Biomedical subjects

J P Lydon

Publications and source records attributed to J P Lydon.

At least 19 recordsLinked to original sources

PubMed2001

Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice.

Progesterone plays a central coordinate role in diverse reproductive events associated with establishment and maintenance of pregnancy. In humans and other vertebrates, the biological activities of progesterone are mediated by two proteins, A (PR-A) and B (PR-B) that arise from the same gene and function as progesterone activated transcription factors that exhibit different transcription regulatory activities in vitro. Mice lacking both PR isoforms (PRKO mice) exhibit pleiotropic reproductive abnormalities. To address the physiological role of the individual isoforms, we have selectively ablated PR-A expression in mice (PRAKO). We have demonstrated that PR-B mediates a subset of the reproductive functions of P. Ablation of PR-A does not affect responses of the mammary gland or thymus to P but results in severe abnormalities in ovarian and uterine function. Analysis of urine function of PRAKP mice reveals an unexpected P-dependent proliferative activity of PR-B in the epithelium and provides evidence that the tissue-specific reproductive effects of this isoform are due to specificity of target gene transactivation rather than differences in tissue-specific expression relative to PR-A. Taken together, our data indicate that PR-A and PR-B act in vivo as two functionally distinct transcription factors.

Animals↗

PubMed2001

Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system.

In males, androgens are essential in maintaining the integrity of the prostate. Androgen-ablation induces apoptosis of the prostatic epithelium. In females, ovariectomy induces apoptosis in uterine epithelium while progesterone inhibits this process. The objective of this study was to determine whether androgen and progesterone inhibit apoptosis, respectively, in mouse prostatic and uterine epithelia via steroid receptors in the epithelium or in the stroma. To address this question, prostatic tissue recombinants were prepared with rat urogenital sinus mesenchyme plus bladder epithelium from wild-type or testicular feminization mutant (Tfm) mice. Thus, prostatic tissue was generated having androgen receptor (AR) in both epithelium and stroma or in the stroma only. Castration of hosts induced apoptosis in the AR-negative Tfm prostatic epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type epithelium. Moreover, this castration-induced prostatic epithelial apoptosis was blocked by testosterone and dihydrotestosterone in both wild-type and Tfm prostatic tissue recombinants. Likewise, uterine tissue recombinants were prepared in which epithelium and/or stroma was devoid of progesterone receptor (PR) by using uterine epithelium and stroma of wild-type and PR knockout mice. Progesterone inhibited uterine epithelial apoptosis only in tissue recombinants prepared with PR-positive stroma. The PR status of the epithelium did not affect epithelial apoptotic index. Therefore, the apoptosis in prostatic and uterine epithelia is regulated by androgen and progesterone via stromal AR and PR, respectively. In both cases, epithelial AR or PR is not required for hormonal regulation of epithelial apoptosis in prostatic and uterine epithelium.

Androgens↗

PubMed2001

A complex role for the progesterone receptor in the response to vascular injury.

Clinical studies of hormone replacement therapy to prevent cardiovascular diseases have heightened interest in the cardiovascular effects of progestins. However, the role of the progesterone receptor (PR) in vascular biology has not been studied in vivo. We studied ovariectomized female PR knockout (PRKO) mice and their wild-type (WT) littermates using the mouse carotid artery injury model. Placebo-treated PRKO mice showed significantly greater vascular medial hypertrophy and vascular smooth muscle cell (VSMC) proliferation in response to vascular injury than did WT mice. Progesterone had no significant effect in the PRKO mice, but worsened the response to injury in WT mice. VSMCs cultured from PRKO mouse aortae were markedly hyperproliferative, and their growth was not affected by progesterone. In contrast to the in vivo findings, progesterone inhibited proliferation of WT-derived VSMCs. Furthermore, reintroduction of PR into PRKO-derived VSMCs using adenoviral methods restored progesterone-mediated inhibition of proliferation to these cells. This effect was reversed by the PR antagonist, RU 486. Thus, the effects of PR and progesterone differ markedly between cultured VSMCs and intact blood vessels. These data demonstrate a direct role for the PR in regulating the response to vascular injury and VSMC proliferation.

