Menstrual cycle variability has been extensively documented, yet this basic physiological fact has not been well integrated into studies of women’s health. We examine the extent, causes, and implications for clinical research of non-pathological variation in ovarian cycling, and propose guidelines for evaluating the potential contribution of cycle variability to study outcomes. This review relied on clinical data accessed through literature searches. Cycle length, occurrence and timing of ovulation, and hormone profiles vary considerably between cycles, women, and populations. The reproductive system is highly responsive to internal and external signals, a consequence of tradeoffs in resource allocation to reproduction versus other bodily functions. Temporary pauses in reproductive effort, which can yield greater lifetime reproductive success, are not necessarily pathological and should, instead, be recognized as a feature of normal reproductive functioning. Research on women’s health should incorporate empirically verified biomarkers of cycle physiology and avoid narrow participant inclusion criteria. Cycle length is not an adequate biomarker of either ovulation or progesterone production. Potential cycle-related confounders (cycle phase, hormone concentrations, ovulation status, early pregnancy loss) should be included in research on women’s health. We can improve our understanding of sex-related differences in the prevalence, severity, diagnosis, and outcomes of disease states, and thereby improve health outcomes for women, through more accurate characterization of menstrual cycle variability and inclusion of relevant empirically grounded cycle biomarkers in research and clinical studies.
Progressive multifocal leukoencephalopathy (PML), is an opportunistic brain infection that is caused by the JC virus. It usually occurs in patients with an underlying disease and therapies used to treat such diseases that inhibit normal immune system function. For example, multiple sclerosis patients treated with natalizumab have been identified at risk for PML. This serious adverse event has been very instructive in improving understanding of PML pathogenesis, biomarkers and patient management with this disease in recent years.
The etiology and pathogenesis of MS is likely to involve multiple factors interacting with each other, and the role of infectious and viral agents is still under debate, however a consistent amount of studies suggests that some viruses are associated with the disease. The strongest documentation has come from the detection of viral nucleic acid or antigen or of an anti-viral antibody response in MS patients. A further step for the study of the mechanism viruses might be involved in can be made using in vitro and in vivo models. While in vitro models, based on glial and neural cell lines from various sources are widely used, in vivo animal models present challenges. Indeed neurotropic animal viruses are currently used to study demyelination in well-established models, but animal models of demyelination by human virus infection have only recently been developed, using animal gammaherpesviruses closely related to Epstein Barr virus (EBV), or using marmosets expressing the specific viral receptor for Human Herpesvirus 6 (HHV-6). The present review will illustrate the main potential mechanisms of MS pathogenesis possibly associated with viral infections and viruses currently used to study demyelination in animal models. Then the viruses most strongly linked with MS will be discussed, in the perspective that more than one virus might have a role, with varying degrees of interaction, contributing to MS heterogeneity.
Recent studies have brought renewed interest to the hypothesis that infection plays a role in the pathogenesis of Alzheimer’s disease (AD). In particular, herpesviruses such as herpes simplex virus-1 (HSV-1) and human herpesvirus-6 (HHV-6) have had an extensive history of association with AD. The interplay between viral infection and a variety of neurological diseases has long been an area of interest but proving causality has been elusive. Two recent studies, Readhead et al. (2018) and Eimer et al. (2018) have again renewed the debate concerning the role of pathogens (herpesviruses) in AD. In this review, we will briefly discuss the literature in support of a herpesvirus role in AD pathogenesis and try to bridge two main observations in AD research; the ability of Aβ to aggregate with pathogens, and the detection of herpesviruses in AD brain material compared to non-AD controls. While the data linking AD and human herpesviruses suggest that these pathogens may contribute to disease progression, further work is needed to determine the significance of these observations, if any, to the etiology of the disease.
•Central to androgenic PCOS are persistent, rapid GnRH pulses of myriad•Rapid LH pulses stimulate androgens, tonically high estrogens, and low progesterone•Progesterone normally slows GnRH and LH pulses (if androgens not elevated).•With normalized GnRH/LH pulses, androgen excess and hyperinsulinemia recover.•Cyclic progesterone for PCOS lowers androgens and restores estradiol-progesterone balance.
•Estrogen is the current hormonal focus for Women’s Health—Progesterone is ignored.•Estradiol, in all cells/tissues, causes important proliferation and necessary growth.•Progesterone inhibits proliferation, causes tissue differentiation and maturation.•Balanced estradiol and progesterone actions are necessary for premenopausal health.•Reproductive life estradiol-progesterone balance could prevent age-related diseases.
