg; n = 5) (Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most striking characteristic of PRKO mice was found to be an absence of preovulatory LH and FSH surges on the late afternoon/early evening of proestrus. Placement of naive PRKO females proximal to male mouse odor failed to evoke surges on the ensuing presumptive proestrus, as normally occurs in WT animals (24). Examination of vaginal cytology also revealed that PRKO mice exposed to male odor do not progress through the estrous cycle in comparison to WT. Instead, PRKO mice exhibit an unvarying vaginal cytology that consists of a mixture of leukocytes, nucleated epithelial cells, and some squamous epithelial cells.
The absence of LH surges is an additional factor contributing to the infertility and anovulation previously demonstrated in PRKO mice (23). Ovarian PRs are clearly required for ovulation to occur in response to gonadotropins, as demonstrated by the lack of an ovulatory response to hCG in PRKO mice (23). However, PRKO mice also appear to be deficient in the ability to generate the gonadotropin signal for the initiation of ovulation. PR could therefore be necessary at multiple levels to ensure reproductive competency. Ovariectomized WT mice, under the proper conditions of E2 priming, can exhibit surge levels that are slightly attenuated in comparison to those found in intact mice (24). It remains to be seen whether an LH surge can be induced in PRKO mice with sufficient E2 priming, but preliminary results in this laboratory suggest that they cannot. This would be consistent with the proposed model of positive feedback in which increasing E2 has a permissive effect upon hypothalamic neuronal systems that are responsible for LHRH surge generation, and that this permissive action is mediated via PR (25). Without hypothalamic PR present to transduce these neural signals, there could be no change in the amplitude of LHRH pulses to elicit a subsequent LH surge (25).
Basal LH levels were significantly higher in PRKO mice in comparison with WT. This elevation in basal LH can be ascribed to the absence of PR-mediated negative feedback upon both the hypothalamus (2) and the pituitary (1), thus leading to increased release of LH. Since hormone measurements are made from plasma collected at the time of death, it is presently unknown whether the evident rise in basal LH reflects an overall increase in LH release, or whether the amplitude or frequency of pulsatile LH secretion is specifically increased. Interestingly, basal FSH levels were not significantly altered in PRKO mice in comparison to WT. This differential effect on the gonadotropins could be due to varying degrees of direct progesterone negative feedback influences on the anterior pituitary. Alternately, elimination of PR-mediated negative feedback at the hypothalamus may lead to an increase in the frequency and/or amplitude of pulsatile LHRH release, and such a condition may elicit higher basal LH release but is still below a threshold of sensitivity to affect FSH release.
An increase in LH levels following OVX was observed in PRKO as well as in WT mice. This suggests that ovarian negative feedback in mice is disproportionately E2-dependent, although progesterone negative feedback still provides a measurable contributing influence. Also, LH levels continued to rise between 5 and 10 days post-OVX in PRKO mice, whereas there was no elevation in LH levels of WT mice within this time period. This further increase observed in PRKO mice could be due to the elimination of extra-ovarian, PR-dependent negative feedback that may operate in the absence of circulating ovarian E2, preventing the basal LH rise seen with OVX from increasing further. In rats, some contribution of adrenal progesterone to negative feedback suppression of gonadotropin secretion has been suggested (26). FSH levels in both PRKO and WT mice were considerably elevated at 5 days post-OVX, reflecting the earlier post-OVX rise in FSH vs. LH typically observed in females (27). The significantly greater increase in FSH in PRKO mice also could be attributed to the removal of extraovarian, PR-mediated negative feedback, in addition to the elimination of the influence of inhibin; however, it is presently unclear why this differential rise is transient and returns to comparable WT levels at 10 days.
Levels of E2 and progesterone in PRKO mice were not significantly different from those measured in WT mice. One would expect levels of progesterone to be elevated as an LH-mediated, compensatory response to lack of PR. However, lack of any functional corpora lutea in PRKO mice could explain an attenuation in a possible rise in circulating progesterone (23). It may also be possible that responsiveness of the ovaries to gonadotropin stimulation may be diminished in PRKO mice, reaching an equilibrium at which the excess of LH may not evoke supraphysiological progesterone secretion.
PRL levels were significantly elevated in PRKO mice, an effect that could be ascribable to many factors. Progesterone has been shown to inhibit E2-stimulated PRL release from the pituitary, as well as to suppress E2-induced increases in pituitary PRL mRNA (28, 29, 30). Intracerebroventricular administration of RU486 to hysterectomized pigs was shown to dramatically increase PRL release, possibly due to removal of PR-mediated inhibition of PRL (31). This is not consistent with observations in primates, however, where progesterone seems to increase PRL secretion following E2-priming (32).
Since it is yet unknown whether PR deletion could have any effects on development of brain regions involved in reproduction, we examined LHRH concentrations in homogenates of mediobasal hypothalami of intact, metestrus mice, as well as that of ovariectomized mice, and observed no significant differences in levels between the two genotypes at metestrus or any significant effect of OVX on LHRH content between genotypes. In rats, both the positive (33) and negative feedback (1) actions of progesterone are likely exerted in part via alterations in hypothalamic LHRH release. Thus, the absence of functional PR in hypothalamic neurons governing LHRH release might have been expected to produce some measurable alteration in LHRH neurosecretory activity. The lack of any discernible difference in LHRH concentrations in PRKO mice, however, may simply reflect the dissociation between LHRH release rate and the steady state concentration of LHRH in tissue. Pending development of methods to monitor LHRH release in mice, the impact of PR deletion on LHRH release patterns remains to be clarified.
Our analysis of the reproductive endocrinology of PRKO mice reveals several underlying defects in neuroendocrine function in these animals. Of most obvious significance are defects in both the positive and negative feedback regulation of gonadotropin secretion. Our observations implicate the PR in the central, neuro-integrative processes that lead to the generation of preovulatory gonadotropin surges, in agreement with the findings of previous experiments that demonstrated the importance of progesterone and its receptor within the hypothalamus (12, 13, 14, 15), as well as in the homeostatic suppression of gonadotropin secretion in the basal secretory state. Characterization of PR involvement in these feedback processes, however, will require further analysis using steroid replacement methodologies in PRKO animals to complement the results of the current study.
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Acknowledgments |
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Footnotes |
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Received March 7, 1997.
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