Increased Estrogen Exposure Research Articles

Exploring New Links Among Keratoconus, Hormonal Factors, and Medications: Insights From a Case-Control Study Utilizing the All of Us Database.

We aimed to identify clinical factors associated with keratoconus (KC) risk in the All of Us database. This retrospective matched case-control study utilized patient data from the All of Us Research Program. All patients with a KC diagnosis (n = 572) were enrolled in the study and matched with three controls (n = 1716) based on age ± 1 year, race, ethnicity, and sex. The patients' medical histories, including diabetes, sleep apnea, obesity, smoking, ocular surface disease (encompassing dry eye, eczema, and allergic or atopic conjunctivitis), allergic rhinitis, pregnancy, estrogen-containing medications, tetracyclines, and vitamin C supplementation, were collected using electronic health records. Multivariable odds ratios (ORs) between KC and health history were calculated using the R programming language. The study included 2288 participants with an average age of 58.7 years. All included variables showed a significant positive correlation with KC except smoking history, which showed a negative correlation. The most significant correlations were ocular surface disease (OR = 6.04) and obesity (OR = 1.82). Significant positive associations were also identified for tetracyclines and estrogen-containing medications with KC. Smoking was negatively correlated. In addition to previously known risk factors, patients with a history of increased estrogen exposure and tetracycline usage were more likely to have a KC diagnosis whereas those with a smoking history were less likely. Understanding the risk factors for KC, including estrogen exposure and tetracycline medications, enhances our ability to identify at-risk patients and implement earlier screening, diagnosis, and interventions.

Predictive value of hemogram parameters in malignant transformation of the endometrium in patients with different risk factors.

To investigate whether the pretreatment hemogram parameters and their ratios can be used in predicting the endometrial transformation in patients with abnormal uterine bleeding. Records of all patients who underwent an endometrial histopathological evaluation between 2011 and 2021 were investigated. Hemogram, neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were analyzed. Chi square and Mann Whitney U tests were used for analysis. P<0.05 was considered statistically significant. 427 patients were included, of whom 117 were presented with endometrial hyperplasia without atypia (27.4%; mean age, 42±9.7; Group II), 70 with atypia (16.3%; mean age, 53.4±9; Group III), 102 with early endometrial cancer (EC) (23.8%; mean age, 63±7.8; Group IV) and 38 with advanced disease (8.8%; mean age, 63.3±10.5; Group V). Patients without pathology constituted the control group (23.4%; mean age, 42.2±9.5; Group I). Risk factors for atypia and carcinoma were determined as age, postmenopausal state, obesity, diabetes, and increased estrogen exposure (each, p<0.05). There was no significant difference in NLR and PLR (p>0.05). However, hemoglobin and hematocrit levels were higher in Groups IV and V (13.9 vs 13.1 mg/dL, and 39.1 vs 38.8%, respectively; p<0.01). Platelet value was significantly higher in Groups III to V (282x109/L, 283x109/L and 295x109/L; p<0.05, p<0.05 and p<0.01, respectively). Our findings support the impact of inflammation on malign transformation from normal endometrial mucosa to atypia and carcinoma. NLR and PLR values showed no statistical difference. Instead, thrombocytosis may have a predictive role in EC.

Single-Cell RNA Sequencing Reveals Novel Populations of Fibroblasts and Transcriptomic Changes Within Abdominal Skeletal Muscle in a Mouse Model of Aromatase-Induced Inguinal Hernia

