Christian J. Gruber

Anatomy of the estrogen response element

Estrogens exert their regulatory potential on gene expression through different nuclear and non-nuclear mechanisms. A direct nuclear approach is the interaction of estrogen with specific target sequences of DNA, estrogen response elements (ERE) or units. EREs can be grouped into perfect and imperfect palindromic sequences with the imperfect sequences differing from the consensus sequence in one or more nucleotides and being less responsive to the activated estrogen-estrogen receptor (ER) complex. Differences in the ERE sequence and the ER subtype involved can substantially alter ER-ERE interaction. In addition, cross-talk between ERs and other nuclear transcription factors profoundly influences gene expression. Here, we focus on the recent advances in the understanding of the structure of EREs and how ERs are recruited to these. Identifying known target genes for estrogen action could help us to understand the potential risks and benefits of the administration of this steroid to humans.

Does the mode of delivery influence sexual function after childbirth

OBJECTIVE The aim of the study was to evaluate the influence of the mode of delivery on female sexuality 12-18 months after childbirth. METHODS Fifty-five primiparae who delivered vaginally without complication and 44 who underwent elective cesarean section after 37 weeks of gestation were included. Sexual function was assessed by a validated self-reported questionnaire, the Female Sexual Function Index (FSFI), 12 months after birth and compared between groups. Additionally, we have analyzed subjective stress variables recorded after birth between the two groups. RESULTS Women with cesarean section were older (p = 0.002) and had a higher body mass index (BMI) (p =0.02). The total score of the FSFI was not significantly different between the groups. Patients recall of dyspareunia at 3 months after childbirth was higher in those who underwent vaginal delivery (p < 0.001). CONCLUSIONS We suggest that there is no significant difference in sexual function 12-18 months after childbirth between women who delivered vaginally without episiotomy, heavy perineal laceration, or secondary operative interventions and women who underwent elective cesarean section.

Body Mass Index, Follicle-Stimulating Hormone and Their Predictive Value in In Vitro Fertilization

Purpose:The objective was to explore whether body mass and day 3 follicle-stimulating hormone have predictive value on odds of pregnancy after in vitro fertilisation. Few studies show that obesity produces a variety of alterations in the reproductive system, and that women with an elevation of day 3 FSH have declining ovarian function.Methods: The data of one-hundred-seventy-one women who underwent a standard regime of controlled ovarian hyperstimulation was analyzed with particular reference to variations in body mass and hormone levels.Results: By raising BMI and FSH (mIU/mL) by one unit, the odds for pregnancy were decreased by the respective factors 0.84 (95% confidence interval 0.73–0.97) and 0.77 (95% confidence interval 0.59–1.00).Conclusions: The results demonstrate that for the purpose of raising the odds of pregnancy BMI should be reduced. A low FSH value may cause the same effect. Nontheless, obesity and hormonal function may be independent risk factors for failure in assisted reproduction.

IL-8 concentrations in maternal serum, amniotic fluid and cord blood in relation to different pathogens within the amniotic cavity.

Abstract Objective: The association between elevated interleukin (IL)-8 concentrations in amniotic fluid and preterm delivery is well described. Little consideration has been given to the impact of different groups of microorganisms within the amniotic cavity on IL-8 concentration. Methods: We collected amniotic fluid, placental tissue and amniotic membranes during preterm cesarean sections for bacterial culture. In addition, we determined IL-8 concentrations in maternal serum, amniotic fluid and cord blood and correlated them with the various intra-amniotic pathogens isolated by bacterial culture. Results: IL-8 concentrations were determined in amniotic fluid in 107 cases, in cord blood in 185 cases and in maternal blood in 158 cases. Women with intra-amniotic Ureaplasma urealyticum infection had significantly higher amniotic fluid concentrations of IL-8 than those without (P<0.001). In cord blood, we found significantly elevated IL-8 concentrations due to intra-amniotic infection with U. urealyticum (P=0.045) and other pathogens (P=0.04). In maternal sera, we found no significant elevation of maternal IL-8 in any of the groups. Conclusion: Intrauterine infection with U. urealyticum seems to play a profound role in the cascade of inflammation and increases IL-8 concentrations in amniotic fluid and cord blood.