Animals↗

PubMed2000

A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors.

The ventromedial hypothalamus (VMH) plays a central role in the regulation of the female reproductive behavior lordosis, a behavior dependent upon the sequential activation of receptors for the ovarian steroid hormones estradiol (E) and progesterone (P). These receptors function as transcription factors to alter the expression of target genes. To discover behaviorally relevant genes targeted by E and P in the VMH, we used the differential display PCR to identify messenger RNAs that are differentially expressed in the hypothalamus of ovariectomized (ovx) rats treated with E alone compared with ovariectomized rats treated with E and P. We show here that one interesting mRNA within the hypothalamus that is repressed by P after E priming encodes the protein 25-Dx, the rat homolog of the human membrane-associated P-binding protein Hpr6.6. Neurons in the brain containing the highest levels of 25-Dx are located in several nuclei of the basal forebrain, including the VMH. 25-Dx expression is also higher in the hypothalamus of female P receptor "knockout" mice than in their wild-type littermates. These findings suggest a mechanism in which the activation of nuclear P receptor represses expression of a membrane P receptor, 25-Dx, during lordosis facilitation.

Animals↗

PubMed2000

Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.

Progesterone regulates reproductive function through two intracellular receptors, progesterone receptor-A (PR-A) and progesterone receptor-B (PR-B), that arise from a single gene and function as transcriptional regulators of progesterone-responsive genes. Although in vitro studies show that PR isoforms can display different transcriptional regulatory activities, their physiological significance is unknown. By selective ablation of PR-A in mice, we show that the PR-B isoform modulates a subset of reproductive functions of progesterone by regulation of a subset of progesterone-responsive target genes. Thus, PR-A and PR-B are functionally distinct mediators of progesterone action in vivo and should provide suitable targets for generation of tissue-selective progestins.

Animals↗

PubMed2000

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases.

Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle. This process is initiated by the pituitary surge of luteinizing hormone (LH), is temporally associated with transcriptional regulation of numerous genes, and is presumed to involve the synthesis and/or activation of specific proteases that degrade the follicle wall. The progesterone receptor (PR), a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, we show that the matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation.

ADAM Proteins↗

PubMed2000

Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus.

The objective of this study was to determine whether uterine stromal and/or epithelial progesterone receptor (PR) is required for the antagonism by progesterone (P(4)) of estradiol-17beta (E(2)) action on expression of PR and lactoferrin in uterine epithelium. Uterine tissue recombinants were prepared with epithelium (E) and stroma (S) from wild-type (wt) and PR knockout (PRKO) mice: wt-S+wt-E and PRKO-S+wt-E. P(4) action on epithelial PR expression was studied in wt-S+wt-E and PRKO-S+wt-E tissue recombinants. E(2) down-regulated epithelial PR in both types of tissue recombinants, but P(4) blocked E(2)-induced down-regulation of epithelial PR only in wt-S+wt-E tissue recombinants. Thus, P(4) requires stromal PR to inhibit E(2)-induced down-regulation of epithelial PR. Epithelial PR is not sufficient in itself. The inhibitory effect of P(4) on lactoferrin expression was studied in 4 types of tissue recombinants (wt-S+wt-E, PRKO-S+wt-E, wt-S+PRKO-E, and PRKO-S+PRKO-E). E(2) induced lactoferrin in all 4 types of tissue recombinants. P(4) blocked E(2)-induced lactoferrin expression only in wt-S+wt-E tissue recombinants. In wt-S+PRKO-E tissue recombinants, P(4) inhibited lactoferrin expression only partially. P(4) failed to block E(2)-induced lactoferrin expression in PRKO-S+wt-E and PRKO-S+PRKO-E tissue recombinants. Thus, both epithelial and stromal PR are essential for full P(4) inhibition of E(2)-induced lactoferrin expression.

Animals↗

PubMed2000

C/EBPbeta (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development.

