Nonhormonal Factors Research Articles

Altered IgG autoantibody levels and CD4+ T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor

Important interactions between female reproduction and autoimmunity are suggested by the female-predominance of systemic lupus erythematosus (SLE) and other autoimmune diseases and the amelioration of certain autoimmune diseases during pregnancy. Sexually dimorphic risk of developing SLE involves modulation of genetic risk by environmental factors, sex hormones and non-hormonal factors encoded on the sex chromosomes. In some lupus models, estrogen, via estrogen receptor alpha (ER-α), enhances production of highly pathogenic IgG2a/c autoantibodies (autoAbs). Some studies indicate that treatment with progesterone, a chief female reproductive steroid, can suppress IgG2a/2c autoAb production. Little is known about how endogenous progesterone impacts lupus autoimmunity. To investigate this, we introduced a disruptive progesterone receptor (PR) gene mutation into lupus-prone mice and tracked the development of spontaneous IgG autoAbs. Here, we present evidence that PR can suppress the emergence of class-switched IgG2c autoAbs, suggesting that PR and ER-α counter-regulate a critical step in lupus autoimmunity. PR's control of IgG2c autoAb production correlates with alterations in the relative abundance of splenic T follicular helper (TFH) cells and non-TFH CD4+ T cells, especially regulatory T cells (TREGS). Surprisingly, PR also appears to help to maintain sexually dimorphic abundance of splenic leukocytes, a feature common to many mouse models of SLE. Together our results identify a novel molecular link between female reproduction and lupus autoimmunity. Further investigation into the immunomodulatory functions of PR promises to inform reproductive health care in women and offers mechanistic insight into important immunologic phenomena of pregnancy.

An update on the role of bariatric surgery in diabetes management.

To review the current state of knowledge on the effects of weight loss (bariatric) surgical procedures in individuals with type 2 diabetes. Observational and randomized studies provide robust data on the efficacy of bariatric surgery for weight loss and improvement in hyperglycemia. Follow-up information up to 20 years is now available. Surgery offers similar benefits in individuals with BMI 30-35, compared with those with higher BMI. There is a better understanding of the role of gut hormones and nonhormonal factors on weight loss and glucose metabolism. Preoperative factors that predict favorable surgical outcomes have been identified. Of commonly performed procedures, adjustable gastric banding has the lowest efficacy for weight loss and diabetes remission and a higher complication rate. Roux-en-Y gastric bypass and sleeve gastrectomy are comparable in terms of efficacy and complications. Remission rates for diabetes range between 40 and 80%; randomized trials show slightly lower remission rates compared with observational studies. At 20 years, approximately 50% of remitters have relapse of diabetes. Complex gut hormonal changes, caloric restriction, and other intestinal factors form the basis for metabolic effects of surgery. Better preoperative β-cell function is the strongest predictor for remission. Long-term follow-up data is still sparse.

Role of hypothalamic neuropeptides in feed intake regulation of livestock species (literary review)

Energy balance is the net result of the energy intake (nutrition) and expenditure (basic metabolic rate). The purpose of the daily feed intake is to provide energy and nutrients for maintenance, production and fill and maintain energy storages in form of glycogen and fat. Animals can adjust their feed intake to ensure their energy demand. Food intake regulation in animals and human is a very complex process, in which the digestive system, the central nervous system, the joining hormonal and non-hormonal factors, and the integrating hypothalamus take part. This review primarily focuses on the action mechanism of some important appetite regulating neuropeptides, and their impacts on the performance traits of the economically significant animal species.

Evaluation of relationship between breast cancer and migraine.

Background:Frequency of migraine changes at different times of a woman's reproductive cycle because of fluctuation of estrogen levels. Breast cancer has also a link with hormonal changes. Given this fact that both migraine and breast cancer are affected by estrogen, the prevalence of migraine may be different in breast cancer patients compared to the normal population.Materials and Methods:In this case–control study, two groups of women with and without breast cancer were compared regarding the prevalence of migraine. Each group consisted of 400 women. The diagnosis of different types of headache was made based on The International Headache Society (IHS) guidelines. Type of headache, type and receptor status of breast cancer, as well as history of taking hormonal medications was recorded. Independent t-test and Chi-square tests were used for data analysis.Results:Relative frequency of migraine headache in the normal woman was 38% compared to 19% in the breast cancer group (P < 0.0001). Tension headache was also significantly more prevalent in the normal group (P < 0.001). The frequency of migraine was significantly lower in estrogen receptor (ER)+/progesterone receptor (PR)− women compared to ER−/PR+ (26 and 43 women, respectively; P = 0.04); however, this difference was not significant for tension headache (P = 0.68).Conclusion:This study confirmed the lower frequency of migraine, as well as tension headache, in breast cancer sufferers. This could be contributed to several non-hormonal factors, such as a history of long term use of nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal factors, although only migraine showed a strong link with hormone status.

