|
|
| General information and FREQUENTLY ASKED QUESTIONS ABOUT INFERTILITY As puberty approaches the anterior pituitary, in response to gonadotropin releasing hormone (GnRH) from the hypothalamus, releases FSH and LH causing the ovaries to become active as endocrine glands and reproductive organs. Interactions between FSH and LH and estrogen and progesterone will establish a cyclic, periodic series of events known as the menstrual cycle (men = month). Menarche (MEN are key, arch = first) is the term referring to the onset of this activity in young females at puberty. It ends with menopause (pause = cease, terminate). The menstrual cycle is a cycle of events, with an average 29 day period, caused by the interactions of 5 major hormones that bring about the release of a secondary oocyts and preparation of the endometrium for its reception should it be fertilized. The cycle, which varies between individuals and within a single individual, is averages 29 days in length but less than 30% of women have cycles of this length. The days are numbered according to externally visible events and the first day of externally visible flow of blood is designated Day 1 (not day 0). Beginning on day 1 [Estrogen] and [progesterone] are low (because there is no follicle or functional corpus luteum to produce them). Low sex hormone levels stimulate release of (relatively small amounts of) FSH (and LH) from the anterior pituitary. (GnRH secretion is stimulated by simultaneous low [E] and [P] or by high [E].) This release of FSH stimulates development of a few follicles. These follicles grow and become functionally endocrine, producing relatively small amounts of estrogens (chiefly estradiol). (The immature follicle cells do not have LH receptors and hence do not respond to LH. They do have FSH receptors though and respond to that hormone.) Under the influence of FSH one of the follicles matures fully to become a large blister-like Graafian follicle on the surface of the ovary. The estrogen produced by the maturing and Graafian follicles stimulates the development of the endometrium which thickens and adds new blood vessels. Estrogen production increases and peaks. The very high estrogen levels also cause the hypothalamus to produce GnRH, which causes the anterior pituitary to release increased amounts of LH in a pulse. The LH and FSH stimulate the rupture of the Graafian follicle (which has by this time developed receptor proteins for LH and can respond to it) and ovulation on day 14. The LH then causes the remnants of the follicle to become a corpus luteum. The corpus luteum, which exists only in the postovulation phase of the cycle, secretes more estrogen and also progesterone, thus maintaining high levels of both. These two together cause the endometrium to continue to develop in preparation for pregnancy. LH and FSH production cease in the face of high [progesterone] and [estrogen]. If a pregnancy occurs, the zygote (blastocyst) will implant about 7 days after fertilization. Special secretory glands, which develop under stimulation of progesterone, nourish the newly implanted embryo. Tissues around the implanted embryo secrete human chorionic gonadotropin (HCG) which mimics LH in causing the corpus luteum to continue functioning to maintain the endometrium with its estrogen and progesterone. If there is no fertilization, the corpus luteum begins to degenerate (because there is no LH to maintain it) and estrogen and progesterone levels in the blood drop. Without these hormones the endometrium breaks down. Arterioles in the endometrium constrict, cells become ischemic (oxygen starved) and die. Arteries rupture and bleed, menstruation begins. Estrogen and progesterone levels drop. When they reach a critical low level the anterior pituitary is stimulated (by GnRH from the hypothalamus) to produce FSH and LH to begin another cycle. Endometriosis: endometrial cells become mesenchymal and wander into the coelom (or other places) via the fallopian tube. Common in women 30-40 who have deferred pregnancy to later in life. Endometrial growth on ovaries, outside uterus, colon, etc. Pain caused by loss of extrauterine endometrial lining during menstrual flow. Hormone treatment for relief. PREGNANCY If fertilization occurs then the second oocyte completes meiotic division, a zygote is formed, and embryonic development begins and early cell divisions produce a blastocyst, which is a hollow ball of cells. The blastocyst makes its way down the fallopian tube and about 7 days after fertilization implants in the endometrium. One of the tissues that form around the embryo, the chorion, has an endocrine function and secretes human chorionic gonadotropin (HCG) (= chorionic LH) which mimics the effects of LH. This causes the corpus luteum to persist, thus maintaining high levels of estrogen and progesterone, especially progesterone, in the blood. These hormones, which are necessary for the maintenance of the endometrium, make it possible for the embryo to remain implanted in and be nourished by the uterus. Progesterone dominance inhibits contractions. Chorionic gonadotropin is released in such a large amount that some of it appears in the urine where its presence is a positive test for pregnancy. After 2 months of pregnancy the placenta takes over the job of producing progesterone and estrogen which still have the role of maintaining the endometrium. At 9 months, estrogen, which stimulates uterine contractions, achieves dominance over progesterone, which inhibits contractions (progesterone often called the "hormone of pregnancy"). Oxytocin is released from the posterior pituitary to induce uterine contractions. The two (estrogen and oxytocin) eventually cause the onset of labor and expulsion of the fetus through the birth canal. The ovaries and placenta secrete relaxin which loosens the articulation of the pelvic symphasis and relaxes the cervix permitting its dilation. Expulsion of the fetus is referred to as parturition (parturit = to bring forth). The time after parturition is postpartim. Infertility is a disease or condition of the reproductive system resulting in the inability to conceive after one year of unprotected well-timed intercourse. Infertility also includes the inability to carry a pregnancy to the delivery of a live baby. One in every six couples of childbearing age have a problem conceiving. Over 80% of all infertile couples can be helped to achieve pregnancy with proper medical treatment. Infertility is a common condition with important psychologic, economic, demographic, and medical implications. Demand for infertility services has grown substantially in recent years, even though the prevalence of infertility has been stable [1, 2, 