Deletion of the transcription factor CCAAT/enhancer binding protein (C/EBP)beta results in a severe inhibition of lobuloalveolar development in the mouse mammary gland. Because progesterone receptor (PR) is requisite for alveolar development, the expression of PR was investigated in C/EBPbeta-/- mice. Unexpectedly, the number of PR-positive cells, as well as the levels of PR mRNA, were elevated 3-fold in the mammary glands of C/EBPbeta-/- mice. Furthermore, in contrast to wild-type nulliparous mice, in which PR distribution shifted from a uniform to nonuniform pattern between 8-12 weeks of age, C/EBPbeta-/- mice exhibited uniform PR distribution throughout all stages of mammary development analyzed. No change in C/EBPbeta mRNA levels was observed in the mammary glands of PR-/- mice, suggesting that PR acts in a pathway either in parallel to or downstream of C/EBPbeta. The overexpression and disrupted cellular distribution of PR in C/EBPbeta-/- mice were coincident with a striking 10-fold decrease in cell proliferation after acute steroid hormone treatment, assayed by incorporation of bromodeoxyuridine. In wild-type mice, PR and bromodeoxyuridine-positive cells were adjacent to each other and rarely colocalized. No differences in the level or pattern of PR expression were observed in the uterus, suggesting that C/EBPbeta influences PR in a mammary-specific fashion. Together, these data suggest that C/EBPbeta may control cell fate decisions in the mammary gland through the appropriate temporal and spatial expression of molecular markers, such as PR, that induce the proliferation of alveolar progenitor cells via juxtacrine mechanisms.

Animals↗

PubMed1999

Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function.

To define the functional relevance of progesterone-initiated intracellular signaling in mammary gland tumorigenesis, the progesterone receptor knockout (PRKO) mouse model was used in the context of an established carcinogen-induced mammary tumorigenesis system. In carcinogen-treated, 7,12-dimethylbenz(a)anthracene (DMBA), pituitary-isografted mice, there was a marked reduction in mammary tumor incidence in PRKO mice as compared with isogenic wild types (WT). Mammary tumors arose in 12 (60%) of 20 WT mice compared with 3 (15%) of 20 PRKO mice by 44 weeks after the initial DMBA treatment. In the absence of a pituitary isograft, mammary tumors developed in 4 (20%) of 20 WT mice versus 4 (20%) of 20 PRKO mice by 47 weeks. At the time of carcinogen administration, the proliferative index of the pituitary-stimulated WT gland was at least 4-fold higher than similarly treated PRKO glands, supporting the importance of PR-mediated proliferative pathways in the genesis of this tumor type. Unlike the WT gland, the PRKO gland was unable to exhibit alveologenesis in response to pituitary isograft stimulation; thus, DMBA-initiated mammary tumors observed in the PRKO were assumed to be exclusively of ductal origin. Compared with previous tested strains, by 47 weeks, a higher incidence of DMBA-induced ovarian tumors was observed in this mouse strain: (a) 4 (20%) of 20 WT mice and 9 (45%) of 20 PRKO mice with a pituitary isograft; and (b) 10 (50%) of 20 WT mice and 10 (50%) of 20 PRKO mice without a pituitary isograft. Despite the host-strain's underlying propensity for DMBA-induced ovarian neoplasms, our studies underscore the specific importance of the PR (as distinct from the estrogen receptor) as a mandatory mediator for those intracellular signaling pathways that are essential for the initiation of the majority of murine mammary tumors induced by DMBA. Apart from providing strong support for progesterone's role in mammary gland tumorigenesis as well as furthering our fundamental understanding of breast cancer etiology, these studies may have implications for the routine use of progestins.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Progesterone regulates proliferation of endothelial cells.