Hormonal therapy for non-obstructive azoospermia: basic and clinical perspectives.

Microdissection testicular sperm extraction (micro-TESE) combined with intracytoplasmic sperm injection is a standard therapeutic option for patients with non-obstructive azoospermia (NOA). Hormonal treatment has been believed to be ineffective for NOA because of high gonadotropin levels; however, several studies have stimulated spermatogenesis before or after micro-TESE by using anti-estrogens, aromatase inhibitors, and gonadotropins. These results remain controversial; however, it is obvious that some of the patients showed a distinct improvement in sperm retrieval by micro-TESE, and sperm was observed in the ejaculates of a small number of NOA patients. One potential way to improve spermatogenesis is by optimizing the intratesticular testosterone (ITT) levels. ITT has been shown to be increased after hCG-based hormonal therapy. The androgen receptor that is located on Sertoli cells plays a major role in spermatogenesis, and other hormonal and non-hormonal factors may also be involved. Before establishing a new hormonal treatment protocol to stimulate spermatogenesis in NOA patients, further basic investigations regarding the pathophysiology of spermatogenic impairment are needed. Gaining a better understanding of this issue will allow us to tailor a specific treatment for each patient.

Modulation of autoimmune rheumatic diseases by oestrogen and progesterone.

Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4(+) T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health--a newly announced directive of the NIH.

Do Hormones Influence Women's Sex? Sexual Activity over the Menstrual Cycle

In mammals, the effects of ovarian steroids influence sexual behavior. In humans, there are a few studies that take into account if ovulation occurs. The study aims to investigate if a woman's sexuality changes during the week and over the menstrual cycle, and if so, in what way. This is a prospective cohort study; 1,957 heterosexual women were involved over the period January 2004-December 2011. Two subgroups were taken into consideration, women having a partner and singles. Sexual interview and the Female Sexual Function Index and Female Sexual Distress Scale questionnaires were used to exclude women with sexual dysfunction. Women with ovulation confirmed by sonography were enrolled. Women were given diary cards on which to report their daily sexual activity. Serum concentrations of estradiol, progesterone, total testosterone, sex hormone binding globulin, and free androgen index were measured during the follicular, periovular, and luteal phase of the menstrual cycle. One thousand one hundred eighty women (age range 18-40 years) were included in the analyses. Of them, 925 had a heterosexual relationship and 255 were single. Women with a partner had more sexual activity during the weekend, while the singles had a constant sexual activity over the week. The sexual activity of singles was higher during the ovulatory phase and lower during menses than that of the women with a partner. A linear correlation between sexual activity and androgenic hormonal profile during the menstrual cycle in women with and without a partner was observed. Ovarian steroids modulate a woman's sexual activity. This aspect was more evident in singles than in women having a partner, in which a variety of nonhormonal factors can have a role.

Are patterns of cortical hyperexcitability altered in catamenial epilepsy?

We used transcranial magnetic stimulation to determine menstrual cycle-related changes in cortical excitability in women with and without catamenial epilepsy and investigated whether these changes differed between ovulatory and anovulatory cohorts. Healthy nonepilepsy women and women with generalized and focal epilepsy were investigated during ovulatory (n=11, 46, and 43, respectively) and anovulatory (n=9, 42, and 41) cycles. Patients were divided based on seizure pattern into catamenial (C1=perimenstrual, C2=periovulatory, C3=luteal seizure exacerbation), noncatamenial, and seizure free. Cortical excitability was assessed using motor threshold (MT) and paired pulse stimulation at short (2-15 milliseconds) and long (100-300 milliseconds) interstimulus intervals twice, at the (1) late follicular and (2) mid luteal phases of the menstrual cycle. In controls, cortical excitability was greatest in the follicular study, where intracortical facilitation was increased (p<0.05). The opposite was seen in women with epilepsy, where intracortical facilitation was greatest and intracortical inhibition was least in the luteal studies (p<0.05). There were no differences between the ovulatory and anovulatory groups in any of the cohorts. No changes were observed in MT. Nonhormonal factors are involved in the cyclicity of cortical excitability across the menstrual cycle. Normal menstrual cycle variations in cortical excitability are altered in a similar pattern in ovulatory and anovulatory women with epilepsy regardless of seizure patterns. The underlying neural changes associated with epilepsy may alter responses to sex hormones. This may be an important underlying mechanism for catamenial seizure clustering.