Introduction: Inguinal hernia is a highly prevalent condition in men, of which the only currently available treatment is invasive surgical repair. An inguinal hernia often results from a protrusion of the intra-abdominal contents through a weakened region of the lower abdominal wall, but the etiology is unknown. One potential cause is aging-related steroid hormonal changes, which coincide with an increased incidence of hernia in aged men. Our group previously developed the first mouse model of inguinal hernia (AromHum) that is generated via the humanized expression of the enzyme aromatase, which converts androgens to estrogens. In the lower abdominal muscle (LAM), an aromatase-mediated increase in tissue estrogen causes fibroblast proliferation, fibrosis, and myocyte atrophy, resulting in hernias. However, the molecular mechanism of this phenotype remains unclear. In this study, we aimed to find genome-wide transcriptomic differences in AromHum compared to WT mice at a single-cell resolution. We hypothesized that in relation to WT mice, AromHum mice would have distinct fibroblast signatures that arise from the increased estrogen exposure to LAM tissue. Methods: LAM was harvested from 9-10-week-old male WT and AromHum mice (n=3 each) and digested into a single-cell suspension. Cells were processed via the 10X Genomics Chromium platform for single-cell RNA sequencing. The 6 samples combined yielded a total of ~63,000 cells. Data was analyzed using Cell Ranger v3, Seurat v3, Slingshot, and PROGENy R packages. Results: UMAP visualization of WT and AromHum LAM tissue revealed 22 cell clusters, which we grouped into 10 broad cell types through known marker gene expression. AromHum LAM contained a significantly higher proportion of fibroblasts than WT (44% vs. 27% of total analyzed cells), and AromHum fibroblasts expressed more pro-fibrotic genes, such as Timp1, Spon2, and Postn. In AromHum and WT combined, we found 6 clusters of fibroblast-like cells. Two of these clusters (clusters 2 and 3) were heavily represented by cells derived from AromHum mice (85-90% of cells in each cluster), which we termed “hernia-associated fibroblasts” (HAFs). Cluster 3 HAFs expressed high levels of Esr1 (gene encoding ERα), as well as estrogen-responsive genes such as Pgr and Greb1, and was enriched for estrogen, hypoxia, and TGFβ signaling pathways. Cluster 2 HAFs expressed genes associated with a pathological state, such as Lbp, Cthrc1, Mmp3, and Il33, and was enriched for the NF-κB and TNF-α signaling pathways. Conclusions: We found that LAM fibrosis in AromHum may result from the expansion of two distinct populations of HAFs - one is estrogen-responsive, and another is pathologic. Further in vitro / in vivo experiments are required to determine the relative contributions of these sub-populations of HAFs to fibrosis and inguinal hernias, leading to developing novel intervention strategies.

SUN-LB8 Cross Sex Hormone Therapy and Breast Cancer in Transgender Male to Female

Case Presentation: We are presenting a 53-year-old Male to Female transgender patient who has been receiving estradiol valerate injections every 14 days for 13 years and had no gender surgical reassignment procedures or breast implants. Her past medical history was significant for HIV on Highly Active Anti-retroviral therapy (HAART). No family history of breast cancer. She presented with severe bilateral left elbow, lower back and bilateral chest pain for 3 days. Chest CT done to exclude pulmonary embolism showed an incidental 4 cm right breast mass. Enlarged lymph nodes in the right axilla, scattered lytic lesions in the axial skeleton and the left humeral head were also noted. Breast exam was not performed until the significant findings were seen in CT chest and it showed a palpable hard-circumscribed subareolar right breast mass without skin changes. Ultrasound guided biopsy of the breast mass confirmed invasive ductal carcinoma of the breast. The patient had no previous mammogram testing. Oncology work-up was positive for estrogen and progesterone receptors but negative for human epidermal growth factor-2 receptor. The patient opted to return home in another state to seek treatment and further oncological workup but subsequently lost follow up. Discussion: Male to female breast cancer was first recognized in 1968. However, risk factors for this condition remain unclear. In our patient, long-term use of Cross-sex Hormone Therapy (CHT) represented a major risk factor for breast cancer. In a Dutch study, the risk of breast cancer increased during a relatively short duration of CHT and the cancer characteristics reassembled female pattern. As theoretically implicated, increased estrogen exposure in males may have a role in the proliferation of neoplastic breast epithelium. There are growing evidence to support increasing rates of breast cancer in HIV-positive population, making it a potential risk factor as well. Loss of CXCR-4 protective effect promoted by HIV virus may explain the increase in the breast cancer incidence after the introduction of HAART. In general, routine screening for breast cancer in MTF transgender population remains controversial. The Endocrine Society Clinical Practice guidelines suggest that MTF transsexual individuals who have no known increased risk of breast cancer should follow screening guidelines for biological women. While the Canadian Cancer Society recommends screening mammography every two years for MTF individuals taking CHT for more than 5 years and those between the ages of 50 and 69 years. Conclusion:Breast cancer in MTF transgender patients is associated with receiving CHT and represents diagnostic and treatment challenge. More research is need to comment on routine breast cancer screening in this population. However, physicians should remember performing a regular breast exam in MTF individuals looking for a possible mass.

FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

Predisposing factors to post-operative adhesion development

Adhesion development is the most common sequelae of intra-abdominal and pelvic surgery and represents a significant, yet poorly understood, cause of morbidity among post-operative patients. It remains unclear, for example, exactly why adhesions form more frequently in certain tissues and/or patients, or at specific locations within them, as opposed to others. This review contributes to the growing knowledge pool by elucidating factors that potentially predispose to the development of adhesions. Given the strong correlation between a hypofibrinolytic state and adhesion formation, this review article will examine not only those factors that have been shown to directly predispose to adhesion development, but also those that are likely do so indirectly by means of altering the coagulation/fibrinolytic profile. A literature search was performed using the PubMed database for all relevant English language articles up to February 2014. All of the identified articles were reviewed with particular attention to predisposing factors to post-operative adhesion development. In addition, the reference lists of each article were reviewed to identify additional relevant articles. Various factors have been shown to directly increase the risk of post-operative adhesion development; namely, certain genetic polymorphisms in the interleukin-1 receptor antagonist, increased estrogen exposure, and endometriosis. In addition, numerous factors are known to increase the risk of fibrosis, therefore likely increasing the risk of adhesion development indirectly. These factors include genetic polymorphisms in plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, diabetes mellitus, metabolic syndrome, hyperglycemia, obesity, depression, binge alcohol consumption, anti-Parkinsonian medications, oral hormone therapy, pregnancy, and cancer. The literature reviewed in this paper will help to direct future research aimed at understanding the mechanisms that underlie the association of certain factors with adhesion development. This information will be crucial in the creation of adequate preventative and treatment strategies.

Reproductive Factors, Exogenous Hormones, and Pancreatic Cancer Risk in the CTS

Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995-1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995-1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.

Falling sperm counts twenty years on: where are we now?

Poor semen quality is an attribute of the human condition that we share with our closest primate ancestors and may be part of our evolutionary inheritance. This characteristic may also reflect the lack of selection pressure on male fertility in advanced societies that have gone through the demographic transition. In the future, such trends may be further exacerbated by the widespread use of ART, which will impair the elimination of low fecundity genotypes from the human gene pool. Environmental pollutants may also be influencing male fertility, however, neither the chemical identity of these factors nor their mechanism-of-action are fully understood. Over 20 years ago, Carlsen et al.1 published a highly cited paper in the British Medical Journal which purported to detect a significant decline in sperm counts over a period of 60 years (1934–1996). This was followed shortly afterwards by the Skakkebaek and Sharpe hypothesis,2 published in Lancet, which argued that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, citing maternal exposure to diethylstilbestrol (DES) during pregnancy as evidence for such a link. These classic papers have now become inextricably linked in the global consciousness and have led to a public misconception that male fertility is declining as a consequence of fetal exposure to environmental estrogens.3 In the 20 years that have elapsed since these landmark papers were published, a great deal of data has appeared that seem to support and refute their validity in equal measure, resulting in a state of confusion. The European Science Foundation4 has recently published a review of the current status of male reproductive health. Using this summary as a guide we are now in an excellent position to dissect some of the key arguments and formulate questions for future consideration.

MR and CT findings of leiomyomatosis peritonealis disseminata with emphasis on assisted reproductive technology as a risk factor

Leiomyomatosis peritonealis disseminata (LPD) is a rare benign smooth muscle tumour located in the peritoneal cavity. Increased oestrogen exposure appears to be an aetiological factor for LPD. We report two cases of LPD after leiomyomectomy and assisted reproductive technology pregnancy, which can cause a high serum concentration of oestrogen. CT and MR scanning demonstrate many intraperitoneal well-demarcated nodules of varying size that mimic widespread intraperitoneal malignancy.

