The role of the bacterial microbiota on reproductive and pregnancy health.

Recent assessments have examined the composition of bacterial communities influencing reproductive, pregnancy and infant health. The Microbiome Project has made great strides in sequencing the microbiome and identifying the vast communities of microorganisms that inhabit our bodies and much work continues to examine the individual contribution of bacteria on health and disease to inform future therapies. This review explores the current literature outlining the contribution of important bacteria on reproductive health among sexually active men and women, outlines gaps in current research to determine causal and interventional relationships, and suggests future research initiatives. Novel treatments options to reduce adverse outcomes must recognize the heterogeneity of the bacteria within the microbiome and adequately assess long-term benefits in reducing disease burden and re-establishing a healthy Lactobacillus-dominant state. Recognizing other reservoirs outside of the lower genital track and within sexual partners as well as genetic and individual moderators may be most important for long-term cure and reduction of disease. It will be important to develop useful screening tools and comprehensively examine novel therapeutic options to promote the long-term reduction of high-risk bacteria and the re-establishment of healthy bacterial levels to considerably improve outcomes among pregnant women and sexually active men and women.

CYP17 genotype modifies the impact of anthropometric variation on salivary estradiol in healthy women.

Several studies demonstrate that human ovarian function is responsive to the energetic environment, which has led to the development of theoretical models that explain this phenomenon. Although many genes are involved in ovarian hormone production, the possibility that genetic polymorphism may affect ovarian response to energetic conditions has not been considered. Cytochrome P450c17α is an enzyme that produces androgen precursors used to make estrogens during ovarian steroidogenesis, and is encoded by the CYP17 gene. A functionally significant variant within the promoter region of CYP17 has been linked to variation in steroid production, and some evidence suggests that this polymorphism could alter transcription of CYP17 in an insulin-dependent manner. We tested the hypothesis that the CYP17 variant affected the relationship between anthropometric measurements and salivary estradiol in healthy women in the United States (n = 28). PCR-RLFP analysis was used to genotype women for the genetic variant, and estradiol was assayed from saliva by EIA. Moderated regression analysis of these preliminary data revealed a significant interaction between waist-to-hip ratio and CYP17 genotype (P = 0.004). Our study provides evidence that gene-environment interactions should be considered in future adaptive models for human ovarian function. Moreover, our results stand to illuminate possible associations between this genetic variant and reproductive disease.

Gene x environment interactions impact endometrial function and the menstrual cycle: PROGINS, life history, anthropometry, and physical activity.

OBJECTIVES: We assessed the impact of a high frequency, functionally significant allelic variant of the progesterone receptor gene (PROGINS) on endometrial function and menstrual cycle characteristics. Further we asked whether PROGINS moderates the impact of life history characteristics, anthropometric measures, and physical activity on endometrial function. METHODS: Fifty-two women were genotyped for the PROGINS variant, provided life history information, and had anthropometric measurements made. Women monitored their menstrual bleeding for three cycles, performed mid-cycle urinary ovulation tests, and recorded physical activity. A subset of women provided daily saliva samples and had mid-luteal endometrial thickness measurements taken during the third menstrual cycle. Salivary progesterone was assayed using ELISAs. The direct impact of PROGINS on endometrial and menstrual cycle characteristics was determined via independent t-tests with Bonferroni correction. Interactions between PROGINS and covariates were assessed by moderated regression. RESULTS: PROGINS did not directly impact any indicator of endometrial function. However, PROGINS caused an increase in menstrual cycle length with increasing mid-luteal progesterone levels; the opposite relationship was present in noncarriers (P < 0.05). Additionally, PROGINS interacted with four of six anthropometric measures (BMI, waist circumference, height, and waist-hip ratio) to impact endometrial function, however, interactions between PROGINS and life history variables, or physical activity was limited. CONCLUSIONS: The gene x environment interactions we report suggest that PROGINS alters endometrial sensitivity to maternal energetic condition. Thus, the possibility of genetically-based variation in sensitivity to energetic stress should be considered in future adaptive models of women's reproduction.

Worldwide distribution of allelic variation at the progesterone receptor locus and the incidence of female reproductive cancers.

OBJECTIVES: Global patterns of the incidence of cancer are often attributed to environmental and lifestyle differences between regions. Less attention has been given to global patterns of allelic variation of genes that may contribute to the risk of developing cancer. METHODS: We genotyped samples from 21 populations for four variants of the progesterone receptor (PR) gene. One is an Alu insertion in intron 7 which defines the PROGINS haplotype. The others include a promoter region SNP 331+ G/A (rs10895068), a haplotype defining T/C substitution in intron 6 (rs561650), and an A/T substitution (rs608995) in the 3' untranslated region of the gene. All variants have been investigated elsewhere in association with female reproductive cancers in western populations. RESULTS: We found population differences in the frequency of each of these alleles across study populations (P < 0.01, log-likelihood G statistic, computed in FSTAT) and therefore examined the correlation between the frequency of each genetic variant and the incidence of three female reproductive cancers (breast, uterine, and ovarian) obtained from the Globocan 2008 database. Breast and ovarian cancer incidence were significantly correlated with the frequency of the Alu insertion (r = 0.86 and 0.53) and the +331 A variant (r = 0.57 and 0.73). CONCLUSIONS: Our data expand the information on genetic variation at the PR locus in non-western populations and support an argument for more work on the genetic epidemiology of cancer among nonwestern populations.

