Human Menstrual Cycle Research Articles

A mathematical model for the human menstrual cycle

A simple mathematical model framework is developed to describe the hormonal interactions of the human menstrual cycle along the hypothalamus-pituitary-ovaries axis. The framework is designed so that it can be readily extended to model processes that disrupt the normal functioning cycle. The model in its most basic formulation exhibits multiple periodic solutions, one of which shows the key characteristics of a menstrual cycle, while the others indicate possible abnormalities sometimes observed in women of reproductive age. The basic model is extended to encompass receptor down-regulation as a mechanism to describe the desensitization of the pituitary to continuous stimulation of hypothalamic hormone, a hormonal therapy that is commonly prescribed prior to the surgical procedure for the removal of uterine myomas. Though the mechanisms for desensitization are likely to be more complex, the model results are in good qualitative agreement with physiological observations.

Assessment of luteal function in the vervet monkey as a means to develop a model for obesity-related reproductive phenotype

The objective of the current study was to characterize luteal function in vervet monkeys. Urine from 12 adult female vervets housed at an academic research center was collected for 10 weeks from single-caged monkeys in order to assess evidence of luteal activity (ELA) as determined by urinary excretion of pregnanediol glucuronide (Pdg) and estrone conjugates (E1c). Dual energy X-ray absorptiometry (DXA) was performed on the monkeys to assess body composition, bone density, and fat mass. Menstrual cyclicity was determined using records of vaginal bleeding. ELA was observed in 9 monkeys and was characterized by a late follicular rise in E1c followed by a progressive increase in Pdg excretion. Mean menstrual cycle length was 26.7 ± 3.8 days and the average day of luteal transition was 14 ± 1.8. Three monkeys without ELA had a clearly defined E1c rise (mean 12-fold from nadir) followed by an E1c drop that was not accompanied by Pdg rise and coincided with vaginal bleeding. Among the 9 ELA monkeys, excretion of E1c tended to negatively associate with fat mass, although this finding did not reach statistical significance (r = -0.61, p = 0.08). Similar to women, vervet monkeys experience an increase in E1c late in the follicular phase of the menstrual cycle which is followed by a subsequent luteal Pdg peak. Assessment of urinary reproductive hormones allows for identification of cardinal menstrual cycle events; thus, the similarity of vervet cycles to human menstrual cycles makes them a useful model for obesity-related human reproductive impairment.

Afferent Neuronal Control of Type-I Gonadotropin Releasing Hormone Neurons in the Human

Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species. In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH) synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis. Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation. Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational-, and circadian signals to the reproductive axis, among other effects. This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic, and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B (NKB) play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons. This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes, and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and NKB systems.

A mathematical model of the human menstrual cycle for the administration of GnRH analogues

The paper presents a differential equation model for the feedback mechanisms between gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), development of follicles and corpus luteum, and the production of estradiol (E2), progesterone (P4), inhibin A (IhA), and inhibin B (IhB) during the female menstrual cycle. Compared to earlier human cycle models, there are three important differences: The model presented here (a) does not involve any delay equations, (b) is based on a deterministic modeling of the GnRH pulse pattern, and (c) contains less differential equations and less parameters. These differences allow for a faster simulation and parameter identification. The focus is on modeling GnRH-receptor binding, in particular, by inclusion of a pharmacokinetic/pharmacodynamic (PK/PD) model for a GnRH agonist, Nafarelin, and a GnRH antagonist, Cetrorelix, into the menstrual cycle model. The final mathematical model describes the hormone profiles (LH, FSH, P4, E2) throughout the menstrual cycle of 12 healthy women. It correctly predicts hormonal changes following single and multiple dose administration of Nafarelin or Cetrorelix at different stages in the cycle.

Female Sexual Activity across the Human Menstrual Cycle

(1994). Female Sexual Activity across the Human Menstrual Cycle. Annual Review of Sex Research: Vol. 5, No. 1, pp. 122-172.

