Relationship of Estradiol and Progesterone with Partnership and Parity Among Bangladeshi and British Women of European Origin.

Recent studies in social endocrinology have explored the effects of social relationships on female reproductive steroid hormones-estradiol and progesterone-investigating whether they are suppressed in partnered and parous women. Results have been mixed for these hormones although evidence is more consistent that partnered women and women with young children have lower levels of testosterone. These studies were sequential to earlier research on men, based on Wingfield's Challenge Hypothesis, which showed that men in committed relationships, or with young children, have lower levels of testosterone than unpartnered men or men with older or no children. The study described here explored associations between estradiol and progesterone with partnership and parity among women from two different ethnicities: South Asian and white British. We hypothesized that both steroid hormones would be lower among partnered and/or parous women with children ≤3 years old, regardless of ethnicity. In this study we analyzed data from 320 Bangladeshi and British women of European origin aged 18 to 50 who participated in two previous studies of reproductive ecology and health. Levels of estradiol and progesterone were assayed using saliva and/or serum samples and the body mass index calculated from anthropometric data. Questionnaires provided other covariates. Multiple linear regressions were used to analyze the data. The hypotheses were not supported. We argue here that, unlike links between testosterone and male social relationships, theoretical foundations for such relationships with female reproductive steroid hormones are lacking, especially given the primary role of these steroids in regulating female reproductive function. Further longitudinal studies are needed to explore the bases of independent relationships between social factors and female reproductive steroid hormones.

Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing.

BACKGROUND: Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. RESULTS: Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women's buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. CONCLUSIONS: SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

No impact of developmental conditions on serum estradiol levels among Bangladeshi women in the UK and Bangladesh.

INTRODUCTION: While many aspects of female ovarian function respond to environmental stressors, estradiol (E2) appears less sensitive to stressors than progesterone, except under extreme ecological conditions. However, earlier studies relied on saliva samples, considered less sensitive than blood. Here, we investigated E2 variation among 177 Bangladeshi and UK white women, aged 35-59, using single serum samples. Bangladeshi women either grew up in Sylhet, Bangladesh (exposed to poor sanitation, limited health care, and higher pathogen loads but not poor energy availability), or in the UK. METHODS: We collected samples on days 4-6 of the menstrual cycle in menstruating women and on any day for post-menopausal women. Participants included: (i) Bangladeshi sedentees (n = 36), (ii) Bangladeshis who migrated to the UK as adults (n = 52), (iii) Bangladeshis who migrated as children (n = 40), and (iv) UK white women matched for neighborhood residence to the migrants (n = 49). Serum was obtained by venipuncture and analyzed using electrochemiluminescence. We collected anthropometrics and supplementary sociodemographic and reproductive data through questionnaires. We analyzed the data using multivariate regression. RESULTS: E2 levels did not differ between migrant groups after controlling for age, BMI, physical activity, psychosocial stress, parity, and time since last birth (parous women). Paralleling results from salivary E2, serum E2 did not differ among women who experienced varying developmental conditions. CONCLUSION: Our results reinforce the hypothesis that E2 levels are stable under challenging environmental conditions. Interpopulation variation may only arise under chronic conditions of extreme nutritional scarcity, energy expenditure, and/or high disease burdens.

Hot flushes and reproductive hormone levels during the menopausal transition.

INTRODUCTION: Evidence suggests that hot flushes are associated with fluctuating levels of oestradiol (E2) during menopause, as well as changes in the levels of follicle-stimulating hormone (FSH) and inhibin B. The relationship between hot flushes and anti-Müllerian hormone (AMH) is unknown. AIM: To examine specific hormone levels and ethnic differences in relation to hot flushes. METHODS: Data were drawn from 108 women aged 40-59 years. There were three groups of participants: European women in London, UK; Bangladeshi women in Sylhet, Bangladesh; and Bangladeshi women who had migrated to London as adults. Symptom information was collected via questionnaires. Serum blood samples were collected to detect inhibin B, AMH, FSH, and E2. RESULTS: AMH and FSH were significantly associated with the experience of hot flushes in the past 2 weeks. Inhibin B and E2 were not associated with hot flushes. Body mass index (BMI), ethnicity, and education level were associated with both the occurrence and the frequency hot flushes. Menopausal status was also associated with the frequency of hot flushes. CONCLUSION: Relationships between AMH, FSH and symptoms are indicative of women's progress through the menopausal transition. The influence of BMI and education suggest that lifestyle changes may contribute to the management of symptoms. This merits further research.

