Pii: s0029-7844(02)02382-7

(ie, the definition of the fertile window) have only re- The purposes of this paper are to discuss new data regarding the fertile window, to provide an overview of the various methods of identifying ovulation and the fertile window, including their physiologic basis, advan- tages, and disadvantages, to summarize the evidence Health Research Center, Department of Family and Preventive Medicine, and regarding their application for couples trying to achieve Division of Reproductive Endocrinology and Infertility, Department of Obstetrics pregnancy, and to make a clinical recommendation for and Gynecology, University of Utah, Salt Lake City, Utah use based on the evidence. Our primary purpose is to update physicians who are in a position to advise patients Physicians who counsel women for preconception concerns who desire to conceive. We also discuss the implications are in an excellent position to give advice to couples regard- of timed intercourse for the identification and definition ing the optimal timing of intercourse to achieve pregnancy.
of infertility, and briefly discuss the important question The currently available evidence suggests that methods of when further evaluation and treatment for infertility that prospectively identify the window of fertility are likely to be more effective for optimally timing intercourse than calendar calculations or basal body temperature. There are several promising methods with good scientific bases to THE FERTILE WINDOW
identify the fertile window prospectively. These include Recent research has defined the days of the menstrual fertility charting of vaginal discharge and a commercially available fertility monitor. These methods identify the cycle during which intercourse is mostly likely to result occurrence of ovulation clinically and also identify a longer in pregnancy. Conception is possible from intercourse window of fertility than urinary luteinizing hormone kits.
beginning about 5 days before ovulation extending Prospectively identifying the full window of fertility may through the day of ovulation.However, conception lead to higher rates of conception. Proper information on the day after ovulation has never been documented.
given early in the course of trying to achieve pregnancy is This implies that ova may only be fertilizable in vivo for likely to reduce time to conception for many couples, and less than a day because spermatozoa can survive for up also to reduce unnecessary intervention and cost. (Obstet to 6 days in properly estrogenized cervical mucus.Stud- Gynecol 2002;100:1333–41. 2002 by The American ies of the timing of fertilization in vitro, including intra- College of Obstetricians and Gynecologists.) cytoplasmic sperm injection, also suggest that mature human ova (in metaphase II) have a more limited opti- Identifying the days of the menstrual cycle when sexual mum fertilization window than previously appreciated intercourse may result in pregnancy is of high clinical (hours instead of days).Data indicate that by 16 hours relevance for most couples who desire pregnancy. Many after oocyte recovery, fertilization by standard insemina- couples desire to time conception as precisely as possible tion is poor.Indeed, in vitro fertilization programs to plan the approximate date of birth. In addition, over generally inseminate ova within 2–6 hours of ovum 10% of couples in the United States have difficulty retrieval in an attempt to optimize fertilization rates.
achieving pregnancy.Although the majority of these Further, current evidence indicates that the highest prob- ability of clinically evident conception occurs with inter- couples need medical intervention, some of them may course 1 or 2 days before ovulation, rather than the day achieve pregnancy by having intercourse during the days when conception is most likely to occur (ie, during This is illustrated in which comes from a the fertile window). Relevant data regarding the proba- reanalysis of two previous studies of women achieving bility of intercourse on specific days relative to ovulation pregnancy, one based on basal body temperature, and the other based on urinary hormones.The latter study has been widely quoted as indicating that the highest Address reprint requests to: Joseph B. Stanford, MD, MSPH, probability of conception occurred on the day of ovula- University of Utah, Health Research Center, Department of tion, but that earlier analysis included clinically unrecog- Family and Preventive Medicine, 375 Chipeta Way, Suite A, nized early pregnancy losses and also did not fully Salt Lake City, UT 84108; E-mail: [email protected].
account for measurement errors.Another large data- The authors thank Richard Fehring, DNSc, and Doug Carrell, PhD, for helpful set has recently confirmed this pattern of the probability of conception relative to ovulation.