Mood and the Menstrual Cycle: A Review of Prospective Data Studies

The human menstrual cycle (MC) has historically been the focus of myth and misinformation, leading to ideas that constrain women's activities. We wished to examine one pervasive idea, that the MC is a cause of negative mood, by studying the scientific literature as a whole. We briefly reviewed the history of the idea of premenstrual syndrome and undertook a systematic review of quality studies. We searched PubMed, PsycINFO, and article bibliographies for published studies using non-help-seeking samples with daily mood data collected prospectively for a minimum of 1 complete MC. We critiqued their methodologies and tabulated the key findings. Of 47 English language studies identified, 18 (38.3%) found no association of mood with any MC phase; 18 found an association of negative mood in the premenstrual phase combined with another MC phase; and only 7 (14.9%) found an association of negative mood and the premenstrual phase. Finally, the remaining 4 studies (8.5%) showed an association between negative mood and a non-premenstrual phase. Considering the only 41 adequately powered studies, the same phase links were reported by 36.6%, 41.5%, and 13.5% of studies, respectively. Their diversity of methods (sampling, instruments, and cycle phase definitions) precluded a meta-analysis. Taken together, these studies failed to provide clear evidence in support of the existence of a specific premenstrual negative mood syndrome in the general population. This puzzlingly widespread belief needs challenging, as it perpetuates negative concepts linking female reproduction with negative emotionality.

Cyclic regulation of LPA3 in human endometrium

Lysophosphatidic acid (LPA) belongs to the group of lipid messengers, which plays a pivotal role in the establishment of implantation via its cellular receptor, LPA3. The aims of the present study were to characterize LPA3 mRNA and protein in human endometrium during the normal human menstrual cycle. Forty-three normally cycling volunteers without reproductive disorders were randomized to undergo endometrial sampling on a specific cycle day. Samples were assessed for relative LPA3 mRNA expression using real-time PCR and for LPA3 protein using immunohistochemistry and western blot. The expression of LPA3 mRNA significantly increased during the early and late secretory phase compared with other menstrual phases. LPA3 protein was localized to the epithelial and stromal cells and expression levels followed the same pattern as for LPA3 mRNA. In the normal human menstrual cycle, LPA3 mRNA and protein expression also change, indicating that this gene may be related to the function of the endometrium.

Expression of hepatic and ovarian antioxidant enzymes during estrous cycle in rats

The regulation of antioxidant enzymes has received increased attention in terms of protection from many diseases. Despite reports that administered estradiol derivatives can change antioxidant enzyme levels, comprehensive information is not available regarding the effects of the human menstrual cycle or the rat estrous cycle on the expression of the antioxidant enzyme system. The present study was performed to determine the expression levels of cytosolic antioxidant enzymes, including superoxide dismutase-1, catalase, glutathione peroxidase-1, glutathione reductase, peroxiredoxin (Prx)-1, Prx-2, thioredoxin-1, gamma-glutamylcysteine ligase catalytic subunit, alpha-class glutathione S-transferase (GST), pi-class GST, and mu-class GST, in the liver and ovaries of female rats during diestrus and proestrus. Our results indicate that hepatic expression of Prx-1 and Prx-2, and ovarian expression of alpha-class GST were increased significantly during the proestrus phase compared with the diestrus phase. These results suggest that the hepatic Prx family and ovarian alpha-class GST are sensitive to changes during the estrous cycle. Further studies are needed to determine the physiological significance of the regulation of the Prx family and alpha-class GST during the estrous cycle.

A comparison of the neuroendocrine mechanisms underlying the initiation of the preovulatory LH surge in the human, Old World monkey and rodent

As recognized for decades, the role of the rodent hypothalamus in timing the LH surge is deterministic and mediated by a GnRH discharge that is generated by an obligatory interaction in the preoptic area (POA) between a threshold level of estradiol and a circadian neural signal: a view consistent with contemporary kisspeptinocentric models of the estrous cycle. In higher primates, generation of the LH surge is emancipated from control by the POA. Woman represents the exemplar of the system in higher primates, as the LH surge appears to unfold in the absence of a midcycle GnRH discharge being generated instead by facilitatory interaction between a pulsatile GnRH input to the pituitary and an action of ovarian estradiol. The neurobiology of GnRH pulse generation is only beginning to emerge but from a translational perspective this aspect of hypothalamic function is critical for understanding the human menstrual cycle and how it may be perturbed.

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Regulation and 3 dimensional culture of tertiary follicle growth

It has been revealed that multiple cohorts of tertiary follicles develop during some animal estrous cycle and the human menstrual cycle. To reach developmental competence, oocytes need the support of somatic cells. During embryogenesis, the primordial germ cells appear, travel to the gonadal rudiments, and form follicles. The female germ cells develop within the somatic cells of the ovary, granulosa cells, and theca cells. How the oocyte and follicle cells support each other has been seriously studied. The latest technologies in genes and proteins and genetic engineering have allowed us to collect a great deal of information about folliculogenesis. For example, a few web pages (http://www.ncbi.nlm.nih.gov; http://mrg.genetics.washington.edu) provide access to databases of genomes, sequences of transcriptomes, and various tools for analyzing and discovering genes important in ovarian development. Formation of the antrum (tertiary follicle) is the final phase of folliculogenesis and the transition from intraovarian to extraovian regulation. This final step coordinates with the hypothalamic-pituitary-ovarian axis. On the other hand, currently, follicle physiology is under intense investigation, as little is known about how to overcome women's ovarian problems or how to develop competent oocytes from in vitro follicle culture or transplantation. In this review, some of the known roles of hormones and some of the genes involved in tertiary follicle growth and the general characteristics of tertiary follicles are summarized. In addition, in vitro culture of tertiary follicles is also discussed as a study model and an assisted reproductive technology model.

