Drug Discovery Today: Disease Models最新文献

Purpose

It was previously thought that estrogen deficiency caused hot flushes and night sweats or vasomotor symptoms (VMS). However, VMS also present in women in the Late Reproductive Transition or “Very Early Perimenopause” who still have regular menstrual cycles and whose estrogen levels have not decreased. Social emotional stresses increase VMS that, in turn, increase stress hormones and mood changes. Evidence suggests that downward swings of estradiol (E2) cause the dramatic neuroendocrine/cytokine release with elevated central norepinephrine levels leading to thermoneutral zone narrowing and VMS. There are aspects of the physiology of VMS that resemble “estrogen addiction”.

The aim of this review is to integrate scientific and clinical VMS knowledge in a new paradigm within the model of balanced estradiol and progesterone levels for women’s optimal health.

Major sources of information

We reviewed studies focusing on VMS and its risk factors, pathophysiology and treatment on PubMed, MEDLINE, and EMBASE.

Data synthesis in the context of E2-P4 balance women’s health model

Estrogen withdrawal stimulates release of a host of cytokines and neurotransmitters most important of which is increased NE. Downward E2 levels are also associated with anxiety and depression. Initially premenopausal women made menopausal by bilateral ovariectomy/chemotherapy with rapid E2 decline are more likely to report severe VMS than those with natural reproductive aging. When E2 levels drop, increased central NE neuroendocrine-thermal dysregulation triggers hot flushes/night sweats. Although E2-based menopausal hormone therapy relieves VMS, its discontinuation often produces a VMS rebound. P4 relieves VMS in both menopausal and perimenopausal women likely by decreasing or stabilizing NE. We hypothesize that the rebound on discontinuing E2 therapy could be prevented by first adding P4 and then gradually weaning off E2.

This paradigm shift’s clinical and research relevance

The effects—of E2 withdrawal, and high E2 levels to increase, and of full dose P4 to suppress central NE levels—need further documentation. Several primate studies and clinical and controlled trials are needed to test this new model.

Conclusions

High brain E2 exposure followed by E2 withdrawal rather than low estrogen per se is the underlying cause of VMS; P4 counterbalances the varying E2 levels in the premenopausal years. P4 therapy in perimenopause/menopause may effectively decrease or prevent hot flushes/night sweats without the risk of withdrawal VMS increases that are related to stopping E2 therapy.

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.

Purpose

To examine the pathophysiology of androgenic PCOS as a model of androgen excess with estradiol (E2) - progesterone (P4) imbalance; to assess therapy with Cyclic P4.

Major sources of information

Brain or hypothalamic origins of PCOS were drawn from basic science, animal, and clinical data, with a focus on the pulse rate of gonadotrophin releasing hormone (GnRH) and effects on luteinizing hormone (LH) pulsatility and ovarian androgen production.

Synthesis of data

PCOS occurs for 10% of reproductive-aged women from a myriad of potential etiologies, including the central pathophysiology of rapidly pulsing GnRH consequent to increased kisspeptin and GABA_A. The inhibitory progesterone feedback that normally slows LH is decreased or absent with PCOS, resulting in chronic LH stimulation of ovarian theca cells and hyperandrogenism.

Standard PCOS therapy with combined hormonal contraceptives (CHC) induces predictable flow and lower androgens but does not correct neuroendocrine disturbances and increases already tonically high E2 levels. In contrast, Cyclic P4 provides predictable withdrawal flow and symptom relief but also decreases LH and androgens. Vaginal progesterone with other therapies appears to improve fertility outcomes.

Incorporating new data into clinical practice and research

Although non-randomized controlled studies of single-cycle progesterone therapy are available, there is no evidence that longer-duration Cyclic P4 reverses the clinical and/or metabolic PCOS disturbances. Longer studies and RCTs are needed.

Conclusion

Ovulatory disturbances, androgen excess, and E2 > P4 imbalance are central to androgenic PCOS. Cyclic P4 therapy, by slowing GnRH pulse rate, may improve both PCOS symptoms and fertility.

Purpose

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.

Major sources of information

This review relied on clinical data accessed through literature searches.

Data synthesis in the model context

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.

Incorporating the new understanding into clinical and/or research relevance

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.

Conclusions

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.

Purpose

To enhance trans-disciplinary understanding of bone changes in women, between the boundaries internal medicine, experimental orthopedics/surgery and gynecology.

Major sources of information

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.

Data synthesis in the model context

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.

Incorporation the new understanding into clinical and/or research relevance

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.

Conclusion

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.

Purposes

This review is to challenge current concepts of women’s reproduction with its cultural over-emphasis on estrogen and positive actions, while progesterone tends to be ignored or associated with negative effects. To explore the physiology, and the clinical implications of understanding that progesterone and estradiol interact in counterbalancing and complementary ways within a complex system that is Women’s Reproductive Health.

Data synthesis in the context of this paradigm shift

Fundamental, descriptive, quantitative and experimental data all show that estradiol’s important cellular action is to promote growth and proliferation; by contrast, despite short-term proliferative effects, progesterone’s dominant actions are to inhibit proliferation, to enhance differentiation and promote maturation. Estradiol and progesterone variably interact in every cell and tissue in women’s bodies and across the life cycle.

Incorporation of the new paradigm into clinical and/or research relevance

Since ovulation and thus progesterone’s presence is subclinical in normal-length cycles, we urgently need a convenient, home, once/cycle, inexpensive test of normal ovulation. Major funding is needed for ovulation-testing cycle-by-cycle over months or years in large population-based cohorts of adolescent, premenopausal and perimenopausal women. These women need to be followed for fertility and their later-life experiences of osteoporotic fracture, myocardial infarction, breast and endometrial cancers. In addition, all research with menstruating women participants and female mammals needs cycle-phase specific testing.

Conclusion

It is difficult to perceive, much less to change, a current paradigm. With this journal issue, however, we have begun the important tasks of transforming concepts about women’s health, and setting the research agenda to advance the innovative understanding that women's reproductive and overall health becomes optimal when premenopausal menstrual cycle estradiol and progesterone actions are balanced within this complex system.

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.

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.