The following disclosure is submitted under 35 U.S.C. 102(b)(1)(A): DISCLOSURE: “Term oocyte maturation and term ovarian stimulation: impact on oocyte competence.” by Dmitri I. Dozortsev, M.D., Ph.D., Antonio Pellicer, M.D., and Michael P. Diamond, M.D., in Inklings, Volume 114, ISSUE 2, P221-222.
If an Application Data Sheet (ADS) has been filed for this application, it is incorporated by reference herein. Any applications claimed on the ADS for priority under 35 U.S.C. §§ 119, 120, 121, or 365(c), and any and all parent, grandparent, great-grandparent, etc. applications of such applications, are also incorporated by reference, including any priority claims made in those applications and any material incorporated by reference, to the extent such subject matter is not inconsistent herewith.
The present application is related to and/or claims the benefit of the earliest available effective filing date(s) from the following listed application(s) (the “Priority Applications”), if any, listed below (e.g., claims earliest available priority dates for other than provisional patent applications or claims benefits under 35 USC § 119(e) for provisional patent applications, for any and all parent, grandparent, great-grandparent, etc. applications of the Priority Application(s)). In addition, the present application is related to the “Related Applications,” if any, listed below.
The present invention relates to the field of obstetrics and gynecology, specifically to achieving a control over ovulation for infertility treatment.
It is generally accepted that egg quality (aka developmental competency or maturity) is the most important predictor for the success of human reproduction, including assisted human reproduction. It is also known that the egg acquires developmental competency gradually, while inside of the follicle growing within the ovary during the follicular phase. Since the egg is very small and is contained within the follicle, it is impossible to directly measure whether it has reached developmental competency. However, is possible to measure the size of the follicle that contains the egg using ultrasound and measure follicles activity by evaluating level of estradiol in blood. Since the size and the amount of estradiol produced by follicle during natural follicular phase is known, those measurements may be used as benchmarks to infer the state of developmental competency of the egg in assisted reproduction. Yet, it has been learned over time that, paradoxically, the correlation between the size of the follicle and egg quality is poor.
Anecdotal clinical observation and inventive insight led to the hypothesis that the duration of the follicular phase is a better predictor of oocytes competency than the size of the follicle or the amount of estradiol it produces. This hypothesis was further confirmed by reviewing epidemiological studies and retrospective analysis of clinical data. Finally, the-hypothesis was confirmed prospectively by several case reports. In some cases, non-steroid anti-inflammatory drug, diclofenac was applied, that extends the follicular phase, providing the egg with more time to gain the developmental competence. In other cases of assisted reproduction cycles, the patient was maintained in the artificial follicular phase by ignoring rupture and loss of the largest follicle or by manipulating with the amount of medications used to stimulate follicles growth, so that the remaining follicles had additional time to nurture the egg, until the target duration of the follicular phase was achieved.
According to one embodiment of the invention, there is provided a method for improving oocytes quality by increasing a follicular phase of an ovarian cycle of a patient. A target duration of the follicular phase of the patient is determined. Non-steroidal anti-inflammatory medications is prescribed to be consumed for at least one day during the target duration by the patient. After achieving the target duration, a fertilization process is prescribed for the patient.
According to one embodiment of the invention, there is provided a method for improving oocytes quality by increasing a duration of follicular phase of an ovarian cycle of a patient. A target duration of the follicular phase is determined for the patient. A plurality of ovary stimulating medications to be consumed only during the target duration to stimulate ovaries of the patient. Ovulation of the patient is triggered once the target duration is achieved. Oocytes are harvested and a fertilization process is prescribed for the oocytes.
The foregoing is a summary and thus contains, by necessity, simplifications, generalizations, and omissions of detail; consequently, those skilled in the art will appreciate that the summary is illustrative only and is not intended to be in any way limiting. Other aspects, inventive features, and advantages of the present invention will be apparent in the non-limiting detailed description set forth below.
The present invention may be better understood, and its numerous objects, features, and advantages made apparent to those skilled in the art by referencing the accompanying drawings, wherein:
An oocyte is the very beginning of human life—in the simplest of terms, it is an immature egg cell. Throughout the process of ovulation, this immature egg cell eventually matures and becomes an ovum, or egg.
A menstrual cycle is divided into a follicular phase (from the first day of the period to ovulation) and the luteal phase (the days after ovulation and before the next period). It is well known that the duration of the luteal phase is highly conserved and varies very little from female to female. The luteal phase does not change with age, while the duration of the follicular phase varies from woman to woman and does change with age. Therefore, when there are changes in the duration of the menstrual cycle, for most woman, one can safely assume that it is solely due to the follicular phase changes.