HCG, the wonder of today's science.

BackgroundhCG is a wonder. Firstly, because hCG is such an extreme molecule. hCG is the most acidic glycoprotein containing the highest proportion of sugars. Secondly, hCG exists in 5 common forms. Finally, it has so many functions ranging from control of human pregnancy to human cancer. This review examines these molecules in detail.ContentThese 5 molecules, hCG, sulfated hCG, hyperglycosylated hCG, hCG free beta and hyperglycosylated free beta are produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells (group 1), and by placental cytotrophoblast cells and human malignancies (group 2). Group 1 molecules are both hormones that act on the hCG/LH receptor. These molecules are central to human menstrual cycle and human pregnancy. Group 2 molecules are autocrines, that act by antagonizing a TGF beta receptor. These molecules are critical to all advanced malignancies.ConclusionsThe hCG groups are molecules critical to both the molecules of pregnancy or human life, and to the advancement of cancer, or human death.

The Unique Impact of Menstruation on the Female Voice: Implications for the Evolution of Menstrual Cycle Cues

AbstractResearch shows that hormonal changes in women across the menstrual cycle affect vocal production. Most work has documented shifts at high fertility times (i.e., ovulation) or during premenstruation. However, hormonal changes at menstruation also affect female physiology and behavior and could affect vocal production. The present studies investigated perceptual differences in voices recorded during menstruation compared with recordings taken at other times of the menstrual cycle. Results show that male raters could reliably identify voices recorded during menstruation with or without the presence of a voice recorded closest to ovulation. In addition, voices recorded at menstruation were identified as being the most unattractive. These findings indicate that voice recordings taken at times of lowest fertility may uniquely impact women’s vocal production and that perceptions of voice based on cycle phase are not specific to the time of heightened fertility. Implications for the evolution of human menstrual cycle cues are discussed.

ANIMAL MODELS FOR THE STUDY OF HUMAN OVARIAN FUNCTION

The study of ovarian function has been of great interest to scientists and clinicians in the human and veterinary health fields for more than 20 centuries. Initial studies of the ovaries were based on anatomical descriptions post-mortem, followed by histological and endocrinological approaches. The introduction of high-resolution ultrasonography provided a long-awaited tool to image the reproductive tissues in situ in both animals and humans. Critical studies of the characteristics and control of ovarian follicular and luteal dynamics in non-human primates, rodents, and domestic farm animals have involved frequent (i.e. daily or multiple times a day) blood sampling and ultrasonography. Studies of this nature in women are difficult, and often unethical to conduct. Differences in antral folliculogenesis between humans and animals appear to be more in detail rather than in essence, and may reflect differences in intrinsic physiology or merely differences in our ability to detect changes in a given species. In women, the presence of endometrial shedding and symmetric luteal and follicular phases are different from that observed during the estrous cycles of domestic farm animals but despite these differences, general similarities in antral follicular dynamics exist. A continuous pattern of antral follicle development was originally proposed in domestic livestock species; however, the use of frequent serial ultrasonography and simultaneous endocrine profiling in these animal species has resulted in a broad understanding of follicular wave dynamics. Follicular waves have now been described in every species in which this approach has been used, including humans. The relatively large diameters of antral follicles in cows and mares, compared to monkeys, sheep, and rodents provide greater feasibility for characterizing antral follicular dynamics ultrasonographically. Profound similarities in the dynamics of follicle development exist between the menstrual cycle in humans and the estrous cycle in cattle and horses. Despite a proportionately longer luteal phase in cows and mares, the growing phase of the dominant ovulatory follicle (defined as the time period from wave emergence to ovulation) is comparable in the human, cow, and mare. Thus, at present, cows and mares may be the most appropriate models for the study of antral follicular dynamics in women. While the use of animal models has increased our understanding of ovarian function and provides the hypothetical basis for studies in women, differences in vocabulary, culture, and research methodologies between scientists in predominantly human versus animal settings has hampered knowledge translation. These differences represent a systemic impediment to a broad understanding of ovarian function and limits progress and innovation in the development of safer and more efficacious treatments for infertility and contraception.