Extensive research on sexually transmitted infections (STI) in the last century has led to a better understanding of disease prevention and treatment options. Nowadays, bacterial infections with chlamydia, gonorrhea or syphilis are curable with antibiotics. Also, infection with HIV has lost its terror as there exists a treatment allowing patients a normal life. Pre- and post-exposure prophylaxis of HIV with anti-retroviral drugs prevents infection of sexual partners. However, health organizations report that STI are on the rise again, being problematic as many infections remain undetected, thereby causing cancers, infertility or congenital infection. To circumvent this, development of vaccines against different STI are urgently needed. As it is difficult to study interaction between host and pathogen in humans, model systems including animal models and in vitro approaches are necessary. Within this review, we give an overview on animal models of STI with a focus on chlamydia infection, discussing advantages and disadvantages of modeling infection with species-specific or human pathogens. Moreover, we present available in vitro models of STI, pointing out current advances in the development of three-dimensional (3D) culture systems closely resembling human tissue architecture. This allows to explore infection under physiological conditions in human cells without ethical concerns. A toolbox full of tightly coordinated in vivo and in vitro infection models will be required to advance STI research and vaccine design in the future.
To enhance trans-disciplinary understanding of bone changes in women, between the boundaries internal medicine, experimental orthopedics/surgery and gynecology. A two-decade literature archive on factors affecting female bone metabolism, supplemented by a search of the recent experimental publications, and including work from our own working group on bone and females hormones. In experiments in human osteoblast cultures from female femur bone, which were sufficiently estrogenized to induce progesterone receptors (PGR), progesterone showed remarkable dose-response curves explaining many clinical observations. In bone research negating progesterone effects, the fact that PGR induction needs a minimum of 4–7 days of estrogen exposure and may need a female genetic endowment is often neglected. There is insufficient information on female animals in many bone models. While ovulation itself shows parallels with inflammatory processes for a short time, lack of progesterone or its receptor may prolong this state of inflammation. Progestin resistance is a feature of endometriosis, and 19% of women with early stage endometriosis are anovulatory. Bone marrow derived tem cells are known to play a role in endometriosis, but bone loss has only been evaluated regarding estrogen deprivation treatment in this diesease. Based on clinical observations of premenopausal women presenting with both endometriosis and osteoporosis without prolonged estrogen-suppressive treatment, a joint mechanism involving inflammatory mechanisms may play a role. Chronic inflammatory processes may be maintained by anovulation and lack of progesterone and may preferentially affect women with PCOS (for whom this has already been investigated) and also with endometriosis. This may also partly explain the preponderance of women in osteoporotic disease.
•Withdrawal from high brain estrogen (E2) causes neuroendocrine stress hormone spikes.•Norepinephrine (NE) causes thermoneutral narrowing of vasomotor symptoms (VMS).•VMS and psychosocial stress (anxiety, depression) bidirectionally relate and to NE.•Progesterone suppresses central NE and decreases VMS in peri- and menopausal women.•Progesterone therapy may allow women to stop E2 for VMS without rebound symptoms.
Papillomaviruses (PVs) are small, non-enveloped, double-stranded DNA tumor viruses, which target epithelial cells of the skin and mucosa of different vertebrate species, including humans, for infection. To date, more than 230 human papillomavirus (HPV) types are known according to the PapillomaVirus Episteme (PaVE) database and classified into 5 different genera, alpha, beta, gamma, mu and nu [1]. Preclinical model systems that mimic HPV infections are essential tools for investigations on viral etiology and pathophysiological processes of human diseases. Herein, we describe different PV infection model systems in animals, focusing on models for skin carcinogenesis.
As the largest organ of the human body, our skin serves as an interface to the environment, as well as a defensive barrier against dangers therein. Its integrity is facilitated by a complex suprastructural network of proteins that tether the epidermis to the underlying dermis. Mutations in single genes that disrupt the function of these proteins lead to severe bullous disorders such as epidermolysis bullosa (EB). This short review focuses on progress in the establishment of different model systems that recapitulate multiple aspects of the pathological phenotype of EB. These models have been used to decipher disease modifying mechanisms and evaluate therapeutic possibilities aimed at reverting the genetic defect or ameliorating disease-associated complications.
Over the past decade there has been growing interest in elucidating the role of neuroinflammation in seizure generation. Several preclinical studies have revealed that infection with neurotropic viruses such as HHV-6 can trigger an inflammatory cascade involving infected CNS cells. These findings are corroborated by clinical studies, that have shown an association with HHV-6 infection and different epilepsy syndromes and have detected HHV-6 viral DNA in saliva, blood, CSF and resected epileptogenic tissue from children and adults with seizures and chronic epilepsy. In this focused review we will analyze main clinical associations that link HHV-6 infection with seizures and proposed pathogenic mechanisms by which infection with HHV-6 can lead to a proinflammatory milieu contributing to seizure generation and in some instances later development of epilepsy.
Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that contributes to the etiology of diverse human cancers and auto-immune diseases. EBV establishes a relatively benign, long-term latent infection in over 90 percent of the adult population. Yet, it also increases risk for certain cancers and auto-immune disorders depending on complex viral, host, and environmental factors that are only partly understood. EBV latent infection is found predominantly in memory B-cells, but the natural infection cycle and pathological aberrations enable EBV to infect numerous other cell types, including oral, nasopharyngeal, and gastric epithelia, B-, T-, and NK-lymphoid cells, myocytes, adipocytes, astrocytes, and neurons. EBV infected cells, free virus, and gene products can also be found in the CNS. In addition to the direct effects of EBV on infected cells and tissue, the effect of chronic EBV infection on the immune system is also thought to contribute to pathogenesis, especially auto-immune disease. Here, we review properties of EBV infection that may shed light on its potential pathogenic role in neurological disorders.
Alkaptonuria (AKU) is a rare metabolic disease of historical and medical interest. Despite the identification of gene and protein defects leading to the accumulation of homogentisic acid (HGA), little is known on how HGA is transformed into an ochronotic pigment (the hallmark of the disease) leading to a range of clinical manifestations. Major obstacles in tackling the pathological features of AKU are the rarity of biological samples, the invasiveness of sampling techniques and the intrinsic difficulties of studying the pigmented tissues. This review provides an overview of the in vitro and ex vivo cell and tissue models that were recently developed and characterized to fill the above-mentioned gaps in the knowledge of AKU.
Neurocognitive disorders associated with HIV-1 infection affect more than half of persons living with HIV (PLWH) under retroviral therapy. Understanding the molecular mechanisms and the complex cellular network communication underlying neurological dysfunction is critical for the development of an effective therapy. As with other neurological disorders, challenges to studying HIV infection of the brain include limited access to clinical samples and proper reproducibility of the complexity of brain networks in cellular and animal models. This review focuses on cellular models used to investigate various aspects of neurological dysfunction associated with HIV infection.
Since the initial description of Chediak-Higashi syndrome (CHS), over 75 years ago, several studies have been conducted to underscore the role of the lysosomal trafficking regulator (LYST) gene in the pathogenesis of disease. CHS is a rare autosomal recessive disorder, which is caused by biallelic mutations in the highly conserved LYST gene. The disease is characterized by partial oculocutaneous albinism, prolonged bleeding, immune and neurologic dysfunction, and risk for the development of hemophagocytic lympohistiocytosis (HLH). The presence of giant secretory granules in leukocytes is the classical diagnostic feature, which distinguishes CHS from closely related Griscelli and Hermansky-Pudlak syndromes. While the exact mechanism of the formation of the giant granules in CHS patients is not understood, dysregulation of LYST function in regulating lysosomal biogenesis has been proposed to play a role. In this review, we discuss the clinical characteristics of the disease and highlight the functional consequences of enlarged lysosomes and lysosome-related organelles (LROs) in CHS.
Rett syndrome (RTT) is a progressive neurodevelopmental disease, which affects almost exclusively the female gender (prevalence of about 1:10,000). RTT symptoms are usually characterized by loss of purposeful hand skills, mental retardation and motor impairment, resulting in a plethora of other systemic co-morbidities. Mutations in the methyl-CpG binding protein 2 gene (MECP2) are the main genetic cause of the disorder, however molecular mechanisms leading from MeCP2 defects to this complicated pathology still need to be clarified. To investigate this and other aspects of RTT, several experimental models have been generated that include animal models, and in vitro approaches. In this article we briefly summarized the main models used for RTT investigations, and special focus is given to the use of primary fibroblasts isolated from RTT patients, since they represent a reliable disease-in-a-dish model, which can help researcher to elucidate cellular and molecular mechanisms of this disease.
Cerebral cavernous malformation (CCM) is a rare disease of genetic origin characterized by dilated and leaky capillaries occurring mainly in the central nervous system. CCM can arise sporadically or may be inherited as an autosomal dominant condition with incomplete penetrance and variable clinical expressivity. The sporadic form accounts for up to 80% of cases, whereas the familial form accounts for at least 20% of cases. Genetic studies have identified three genes associated with CCMs: KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3).