2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
bility of pregnancy. Although sperm concentrations drop with increasing frequency of intercourse, in most men performing daily intercourse the drop does not reach a threshold that would reduce the added concep- tion benefit of each act of daily intercourse.Whether intercourse less often than daily would be of benefit in men with baseline low sperm concentrations has not Because sperm counts are maximized after about 5 days of abstinence, couples may be advised to abstain from intercourse for 5 days before the beginning of the fertile window. This would theoretically maximize the sperm count at the first act of intercourse during the fertile interval and throughout the rest of the interval.
However, this has not been studied empirically.
Figure 1. Probability of clinically recognized pregnancy
resulting from a single act of intercourse by timing of
Frequency of Intercourse if Fertile Window Is
intercourse relative to estimated day of ovulation (day 0).
Data are from two separate studies: Barrett and Marshall9 An alternative approach to identifying the fertile window and Wilcox et al.Details of the data and analysis are given is simply to have frequent intercourse throughout the in Dunson et al.(Reprinted with permission from Dunson menstrual cycle. Wilcox et al proposed that simply hav- D, Baird D, Wilcox A, Weinberg C. Day-specific probabili- ing intercourse consistently two to three times per week ties of clinical pregnancy based on two studies with imperfectmeasures of ovulation. Hum Reprod 1999;14:1835–9.
will likely result in one or two acts of intercourse occur- ஽ European Society of Human Reproduction and Embryology.
ring during the fertile window, and that this should be Reproduced by permission of Oxford University Press/Human sufficient for couples of normal fertility to conceive.
However, this approach may be less satisfactory for Stanford. Timing Intercourse to Conceive. Obstet Gynecol 2002. couples who wish to be certain of timing intercourse correctly, and it provides less accurate documentation for the physician. Further, it may be more difficult for some couples to maintain a schedule of regular inter- What may this mean clinically? We suggest that if the course constantly throughout the cycle than to assure a more recent data analyses are correct, then a single act of high frequency of intercourse during the fertile window.
intercourse during the fertile window that occurs on the day of ovulation may by chance occur sufficiently late in the 24-hour period that the ovum may have already lost IDENTIFYING THE FERTILE WINDOW
its ability to become fertilized. This contrasts to a single To optimize the timing of intercourse during the fertile act of intercourse during a cycle occurring on the day window, a couple must be able to identify this 6-day before ovulation. With normal sperm longevity, there interval before and including the day of ovulation. Tra- would be capacitated sperm present in the female repro- ditional and widely used means of identifying the day of ductive tract before, during, and after ovulation, increas- ovulation and the fertile window include basal body ing the chance of fertilization. Therefore, prospective temperature and calendar calculations. Newer means methods that identify the approach of ovulation before it include serial ovarian ultrasound, monitoring of hor- occurs would be expected to result in higher conception mones in urine, and fertility charting of vaginal dis- charge. The physiologic basis for these approaches is illustrated in Each of these is summarized in Timing and Frequency of Intercourse During the
and is described below in more detail. We also Fertile Window
briefly describe several other approaches to identifying Intercourse on multiple days throughout the 6 days of the fertile window that are currently marketed or in the “fertile window” raises the overall probability of conception further, though not additively.In couples of apparently normal fertility, daily intercourse during Calendar Calculations
the fertile window is preferable to less frequent inter- Calendar calculations do not identify the actual ap- course because each day of intercourse raises the proba- proach of ovulation, but are based on statistical averages Stanford et al
Figure 2. Physiologic parameters of the menstrual cycle that can be used to identify days during which intercourse may
result in pregnancy (the fertile window). LH ϭ luteinizing hormone; P ϭ peak day.
