An energetics-based approach to understanding the menstrual cycle and menopause

To explain the menstrual cycle and menopause, human biologists during the past several decades have developed new models of the evolutionary origins and maintenance of female reproductive patterns that address both ultimate and proximate causation. Hypotheses proposed for these processes generally offer explanations for menstruation or for menopause, but not for both; ultimately, these explanations must be integrated. Reviewing current explanations, this paper offers an energetics-based evolutionary rationale compatible with past adaptations of Homo sapiens and with ecological patterns in small-scale, preindustrial social systems in which food resources vary and sometimes are scarce. This paper is an expansion of a poster paper presented at the 2002 Human Biology Association meetings in Buffalo, New York. Roberta L. Hall is professor of anthropology at Oregon State University. Her main interest is in evolutionary aspects of human biological variation. Current research involves body composition relationships with resting metabolic rate in males and females and climatic adaptions of nasal morphology. She also enjoys working with the Coquille Indian Tribe of southern Oregon on research concerning their prehistory and is studying ramifications of the coastal hypothesis of North American settlement.     

Therapeutic effects of menstrual blood-derived endometrial stem cells on mouse models of streptozotocin-induced type 1 diabetes

BACKGROUND Type 1 diabetes(T1D),a chronic metabolic and autoimmune disease,seriously endangers human health.In recent years,mesenchymal stem cell(MSC)transplantation has become an effective treatment for diabetes.Menstrual bloodderived endometrial stem cells(MenSC),a novel MSC type derived from the decidual endometrium during menstruation,are expected to become promising seeding cells for diabetes treatment because of their noninvasive collection procedure,high proliferation rate and high immunomodulation capacity.AIM To comprehensively compare the effects of MenSC and umbilical cord-derived MSC(UcMSC)transplantation on T1D treatment,to further explore the potential mechanism of MSC-based therapies in T1D,and to provide support for the clinical application of MSC in diabetes treatment.METHODS A conventional streptozotocin-induced T1D mouse model was established,and the effects of MenSC and UcMSC transplantation on their blood glucose and serum insulin levels were detected.The morphological and functional changes in the pancreas,liver,kidney,and spleen were analyzed by routine histological and immunohistochemical examinations.Changes in the serum cytokine levels in the model mice were assessed by protein arrays.The expression of target proteins related to pancreatic regeneration and apoptosis was examined by western blot.RESULTS MenSC and UcMSC transplantation significantly improved the blood glucose and serum insulin levels in T1D model mice.Immunofluorescence analysis revealed that the numbers of insulin+and CD31+cells in the pancreas were significantly increased in MSC-treated mice compared with control mice.Subsequent western blot analysis also showed that vascular endothelial growth factor(VEGF),Bcl2,Bcl-xL and Proliferating cell nuclear antigen in pancreatic tissue was significantly upregulated in MSC-treated mice compared with control mice.Additionally,protein arrays indicated that MenSC and UcMSC transplantation significantly downregulated the serum levels of interferonγand tumor necrosis factorαand upregulated the serum levels of interleukin-6 and VEGF in the model mice.Additionally,histological and immunohistochemical analyses revealed that MSC transplantation systematically improved the morphologies and functions of the liver,kidney,and spleen in T1D model mice.CONCLUSION MenSC transplantation significantly improves the symptoms in T1D model mice and exerts protective effects on their main organs.Moreover,MSC-mediated angiogenesis,antiapoptotic effects and immunomodulation likely contribute to the above improvements.Thus,MenSC are expected to become promising seeding cells for clinical diabetes treatment due to their advantages mentioned above.     

Regulation of endometrial transglutaminase activity during the menstrual cycle

When human endometrial transglutaminase was measured a 10-fold higher activity was detected during the secretive phase. This change was not related to either differences in solubility of the enzyme or to selective contamination by plasma factor XIII and rather appears to depend on the expression of the tissue form of transglutaminase, suggesting that this enzyme is regulated in vivo by progesterone.     