Gestational diabetes mellitus is associated with increased C-reactive protein concentrations in the third but not second trimester

Objective Serum C‐reactive protein (CRP) concentrations were measured longitudinally throughout pregnancy to test the hypothesis that CRP could relate more closely to glucose tolerance than to adiposity.

Calpain-10 haplotype combination and association with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a frequent complication of pregnancy. Epidemiologic and pathophysiologic data suggest a close link of this disease to non-insulin-dependent diabetes mellitus. Within the calpain-10 gene various single-nucleotide polymorphisms have been identified that increased the risk for non-insulin-dependent diabetes mellitus. Therefore, we examined single-nucleotide exchanges of this gene in women with GDM. METHODS: A total of 875 unselected women were prospectively screened for GDM. Eighty women of this population, 40 patients with an abnormal oral glucose tolerance test and 40 normal controls, were randomly selected. DNA samples isolated from sera of the control and study groups were analyzed with respect to single-nucleotide polymorphisms of the calpain-10 gene at positions 43, 19, and 63 using polymerase chain reaction amplification and restriction analysis. RESULTS: Women with GDM were more likely to be homozygous for the allele 1 of single-nucleotide polymorphism 63 (P = .02 by χ2 test). With respect to single-nucleotide polymorphisms 19 and 43, no significant differences in allele distribution were detected between controls and women with GDM. When comparing the different haplotypes for calpain-10 (single-nucleotide polymorphisms 43, 19, and 63), all women with the haplotype combination 121/221 (n = 8) had gestational diabetes (P = .005 by Fisher exact test). CONCLUSION: Our results indicate that the haplotype 121/221 of the calpain-10 gene may be associated with disturbances of glucose metabolism during pregnancy. LEVEL OF EVIDENCE: II-1

Plasminogen activator inhibitor 1 gene polymorphism and gestational diabetes mellitus.

OBJECTIVE: Plasminogen activator inhibitor 1 is thought to play a role in the pathogenesis of obesity and insulin resistance. Therefore, we examined a single nucleotide exchange in this gene in women with gestational diabetes mellitus. METHODS: A total of 887 unselected women were prospectively screened for gestational diabetes mellitus by oral glucose testing between the 24th and 28th weeks of gestation. Eighty white women of this collective, 40 patients with a pathological oral glucose tolerance test and 40 normal control subjects, were randomly selected. DNA samples were isolated from the sera and analyzed for the functional −675 4G/5G promotor polymorphisms of the plasminogen activator inhibitor 1 gene. RESULTS: Women with gestational diabetes mellitus were significantly older and had a significantly higher body mass index (BMI) than those who did not have gestational diabetes mellitus. Women with normal glucose tolerance were significantly more often homozygous for the 5G allele (P = .01), independently of maternal age or BMI. Low fasting glucose values in the oral glucose tolerance test were significantly related to homozygosity for 5G (P = .02). CONCLUSION: Homozygosity for the 5G allele of the plasminogen activator inhibitor 1 gene is associated with normal glucose tolerance in pregnant women. These findings further support a possible role of plasminogen activator inhibitor in the development of gestational diabetes mellitus. LEVEL OF EVIDENCE: II-2

Current concepts in aesthetic endocrinology

The extragenital effects of ovarian steroids are relevant to the metabolism of skin and hair, the changes in body composition and the alterations of the subcutaneous fat distribution throughout life. When ovarian steroids become deficient or are produced in excess, different problems may arise in these tissues and some of these problems, i.e., obesity and cellulite, display gender-specific components. Therefore, a new field in endocrine research known as aesthetic endocrinology is gaining more interest. Because sex steroids are small molecules they can be transported into the skin by topical application when properly formulated. This possibility is used in aesthetic endocrinology in order to achieve local effects but to avoid systemic reactions. After reviewing the current data it collectively seems legitimate to recommend estrogens, either orally or topically, in order to counteract the aging of the skin after menopause. Although a reconstitution of juvenile skin cannot be achieved through this method, a slowing in the skin aging process seems a reasonable expectation. In contrast, the successful treatment of hair loss in women is only confirmed for the application of the non-hormonal compound minoxidil. Apart from the difficult problem of hirsutism, acne and changes in body composition offer promising therapeutical options for endocrinological methods.

