The Illinois Women's Health Registry: advancing women's health research and education in Illinois, USA.

To achieve the goal of personalized medicine, we must first improve our understanding of the differences in health and illness between men and women. The purpose of the Illinois Women's Health Registry (USA) is to provide a research and education tool that advances scientific knowledge of sex- and gender-based differences in health and disease. Specifically, the Registry is a confidential 30-min health and lifestyle survey for female residents of Illinois over the age of 18 years. The survey includes questions regarding health, environment, health-related behaviors, symptoms and illnesses or conditions that a participant may have now or has had in the past. By enrolling in the Registry, women throughout the state are provided with information and access to clinical research studies that they may be eligible for, based on their self-reported health information. The Registry not only serves as a platform for recruitment into pivotal research studies, but also represents the beginning of a state-wide database that enables researchers to examine the collective de-identified health information provided by women living in Illinois. Ultimately, a cross-sectional and longitudinal analysis of these data will help to clarify the issues that women themselves identify as their main health concerns. In response to these concerns, specific research studies can be designed and launched, allowing us to eventually deliver tailored treatment and prevention options to women. Finally, by creating a reliable state-focused research tool, developed by staff that are trained in women's health research, we can compare health issues across the state and apply strategies for improvement where it is needed most. This article will provide examples of sex differences in disease, the lack of federal enforcement for inclusion of women in studies, researcher-perceived burdens and sex-based reasons as to why recruitment of women is considered to be more challenging. In addition, this article will discuss what a women's health registry is and why we need one in Illinois, how we have recruited women and our successes and challenges. Our goal is to inform the reader about the utility of a state-based tool and to provide a discussion regarding the lessons learned in order to aid other states in implementing this kind of program.

Prepubertal primordial follicle loss in mice is not due to classical apoptotic pathways.

More than half of the primordial follicles that are formed by Day 6 of postnatal life in the mouse will be eliminated from the ovary by the time of puberty. Apoptosis, a form of programmed cell death, is one mechanism by which these follicles could be actively lost. To investigate whether apoptosis is responsible for the loss of primordial follicles, follicular atresia was examined during the prepubertal period, when follicles die and are cleared from the ovary at an extremely high rate. Four hallmarks of classical apoptosis were measured in follicles present in prepubertal ovaries. The primordial follicle cohort was not positively associated with nuclear condensation or cell shrinkage, activation of caspase 3, cleavage of poly(ADP ribose) polymerase 1 (PARP1), or fragmentation of DNA. These data are consistent with a nonapoptotic pathway that is responsible for small follicle death.

Neonatal exposure to estrogens suppresses activin expression and signaling in the mouse ovary.

In the ovary, the steroid hormone estrogen and the TGF-beta superfamily member activin are both produced by granulosa cells and they both have intraovarian functions. Emerging evidence has indicated an interaction of these two signaling pathways. Based on the fact that estrogen and activin can impact early follicle formation and development, we hypothesize that estrogen treatment may alter activin signaling in the neonatal ovary. Therefore, this study was designed to examine the effect of neonatal diethylstilbestrol (DES) and estradiol (E(2)) exposure on the mRNA and protein levels of the key factors involved in activin signaling in the mouse ovary. CD-1 mouse pups were given daily injections of DES, E(2), or oil on postnatal d 1-5, and ovaries and sera were collected on d 19. Neonatal DES or E(2) exposure decreased the number of small antral follicles, induced multioocytic follicle formation, and decreased activin beta-subunit mRNA and protein levels. Consistent with local loss of beta-subunit expression, the phosphorylation of Smad 2, a marker of activin-dependent signaling, was decreased in the estrogen-treated ovaries. The decreased beta-subunit expression resulted in a decrease in serum inhibin levels, with a corresponding increase in FSH. Estrogen also suppressed activin subunit gene promoter activities, suggesting a direct transcriptional effect. Overall, this study demonstrates that activin subunits are targets of estrogen action in the early mouse ovary.

Fate of the initial follicle pool: empirical and mathematical evidence supporting its sufficiency for adult fertility.

The importance of the initial follicle pool in fertility in female adult mammals has recently been debated. Utilizing a mathematical model of the dynamics of follicle progression (primordial to primary to secondary), we examined whether the initial follicle pool is sufficient for adult fertility through reproductive senescence in CD1 mice. Follicles in each stage were counted from postnatal day 6 through 12 months and data were fit to a series of first-order differential equations representing two mechanisms: an initial pool of primordial follicles as the only follicle source (fixed pool model), or an initial primordial follicle pool supplemented by germline stem cells (stem cell model). The fixed pool model fit the experimental data, accurately representing the maximum observed primary follicle number reached by 4-6 months of age. Although no germline stem cells could be identified by SSEA-1 immunostaining, the stem cell model was tested using a range of de novo primordial follicle production rates. The stem cell model failed to describe the observed decreases in follicles over time and did not parallel the accumulation and subsequent reduction in primary follicles during the early fertile lifespan of the mouse. Our results agree with established dogma that the initial endowment of ovarian follicles is not supplemented by an appreciable number of stem cells; rather, it is sufficient to ensure the fertility needs of the adult mouse.

Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool.

Mammalian females enter puberty with follicular reserves that exceed the number needed for ovulation during a single lifetime. Follicular depletion occurs throughout reproductive life and ends in menopause, or reproductive senescence, when the follicle pool is exhausted. The mechanisms regulating the production of a species-specific initial follicle pool are not well understood. However, the establishment of a follicular reserve is critical to defining the length of reproductive cyclicity. Here we show that activin A (rh-ActA), a known regulator of follicle formation and growth in vitro, increased the number of postnatal mouse primordial follicles by 30% when administered to neonatal animals during the time of germline cyst breakdown and follicle assembly. This expansion in the initial follicle pool was characterized by a significant increase in both germ cell and granulosa cell proliferation. However, the excess follicles formed shortly after birth did not persist into puberty and both adult rh-ActA- and vehicle-treated animals demonstrated normal fertility. A follicle atresia kinetic constant (k(A)) was modeled for the two groups of animals, and consistent with the empirical data, the k(A) for rh-ActA-treated was twice that of vehicle-treated animals. Kinetic constants for follicle formation, follicle loss and follicle expansion from birth to postnatal day 19 were also derived for vehicle and rh-ActA treatment conditions. Importantly, introduction of exogenous rh-ActA revealed an intrinsic ovarian quorum sensing mechanism that controls the number of follicles available at puberty. We propose that there is an optimal number of oocytes present at puberty, and when the follicle number is exceeded, it occurs at the expense of oocyte quality. The proposed mechanism provides a means by which the ovary eliminates excess follicles containing oocytes of poor quality prior to puberty, thus maintaining fertility in the face of abnormal hormonal stimuli in the prepubertal period.

Testis-specific lactate dehydrogenase (LDH-C4; Ldh3) in murine oocytes and preimplantation embryos.

LDH-C(4) (Ldh3) is a member of the lactate dehydrogenase family of isozymes that catalyze the terminal reaction in the glycolytic pathway. In mammals, 3 genes, ldha, ldhb, and Ldhc, encode the subunits that assemble into catalytically active homo- and heterotetramers. Differential expression of these genes determines the lactate dehydrogenase (LDH) isozyme composition of tissues, and, as is well known, A subunits predominate in skeletal muscle and B subunits are abundantly produced in brain and heart, with the Ldh2 isozyme the most abundant form in oocytes. The C peptide can be detected first in pachytene spermatocytes and constitutes the primary LDH of spermatozoa. Originally the Ldhc gene (Ldh3 in terminology applied to murine cells) was considered to be testis specific on the basis of immunochemical, enzymatic, and molecular analyses. Here we report the detection of this isozyme in the murine oocyte and early embryo. Our results indicate that Ldh3 mRNA is transcribed in oocytes and cannot be detected in fertilized eggs. Ldh3 protein, however, persists to the blastocyst stage of embryonic development localizing mainly to the cortex region of oocytes, eggs, zygotes, and embryonic blastomeres.

Folliculogenesis in the domestic cat (Felis catus).

The dynamic regulation of mammalian folliculogenesis is a key component of the reproductive process. Traditionally, the rodent had been used as a model to study ovarian function and reproductive physiology due to the availability of animals, their relatively short cycle length, high rate of fecundity and short generation interval. We maintain that much basic information can be determined using domestic cat ovaries retrieved from local veterinary clinics following routine spaying, without having the expense of maintaining a colony of laboratory cats. Studies of normal feline reproductive physiology and advances in reproductive technology may be extrapolated for use in endangered non-domestic felids. Increased understanding of feline reproduction will be beneficial to veterinary medicine, and to groups working to control feral cat populations. It is important to examine reproductive mechanisms in alternative animal models as there are a vast number of threatened and endangered species in which we lack the critical reproductive information needed to assist in preserving their long-term survival.

The development of a mouse model of ovarian endosalpingiosis.

Pelvic pain is a common presenting ailment in women often linked to ovulation, endometriosis, early pregnancy, ovarian cancer, and cysts. Clear differential diagnosis for each condition caused by these varied etiologies is difficult and may slow the delivery of therapy that, in the case of ovarian cancer, could be fatal. Ovarian endosalpingiosis, a pelvic condition typified by the presence of cystic glandular structures lined by benign tubal/salpingeal epithelium, is also associated with pelvic pain in women. The exact cellular antecedents of these epithelial lined cystic structures are not known, nor is there a known link to ovarian cancer. A mouse model of ovarian endosalpingiosis has been developed by directing a dominant-negative version of the TGF-beta transcription factor, Smad2, to the ovary using the Müllerian-inhibiting substance promoter (MIS-Smad2-dn). Female mice develop an ovarian endosalpingeal phenotype as early as 3 months of age. Importantly, cysts continuous with the ovarian surface epithelial have been identified, indicating that these cyst cells may be derived from the highly plastic ovarian surface epithelial cell layer. A second transgenic mouse model that causes loss of activin action (inhibin alpha-subunit transgenic mice) develops similar cystic structures, supporting a TGF-beta/activin/Smad2 dependence in the onset of this disease.