基于经血源性子宫内膜干细胞的中枢神经系统疾病治疗的研究进展

干细胞研究已成为当今生命科学领域中的前沿和热点问题,该研究为探讨胚胎发生、组织细胞分化以及基因表达调控等生物学问题提供了理想的模型,同时也为临床组织缺陷性疾病和遗传性疾病的细胞治疗和基因治疗开辟了新的手段。其中,经血源性子宫内膜干细胞(Menstrual blood-derived stem cells,MenSCs)来源丰富,具有多向分化潜能和较低的免疫排斥的特性,可以实现个体化治疗,是临床最具有应用优势的干细胞。脑与脊髓作为中枢神经系统,其损伤极为常见,致死率和致残率居各类创伤之首。与周围神经系统损伤相比,中枢神经受损后恢复较为困难,其治疗仍缺乏突破。而MenSCs的治疗有希望解决此难题,故结合近年来国内外对MenSCs的生物学特性及其对中枢神经系统疾病治疗的研究作一综述,从而为中枢神经系统疾病的治疗提供参考。     

Generation of mesenchymal stem-like cells for producing extracellular vesicles

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with therapeutic potential against autoimmune diseases, inflammation, ischemia, and metabolic disorders. Contrary to the previous conceptions, recent studies have revealed that the tissue repair and immunomodulatory functions of MSCs are largely attributed to their secretome, rather than their potential to differentiate into desired cell types. The composition of MSC secretome encompasses cytokines and growth factors, in addition to the cell-derived structures known as extracellular vesicles (EVs). EVs are membrane-enclosed nanoparticles that are capable of delivering biomolecules, and it is now believed that MSC-derived EVs are the major players that induce biological changes in the target tissues. Based on these EVs’ characteristics, the potential of EVs derived from MSC (MSC-EV) in terms of tissue regeneration and immune modulation has grown during the last decade. However, the use of MSCs for producing sufficient amount of EVs has not been satisfactory due to limitations in the cell growth and large variations among the donor cell types. In this regard, pluripotent stem cells (PSCs)-derived MSC-like cells, which can be robustly induced and expanded in vitro, have emerged as more accessible cell source that can overcome current limitations of using MSCs for EV production. In this review, we have highlighted the methods of generating MSC-like cells from PSCs and their therapeutic outcome in preclinical studies. Finally, we have also discussed future requirements for making this cell-free therapy clinically feasible.     

Fear recognition across the menstrual cycle

This study assesses the mediating role of stage of menstrual cycle in the recognition of emotional expressions. It was hypothesised that fear recognition ability would be stronger at high-oestrogen stages of the menstrual cycle. The accuracy of recognising emotional expressions was compared across 50 women who were at different stages of their menstrual cycle. It was found that accuracy to recognise emotions was significantly affected by the interaction between stages of the menstrual cycle and the emotion being displayed. Further analysis revealed that for the emotion expression of fear alone, participants were significantly more accurate at the preovulatory surge (highest oestrogen levels) than at menstruation (oestrogen levels at lowest point). The results have implications for the processes that underlie fear processing and a possible insight into the sexual dimorphism of this ability and conditions that show variations in fear recognition (e.g., autism, Turner syndrome).     

Domain-specific variation in disgust sensitivity across the menstrual cycle

Disgust operates in many domains of behavior. On the presumption that facets of this emotion evince adaptive design, we conducted a cross-sectional study of 307 women, investigating changes in disgust sensitivity across the menstrual cycle. Two hypotheses were tested, namely (i) sexual disgust is an adaptation that serves to reduce participation in biologically suboptimal sexual behaviors, and (ii) many facets of disgust sensitivity compensate for cyclic changes in immunological robusticity via patterned alterations in behavioral prophylaxis against pathogens. Hypothesis (i) was supported, as disgust sensitivity in the sexual domain, and only in the sexual domain, was positively correlated with presumed conception risk as assessed on the basis of self-reported position in the menstrual cycle. Hypothesis (ii) was not supported, as no facet of disgust sensitivity changed as a function of the presumed level of immunosuppression assessed on the basis of self-reported position in the menstrual cycle. Results are discussed in light of published ethnographic evidence indicating that, in disparate cultures, disgust is elicited by aberrant sexual behaviors, and sex is equated with eating. Together with published findings on an animal model of sexual conditioning, this corpus suggests that sexual disgust may be a panmammalian adaptation.     

Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells

Human bone marrow mesenchymal stem cells (hMSCs) are a promising source for clinical stem cell transplantation. However, telomere regulation mechanisms, as one of the possible major mechanisms by which hMSCs sustain their stem cell characteristics, remain unknown. We isolated hMSCs by plastic adhesion and characterized these cells by morphology, immune phenotype and differentiation capacity. Telomerase was found negative in hMSCs, but slightly up-regulated in hMSC-derived adipocytes by the Telomeric Repeat Amplification Protocol (TRAP) assay. Moreover, hMSCs lack the alternative lengthening of telomeres (ALT) mechanism, because the hallmarks of ALT, such as very long and heterogeneous telomeres, extra-chromosome telomere repeat DNA (ECTR), and ALT-associated promyelocytic leukemia bodies (APBs), were not evident. However, when hMSCs were arrested in S phase with a combination of serum deprivation and aphidicolin, previously undetectable telomerase activity became predominantly positive. Meanwhile, the expression level of hTERT protein and mRNA increased, paralleled with the appearance of a large cohort of synchronized hMSCs at S phase. These findings provide a profile of telomere regulation by cell cycle dependent expression of telomerase in hMSCs and may lead to a better understanding of the stem cell nature of these cells.     

Isolation and characterization of porcine adult muscle-derived progenitor cells

Here, we report the isolation of progenitor cells from pig skeletal muscle tissue fragments. Muscle progenitor cells were stimulated to migrate from protease-digested tissue fragments and cultured in the presence of 5 ng/ml basic fibroblast growth factor. The cells showed a sustained long-term expansion capacity (>120 population doublings) while maintaining a normal karyotype. The proliferating progenitor cells expressed PAX3, DESMIN, SMOOTH MUSCLE ACTIN, VIMENTIN, CD31, NANOG and THY-1, while MYF5 and OCT3/4 were only expressed in the lower or higher cell passages. Myogenic differentiation of porcine progenitor cells was induced in a coculture system with murine C2C12 myoblasts resulting in the formation of myotubes. Further, the cells showed adipogenic and osteogenic lineage commitment when exposed to specific differentiation conditions. These observations were determined by Von Kossa and Oil-Red-O staining and confirmed by quantitative RT-PCR analysis. In conclusion, the porcine muscle-derived progenitor cells possess long-term expansion capacity and a multilineage differentiation capacity.     

Changes in the extracellular matrix of the normal human breast during the menstrual cycle

Summary The normal human mammary gland undergoes a well defined sequence of histological changes in both epithelial and stromal compartments during the menstrual cycle. Studies in vitro have suggested that the extracellular matrix surrounding the individual cells plays a central role in modulating a wide variety of cellular events, including proliferation, differentiation and gene expression. We therefore investigated the distribution of a number of extracellular matrix molecules in the normal breast during the menstrual cycle. By use of indirect immunofluorescence, with specific antibodies, we demonstrated that laminin, heparan sulphate proteoglycan, type IV collagen, type V collagen, chondroitin sulphate and fibronectin undergo changes in distribution during the menstrual cycle, whereas collagen types I, III, VI and VII remain unchanged. These changes were most marked in the basement membrane, sub-basement membrane zone and delimiting layer of fibroblasts surrounding the ductules where basement membrane markers such as laminin, heparan sulphate proteoglycan, and type IV and V collagens appear greatly reduced during the mid-cycle period (days 8 to 22). These results suggest that some extracellular matrix molecules may act as medittors in the hormonal control of the mammary gland, whereas others may have a predominantly structural role.     

Effects of the menstrual cycle on auditory event-related potentials

Gonadal steroids (estradiol and progesterone) can alter neuronal functioning, but electrophysiological evidence in women is still sparse. Therefore, the present study investigated event-related potentials (ERPs) to neutral stimuli over the course of the menstrual cycle. In addition, associations between ERPs and salivary estradiol and progesterone concentrations were investigated. Eighteen young healthy women were tested at three different phases of their menstrual cycle (menses, and follicular and luteal phases). ERPs (i.e., the N1 and P2 components, reflecting cortical arousal and the orienting response, the N2, P3, and the Slow Wave (SW), reflecting controlled processing) were measured using two different paradigms. In the luteal phase, early ERPs reflecting the cortical arousal response were diminished in the first stimulus block indicating an attenuated orienting response. These changes were significantly correlated with estradiol as well as progesterone levels. As to the later ERP components, the N2 latency was shorter during menses compared to the other two phases. No menstrual cycle-associated changes were apparent in other late ERP components. In sum, this study documents changes in auditory ERPs across the menstrual cycle with the most prominent changes occurring during the luteal phase. Future ERP studies therefore need to be more attentive to the issue of menstrual phase when studying female subjects or female patients.     

