Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
2001-03-08
2004-05-11
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S007100
Reexamination Certificate
active
06733962
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the fields of infertility, endometrial hyperplasia, assisted reproduction, and hormone replacement therapy for women, and methods of assessing and monitoring endometrial development in connection with diagnoses and therapies related to the same.
BACKGROUND OF THE INVENTION
Over 10% of reproductive age couples suffer from infertility. While many of these couples are successfully diagnosed and treated for their underlying conditions, nearly 20-25% are found to have no proven cause for their difficulties in achieving a successful pregnancy. Many of these couples further pursue costly procedures using assisted reproductive technology (ART) in an attempt to overcome their unidentified problems. The ART procedures used in the United States are IVF (in vitro fertilization), GIFT (gamete intrafallopian transfer), and ZIFT (zygote intrafallopian transfer). Yet, even with ART, only 29.5% of fresh, nondonor cycles result in pregnancies and only 24% result in live births. Rates vary between 19% and 25% depending on the cause of the infertility and older women generally have lower rates of success. Also, the live birth rate decreases to 18.6% when frozen embryos are used.
Clearly, despite improvements in embryo quality and culture conditions, some women are still unable to become pregnant. Their infertility, as well as the infertility experienced by many women, is likely caused in part by implantation difficulties. Thus, predictors of implantation potential are needed, both to better understand the causes of infertility in women and to improve the efficacy and reliability of embryo transfer. Despite over two decades of ART, no tools for endometrial evaluations exist which can adequately predict whether implantation will occur during any given ART cycle.
The Menstrual Cycle
The normal human menstrual cycle proceeds, on average, over the course of 28 days. However, menstrual cycle lengths in individual women vary considerably. For example, Trelar and his associates at the University of Minnesota found that three years after menarche, the range of menstrual intervals for 90% of the recorded cycles was 20.4 to 47.7 days. Their study, which analyzed 275,947 menstrual intervals recorded by more than 2700 women over extended periods, found similar variations during all periods of a woman's reproductive life. This variability is generally a reflection of the varying length of the follicular phase as opposed to the luteal phase, which lasts a relatively constant and predictable 14 days. While the length of a woman's menstrual cycle is rarely the idealized 28 days, investigations of the endometrium are based on this average 28 day cycle.
During the natural menstrual cycle, the normal human endometrium undergoes a hormone dependent cyclical series of changes, which involve the progression of proliferation to differentiation. Following menstruation, the endometrium enters the proliferative phase where, under the influence of estrogen, there is marked proliferation of epithelial and stromal cells as well as an increase in the length and tortuosity of the glands. These processes lead to an increase in endometrial thickness, culminating in a characteristic maximal 10-12 mm thickness at midcycle. Then, the luteinizing hormone (LH) surge on cycle day (CD) 13 causes ovulation to occur on CD 14. At this point the endometrium enters the secretory phase where, under the influence of progesterone, the endometrium differentiates, blood vessel and glandular tortuosity, as well as secretory activity, increases to a maximum and the stroma becomes edematous and increasingly vascular. It is during the middle of the secretory phase (CD 20-22) that the endometrium is best prepared for the trophoblast invasion portion of implantation. Estimates for the exact timing of the receptive period range from CD 17-19 to CD 20-24.
Histologic Evaluation of the Naturally Cycling Endometrium
The Noyes, Hertig and Rock Study
Histologically, there are a series of changes during the menstrual cycle that can be seen in the hematoxylin and eosin (H & E) stained endometrial slide. These changes in the histologic appearance of the endometrium were first described by Noyes, Hertig and Rock in 1950 and further elucidated several years later. In their study, “Dating the Endometrial Biopsy”, Noyes and co-workers focused on the components which they felt changed most “rapidly, constantly, and characteristically” during the menstrual cycle. Those changes included features such as gland mitoses, pseudostratification of nuclei, basal vacuolization of gland cells, secretion into the gland lumen, the presence of stromal edema, stromal mitoses, and leukocyte infiltration. Based on their study of the temporal progression of each variable through a 28 day menstrual cycle and the cyclical changes in the histologic appearance of the endometrium, Hertig and co-workers proposed a method by which the endometrium could be dated within the menstrual cycle where the endometrium was assigned a date consistent with the most advanced component of the biopsy. They based the physiologic day on the date of ovulation, which they determined by the low end point of the first basal body temperature phase.
While Noyes et al. described a progressive series of changes in endometrial histology, their methods are neither necessarily appropriate for precise dating nor are they necessarily reflective of the normal, fertile endometrium. For example, they found that dating with their method was better correlated with the date of ovulation than with the onset of the next menstrual period. From this they concluded that the histologic evaluation was best suited to be a form of hormone assay intended to give a rough idea of quantitative progesterone effect, thus only indirectly indicating the time of ovulation and thus cycle day. This was a useful tool in 1950 to document ovulation—a tool that is secondary today to the documentation of the luteinizing hormone (LH) surge. Also, their findings were described as being applicable to what was referred to as “normal” endometrium. Subsequent clinical investigators as well as clinical practitioners have come to interpret this to mean normal fertile endometrium. However, most of the biopsies (percentages not given) were selected from sterility studies (from the hospital sterility clinic and the sterility practices of two staff members). Noyes and co-workers felt justified in claiming that these biopsies were representative of normally menstruating women because of an internal hospital report which claimed that 84.3% of the biopsies from these sterility patients were “normal.”
Accuracy of the Noyes, Hertig and Rock Criteria for Endometrial Dating
Despite the limitations in using the Noyes et al. criterion to precisely date the normal, fertile endometrium, dating the endometrium using their criteria is used virtually exclusively by pathologists in both their clinical and experimental work. This reliance on what has come to be seen as the “gold standard” dating method is based on early evaluations such as the study by Noyes and Hamen in 1953. In this study, there was a reported agreement between two specially trained gynecopathologists of ±1 day in 82% of cases (i.e., if one pathologist assigned a biopsy as day 24, then another would interpret it as day 23, 24 or 25 82% of the time). Correlation was best in the middle and late secretory phases. Also, 80% of the histologic dates were found to be within 2 days of the physiologic date. Physiologic dating was determined by the midcycle change in basal body temperature (BBT) and the next menstrual period (NMP), which were found to bound a consistent 14.1 day secretory phase (standard deviation 1.7 days). In the 20% of cases where histologic and physiologic dates did not correlate the histologic dating tended to be earlier than the menstrual dating.
Although Noyes and Haman concluded from their study that histologically dating the endometrial was both useful and accurate, it is questionable whether a 82% interobserver
Dubowy Rebecca L.
Kliman Harvey J.
Kliman Harvey J.
Nolan Patrick J.
O'Connor P.C. Cozen
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