The role of dydrogesterone in recurrent (habitual) abortion.

The published evidence regarding the administration of dydrogesterone in the treatment of habitual abortion is summarised in this review. Habitual abortion is defined as the loss of three or more consecutive pregnancies without known maternal or foetal pathology. The immunology of early pregnancy seems to determine the rejection or non-rejection of the allogenic embryo. When peripheral mononuclear cells from recurrent aborters are incubated with progesterone or dydrogesterone in vitro, T-helper (Th)2 cytokines such as interleukin (IL)-4 and IL-6 markedly increase whereas the Th1 cytokine interferon-gamma decreases. Additionally, both progesterone and dydrogesterone are thought to inhibit the activity of natural killer cells at the foeto-maternal interface in humans. Progesterone-induced blocking factor (PIBF) mediates the immunological effects of progesterone and dydrogesterone in pregnancy. It affects various phases of the maternal immune response involving both the cellular and humoral immune system, exerts anti-abortive effects and inhibits the release of arachidonic acid. It also favours the production of so-called asymmetric, pregnancy-protecting antibodies. In rodents, blockade of this factor results in the termination of pregnancy and in women considerably lower levels are found in those with threatened abortion or pre-term labour. In order to draw final conclusions as to the usefulness of dydrogesterone in women with a history of recurrent miscarriage, further controlled, blinded, randomised clinical trials are needed.

Genetic factors in assisted reproduction.

ZusammenfassungOb die Anwendung der Reproduktionsmedizin zu einer erhöhten Anzahl von Kindern mit angeborenen Missbildungen führt, ist bis dato nicht gesichert. Die Schwierigke it besteht vor allem darin, etwaige Missbildungen, die durch die Techniken der Reproduktionsmedizin entstanden sein könnten, von jenen zu unterscheiden, die durch das erhöhte genetische Hintergrundrisiko von Infertilitätspatienten erklärbar sind. Vom genetischen Standpunkt sind Infertilitätspatienten nämlich als Hochrisikokollektiv einzustufen. Bei diesen beträgt die Prävalenz von numerischen Chromosomenaberrationen rund 10% im Vergleich zu 0,85% in der Allgemeinbevölkerung. Strukturelle Chromosomenaberrationen kommen in der Allgemeinbevölkerung zu rund 0,1% vor; bei IVF-Patienten jedoch bis zu 1%. Daneben sind Mikrodeletionen am Y-Chromosom und Mutationen im CFTR-Gen Infertilitätsgründe, die der Reproduktionsmediziner in seinem Klientel antreffen kann. Genetische Beratung und gegebenenfalls genetische Untersuchungen sollten daher routinemäßig bei Infertilitätspatienten durchgeführt werden. Zukünftige Eltern sollten außerdem aufgeklärt werden, dass verschiedene paternale und maternale Gendefekte an das mit den Methoden der assistierte Reproduktion gezeugte Kind übertragen werden können, während dasselbe Kind auf natürlichem Weg vermutlich nie empfangen worden wäre.SummaryIt is still unclear whether the procedures of assisted reproduction increase the risk of congenital malformations. Thus, it remains to be clarified whether an increased risk, if any, of congenital malformations in these children is caused by the procedure of assisted reproduction itself or by the underlying maternal and paternal background. From the genetic point of view, infertility patients seeking assisted reproduction have to be classified as a high-risk group. The prevalence of numerical chromosomal abnormalities is around 10% in these patients, compared with 0.85% in the general population. The prevalence of structural chromosomal abnormalities is around 0.1% in the general population and is increased up to 1% in patients seeking assisted reproduction. In addition, patients with microdeletions of the Y-chromosome or mutations in the cystic fibrosis transmembrane-conductance regulator gene are likely to be encountered at the fertility clinic. Therefore, genetic screening and counselling should be routinely offered to infertility patients. They also need to understand that parental factors can be transferred to offspring that would most likely not have been conceived by natural means.