The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety.

The conjugated estrogen /: bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen-target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor α (ERα)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ERα interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERα-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERα protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERα-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERα interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERα protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERα inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein.

A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis.

Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.

Vasopressin-like peptide and its receptor function in an indirect diuretic signaling pathway in the red flour beetle.

The insect arginine vasopressin-like (AVPL) peptide is of special interest because of its potential function in the regulation of diuresis. Genome sequences of the red flour beetle Tribolium castaneum yielded the genes encoding AVPL and AVPL receptor, whereas the homologous sequences are absent in the genomes of the fruitfly, malaria mosquito, silkworm, and honeybee, although a recent genome sequence of the jewel wasp revealed an AVPL sequence. The Tribolium receptor for the AVPL, the first such receptor identified in any insect, was expressed in a reporter system, and showed a strong response (EC(50)=1.5 nM) to AVPL F1, the monomeric form having an intramolecular disulfide bond. In addition to identifying the AVPL receptor, we have demonstrated that it has in vivo diuretic activity, but that it has no direct effect on Malpighian tubules. However, when the central nervous system plus corpora cardiaca and corpora allata are incubated along with the peptide and Malpighian tubules, the latter are stimulated by the AVPL peptide, suggesting it acts indirectly. Summing up all the results from this study, we conclude that AVPL functions as a monomer in Tribolium, indirectly stimulating the Malpighian tubules through the central nervous system including the endocrine organs corpora cardiaca and corpora allata. RNA interference in the late larval stages successfully suppressed mRNA levels of avpl and avpl receptor, but with no mortality or abnormal phenotype, implying that the AVPL signaling pathway may have been near-dispensable in the early lineage of holometabolous insects.

Synthesis of antimalarial yingzhaosu A analogues by the peroxidation of dienes with Co(II)/O2/Et3SiH.

Co(II)-catalyzed peroxidation of dienes including (S)-limonene in the presence of molecular oxygen and triethylsilane provided in each case the corresponding 2,3-dioxabicyclo[3.3.1]nonane derivatives via the intramolecular cyclization of the unsaturated peroxy radical intermediates. The product composition was remarkably influenced by the structure of the dienes, the nature of the solvents, and the concentration of the substrates and the catalyst. Some of the yingzhaosu A analogues obtained in this study showed notable antimalarial activities in vitro.

Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite.

Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4' '- and 6' '-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1' '-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.

Antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes.

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide and a 1,omega-diiodoalkane to provide the tricyclic peroxides 12. Trimethylsilylation of 3 followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 14 containing a 1,2,4,5-tetroxepane structure. Photooxygenation of 1 in the presence of either unsaturated hydroperoxides or unsaturated alcohols followed by bis(collidine)iodine hexafluorophosphate promoted cyclization gave the corresponding cyclic peroxides 15-17. Several of these cyclic peroxides showed substantial antimalarial activity particularly in vitro.

New semisynthetic quassinoids with in vivo antimalarial activity.

On the basis of a comparative analysis for stability in mouse serum between 15-O-acetylbruceolide and bruceolide 15-methyl carbonate, several 3,15-dialkyl carbonates of bruceolide were synthesized and their in vitro antimalarial activity was assessed. Methyl, ethyl, and isopropyl carbonates with pronounced in vitro activity were further evaluated for in vivo antimalarial potency. Both the methyl and ethyl carbonates significantly increased the life span of mice as compared with 3,15-di-O-accetylbruceolide and chloroquine.