Polymorphisms in DNA double-strand break repair genes and breast cancer risk.

Enhanced chromosomal radiosensitivity (CR) has been observed in a significant number of breast cancer patients. Since ionising radiation induces double-strand breaks (DSB), polymorphisms in DSB repair genes could be involved in genetic predisposition to breast cancer. A family history of breast cancer is a well known risk factor for the disease. Other risk factors are also associated with breast cancer, such as early age of first menarche, nulliparity or late first childbirth, and late menopause. The principle culprit common for these risk factors is said to be the prolonged exposure to elevated levels of estrogens. As non homologous end-joining (NHEJ) is the major DSB repair pathway in mammalian cells, we investigated the association of 5 SNPs in 3 different NHEJ genes with breast cancer in a population-based case-control setting. The total patient population was composed of a selected group of patients with a family history of the disease and an unselected group. CR was previously studied in both patient groups. SNP analysis showed that the c.2099-2408G>A SNP (Ku80) has a significant odds ratio (OR) of 2.81 (95% confidence interval (CI): 1.30-6.05) for the heterozygous (He) and homozygous variant (HV) genotypes in the group of familial patients. The He+HV genotypes of the c.2099-2408G>A SNP (Ku80) also showed high and significant ORs in the group of radiosensitive, familial breast cancer patients (OR=4.62 ,95%CI: 1.28-16.74). For the c.-1310 C>G SNP (Ku70) a significant OR of 1.85 (95%CI: 1.01-3.41) was found for the He genotype in the unselected patient group. For the radiosensitive, unselected patients, increased, but non-significant ORs were observed. The c.-1310 C>G SNP (Ku70) SNP exhibits significant results in the unselected patient group only, indicating an influence of other, environmental factors besides genetic factors. As breast epithelium is exposed to endogenous oxidative stress through increased estrogen exposure, the possible effect of hormone exposure was examined in an enlarged, unselected patient population (OR enlarged population =1.68, 95%CI:1.09-2.60). The ORs of the c.-1310 C>G SNP (Ku70) SNP for patients with a longer estrogen exposure were high and significant (early menarche: OR=1.85, 95%CI:1.20-2.92; late menopause: OR=1.94, 95%CI:1.08-3.51) while the ORs for patients with a short hormone exposure were lower and non-significant. These results provide preliminary evidence that the variant allele of c.-1310C>G (Ku70) and c.2099-2408G>A (Ku80) are risk alleles for breast cancer as well as CR. Furthermore, the association of c.-1310C>G (Ku70) with breast cancer risk was stronger in women with a long estrogen exposure.

The origins of oestrogen receptor negative breast cancer

The origins of oestrogen receptor negative breast cancer

ROLE OF OESTROGEN IN THE CENTRAL REGULATION OF AUTONOMIC FUNCTION

1. In recent years, the role of oestrogen in women's health has been a subject of considerable scientific and popular debate. There is unquestionable evidence that oestrogen has both potent and long-lasting effects on several vital organ systems, including the cardiovascular system, the autonomic nervous system and, most recently, within the central nervous system itself. 2. The research and medical community continues to debate whether the benefits of oestrogen therapy outweigh the risks in the treatment of the symptoms of menopause, the attenuation of the risk for cardiovascular insults, such as stroke and heart disease, and even the retardation of the progression of Alzheimer's disease. 3. The recent evidence provided by the Heart and Estrogen/Progestin Replacement Study (HERS) II clinical trial suggesting that long-term exposure to combined oestrogen and progestin in post-menopausal women who have previously had a heart attack or stroke (for secondary prevention) may actually increase their risk of a subsequent cardiovascular insult has further fuelled the debate. However, there remain considerable gaps in our knowledge with respect to the actual mechanisms by which oestrogen exerts its various beneficial effects at the cellular level for the primary prevention of cardiovascular disease. This information is essential if we are to harness the positive aspects of oestrogen therapy in such a manner as to avoid or minimize the associated risks of increased oestrogen exposure in women who we know, with some certainty, to be at an increased risk of cancers of the uterus, cervix and breast tissue.