The use of steroid hormones in postmenopausal replacement therapy has been associated with prevention of cardiovascular disease. Although the contribution of estradiol to endothelial cell function has been addressed, little information is available on the effect of progestins on this cell type. Here, we provide direct evidence for the presence of functional nuclear progesterone receptor in endothelial cells and demonstrate that physiological levels of progesterone inhibit proliferation through a nuclear receptor-mediated mechanism. The effects of progesterone were blocked by pretreatment with a progesterone receptor antagonist, and progesterone receptor-deficient endothelial cells failed to respond to the hormone. We evaluated the effect of progesterone by analysis of aorta re-endothelialization experiments in wild-type and progesterone receptor knockout mice. The rate of re-endothelialization was significantly decreased in wild-type mice when in the presence of progesterone, whereas there was no difference between control and progesterone-treated progesterone receptor knockout mice. FACS analysis showed that progestins arrest endothelial cell cycle in G1. The lag in cell cycle progression involved reduction in cyclin-dependent kinase activity, as shown by down-regulation in retinoblastoma protein phosphorylation. In addition, treatment of endothelial cells with progestins altered the expression of cyclin E and A in accordance with G1 arrest. These results have important implications to our current knowledge of the effect of steroids on endothelial cell function and to the overall contribution of progesterone to vascular repair.

Animals↗

PubMed1999

Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice.

It is well known that estrogen (E2) stimulates expression of progesterone receptors (PRs), thereby inducing responsiveness of several tissues to the actions of progesterone (P). Recent studies have also suggested, however, that biological actions previously ascribed to E2 alone may also be mediated by activation of E2-induced PRs, even independently of signal changes in P concentrations. In the present experiments, the progesterone receptor knockout (PRKO) mice were used to assess the role of PR activation in the positive feedback actions of E2 on gonadotropin release. Ovariectomized (OVX) PRKO mice were tested for their capacity to mount primary gonadotropin surges in response to exogenous E2, and to exhibit a GnRH self-priming effect in response to sequential injections of the decapeptide. Wild-type (WT) and PRKO mice were OVX, treated with both 17beta-estradiol and estradiol benzoate (EB), and then killed at 1900 h on day 7 postOVX. Plasma LH RIA revealed that WT mice exhibited surges in response to the E2 treatment; the PRKO mice, however, showed no elevation in plasma LH above untreated controls. Instead, plasma LH levels in E2-treated, OVX PRKO mice decreased significantly in comparison to untreated OVX PRKO mice, suggesting that E2 can exert a negative feedback influence on LH release in PRKO mice, despite the absence of positive feedback effects. A slight but significant rise in plasma FSH was observed in E2-treated OVX WT mice in comparison to untreated controls: an effect not seen in E2-treated OVX PRKO mice, reinforcing the observation that estrogen's positive feedback effects are compromised in PRKO mice. In a second experiment, E2-treated OVX WT and PRKO mice were given either one or two pulses of GnRH 60 min apart, and killed 10 min later. The WT mice were found to exhibit a robust GnRH self-priming effect, as WT mice receiving two GnRH pulses displayed LH responses approximately 2-fold greater than those receiving only one pulse. By contrast, PRKO mice receiving two GnRH pulses exhibited no additional increase in plasma LH levels. We conclude that PR activation is obligatory for expression of the GnRH self-priming effect as well as for generation of E2-induced LH and FSH surges. The extent to which failure of LH surge secretion in PRKO mice is due to the absence of GnRH self-priming, lack of hypothalamic GnRH surges, and/or defects in other processes remains to be determined. These observations clearly demonstrate, however, that the presence of PR is an absolute requirement for the transmission of E2-induced signals leading to gonadotropin surges.

Animals↗

PubMed1998

A paracrine role for the epithelial progesterone receptor in mammary gland development.

Recently generated progesterone receptor (PR)-negative (PR-/-) mice provide an excellent model for dissecting the role of progesterone in the development of the mammary gland during puberty and pregnancy. However, the full extent of the mammary gland defect in these mice caused by the absence of the PR cannot be assessed, because PR-/- mice do not exhibit estrous cycles and fail to become pregnant. To circumvent this difficulty, we have transplanted PR-/- breasts into wild-type mice, and we have demonstrated that the development of the mammary gland in the absence of the PR is arrested at the stage of the simple ductal system found in the young virgin mouse. Mammary transplants lacking the PR in the stromal compartment give rise to normal alveolar growth, whereas transplants containing PR-/- epithelium conserve the abnormal phenotype. Chimeric epithelia in which PR-/- cells are in close vicinity to PR wild-type cells go through complete alveolar development to which the PR-/- cells contribute. Together, these results indicate that progesterone acts by a paracrine mechanism on a subset of mammary epithelial cells to allow for alveolar growth and that expression of the PR is not required in all the cells of the mammary epithelium in order for alveolar development to proceed normally.