Dexamethasone enhances fertility and preovulatory serum prolactin levels in eCG/hCG primed immature rats.

Glucocorticoids have heterogeneous effects on reproductive function. We used a gonadotropin-primed, immature rat model to study the influence of dexamethasone (1 mg/kg), given during the latter stages of follicular development, on litter size, the number of oocytes released, and pituitary hormone levels. Dexamethasone-treated females released a larger number of oocytes at ovulation and gave birth to larger litters indicating the oocytes were viable. Survival to weaning age was not affected but average weight at weaning was lower for pups born to DEX-treated females. Serum FSH and LH were assayed at 12, 24 and 48 h following eCG and did not differ between dexamethasone-treated and control animals, but prolactin showed a prolonged pattern of elevation in DEX-treated females. Prolactin, which normally exhibits an elevation on proestrous, may modulate follicular development. Dexamethasone enhances fertility and fecundity possible through an effect of prolactin on follicle development, or by other direct effects on the ovary. These results may improve our understanding of the usefulness of DEX in assisted reproductive therapies for women.

Chronic hypoxia diminishes the proliferative response of Guinea pig uterine artery vascular smooth muscle cells in vitro.

The pregnancy-related size enlargement of the guinea pig uterine artery is partially accomplished by hyperplasia in all layers of the vessel wall. We sought to determine the separate and combined effects of chronic hypoxia and pregnancy on the proliferative capacity of uterine artery vascular smooth muscle cells (UA VSMCs). We established primary UA VSMC cultures from a total of 13 guinea pigs using an enzymatic digestion technique. Animals were bred and kept in normoxia or hypoxia (P(B) = 463 mmHg, simulated elevation = 3962 m) for 45 days, a duration equivalent to midpregnancy in the guinea pig 63-day gestation. Nonpregnant matched controls were included. The proliferative response of UA VSMCs to 1, 3, 5 or 7 days of serum stimulation in vitro was compared. Exposure to hypoxia reduced UA VSMC proliferative response to serum stimulation relative to that seen in cells harvested from normoxic females. The inhibitory effect was present both in cells harvested from nonpregnant and pregnant animals and resulted in a lower UA VSMC proliferative response in the cells harvested from hypoxic compared with normoxic pregnant animals. Our data were consistent with our hypothesis that chronic maternal hypoxia compromises the capacity for growth and remodeling of the uterine artery during pregnancy, perhaps by interfering with the ability of vascular smooth muscle cells to de-differentiate to a proliferative phenotype. Noteworthy was that such effects of chronic hypoxia were retained in cultured cells.

Human physiological adaptation to pregnancy: inter- and intraspecific perspectives.

Reproductive success requires successful maternal physiological adaptation to pregnancy. An interspecific perspective reveals that the human species has modified features of our haplorhine heritage affecting the uteroplacental circulation. We speculate that such modifications - including early implantation and deep, widespread invasion of fetal (trophoblast cells) into and resultant remodeling of maternal uterine vessels - are responses to or compensation for the biomechanical constraints imposed by bipedalism which, in turn, render our species susceptible to the pregnancy complication of preeclampsia. Preeclampsia is characterized by incomplete remodeling of maternal uterine vessels as the result of shallow trophoblast invasion, which in turn reduces uteroplacental blood flow and frequently leads to intrauterine growth restriction (IUGR). Using an intraspecific perspective, we consider the fitness-related consequences of variation in uteroplacental blood flow during high-altitude pregnancy. Although birth weights are reduced at high altitudes in Bolivia, multigenerational Andean residents are relatively protected from altitude-associated IUGR. Our preliminary data suggest that Andean women have greater uteroplacental oxygen delivery than European high-altitude residents due to more complete growth and remodeling of maternal uterine vessels. Identification of the physiological and genetic mechanisms involved in such inter- and intraspecific variations in pregnancy physiology will likely be useful for understanding human evolution and contemporary challenges to successful reproduction.

Inhibition of vascular endothelial growth factor/vascular permeability factor action blocks estrogen-induced uterine edema and implantation in rodents.

Estrogen induces a rapid increase in microvascular permeability in the rodent uterus, leading to stromal edema and a marked increase in uterine wet weight. This edema is believed to create an environment optimal for the growth and remodeling of the endometrium in preparation for implantation and pregnancy. Increased endometrial microvascular permeability also occurs in conjunction with implantation. Estrogen-induced uterine edema is immediately preceded by an increase in the expression of vascular endothelial growth factor (VEGF), a potent stimulator of microvascular permeability. The objective of this study was to determine to what degree immunoneutralization of VEGF would interfere with a) estradiol-induced uterine edema and b) pregnancy. In the first set of experiments, immature female rats were injected with either VEGF antiserum or normal rabbit serum (NRS) prior to 17beta-estradiol treatment. Rats treated with estradiol alone showed a 57% increase in uterine wet weight at 6 h compared with controls. Injection of 200 or 300 micro l of VEGF antiserum reduced the response to only 20% and 10% above controls, respectively. In the second set of experiments, young adult female mice were treated with 100 micro l of either VEGF antiserum or NRS at 1200 h on the fourth day after mating. NRS-treated mice had normal pregnancies. VEGF antiserum, however, completely blocked pregnancy. When VEGF antiserum-treated females were examined on Day 5 for the presence of implantation sites, none were found. These results show that a) VEGF is the major mediator of estrogen-induced increase in uterine vascular permeability and b) VEGF-induced edema is absolutely essential for implantation to take place.