Clinical factors used to support prophylactic mastectomy for a male BRCA2 mutation carrier

Male breast cancer accounts for less than 1% of male cancers and of all diagnosed breast cancers in the United States. Male breast cancer is treated with mastectomy and, more recently, mastectomy combined with sentinel node surgery. For female BRCA gene mutation carriers requiring mastectomy, the use of prophylactic mastectomy for the contralateral breast is well supported. Whether this should be done for male BRCA mutation carriers has not yet been established. This case report describes the treatment of a male with a known BRCA2 mutation who was found to have breast cancer and had an opposite side prophylactic mastectomy at the time of his breast cancer surgery. His tumor was strongly estrogen receptor positive and moderately progesterone receptor positive, and his estradiol level was elevated. Increased estrogen exposure is a probable risk factor for breast cancer in men and women. Examples of conditions leading to hyperestrogenism in males include cirrhosis of the liver and genetic syndromes such as Klinefelter Syndrome. Some studies support the use of a single measurement of bioavailable estradiol to stratify women into risk categories for breast cancer, although not all re-

Anthropometry and the risk of epithelial ovarian cancer

The association between anthropometric factors and ovarian cancer risk was investigated using data from 762 cases and 1348 controls participating in a population-based case-control study in the Delaware Valley from 1994-1998. Because factors such as oral contraceptive (OC), hormone therapy (HT), and parity may affect weight and hormone levels, the associations were examined in women with and without these characteristics. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals while controlling for age, race, parity, family history of ovarian cancer, tubal ligation, and OC use. Compared with controls, cases were taller and heavier in recent years and at age 18. Results did not differ by OC or HT use. However, anthropometric associations differed significantly based on parity, as increasing anthropometric measures were associated with increased ovarian cancer risk among nulliparous women only. Adjusted OR for recent body mass index (BMI) quartile 4 compared with quartile 1 for nulliparous women was 2.53 (95% confidence interval [CI]: 1.39, 4.61) compared with 0.96 (95% CI: 0.70, 1.31) for parous women. Additionally, adult weight gain was significant only for nulliparous women. Adjusted OR for weight change (recent to age 18) quartile 4 compared with quartile 1 for nulliparous women was 3.73 (95% CI: 1.88, 7.42) versus 1.09 (95% CI: 0.78, 1.51) for parous women. BMI and weight in women's adult lifetime may be positively associated with ovarian cancer risk. Observations were most apparent for nulliparous women, possibly reflecting an interaction between local inflammation caused by incessant ovulation and increased estrogen exposure on ovarian epithelium.