The follicular phase is the longest step in the menstrual cycle, lasting from the first day of a period to ovulation, meaning the release of the egg. This critical step in the acquiring developmental competency and can last between 11 and 27 days.
In most cases, eggs developmental competency, aka egg/oocyte quality is the most important variable determining the success of reproduction.
Yet, there is no clinically useful marker to predict oocyte quality. Therefore, reproductive endocrinologist monitors the size of the follicles during ovarian stimulation and when the largest follicle reaches about 22-25 mm in diameter, the ovulation is triggered so that the oocytes can be forced to ovulate or can be retrieved for in vitro fertilization (IVF). The follicular size range above was chosen because it is close to the follicle's size just before ovulation in the natural cycle with an underlying assumption that it signifies the oocyte's competency. In addition, physicians also use the serum level of estradiol (E2) produced by follicle as a secondary indirect marker of egg's competency.
However, observations from assisted reproduction show that the size of the follicle has only a weak if any association with the egg quality.
The misconception that follicular size reflects the oocyte's properties can be traced to the early stages when the oocyte does indeed control the follicle (by secreting several specific growth factors). But once the cavity is formed and expanded, the gradient of oocyte-derived growth factors becomes too diluted to reach distal granulose cells. This allows those granulosa cells to escape the oocyte's control, differentiate into mural granulosa, and begin expressing receptors to FSH. Once this happens, the corona-cumulus complex will remain under the control of the oocyte-produced growth factors. However, the enlargement of the follicle, the result of mural granulosa proliferation and fluid accumulation, is initially controlled by FSH and later by both FSH and luteinizing hormone (LH). Full recognition of this dual control is very important, because it helps to appreciate that the processes responsible for the egg acquiring competency (nursing with corona-cumulus), and the process responsible for the ultimate egg release from the follicle (ovulation), are driven by completely different, independent, and uncoordinated mechanisms. Thus, using the size of the follicle to predict egg's competency is not unlike trying to identify an age of a fetus by measuring the size of the woman's belly. It is common knowledge that while woman's belly size does not correlate with the maturity of the fetus, the duration of pregnancy does. For this reason, the duration of pregnancy of 39 weeks is referred to—term pregnancy.
Another common misconception regarding egg quality underlying the misconception about the relevance of the follicle's size, is that an ability to extrude so-called polar body signifies egg's competency.
One may wonder how size, E2 and polar body can be inadequate benchmarks of egg developmental competency if IVF is so successful. “Success” depends on the definition of success. On average only about 30-40% of retrieved oocytes develop to the blastocyst and only about half of them are chromosomally normal. If a female has a lot of oocytes, this is acceptable. However, if oocytes are in short supply, that “success” rate is no longer acceptable.
We hypothesized that perhaps, similarly to pregnancy, the duration of the follicular cycle would be a better predictor of oocyte quality than the parameters of the follicle containing the egg.
Indeed, it is known that the length of time of the ovarian cycle correlates with a woman's fertility rate. Epidemiological data point to the strong correlation between the duration of the follicular cycle and successful outcome (
Thus, understanding what controls the duration of the follicular phase is important not only because it is central to reproduction, but also because this is the only time when it could be controlled by a physician.
Just like a fetus in the womb does not have control over the time of uterine contractions of delivery, the oocyte has no control over the duration of the follicular phase, as we explained earlier. Instead, it is determined by the lifespan of the follicle. To better understand the life cycle of the ovarian follicle it is useful to look at its simpler cousin, the hair follicle. Both types of follicles are comparable histologically and in other key features. It is a common knowledge that inflamed hair follicle (a pustule) progresses through several distinct phases. First, it is just a small bump, then it fills with fluid, then a black spot appears, and at some point, it reaches its maximum size, and then it ruptures (“ovulates”). The life cycle, from the bump to rupture, has a predictable duration, which is determined by the ability of local tissue to accommodate the follicle's expansion. Once the maximum size is reached, the follicle begins to disintegrate without any additional forces required.
Important points here is that the maximum size that the hair follicle can expand to is determined by surrounding tissues and there is a distinctive “ripe to rupture” stage.
Unlike the hair follicle, the expansion of the ovarian follicle is driven by FSH and LH. However, the limitations of expansion by the local environment still apply once the follicle reaches a certain size, the inflammation sets in (that is why the basal temperature rises), and at about 25 mm it begins to disintegrate spontaneously in a manner like the pustule—independent of the reproductive hormones. According to the new ovulation paradigm, this spontaneous disintegration of the ovarian follicle results in LH-independent rise of the progesterone, which triggers gonadotropins surge that signals the end of the follicular phase. If this happens at about 16 days after the start of the follicular phase, the oocyte will ovulate fully competent—term. If it happens earlier, the oocyte will also ovulate, but this ovulation may end up “pre-term”.