Animals↗

PubMed1998

Regulation of male sexual behavior by progesterone receptor, sexual experience, and androgen.

Recent studies have demonstrated that physiological doses of progesterone may facilitate the androgen-dependent display of male sexual behavior in laboratory rats and three species of lizard. We used mice with a targeted disruption of the progesterone receptor to investigate whether such interactions exist in male mice and whether they may be modified by sexual experience. We found that naive intact male progesterone receptor knockout (PRKO) mice exhibit reduced mount frequencies compared to wild-type (WT) mice. Also unlike WT mice, sexually experienced PRKO males show profound losses in many measures of sexual behavior following castration. In a second experiment, we tested whether male mice heterozygous for a null mutation at the progesterone receptor locus were responsive to testosterone and progesterone treatment. We found that heterozygous males showed a reduced response to testosterone. The data are consistent with experiments indicating that the progesterone receptor is able to facilitate male-typical sex behaviors in other species and suggest novel mechanisms underlying the interaction of androgens and experience.

Androgens↗

PubMed1998

Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis.

The role of epithelial and stromal progesterone (P) receptors (PR) in the regulation of uterine epithelial DNA synthesis by P was investigated by analyzing the four types of tissue recombinants prepared with uterine stroma (S) and epithelium (E) from wild-type (wt) and PR knockout (PRKO) mice: wt-S + wt-E, PRKO-S + PRKO-E, wt-S + PRKO-E, and PRKO-S + wt-E. 17-Beta estradiol (E2) stimulated DNA synthesis in all four types of tissue recombinants. On the other hand, P inhibited E2-induced DNA synthesis only in tissue recombinants prepared with wild-type (PR-positive) stroma (wt-S + wt-E or wt-S + PRKO-E) but not knockout (PR-negative) stroma (PRKO-S + wt-E or PRKO-S + PRKO-E). These results clearly demonstrate that the inhibitory effect of P on uterine epithelial DNA synthesis is mediated by stromal PR. Epithelial PR is neither necessary nor sufficient for P inhibition of E2-induced epithelial DNA synthesis.

Animals↗

PubMed1997

Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization.

The COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. Multiple COUP-TF members have been cloned and they share a high degree of sequence homology between species as divergent as Drosophila and humans, suggesting a conservation of function through evolution. The COUP-TFs are highly expressed in the developing nervous systems of several species examined, indicating their possible involvement in neuronal development and differentiation. In the mouse, there are two very homologous COUP-TF genes (I and II) and their expression patterns overlap extensively. To study the physiological function of mCOUP-TFI, a gene-targeting approach was undertaken. We report here that mCOUP-TFI null animals die perinataly. Mutant embryos display an altered morphogenesis of the ninth cranial ganglion and nerve. The aberrant formation of the ninth ganglion is most possibly attributable to extra cell death in the neuronal precursor cell population. In addition, at midgestation, aberrant nerve projection and arborization were oberved in several other regions of mutant embryos. These results indicate that mCOUP-TFI is required for proper fetal development and is essential for postnatal development. Furthermore, mCOUP-TFI possesses vital physiological functions that are distinct from mCOUP-TFII despite of their high degree of homology and extensive overlapping expression patterns.

Animals↗

PubMed1997

Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1.

NURR1 is an immediate early gene product and a member of the nuclear receptor superfamily of transcription factors. Using the NURR1 cDNA as a probe, we isolated the genomic DNA encoding NURR1 from a mouse 129SvEv genomic library. The NURR1 gene is approximately 6.2 kb long and is organized into 7 exons separated by 6 introns. Structural analysis of the NURR1 reveals that this gene shares a similar structure with that of the nuclear receptor NUR77/NGF1-B. As in NUR77, the promoter region of NURR1 lacks an identifiable TATA box, but is GC-rich. The proximal promoter region also contains an ATF/CREB consensus binding site that may participate in cAMP-mediated induction of this immediate early gene product. Isolation and structural characterization of the NURR1 gene provides information for further developmental and transcriptional regulation studies of this gene.