Spotlight

Cheng et al., pp.345–353 Prolonged exposure to estrogens can induce tumors in laboratory animals and has been associated with breast and uterine cancers in humans. The proliferative effect of estrogen on breast epithelium is part of the mechanism. In addition, recently surfaced evidence demonstrated that estrogen metabolites can cause DNA damage and mutations, an important step in tumor initiation. Oxidation of two catechol estrogen (CE) metabolites, 4-hydroxyestradiol and 4-hydroxyestrone, generates quinone intermediates. They can react with purine bases to form DNA adducts that generate highly mutagenic apurinic sites; CEs can also generate oxygen radicals and DNA double strand breaks (DSB). Cheng et al. examined whether breast tumorigenesis is linked to inherited variants in five genes that are involved in detoxifying pathways of estrogen metabolites. Women harboring a greater number of high-risk genotypes of CE-metabolizing genes faced an increased risk of breast cancer. This trend was more pronounced in women who had never been pregnant or older at their first full-term pregnancy and therefore at greater risk for breast cancer. Cheng also examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes. They found that a joint effect was significantly associated with breast cancer development. This study supports the hypotheses that increased estrogen exposure confers a higher risk of breast cancer, in part caused by DSB in DNA. Brennetot et al., pp.446–450 High-frequency microsatellite instability (MSI-H) is due to either insertion or deletion of repetitive sequences during DNA replication and failure of the mismatch repair system (MMR) to correct these errors. As a consequence, MMR-deficient tumors accumulate thousands of small mutations genome-wide. Almost all tumors from patients with human non-polyposis colorectal cancer (HNPCC) are MMR deficient, as are 10–15% of sporadic colorectal, gastric and endometrial cancers.2 Allelic profiles of BAT-26 and BAT-25 obtained by independent fluorescent PCR of these markers. MSI-H tumors differ from microsatellite-stable (MSS) tumors in molecular and in clinicopathological attributes. Generally, patients with MSI-H tumors are reported to have a better clinical outcome than patients with MMR-proficient tumors. Hence, screening of all human tumors where the MSI phenotype is frequent would not only allow the treatment to be custom-tailored but also assist in the diagnosis of ambiguous HNPCC cases. The present study demonstrates that together the markers BAT-25 and BAT-26, two mononucleotide repeats widely used as part of a larger set of markers, are sensitive enough to establish the MSI status of human tumors. Furthermore, they can detect instability when the tumor cell content of a sample is as low as 5–10%. This observation is very important in the context of proposed regular MSI screening for all colorectal, gastric and endometrial cancers. Not only might fewer markers than the routinely suggested panel of five suffice to reliably establish the microsatellite status of tumors, the labor-intensive and time-consuming process of enriching tumor cells in contaminated samples may only be required in a small subset of biopsies. Merchan et al., pp.490–498 Most angiogenesis inhibitors were developed intentionally to interrupt new blood vessel formation. In an unexpected twist, the antiangiogenic activity of several cytotoxic agents was discovered accidentally, among them the widely used chemotherapeutic paclitaxel. In addition to its well-known microtubule-interfering effect, paclitaxel inhibits endothelial cell (EC) migration, invasion, capillary tube formation and proliferation at low concentrations in vitro. In vivo, it significantly reduces microvessel density and decreases vascular endothelial growth factor (VEGF) production. While paclitaxel's effects on ECs are well studied and clinical trials investigating its antiangiogenic potential are underway, the underlying mechanism has not yet been elucidated. Based on the latest results by Merchan et al. it appears that an approximately fivefold increased ability of human ECs to accumulate the drug when compared to other cell types is responsible for the enhanced sensitivity of ECs. However, at the same time low concentrations of paclitaxel upregulate the expression of Cox-2, an enzyme also known for its angiogenesis-stimulating activity. Combined treatment with the specific Cox-2 inhibitor celecoxib resolved the undesirable dichotomy and resulted in more pronounced antiendothelial effects than applying either compound alone. These findings could be extended to a clinical setting, where four patients with prostate cancer or malignant melanoma were treated with prolonged intravenous infusions of paclitaxel and celecoxib. The potent antiangiogenic activity observed in plasma specimens suggests that a combination treatment may be an attractive strategy to capitalize on the intrinsic antiangiogenic and cytotoxic effects of each agent alone.

The 'oestrogen hypothesis'- where do we stand now?