Sex Chromosomes Regulate Nighttime Sleep Propensity during Recovery from Sleep Loss in Mice

Sex differences in spontaneous sleep amount are largely dependent on reproductive hormones; however, in mice some sex differences in sleep amount during the active phase are preserved after gonadectomy and may be driven by non-hormonal factors. In this study, we sought to determine whether or not these sex differences are driven by sex chromosome complement. Mice from the four core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of phenotype (male or female), were implanted with electroencephalographic (EEG) and electromyographic (EMG) electrodes for the recording of sleep-wake states and underwent a 24-hr baseline recording followed by six hours of forced wakefulness. During baseline conditions in mice whose gonads remained intact, males had more total sleep and non-rapid eye movement sleep than females during the active phase. Gonadectomized FCG mice exhibited no sex differences in rest-phase sleep amount; however, during the mid-active-phase (nighttime), XX males had more spontaneous non-rapid eye movement (NREM) sleep than XX females. The XY mice did not exhibit sex differences in sleep amount. Following forced wakefulness there was a change in the factors regulating sleep. XY females slept more during their mid-active phase siestas than XX females and had higher NREM slow wave activity, a measure of sleep propensity. These findings suggest that the process that regulates sleep propensity is sex-linked, and that sleep amount and sleep propensity are regulated differently in males and females following sleep loss.

Phosphate Transporters and Their Function

Plasma phosphate concentration is maintained within a relatively narrow range by control of renal reabsorption of filtered inorganic phosphate (P(i)). P(i) reabsorption is a transcellular process that occurs along the proximal tubule. P(i) flux at the apical (luminal) brush border membrane represents the rate-limiting step and is mediated by three Na(+)-dependent P(i) cotransporters (members of the SLC34 and SLC20 families). The putative proteins responsible for basolateral P(i) flux have not been identified. The transport mechanism of the two kidney-specific SLC34 proteins (NaPi-IIa and NaPi-IIc) and of the ubiquitously expressed SLC20 protein (PiT-2) has been studied by heterologous expression to reveal important differences in kinetics, stoichiometry, and substrate specificity. Studies on the regulation of the abundance of the respective proteins highlight significant differences in the temporal responses to various hormonal and nonhormonal factors that can influence P(i) homeostasis. The phenotypes of mice deficient in NaPi-IIa and NaPi-IIc indicate that NaPi-IIa is responsible for most P(i) renal reabsorption. In contrast, in the human kidney, NaPi-IIc appears to have a relatively greater role. The physiological relevance of PiT-2 to P(i) reabsorption remains to be elucidated.

Early first-trimester crown-rump length measurements in male and female singleton fetuses in IVF pregnancies

Objectives: The generally higher birth-weight of male newborns compared to female newborns is attributed mainly to intrauterine exposure to testosterone. We aimed to determine if crown-rump length (CRL) differs between male and female fetuses early in the first trimester. Methods: A retrospective cohort study of 333 women with nondiabetic singleton IVF pregnancies attending a single university-affiliated tertiary medical center in 2000–2007 who underwent CRL measurement before 50 days of pregnancy (date of measurement minus oocyte retrieval date plus 14 days). Data on pregnancy outcome, including fetal sex, were collected by routine follow-up telephone interview and combined with the delivery data. Results: There were 169 female and 164 male fetuses according to the reported fetal sex at delivery. Most of the CRL measurements (68.7%) were performed at an actual gestational age of 43–45 days. On linear regression analysis, male fetal sex was a significant (p = 0.011) predictor of larger CRL: CRL (mm) = –23.851 + GA (days) × 0.621 + 0.334 × Sex (F = 1, M = 2), R2 = 0.512, p <0.001. A general linear model, adjusted for gestational age (40–50 days), revealed that mean CRL was significantly higher in male than in female fetuses (4.58 ± 0.09 mm, [95% CI: 4.3–4.7] vs 4.24 ± 0.09 mm [4.0–4.4]; p < 0.001). Conclusions: Male fetuses are larger than female fetuses in the early first trimester. Given that gonadal differentiation has not yet occurred, still unidentified nonhormonal factors are apparently responsible for this difference.