Effects of gender and phase of the menstrual cycle on the kinetics of ranitidine in healthy volunteers

The present study was undertaken to determine if differences exist in the pharmacokinetic parameters of oral ranitidine caused by gender and stage of the menstrual cycle. The study was performed in two steps, in the first a pharmacokinetic study was performed on 10 men (average age 35.5 yrs) and 10 women (average age 34.7 yrs) during the follicular phase, and in the second the pharmacokinetic study was performed only on the same women in their luteal phase. Subjects received a tablet dose of 300 mg ranitidine, and blood samples were drawn at several times after its ingestion. Plasma ranitidine concentration was determined by high performance liquid chromatography. Comparison of the pharmacokinetic parameters of women and men revealed statistically significant differences both in distribution volume (Vd) with values of 2.0 and 6.3 l/kg, Area Under Curve (AUC) with values of 7312.15 and 11471.94 ng/ml/h, and clearance (CLt) with values of 0.65 and 0.59 l/kg/h, respectively. Several pharmacokinetic parameters in women were different in the follicular compared to the luteal phase; for example, Vd was 2.0 and 5.6 l/kg, AUC was 7312.15 and 5195.83 ng/ml/h, and CLt was 0.65 and 0.97 l/kg/h, in the respective phases. Moreover, the maximum concentration (Cmax) was 1086 ng/ml in the follicular vs. 864 ng/ml in the luteal phase. The first study detected differences between men and women in several pharmacokinetic parameters, mainly those indicative of drug availability, for example, Vd, AUC, and CLt. Comparison of data obtained in the follicular phase with those obtained in the luteal phase revealed differences in most pharmacokinetic parameters, which is seemingly indicative of the characteristic physiological changes associated with the luteal phase that largely affect the kinetics and availability of drugs such as ranitidine. Although it has been postulated that hormonal fluctuation within the menstrual cycle phase is the primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs, further study of related factors is required to fully understand how gender and menstrual cycle rhythms affect the pharmacokinetic process in their entirety.     

Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression

To investigate whether depression is accompanied by changes in diurnal rhythms of free estradiol and cortisol in different phases of the menstrual cycle, we measured these two hormone levels in saliva samples collected every 2 h for 24 h from 15 healthy normally cycling women and 12 age-matched normally cycling women suffering from major depression taking antidepressants. The assessments were repeated four times over one menstrual cycle: during menstruation and in the late follicular/peri-ovulating, early to mid-luteal and late luteal phases, respectively. Quantification with a nonlinear periodic regression model revealed distinct diurnal rhythms in free estradiol and free cortisol in all subjects. For the diurnal cortisol rhythm, significant differences were found in the peak-width and ultradian amplitude among different menstrual phases, both in controls and depressed patients, while no significant differences were found between the two groups. The diurnal estradiol rhythm, on the other hand, was quite consistent among different menstrual phases within both groups, while the depressed patients had overall larger amplitudes than controls, which is negatively correlated with disease duration. Significant positive correlations between the two hormone rhythms were found for 24-h mean level (mesor), peak, and trough in late luteal phase, and for ultradian harmonics in early to mid-luteal phase in controls, but only for ultradian harmonics in late follicular/peri-ovulating phase and for acrophase in the menstruation phase in depressed patients. A sub-analysis was also performed in patients who received Fluoxetine (n = 7). The findings implicate a close correlation between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, both of which may be involved in depression.     

