Surgery – Diagnostic testing – Monitoring fertility cycle
Reexamination Certificate
1996-10-10
2002-09-24
Nasser, Robert L. (Department: 3736)
Surgery
Diagnostic testing
Monitoring fertility cycle
Reexamination Certificate
active
06454726
ABSTRACT:
This invention relates to methods, devices and test kits for use in monitoring the ovulation cycle in female mammals, especially humans.
The invention is particularly, although not solely, concerned with the provision of reliable information concerning fertility status as an aid to contraception by the use of simple practical procedures that can readily be applied by unskilled persons, e.g. in the home.
Throughout this specification, the expression “fertile phase” is used to mean that interval in a female menstrual cycle, spanning the event of ovulation, during which it is most likely that intercourse will result in fertilization, because of the normal viability of spermatozoa and ova.
There is a wealth of scientific literature on the urinary hormone profiles during the ovulation cycle. The relative usefulness of estradiol derivatives, especially estrone-3-glucuronide (E3G), lutenising hormone (LH), and progesterone derivatives, especially pregnanediol-3-glucuronide (P3G), as indicators of the status of the cycle, has been studied extensively.
Procedures are already available commercially to enable LH to be used to enhance the likelihood of conception.
The article “A prospective multicentre study to develop universal tests for predicting the female phase in women” (WHO, Int J Fertil 30(3) 1985 p 18-30) discusses the prediction of the fertile phase in an ovulation cycle by measuring the daily levels of the hormones E3G and Pd-3-G (ie. P3G) in early morning urine. Although the primary purpose of this study is to analyse for differences in fertile phase calculation in different races of women, this paper does suggest that the relative levels of E3G and Pd-3-G may be used in predicting the start and end of the fertile phase. If the start of the fertile phase is defined by the sustained rise in the level of urinary E3G, then the end of that fertile phase (ie the start of the luteal phase) may be assumed to be 5 days after the E3G peak is observed. Similarly, if the start of the fertile phase is taken to be an increase in the E3G: Pd-3-G ratio, the end is defined as being 6 days after the peak value of this index is observed.
The article “New assays for identifying the fertile period” by Brown, Blackwell, Holmes and Smyth (
Int J Gynecol Obstet
1989 Suppl 1 p111-122) discusses the use of estrogen level measurements as an ovulation predictor, although estrogen on its own is stated as being an unreliable ovulation predictor. Pregnanediol is also suggested as a hormone marker to signify the end of the fertile phase. In the studies referred to in this paper, the average number of days of abstinence from intercourse per menstrual cycle was seventeen; furthermore, the user satisfaction with this method of contraception, and the willingness of test couples to continue using it, was found to be inversely related to length of the abstinence phase. Daily hormone measurements were made, although the article does speculate that, when the fertile phase is predicted by E3G and P3G measurements, that 12 tests per month may be sufficient. In an effort to get the abstinence period down to the quoted “theoretical” minimum of seven days, it is suggested that it may be possible to use a method of fertile phase prediction using a combination of cervical mucus symptoms and non-symptomatic markers.
The article “Biochemical Indices of Potential Fertility” by Collins (
Int J Gynecol Obstet
, 1989, Suppl. 35-43) discusses the possible use of multiple analytes in urine to delineate the fertile phase. However, the tests carried out had a success rate in predicting the fertile phase of around 80% or less; also, the fertile period predicted (and hence the abstinence period) was in all cases more than 10 days.
EP 367 615 (Monoclonal Antibodies Inc) provides a method of natural birth control in which the level of a urinary metabolite (progesterone) is measured as an indicator or the stage reached in the menstrual cycle. However, the only hormones suggested are progesterone metabolites, and hence the method can only be an indicator of the luteal phase safe period.
The article “Fertility Awareness: Jet-Age Rhythm Method?” by Djerassi (
Science
, June 1, 1990, p 1061-2) suggests the prediction of the fertile phase for contraceptive, and in particular conception purposes by the analysis of body fluids (eg blood, urine or saliva). In this article, it is suggested that the start of the fertile phase could be predicted safely by detecting the rise in estradiol (or its metabolites). The start of the luteal phase could be predicted by either a second increase in estradiol concentration, or a major increase in progesterone (or its metabolites).
The clear inferences to be drawn from this literature are:
estradiol and its metabolites, especially E3G, are the only urinary hormones that can be used to provide sufficiently early warning, during the pre-ovulation phase of the cycle, for contraceptive purposes; and
any successful fertility awareness test which aims to provide adequate contraceptive information, must involve measurement of E3G or an equivalent molecule, and must identify the rise in E3G concentration that precedes ovulation.
Nevertheless, the literature (for example, Djerassi) also indicates that no satisfactory test based on E3G has yet been developed.
It is generally accepted that the background level of urinary E3G fluctuates so widely from individual to individual that no simple, universally applicable assay can be devised.
To try to overcome this problem, complicated mathematical procedures, eg. “CUSUM”, have been evolved to calculate a threshold E3G concentration during a current ovulation cycle, and to identify any significant rise above the calculated threshold. Such systems have the disadvantage that by the time the mathematics has recognised that a significant rise is taking place, it may already be “too late” if the objective is contraception. Accordingly it is generally accepted that the CUSUM approach cannot provided prospective information about fertility status. A review of CUSUM-based methods is found in Royston:
Statistics in Medicine
, Vol. 10 (1991) 221-240.
Overall, from this general survey of the prior art, it can be seen that in previously known techniques of fertile period prediction, the period predicted is unduly long, giving rise to an unduly long period of abstinence. Very often, such as for example shown in EP 367 615, the long period of abstinence extends from menstruation to the end of the fertile period. This, in part, is due to the difficulty in pinpointing the start of the fertile period. It has also been a feature of prior art methods that frequent, often daily, measurements of urinary hormone levels throughout the current cycle have been necessary for the method to be deemed reliable as a method of contraception.
For the purposes of this specification, estradiol and all measurable estradiol metabolites, will collectively be referred to henceforth as “E3G”. In addition to estrone-3-glucuronide already mentioned, estradiol metabolites that can also be assayed for the purposes of the invention include estradiol-3-glucuronide, estradiol-17-glucuronide, estriol-3-glucuronide, estriol-16-glucuronide and (principally for non-human subjects) estrone-3-sulphate. As will be appreciated from the following description, the invention can readily be applied to data derived from the measurement of body fluid concentrations of other analytes of significance in relation to the status of the ovulation cycle. Generally, the most suitable analytes are hormones and their metabolites. Follicle stimulating hormone (FSH) is an example. Examples of alternative body fluids, which are relatively accessible, are saliva, crevicular fluid, sweat, sebum, tears and vaginal fluid. In principle internal fluids, such as blood, can be used but are generally not preferred because they can only be accessed readily by invasive techniques.
The skilled reader will also appreciate that the body fluid “concentration” of the chosen analyte or analytes need not be measured in absolute terms, although this can of cou
Catt Michael
Coley John
Davis Paul J
Inverness Medical Switzerland GmbH
Nasser Robert L.
Oppedahl & Larson LLP
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