Ovarian antral folliculogenesis during the human menstrual cycle: a review

BACKGROUND Ovarian follicles undergo dynamic morphologic and endocrinologic changes during the human menstrual cycle. The physiologic mechanisms underlying recruitment and selection of antral follicles in women are not fully elucidated. METHODS A comprehensive review of >200 studies was conducted using PubMed. The objective was to compare and contrast different perspectives on human antral folliculogenesis. RESULTS Antral folliculogenesis has been studied using histologic, endocrinologic and/or ultrasonographic techniques. Different theories of antral follicle recruitment include: (i) continuous recruitment throughout the menstrual cycle; (ii) recruitment of a 'cohort' of antral follicles once in the late-luteal phase or early-follicular phase of each cycle and (iii) recruitment of two or three 'cohorts' or 'waves' during each cycle. Generally, a single dominant follicle is selected in the mid-follicular phase of each cycle and this follicle ovulates at mid-cycle. However, a dominant follicle may also be selected during anovulatory waves that precede the ovulatory wave in some women. CONCLUSIONS There is increasing evidence to indicate that multiple waves of antral follicles develop during the human menstrual cycle. Ovarian follicular waves in women are comparable with those documented in several animal species; however, species-specific differences exist. Enhancing our understanding of the endocrine and paracrine mechanisms underlying antral follicular wave dynamics has clinical implications for understanding age-related changes in reproductive function, optimizing hormonal contraceptive and ovarian stimulation regimens and identifying non-invasive markers of the physiologic status of follicles which are predictive of oocyte competence and assisted reproduction outcomes.

Expression of hepatic and ovarian cytochrome P450 during estrous cycle in rats

It is known that gender differences in drug metabolism are largely attributed to changes in sex and growth hormones. Serum concentrations of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone change markedly during the human menstrual cycle and the rat estrous cycle. However, little information is available regarding the effects of the human menstrual cycle or the rat estrous cycle on expression and activity of cytochrome P450 (CYP) isoforms. The present study was carried out to determine the expression and activity of CYP-dependent drug-metabolizing enzymes in the liver and ovary during the estrous cycle. The expression and activity of microsomal CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2B1, CYP2C11, CYP2C12, CYP2E1, CYP3A1, CYP3A2, and CYP4A), cytochrome b(5) and NADPH-dependent CYP reductase in the liver and ovary were measured in female rats in diestrus and proestrus. Our results indicated that hepatic and ovarian expression and activity of CYP isoforms, cytochrome b(5), and NADPH-dependent CYP reductase were not different between diestrus and proestrus, although serum estradiol concentration and uterus weight were markedly increased in the proestrus phase. These results suggest that the cytochrome P450-dependent system is not sensitive to changes in the estrous cycle, and further studies are warranted to determine the effects of the estrous cycle on in vivo metabolism of xenobiotics.

Distinct Expression of the Calcium Exchangers, NCKX3 and NCX1, and Their Regulation by Steroid in the Human Endometrium During the Menstrual Cycle

Plasma membrane sodium/calcium exchangers are an important component of intracellular calcium homeostasis and electrical conduction. The potassium-dependent sodium/calcium exchangers NCKX3 (gene SLC24A3) and NCX1 (gene SLC8A1) play a critical role in the transport of intracellular calcium across the cell membrane in exchange for extracellular sodium ions. NCKX3 and NCX1 transcripts are most abundant in the brain and smooth muscle, but many other tissues, particularly the uterus, aorta, and intestine, also express this gene at lower levels. However, the expression patterns and physiological roles of NCKX3 and NCX1 in the human endometrium during the menstrual cycle are unknown. Thus, we examined the endometrial expression of NCKX3 and NCX1 messenger RNA (mRNA) and protein throughout the different phases of the menstrual cycle. Endometrial expression of NCKX3 mRNA and protein was increased 1.5- to 2.5-fold during the early-proliferative, mid-proliferative, and early-secretory phases compared with the other phases; however, no significant alteration in NCX1 expression level was observed. The effects of the sex-steroid hormones, 17β-estradiol (E2) and progesterone (P4), on the expression of NCKX3 and NCX1 in Ishikawa cells was also investigated. NCKX3 expression was significantly increased by E2 (10(-8) mol/L). However, the expression of NCX1 was not affected by E2 and P4. Subsequent immunohistochemical analysis revealed that the uterine NCKX3 and NCX1 proteins were abundantly localized in the cytoplasm of luminal and glandular epithelial cells throughout the menstrual cycle. Taken together, these results indicate that NCKX3 is abundantly expressed within the human endometrium at the transcriptional and translational levels, and its level appears to be regulated by a steroid hormone, in particular, E2 during the human menstrual cycle.

Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium

BackgroundPMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium.MethodsUsing a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices.ResultsIn this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression.ConclusionThese findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the maintainence of endometrial integrity and to the disease biology associated with altered levels of α6 integrin expression in the endometrium.

Abstract 2395: Effect of Brca1 knockout on gene expression in mouse ovarian granulosa cells

Abstract We previously reported that conditional inactivation of Brca1 in ovarian granulosa cells leads to the development of benign epithelial tumors in two thirds of the mutant mice. The tumors were localized either in the ovarian hilum, oviducts, or on the external surface of the uterine horns. They resembled human ovarian serous cystadenomas, which are the benign counterparts of the tumors seen in human BRCA1 mutation carriers. The tumors did not harbor mutant Brca1 alleles, implying that the mechanism of tumor predisposition in this model is driven by a cell non-autonomous mechanism. We recently showed that mutant mice had increased estrogen stimulation unopposed by progesterone due to higher circulating levels of estradiol and to a prolongation of pro-estrus phase of the estrus cycle, the equivalent of the estrogen-dominating follicular phase in the human menstrual cycle, providing evidence that such stimulation was instrumental in mediating tumor predisposition in this mouse model. We sought to get further insights into the consequences of Brca1 inactivation on gene expression in ovarian granulosa cells. We used laser capture microdissection to isolate granulosa cells from mutant and wild type mice at the age of 8 months when the mutant mice displayed most significant elongation in pro-estrus phase. All mice were synchronized in pro-estrus phase, with 5IU of Pregnant Mare Serum Gonadotropin inoculated 48 hours before they were harvested. Granulosa cell mRNA from each group was pooled and analyzed using mouse all-exon arrays. The expression of 2,972 genes was changed more than 2-fold in mutant versus wild type animals. Selected differentially expressed genes were further analysed by quantitative RT-PCR to verify the authenticity of the differential expression. Linear regression analysis showed excellent correlation between the qRT-PCR and microarray data, with a coefficient of variation R2 of 0.8088. Here we report that the gene family that was most frequently influenced by Brca1 inactivation in ovarian granulosa cells was that of olfactory receptors. The second most significant difference based on magnitude of changes in expression level between the 2 groups of mice involved an olfactory receptor. Ten of the thirty genes that showed the highest fold increase in expression in mutant animals were olfactory receptors. These data are interesting in light of Kallmann syndrome, characterized by hypogonadism and loss of ability to smell. Our data suggest that olfactory receptors may play an important role in signal transduction in granulosa cells. Assuming that the decrease in gene dosage present in BRCA1 mutation carriers is sufficient to induce changes in gene expression similar to those seen in homozygous Brca1 knockouts, the results also suggest that such signaling is altered in human BRCA1 mutation carriers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2395. doi:10.1158/1538-7445.AM2011-2395

Expression of calbindin-D28k and its regulation by estrogen in the human endometrium during the menstrual cycle

Human endometrium resists embryo implantation except during the 'window of receptivity'. A change in endometrial gene expression is required for the development of receptivity. Uterine calbindin-D28k (CaBP-28k) is involved in the regulation of endometrial receptivity by intracellular Ca2+. Currently, this protein is known to be mainly expressed in brain, kidneys, and pancreas, but potential role(s) of CaBP-28k in the human uterus during the menstrual cycle remain to be clarified. Thus, in this study we demonstrated the expression of CaBP-28k in the human endometrium in distinct menstrual phases. During the human menstrual cycle, uterine expression levels of CaBP-28k mRNA and protein increased in the proliferative phase and fluctuated in these tissues, compared with that observed in other phases. We assessed the effects of two sex-steroid hormones, 17beta-estradiol (E2) and progesterone (P4), on the expression of CaBP-28k in Ishikawa cells. A significant increase in the expression of CaBP-28k mRNA was observed at the concentrations of E2 (10(-9 to -7) M). In addition, spatial expression of CaBP-28k protein was detected by immunohistochemistry. CaBP-28k was abundantly localized in the cytoplasm of the luminal and glandular epithelial cells during the proliferative phases (early-, mid-, late-) and early-secretory phase of menstrual cycle. Taken together, these results indicate that CaBP-28k, a uterine calcium binding protein, is abundantly expressed in the human endometrium, suggesting that uterine expression of CaBP-28k may be involved in reproductive function during the human menstrual cycle.