Stanford. Timing Intercourse to Conceive. Obstet Gynecol 2002.
around which there is large variation, both between Serial Ovarian Ultrasound
women and within the same woman. Most of the vari- Ovarian follicular ultrasound (by transvaginal scanning) ability in cycle length occurs in the preovulatory portion is highly accurate for identifying the approach and oc- of the cycle though there is also some post- currence of ovulation. By serial examination, the devel- ovulatory variability. For example, in a previously refer- opment of the follicle can be tracked, and rupture can enced study of women with normal fertility trying to get usually be documented. However, its high cost and pregnant,only 30% had their entire fertile window (as determined by urinary hormones) completely within limited availability preclude its routine use for couples to days 10 and 17 of the menstrual cycle, and on each day between cycle days 6 and 21, at least 10% of women with regular cycles were within their fertile window.Even Basal Body Temperature
on the day of expected menses (by calendar calculation), Basal body temperature is a time-honored technique to about 3% of women with regular cycles were still in their document ovulation, but the temperature rise usually fertile window. These considerations make calendar cal- occurs after ovulation (up to several days after), making culations unreliable for the purpose of timing intercourse it nearly impossible to identify the days of fertility to achieve pregnancy within the same cycle prospective- Stanford et al
Table 1. Methods to Time Intercourse to Seek Pregnancy
Creighton Model Identifies the changes in Usually 5–7 d before Prospectively identifies Requires health education Prospectively identifies Requires about 15 min a Prospectively identifies Does not apply to women LH ϭ luteinizing hormone; EIC ϭ estrone conjugates; PdG ϭ pregnanediol-glucuronide; E3G ϭ estrone-3-glucuronide.
* Approximate cost in US $ based on 6 mo of use. Costs may vary depending on local prices and availability.
ly.Some women have basal body temperature charts Bioself [Bioself Inc., Thoˆnex, Switzerland] and Sophia that are unreliable or difficult to interpret, especially Ltd. [Japan]) have been approved by the United States women with infertility.Interrater reliability in interpre- Food and Drug Administration for use to achieve preg- tation of temperature curves has been found to be nancy. Data on the clinical reliability of these devices to poor.Several computerized devices based on basal achieve pregnancy are extremely limited.
body temperature have been developed, which rely on the time of the basal body temperature shift in the Urine Luteinizing Hormone (LH) Kits
previous cycle to estimate the time of ovulation in the Kits for home measurement of urine LH are commer- subsequent cycle, and several of these devices (such as cially available from a variety of companies.Urine LH Stanford et al
is an accurate prospective marker for ovulation. The rise the LH surge and day immediately after as days of in urine LH occurs on average about 24 hours before “peak” fertility, and the second day after the LH surge as ovulation, although there is significant variability in this 1 more day of “high” fertility. In a validation study of the (from about 16 hours to 48 hours before ovulation).
ClearPlan Easy Fertility Monitor involving 150 cycles, Therefore, in a significant proportion of women, the time the measurement of urinary hormones correlated very of highest probability of conception may have already closely to serum levels, and ovulation was detected by passed by the time the LH surge is detected A ultrasound within the 2 days of “peak” fertility in 91% of common protocol for couples having difficulty achieving cycles. In no cases did ovulation occur before “peak” pregnancy is to advise men to abstain for several days fertility.A separate validation study found close corre- when possible before the anticipated LH surge to accu- lation between the results of the monitor and laboratory mulate a higher volume ejaculate for insemination. How- measurements from urine. In 66% of cycles, the LH ever, these days of abstinence appear to be the most surge detected by the monitor was on the day of the LH fertile days for intercourse. Even if the LH surge identi- surge detected by laboratory analysis, whereas in 24% it fies a day with good probability of conception, the brief window of time identified prospectively limits the oppor- For many cycles, it is likely that the 2 days of “peak” tunity to have multiple acts of intercourse before ovula- fertility identified by the ClearPlan Easy Fertility Moni- tion. In a randomized trial, no difference in conception tor do not fully coincide with the 2 days when inter- rates was found between using basal body temperature course is most likely to result in pregnancy. As illustrated or urine LH to time artificial insemination in couples in the 2 days with the highest probability of pregnancy will probably be the day before the LH surge and the day of the LH surge itself. However, the monitor Ovarian Monitor
identifies the day of the LH surge and the day immedi- A number of methods have been developed to directly ately after as the days of “peak” fertility. Because the measure multiple hormonal markers of fertility in the computer algorithm in the monitor also incorporates clinical setting. The first system (and probably the best some calendar calculations, it is not suitable for use in studied) was developed in Australia, and is known as the women with cycles longer than 42 days or shorter than Ovarian Monitor (St. Michael NFP Services Pty. Ltd., 21 days. This device has been approved by the United Victoria, Australia). This system is based on an enzyme States Food and Drug Administration for use to time immunoassay for urinary metabolites of estrogen and intercourse to achieve pregnancy and is available for progesterone. The beginning of the fertile window is retail sale in the United States. Studies are underway to marked by the rise in estrogen above a certain thresh- old,and the end is marked by the rise in progesterone assess its clinical effectiveness to achieve pregnancy.