Organizational and activational effects of sex steroids on kisspeptin neuron development

Kisspeptin, encoded by the Kiss1 gene, is a neuropeptide required for puberty and adult reproductive function. Understanding the regulation and development of the kisspeptin system provides valuable knowledge about the physiology of puberty and adult fertility, and may provide insights into human pubertal or reproductive disorders. Recent studies, particularly in rodent models, have assessed how kisspeptin neurons develop and how hormonal and non-hormonal factors regulate this developmental process. Exposure to sex steroids (testosterone and estradiol) during critical periods of development can induce organizational (permanent) effects on kisspeptin neuron development, with respect to both sexually dimorphic and non-sexually dimorphic aspects of kisspeptin biology. In addition, sex steroids can also impart activational (temporary) effects on kisspeptin neurons and Kiss1 gene expression at various times during neonatal and peripubertal development, as they do in adulthood. Here, we discuss the current knowledge--and in some cases, lack thereof--of the influence of hormones and other factors on kisspeptin neuronal development.

Hormone Replacement Therapy in Female Sexual Dysfunction

Female sexual function is highly complex and deeply influenced by hormonal and non-hormonal factors. As sexual dysfunction becomes a common and important problem for women of all ages with related quality of life issues, we need to understand more about the effect of sex steroid hormones in female sexual function. However, there are limited data about the correlation between the value of sex steroid hormonestestosterone, in particular-and female sexual function. In a certain type of female sexual dysfunction (FSD), hypoactive sexual desire disorder, for example, there is evidence that treatment with androgens or with estrogens is effective. To widen the therapeutic options of hormone replacement therapy in FSD, further research is needed as to the benefits and risks of hormonal treatments in both preand post-menopausal women. Although important unanswered questions still exist in hormonal treatment of FSD, new therapeutic strategies are being studied and many ongoing clinical trials are expecting favorable results leading to more successful treatment of FSD. 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Hormones and prostate carcinogenesis: Androgens and estrogens

Prostate cancer is the leading non-skin malignancy detected in US males and the second cause of death due to male cancer in the US. Androgenic hormones are generally believed to be causatively associated with prostate carcinogenesis, but human evidence, mostly epidemiological, for this is minimal. Circulating hormone levels are not associated with the risk of prostate cancer and neither are polymorphisms in various genes encoding the androgen metabolizing enzymes or androgen receptors. Evidence in support of the involvement of androgens in prostate cancer development is derived from clinical trials with 5α-reductase inhibitors, which reduced the risk by approximately 25%. Animal studies using rat models, however, provide clear evidence that testosterone can induce prostate cancer and can act as a strong tumor promoter in concert with genotoxic carcinogens. One such genotoxic factor may be 17β-estradiol, which is generated from testosterone by the aromatase enzyme. Estradiol can be converted to catecholestrogens, which through redox cycling, generate reactive metabolites that can adduct the DNA and potentially lead to mutations. Animal studies and limited human evidence suggest that estrogens can be involved in prostate carcinogenesis by such a genotoxic mechanism. However, how androgens exert their tumor-promoting effect is not clear. It is likely that hormonal and non-hormonal factors as well as genetic and non-genetic (environmental) factors interact in a highly complex and poorly understood manner to determine the risk of prostate cancer.

Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis

Objective To determine the effect of sex on the risk of recurrent venous thromboembolism in all patients and in patients with venous thromboembolism that was unprovoked or provoked (by non-hormonal...

Is antibiotic use a risk factor for breast cancer? A meta‐analysis

Breast cancer is a disease integrating hormonal and non-hormonal factors. Given the widespread antibiotic use, attention has been recently drawn upon the association between antibiotic use and breast cancer; however, the published studies have yielded contradictory results. In addition, various types of quantification in antibiotic use have been adopted. This meta-analysis aims to examine whether antibiotic use is associated with breast cancer risk presenting two analyses: one on antibiotic ever-use and one on the number of antibiotic prescriptions. Eligible studies were retrieved by a search in MEDLINE, Cochrane, and EMBASE databases till July 2009. Odds ratios (OR) pertaining to antibiotic ever-use were appropriately calculated. The random effects model was used to estimate the pooled OR. Publication bias was assessed through Begg's and Egger's tests. Meta-regression with the number of antibiotic prescriptions was performed. Five case-control studies were eligible at the ever-use versus never-use analysis (13 069 cases and 73 920 controls). Antibiotic ever-use was associated with slightly elevated breast cancer risk (pooled OR = 1.175, 95%CI: 0.994-1.387). No publication bias became apparent. Meta-regression showed a borderline dose-response effect implicating the number of antibiotic prescriptions. Antibiotic use seems associated with slightly elevated breast cancer risk. The underlying nature of the association remains elusive, as it may be direct or due to secondary associations, that is, causal or confounding. At any case, this is a finding with potentially important public health implications, which should be further examined in the literature.