To summarize, the ability of an oocyte to reach term maturation is determined by the duration of the follicular phase, which in its own turn is determined by properties of the ovarian cortex, inflammation, level of FSH and LH, and the activity of mural granulosa within the follicle, which is responsible for the production of a fluid, which causes the follicle to expand.
Based on clinical observations, 10 days of controlled follicular phase during IVF cycle (about 8 days of stimulation) represents the time-cliff, when many patients will not be able to produce competent eggs.
Instead of looking for specific markers, the disclosed method improves the oocyte quality by increasing a duration of time the oocyte stays in the follicle allowing the oocyte to receive nourishment from the follicle. The following approaches may be used to facilitate reaching a target time for the oocyte to obtain the nourishment from the follicle.
1) Prevent premature rupture of the follicle.
a) Medication, for example, nonsteroid such as diclofenac
a) Less FSA, for example every other day
Furthermore, during controlled ovarian stimulation, a woman receives additional amounts of FSH, which makes the follicle “grow” about 1.2 times faster than during the natural cycle (in many cases the pace is even higher). At the same time, the pace of the oocyte's acquisition of its developmental competence is unaffected. This creates a potential for asynchrony between the follicular growth and oocyte acquisition of developmental competence—“term maturation.”
It must be noted that in a natural cycle, the duration of the follicular phase will also affect the size of the so-called corpus-luteum, which is an independent variable for a viable pregnancy.
Importantly, unlike the term pregnancy, which is the same for any woman, it is assumed that term maturation has considerable variability from woman to woman. Also, with age, it may take longer for an oocyte to reach term maturation.
Case report 1 Patient 35 years old. G-o, P-0
This case is of particular interest because it demonstrates that not only Term Stimulation™ achieves better results than conventional stimulation, but also that Term Stimulation seems to be improving oocyte quality compared to the natural cycle. Curiously, the husband's sperm, in this case, was also a suspect contributing factor to infertility.
Case report 2. Patient 34 years, G-0, P-0.
Clomid, Timed intercourse. The patient's medication was identical in Cycle 1 and 2.
Case report 3. Patient 31 years old. G-0, P-0. IVF. Two identical ovarian stimulation regimens two months apart.
Term Maturation explains why very young patients and patients with polycystic ovary syndrome (PCOS) have poor quality oocytes in IVF. Term maturation is the state of the oocyte when it acquires the ability to develop to term after fertilization. It is counted from the first day of the period to the beginning of the gonadotropins surge (or administration of ovulation trigger). There is evidence that attaining a target duration of the follicular phase of 18 days increase the chances of pregnancy. To determine the duration of term maturation, first, we need to know the duration of the follicular phase that would most likely result in pregnancy.
A new theory should explain at least one paradox, which does not have a satisfactory explanation under the current paradigm. One of such paradoxes is the unexplainably low oocyte quality in very young IVF patients, despite their excellent response to ovarian stimulation. The phenomenon has been puzzling physicians for many years.
The concept of term maturation provides a simple and very plausible explanation for this paradox. Young patients have a lot of follicles at the start of the follicular phase and respond to hormonal stimulation with most of them recruited into the cycle. Because of an unusually large number of growing follicles, estradiol is rising at a higher pace and the follicles reach ovulatory size earlier than in the natural cycle. This makes it necessary to trigger these patients early before oocytes would be expected to reach term maturation. As the result, they do not produce good quality embryos, creating a false impression that they were intrinsically poor quality. In truth, they were probably perfectly good oocytes, which simply did not get enough time to acquire full development potential. The same reasoning applies to PCOS patients with high anti-mullerian hormone (AMH).
The flowchart and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present invention. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions noted in the blocks may occur out of the order noted in the Figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.
While embodiments have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, that changes, and modifications may be made without departing from this invention and its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. Furthermore, it is to be understood that the invention is solely defined by the appended claims. It will be understood by those with skill in the art that if a specific number of an introduced claim element is intended, such intent will be explicitly recited in the claim, and in the absence of such recitation no such limitation is present. For non-limiting example, as an aid to understanding, the following appended claims contain usage of the introductory phrases “at least one” and “one or more” to introduce claim elements. However, the use of such phrases should not be construed to imply that the introduction of a claim element by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim element to inventions containing only one such element, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an”; the same holds true for the use in the claims of definite articles.
For purposes of the USPTO extra-statutory requirements, the present application constitutes a utility application related to and claims the benefit of priority from U.S. Provisional Patent Application No. 63/186,135 filed on May 9, 2021.
Number | Date | Country | |
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63186135 | May 2021 | US |