been shown to be accurate in clinical use,but it requires Changes in Cervical and Vaginal Discharge
that a woman collect her urine specimen to a standard One of the best established markers of ovulation is the volume, and spend about 10–15 minutes running the changes in vaginal discharge that result from the changes assay on days that she is checking her fertility status.
in cervical mucus secretion throughout the menstrual This system is not currently available in the United cycle.About 5–6 days before ovulation, estrogen is secreted in increasing amounts from the developing ovarian follicle. The estrogen rise over the 5–6 days ClearPlan Easy Fertility Monitor
before ovulation stimulates the uterine cervix to secrete The ClearPlan Easy Fertility Monitor (Unipath Diag- type E (estrogenic) mucus, which is biochemically and nostics Inc., Waltham, MA) is based on an enzyme biophysically designed to facilitate the transport and immunoassay for the estrogen metabolites estrone-3- survival of sperm within the cervix. After ovulation, glucuronide and LH in the urine. It is designed for progesterone is secreted in increasing amounts by the simplicity and requires that a woman dip a test strip into corpus luteum. Progesterone stimulates the cervix to her urine stream for 3 seconds while voiding, cap it, and produce a different type of mucus, type G mucus, which place it in the computerized monitor where it renders a is biochemically and biophysically designed to block the reading and interpretation within 5 minutes. The moni- passage and prevent survival of sperm. This has led to tor identifies a time of “high” fertility coinciding with the the concept of a biologic valve for the cervix, which is initial rise in estrogen, usually 1-5 days before the urine turned on by estrogen and turned off by progester- LH surge The monitor identifies the day of Stanford et al
Fertility Charting of Vaginal Discharge
peak day have a 67% probability of pregnancy, and that This biologic valve also results in a biomarker of vaginal intercourse up to 3 days before the peak day with favor- discharge that women can easily use for fertility charting.
able vaginal discharge resulted in a 55% probability of Type E mucus is clear, stretchy, and slippery, and results pregnancy.However, this study was limited by rela- in vaginal discharge with these same characteristics (in tively few pregnancies in this category, and by the fact varying degrees), which first appears an average of 5–6 that not all acts of intercourse were recorded. A recent days before ovulation. Type G mucus results in minimal study found that if intercourse occurs on any given day or no vaginal discharge, signaling that ovulation has relative to ovulation, the presence of vaginal discharge occurred.It has been found that women of diverse from cervical mucus was associated with a two-fold educational and cultural backgrounds can easily learn to increase in the probability of clinically evident concep- review and interpret the changes in their external vulvar tion as compared with no discharge.This provides discharge to identify the onset of the production of type direct empirical evidence that the presence of vaginal E mucus, and the “peak day” (which is identified 1 day discharge from type E mucus strongly correlates with the later as the last day of any vaginal discharge that has type probability of conception. There are no published stud- ies on the use of fertility charting to achieve pregnancy in E characteristics).It has also been demonstrated that couples with infertility, or with long or irregular cycles.
the external observations made by women during rou- tine use of the bathroom accurately reflect the changes in Salivary Electrolytes and Ferning
mucus secretion that occur at the level of the cervix.