Activating Transcription Factor 1↗

PubMed1997

Use of PRKO mice to study the role of progesterone in mammary gland development.

To better understand the distinct physiological roles played by progesterone and estrogen receptors (PR and ER) as well as to study directly PR function in an in vivo context, a novel mutant mouse strain, the PR knockout (PRKO) mouse, was generated carrying a germline loss of function mutation at the PR locus. Mouse mammary gland development has been examined in PRKO mice using reciprocal transplantation experiments to investigate the effects of the stromal and epithelial PRs on ductal and lobuloalveolar development. The absence of PR in transplanted donor epithelium, but not in recipient stroma, prevented normal lobuloalveolar development in response to estrogen and progesterone treatment. Conversely, the presence of PR in the transplanted donor epithelium, but not in the recipient stroma, revealed that PR in the stroma may be necessary for ductal development. Stimulation of ductal development by the PR may, therefore, be mediated by an unknown secondary signaling molecule, possibly a growth factor. The continued stimulation of the stromal PR appears to be dependent on reciprocal signal(s) from the epithelium. Thus, the combination of gene knockout and reciprocal transplantation technologies has provided some new insights into the role of stromal-epithelial interactions and steroid hormones in mammary gland development.

Animals↗

PubMed1997

Endocrine defects in mice carrying a null mutation for the progesterone receptor gene.

Mice carrying a null mutation of the progesterone receptor gene exhibit several reproductive abnormalities, including anovulation, attenuated lordotic behavior, uterine hyperplasia, and lack of mammary gland development. The hormonal correlates of these abnormalities are unknown, however, and were the focus of these studies. Serum samples from female wild-type (WT) and progesterone receptor knockout (PRKO) mice were obtained and analyzed by RIA for LH, FSH, PRL, estrogen (E2), and progesterone. Hypothalamic tissues were also processed for measurement of LHRH by RIA. Serum LH levels in PRKO mice were found to be elevated by approximately 2-fold over basal (metestrus) values in WT mice. By contrast, basal FSH levels were not different in PRKO and WT mice. Basal levels of E2 and progesterone in serum were likewise similar in the two groups, as were hypothalamic LHRH concentrations. Basal PRL levels were slightly higher in PRKO vs. WT mice. Ovariectomy of both groups of mice was accompanied by significant increases in both LH and FSH. At 5 days following ovariectomy, LH levels were elevated in both groups by 2-fold over PRKO basal and 4-fold over WT basal levels; however, by 10 days postovariectomy LH levels had continued to rise to a greater extent in PRKO mice than in WT animals. The FSH response to ovariectomy was greater for the PRKO mice at 5 days, but was no different from WT at 10 days. Of seven PRKO mice that were exposed to male odor, none exhibited preovulatory surges 3 days later, on the day of presumptive proestrus; this was in marked contrast with WT females, in which 100% exhibited robust LH surges. These results confirm the essential role of progesterone receptors in the regulation of hypothalamic and/or pituitary processes that govern gonadotropin secretion. The finding that basal LH levels are elevated in PRKO mice confirms that circulating progesterone normally conveys a significant portion of the total ovarian negative feedback control of the gonadotropin. That gonadotropin responses to ovariectomy are slightly enhanced in PRKO mice suggests that adrenal progesterone may contribute to the imposition of negative feedback control. The apparent inability of PRKO mice to respond to male odor suggests that anovulation in these mice may not be solely due to reproductive abnormalities within the ovary itself; rather, PRKO mice additionally harbor neuroendocrine defects that render them incapable of mounting normal preovulatory gonadotropin surges. It remains to be determined how the absence of PR in brain and pituitary of PRKO mice may produce this hormonal acyclicity and, conversely, how the presence of PR in brain and pituitary of WT mice may be obligatory in the generation of gonadotropin surges.

Animals↗