Women's attractiveness judgments of self-resembling faces change across the menstrual cycle

Two lines of reasoning predict that women's preferences for people exhibiting cues to kinship will be lower in the follicular phase than in the luteal phase of the menstrual cycle. Women may avoid kinship cues during the follicular phase when they are most fertile due to the costs of inbreeding. Alternatively, women may seek kinship cues during the luteal phase as a byproduct of the benefits of associating with kin during pregnancy, which is also characterized by high progesterone. We find that preferences for facial resemblance, a putative kinship cue, follow this predicted pattern and are positively correlated with estimated progesterone levels based on cycle day. Neither estimated estrogen levels nor conception risk predicted preferences for self-resemblance, and the cyclic shift was stronger for preferences for female faces than male faces. These findings lead to the possibility that this cyclic change in preference for self-resemblance may be a byproduct of a hormonal mechanism for increasing affiliative behavior toward kin during pregnancy rather than a mechanism for preventing inbreeding during fertile periods.     

Importance of an appropriate visual presentation for avoiding a misconception of the menstrual cycle

Family planning, the prevention of unwanted pregnancy, and women’s reproductive health are topics that have received close attention for decades. It would therefore be fair to assume that there exists a good knowledge of the menstrual cycle. However, it is clear that many people have various misconceptions about the menstrual cycle and fertile days or ovulation, and that this process is still largely taught with the aid of materials and images that have not changed for many years. We investigated the effect of moving away from the usual teaching practice of using a 28-day diagram showing ovulation on the 14th day. A total of 184 students from three different high schools, aged between 17 and 18, participated in this research. The students who were taught using three diagrams showing different durations of the menstrual cycle showed a significantly better adoption of the facts and concepts compared to the students who were taught using a diagram of the average 28-day cycle. Our results confirmed that it is highly important to use appropriate visual displays in the teaching of the menstrual cycle and that it is essential to enhance the visual literacy of students and teachers.     

The resting frontal alpha asymmetry across the menstrual cycle: a magnetoencephalographic study

Gonadotropic hormones play an important role in the regulation of emotion. Previous studies have demonstrated that estrogen can modulate appetitive (approach/positive) and aversive (avoidance/negative) affective behaviors during the menstrual cycle. Frontal alpha asymmetry (a measure of relative difference of the alpha power between the two anterior hemispheres) has been associated with the trait and state reactivity of different affective styles. We studied the pattern change of frontal alpha asymmetry across the menstrual cycle. 16 healthy women participated in this resting magneto-encephalographic (MEG) study during the peri-ovulatory (OV) and menstrual (MC) phases. Our results showed significant interaction of resting MEG alpha activity between hemispheric side and menstrual phases. Difference in spontaneous frontal alpha asymmetry pattern across the menstrual cycle was also noted. Relatively higher right frontal activity was found during the OV phase; relatively higher left frontal activity was noted during the MC phase. The alteration of frontal alpha asymmetry might serve a sub-clinical correlate for hormonal modulation effect on dynamic brain organization for the predisposition and conceptualization of different affective styles across the menstrual cycle.     

Influence of the menstrual cycle on the sweating response measured by direct calorimetry in women exposed to warm environmental conditions

The whole body sweating response was measured at rest in eight women during the follicular (F) and the luteal (L) phases of the menstrual cycle. Subjects were exposed for 30-min to neutral (N) environmental conditions [ambient temperature (Ta) 28 degrees C] and then for 90-min to warm (W) environmental conditions (Ta, 35 degrees C) in a direct calorimeter. At the end of the N exposure, tympanic temperature (Tty) was 0.18 (SEM 0.06) degrees C higher in the L than in the F phase (P less than 0.05), whereas mean skin temperature (Tsk) was unchanged. During W exposure, the time to the onset of sweating as well as the concomitant increase in body heat content were similar in both phases. At the onset of sweating, the tympanic threshold temperature (Tty,thresh) was higher in the L phase [37.18 (SEM 0.08) degrees C] than in the F phase [36.95 (SEM 0.07) degrees C; P less than 0.01]. The magnitude of the shift in Tty,thresh [0.23 (SEM 0.07) degrees C] was similar to the L-F difference in Tty observed at the end of the N exposure. The mean skin threshold temperature was not statistically different between the two phases. The slope of the relationship between sweating rate and Tty was similar in F and L. It was concluded that the internal set point temperature of resting women exposed to warm environmental conditions shifted to a higher value during the L phase compared to the F phase of the menstrual cycle; and that the magnitude of the shift corresponded to the difference in internal temperature observed in neutral environmental conditions between the two phases.