As ovulation approaches and estrogen levels rise, the The peak day as identified by women correlates well sodium and potassium concentrations in saliva change, with the timing of ovulation (Ϯ2 or 3 days in all cases), as resulting in changes in salivary electrical resistance. A device known as the CUE monitor (Zetek Inc., Aurora, CO) uses an oral probe to measure salivary resistance on peak day has also been found to have reasonable inter- a daily basis. It was shown to measure a peak in salivary resistance an average of 7.9 days (range 6–12) days Although vaginal discharge changes are usually easy before follicular collapse assessed by ultrasound in 42 for women to learn and interpret, we recommend that cycles from ten women.To confirm the occurrence of for optimum understanding and application, women ovulation, the CUE monitor requires the use of a sepa- should learn how to observe these from a trained natural rate vaginal probe to measure a rise in vaginal electrical family planning teacher. Two systems that have pub- resistance (resulting from electrolyte changes in cervical lished research documenting their effectiveness in teach- mucus). In the previously mentioned study, the rise in ing fertility charting to women are the Creighton Model vaginal resistance occurred within 1 day before or after FertilityCare Systemand the Billings Ovulation Meth- ovarian follicular collapse. In another study of 21 cycles from 11 women, the CUE monitor and the associated thermal method of family planning, which combines interpretive algorithms identified a window of fertility mucus observation with basal body temperature. There that was nearly identical to that identified by the Creigh- are also a variety of self-help books available to teach ton Model FertilityCare System.A computerized ver- women how to monitor their vaginal discharge to chart sion of this device, the OvaCue (Zetek Inc., Aurora, fertility to achieve or avoid pregnancy (usually com- CO), automatically records and interprets readings and bined with basal body temperature), but the effectiveness is commercially available. However, the invasive nature of use based on learning from these books has not been of the vaginal probe may limit the use of this device.
empirically demonstrated. Most of these books recom- The changes in salivary electrolyte concentrations mend that a woman learn from a trained instructor may also change ferning patterns that can be observed in dried saliva. Theoretically, increased salivary ferning There are three studies addressing the effectiveness of should indicate times of estrogen dominance and greater fertility charting of vaginal discharge to achieve preg- fertility. A variety of devices to observe the ferning nancy. A study of 50 couples of normal fertility who used patterns of dried saliva have been developed and mar- the Creighton Model FertilityCare System to achieve keted to identify days when intercourse can result in pregnancy found that 76% did so within the first pregnancy. However, a small study of one such device month.However, this study did not include couples found that although the “peak” salivary ferning corre- who tried unsuccessfully to achieve pregnancy. Another lated with the LH surge, the beginning and end of the study of the Billings Ovulation Method suggested that fertile period could not be identified.We could identify couples of normal fertility who have intercourse on the no other scientific studies of these devices.
Stanford et al
Other devices are being developed to quantitatively A study of physicians in Missouri found that for assess changes in cervical mucus and associated proper- couples having difficulty conceiving, physicians were ties.However, none of these devices is yet commer- most likely to recommend the initial steps of basal body temperature or calendar calculations.This suggests that physicians in the United States may currently be recommending methods that are less than optimal for CLINICAL RECOMMENDATION FOR COUPLES WANTING
timing intercourse to achieve pregnancy. (At the time TO CONCEIVE
this study was conducted, the ClearPlan Easy Fertility Which of these methods should physicians recommend Monitor was not yet available in the United States, but to couples trying to conceive with minimum time to both the Creighton Model System and the Billings Ovu- pregnancy, or couples who would like to know the days lation Method were widely available, as well as other when intercourse is most likely to result in pregnancy? sources of information and instruction for fertility chart- There are currently no comparative studies to directly answer this question. However, based on the data that we have reviewed, we suggest that the most appropriate Implications of Timed Intercourse for Older Women
methods to identify the entire fertile window prospec- Seeking Pregnancy
tively for the purpose of achieving pregnancy would be One practical application of timed intercourse is for either fertility charting of vaginal discharge (specifically women without any known infertility factors except the Creighton Model FertilityCare System or the Billings age-related diminished ovarian reserve. In this situation, Ovulation Method), or the ClearPlan Easy Fertility aside from egg donation, advanced reproductive tech- Monitor. Efficacy of the two approaches is likely to be nologies such as superovulation and in vitro fertilization comparable for most women. Some women may prefer have limited utility.Although prospective comparisons the ClearPlan Easy Fertility Monitor because it is a are lacking, advanced reproductive technologies appear “high-tech” device that takes little time to learn to use.