Risk Factors for Ductal, Lobular, and Mixed Ductal-Lobular Breast Cancer in a Screening Population

Biological distinctions between histologic subtypes of breast cancer suggest etiologic differences, although few studies have been powered to examine such differences. We compared associations between several factors and risk of ductal, lobular, and mixed ductal-lobular breast cancers. We used risk factor data from the Breast Cancer Surveillance Consortium for 3,331,744 mammograms on 1,211,238 women, including 19,119 women diagnosed with invasive breast cancer following mammography (n = 14,818 ductal, 1,602 lobular, and 1,601 mixed ductal-lobular). Histologic subtype-specific risk factor associations were evaluated using Cox regression. Significant positive associations with family history and breast density were similar across subtypes. Hormone therapy use was associated with increased risk of all subtypes, but was most strongly associated with lobular cancer [hazard ratio (HR) = 1.46; 95% confidence interval (CI), 1.25-1.70]. Relative to nulliparous women, parous women had lower risk of ductal and mixed but not lobular cancers (HR = 0.80; 95% CI, 0.76-0.84; HR = 0.79; 95% CI, 0.68-0.93; HR = 0.96; 95% CI, 0.81-1.15, respectively). Late age at first birth was associated with increased risk of all subtypes. Similarities in risk factor associations with ductal, lobular, and mixed breast cancer subtypes were more pronounced than differences. Distinctions between subtype-specific associations were limited to analyses of hormone therapy use and reproductive history. The results of this study indicate that the strongest risk factors for breast cancer overall (that is, family history and breast density) are not histologic subtype specific. Additional studies are needed to better characterize subtype-specific associations with genetic, hormonal, and nonhormonal factors.

Masculinization of the mammalian cochlea

Otoacoustic emissions (OAEs) differ between the sexes in humans, rhesus and marmoset monkeys, and sheep. OAEs also are different in a number of special populations of humans. Those basic findings are reviewed and discussed in the context of possible prenatal-androgen effects on the auditory system. A parsimonious explanation for several outcomes is that prenatal exposure to high levels of androgens can weaken the cochlear amplifiers and thereby weaken otoacoustic emissions (OAEs). Prenatal androgen exposure apparently also can alter auditory evoked potentials (AEPs). Some non-hormonal factors possibly capable of producing sex and group differences are discussed, and some speculations are offered about specific cochlear structures that might differ between the two sexes.

New Theories in the pathogenesis of menstrual migraine

Hormonal and nonhormonal factors play a role in the pathophysiology of menstrual migraine, but estrogen withdrawal appears to be the most potent of these factors. It is postulated that estrogen withdrawal directly enhances excitability of trigeminal afferents, modulates the synthesis of neuropeptides, activates/deactivates specific neurotransmitter systems, and influences the function of microglia. These changes could activate and/or sensitize the trigeminal system and increase the likelihood of migraine headache during perimenstrual time periods. Three new theories are advanced in this article to explain the pathophysiology of menstrual migraine. Only through an understanding of the mechanisms involved in menstrual migraine can we gain insight into the management of this severe and debilitating form of migraine headache.

Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma

To assess blood pressure outcome in patients with primary aldosteronism, who were operated on the basis of a unilateral adenoma detected by computed tomography or a lateralized aldosterone hypersecretion detected by adrenal venous sampling, and to analyze the hormonal and nonhormonal factors associated with the outcome. A retrospective study of 168 patients with primary aldosteronism undergoing surgery: 109 patients with a unilateral adenoma detected by computed tomography and 59 without a unilateral adenoma who underwent surgery because of an aldosterone to cortisol ratio at least five times higher on the dominant side than on the nondominant side. Patients with a unilateral adenoma were more likely to be women, had a shorter history of hypertension and had lower blood pressure levels and treatment scores than patients without a unilateral adenoma. The mean systolic blood pressures of patients with and without unilateral adenomas at follow-up were 133 +/- 16 and 137 +/- 16 mmHg, respectively. Hypertension cure or improvement was observed in 77% (95% confidence interval 69-85%) and 68% (95% confidence interval 56-80%) of patients, respectively. Using a linear regression model, baseline urinary aldosterone was positively associated, and baseline serum potassium was negatively associated, with decrease in systolic blood pressure. Adrenalectomy improves blood pressure control in patients with primary aldosteronism operated on the basis of either unilateral adenoma detected by computed tomography or a lateralized aldosterone hypersecretion. A high urinary aldosterone excretion and a low serum potassium level predict a more favorable outcome of surgery.