The original 'oestrogen hypothesis' postulated that the apparent increase in human male reproductive developmental disorders (testis cancer, cryptorchidism, hypospadias, low sperm counts) might have occurred because of increased oestrogen exposure of the human foetus/neonate; five potential routes of exposure were considered. This review revisits this hypothesis in the light of the data to have emerged since 1993. It addresses whether there is a secular increasing trend in the listed disorders and highlights the limitations of available data and how these are being addressed. It considers whether new data has emerged to support the suggestion that increased oestrogen exposure could cause these abnormalities and reviews new data on potential routes via which such increased exposure could have occurred. Secular trends: The disorders listed above are now considered to represent a syndrome of disorders (testicular dysgenesis syndrome, TDS) with a common origin in foetal life. Testicular cancer has increased in incidence in Caucasian men worldwide and lifetime risk is 0.3-0.8%. Secular trends in cryptorchidism are unclear but it is by far the commonest (2-4% at birth) congenital abnormality in either sex. Secular trends for hypospadias are not robust, although most studies suggest a progressive increase; registry data probably under-estimates incidence, but based on this data hypospadias is the second most common (0.3-0.7% at birth) congenital malformation. Retrospective analyses of sperm count data show a global downward trend but this is inconclusive - prospective studies using standardized methodology show significant differences between countries and very low sperm counts in the youngest cohort of men. For all disorders, other then testis cancer, standardized prospective studies are the best way forward and are in progress across Europe. Oestrogen effects: Evidence that foetal exposure to oestrogens can induce the above disorders has strengthened. New pathways via which such changes could be induced have been identified, including suppression of testosterone production by the foetal testis, suppression of androgen receptor expression and suppression of insulin-like factor-3 (InsL3) production by foetal Leydig cells. Other evidence suggests that the balance between androgen and oestrogen action may be important in induction of reproductive tract abnormalities. Oestrogen exposure: Although many new environmental oestrogens have been identified, their uniformly weak oestrogenicity excludes the possibility that they could induce the above disorders. However, emerging data implicates various environmental chemicals in being able to alter endogenous levels of androgens (certain phthalates) and oestrogens (polychlorinated biphenyls, polyhalogenated hydrocarbons), and the former have been shown to induce a similar collection of disorders to TDS. Other mechanisms via which increased fetal exposure to pregnancy oestrogens might occur (increasing trend in obesity, dietary changes) are also discussed.

ELEVATED PLACENTAL ESTRADIOL: A POSSIBLE ETIOLOGICAL FACTOR OF HUMAN CRYPTORCHIDISM

It has been convincingly argued that the increasing incidence of reproductive abnormalities in human males may be associated with increased estrogen exposure during gestation. We documented the expression of estradiol in the syncytiotrophoblast and placenta of males born with cryptorchidism and normal genitalia, respectively. Tissue from newborn placentas was fixed in glutaraldehyde and embedded in ePON for immunohistological procedures. Cryptorchidism was unilateral in 6 males and bilateral in 1. Semithin histological sections of placental biopsies of these 7 males and 7 randomly selected, normal male placentas were analyzed immunohistochemically with a polyclonal anti-estradiol-17 beta, 6-keto antibody. The weak expression of estradiol in the placentas of normal males was localized predominantly at the basal part of the syncytiotrophoblast in the terminal placental villi. In contrast, all placentas of cryptorchid males had strong expression of estradiol at the basal portion of the syncytiotrophoblast. The increased expression of estradiol in the syncytiotrophoblast may have an impact on testicular descent.

Junctional tachycardia and the role of catheter ablation

The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy. We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur

Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?

The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy. We argue that the increasing incidence of reproductive abnormalities in the human male may be related to increased oestrogen exposure in utero, and identify mechanisms by which this exposure could occur.

Factors influencing estrogen production and metabolism in postmenopausal women with endocrine cancer.

The role which steroid hormones play in the development and maintenance of human cancer is a problem which has attracted the attention of research investigators for many years. Oestrogens have come under particular scrutiny, since there is a good deal of indirect evidence that altered oestrogen production may be protective in some situations (e.g. the diminished risk of female breast cancer conferred by earlier castration) and disadvantageous in others (e,g, the enhanced risk of endometrial cancer attributable to increased oestrogen exposure in women bearing oestrogen-secreting tumours). Furthermore, in the last decade or so, studies of cellular receptors have clearly delineated the importance of oestrogens amongst other hormones in the maintenance of tumour growth. It is therefore entirely logical to investigate oestrogen metabolism in detail in the hope and expectation that some metabolic abnormality exists in women who are predisposed to these types of endocrine cancer, which may be revealed by careful biochemical examination. As a group, postmenopausal women are particularly important in this context, not only because of the increased incidence of breast and endometrial cancer at and around the menopause, but because it is at this time that major changes occur in the endocrine milieu which may relate directly to the risk of developing cancer.