to offer little advantage over well-timed intercourse Other women may prefer the fertility charting because it alone when diminished ovarian reserve is documented, is low cost, puts them in tune with their body, and does especially given their high cost. (Generally the dominant not require devices. The ClearPlan Easy Fertility Mon- follicle is expected to represent the healthiest ovum of the itor is not suitable for women with unusually long or small cohort of ova that may have been retrieved with in short cycles (less than 21 days or more than 42 days).
vitro fertilization.) Therefore, optimizing the timing of Fertility charting of vaginal discharge should be helpful intercourse may have a nearly equal (albeit low) chance to these women if they are ovulatory.
of success as an in vitro fertilization attempt in this For couples who have some difficulty conceiving in a timely manner, or for women who have a history of irregular or infrequent cycles, the logical first step of Implications of Timed Intercourse for Infertility at Any
evaluation is the ascertainment of ovulation. This can be accomplished with fertility charting of vaginal discharge A major advantage of optimizing the timing of inter- or by urinary hormonal assessment. Thus, the prospec- course may be the ability to condense the time required tive methods are able to accomplish two important steps before making the diagnosis of infertility, such that ap- simultaneously: the assessment of ovulation and the propriate further evaluation can be pursued in a timely proper timing of intercourse for ovulation.
manner when necessary. In a study of 100 couples who Alternatively, it is possible to use urine LH alone (for conceived without fertility awareness, half had done so women with reasonably regular cycles) or basal body by 3 months, 75% by 6 months, and over 90% by 12 temperature alone to provide evidence for the occur- months.As mentioned earlier, a similar study with the rence of ovulation, and together with charting of inter- Creighton Model FertilityCare System found that 76% course on a calendar, to assess retrospectively whether a conceived in the first month, and all by the seventh couple had appropriately timed intercourse during the month.It has been suggested that with timed inter- fertile period. Urine LH or basal body temperature do course, a diagnosis of infertility can be established in 6 not prospectively identify the full fertile period. Properly timed serum progesterone assay, endometrial biopsy, or Even many women with diagnosed infertility con- ovarian ultrasound may also be used to confirm the ceive spontaneously with random intercourse. In a clas- occurrence of ovulation, but these approaches are more sic cohort study, 35% of untreated infertile couples (av- invasive and costly and should be reserved for cases erage length of infertility at entry 3.1 years) conceived in where uncertainty remains despite previous approaches.
follow-up up to 7 years (with about 75% of the pregnan- Stanford et al
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Source: http://www.npr.pl/badania/timing_intercourse.pdf


Antioxidative Activity and Anti-inflammatory Effects on the Murine Macrophages of Methanol Extracts Sang-Bum Kim, Min-Ho Chang1, Sang-Hyun Han2 and Hong-Shik Oh2,* Ohyun Middle School, Jeju 690-061, Korea 1 National Park Research Institute, Korea National Park Service, Namwon 590-811, Korea 2 Department of Science Education, Jeju National University, Jeju 690-756, Korea Abstract - Oxidati


Reporting period: April 1, 2011-March 31, 2012Submitted February 29, 2012 by Yvonne Herivaux (212-746-4746). Review the description of your project. If there have been any changes to the project over the past year, update the description.     Short project title (< 90 characters):  Androgen Hormones in PMDD     Full title:  Androgen Hormones in PMDD     Proje

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