3]. This phenomenon is due to entry of the "baby boom" generation into the reproductive age group during a period of highly publicized technologic advances. Infertility is a medical condition, not a sexual disorder. Sperm can be inseminated for 12 well-timed cycles as a measure of infertility for women with no male partner or for couples unable to have normal intercourse for medical reasons. There are some cases of inability to conceive due tofailure to achieve intercourse for medical reasons, such as spinal injury in the male partner. Much of the current emphasis in infertility is on treatment technologies (assisted reproduction, operative endoscopy, donation and storage of gametes and embryos, preimplantation genetics, etc). Nevertheless, it important first to consider the evaluation of infertility that directs treatment. Many practitioners take as a "given" the elements of a standard infertility evaluation, but review of the available data raises questions about the predictive validity of many of these tests. This topic review will briefly discuss the definition and epidemiology of infertility, with the main focus upon a critical assessment of the standard infertility tests. Emphasis will be placed upon the evaluation of the women since the evaluation of the infertile man is discussed in detail separatel. However, data on thresholds for defining are normal semen analysis are reviewed. DEFINITION : Infertility is defined as the inability to conceive after one year of intercourse without contraception. This definition has deep historical roots; it was based in part upon a study of 5574 English and American women engaging in unprotected intercourse who ultimately conceived between 1946 and 1956 . Among these women, 50 percent conceived within three months, 72 percent within six months, and 85 percent within 12 months. The one-year definition also has probabilistic appeal. Assuming a 20 percent monthly probability of pregnancy among normally fertile couples, the cumulative probability of pregnancy after 12 months is 93 percent Thus, the likelihood of being normally fertile and not pregnant after 12 months is only 7 percent. This figure is close to the 5 percent that researchers often use as a threshold for a type I error (in this case, falsely rejecting the null hypothesis of normal fertility). The likelihood of fertility decreases to 1 percent after three years of intercourse without conception; however, this definition is not practical or realistic from the standpoint of a patient's desire for timely evaluation and treatment. Thus, use of one year as a time interval for attempted conception before assigning a diagnosis of infertility is both clinically and statistically meaningful. Infertility is a female problem in 35% of the cases, a male problem in 35% of the cases, a combined problem of the couple in 20% of cases, and unexplained in 10% of cases. It is essential that both the man and the woman be evaluated during an infertility work-up. Most physicians advise you not to be concerned unless you have been trying to conceive for at least one year. If the female partner is over 30 years old, has a history of pelvic inflammatory disease, painful periods, recurrent miscarriage, or irregular periods then it might be prudent to seek help sooner. Waiting only 6 months before having an initial consultation for women 35 years and older is often recommended since if a problem is found there is less time for correction. If the male partner has a known or suspected low sperm count, then it would also be prudent to seek help sooner than waiting a year The fertile interval extends from approximately six days prior to ovulation to the day of ovulation [5]. The highest probability of conception occurs when intercourse takes place two days prior to ovulation, but is dependent upon maternal, and to a lesser extent, paternal age [6]. In a large well-designed study, the probability of clinical pregnancy following intercourse on the most fertile day in women of average fertility aged 19 to 26 years, 27 to 34 years, and 35 to 39 years was approximately 50, 40, and 30 percent, respectively, if the male partner was the same age, but 45, 40, and 15 percent, respectively, if he was five years older [6]. PREVALENCE Estimating the prevalence of infertility is difficult; both the numerator (the number of infertile couples) and denominator (the number of women "at risk" for pregnancy) depend upon the definitions used and the question being asked. In a 1985 study from an era that predated contemporary methods of sterilization and contraception, parish registries in Cambridge, England between 1550 and 1850 were examined for dates of birth, marriage, and death, including only women whose marriages lasted with the same spouse until age 50 [7]. It was estimated that 8 percent of married women were sterile throughout their reproductive life. This is clearly a lower boundary on the incidence of clinically defined infertility, which requires only the absence of pregnancy for any 12-month interval. Data on infertility in the United States come from the National Survey of Family Growth, conducted by the National Center for Health Statistics in 1976, 1982, and 1988; similar data for 1965 are also available from the National Fertility Study [8]. These surveys were based upon interviews of a representative cohort of 8000 women. Infertility was diagnosed if the women had engaged in unprotected intercourse for at least a 12-month period without having a pregnancy during the three years before the interview. The prevalence of infertility during the three years preceding each interview, expressed as a percentage of all married women, was stable (13 percent in 1965 and 14 percent in 1988, excluding women who were voluntarily sterilized) . EVALUATION OF THE INFERTILE COUPLE : A standard infertility evaluation is warranted for couples who have not been able to conceive despite 12 months of unprotected intercourse. The factors that should be evaluated and the relevant tests that should be performed include the following: Male factor semen analysis Ovulatory function endometrial biopsy or serum progesterone Cervical factor postcoital test Uterine factor hysterosalpingography and/or hysteroscopy; pelvic ultrasonography Tubal factor hysterosalpingography and laparoscopy Endometriosis or other pelvic pathology laparoscopy Some causes of infertility are easily identifiable, such as azoospermia, longstanding amenorrhea, or bilateral tubal obstruction. However, the situation is less clear in most couples: the sperm may be reduced in number but are not absent; there may be oligomenorrhea with some ovulatory cycles; the woman may have partial tubal obstruction; a postcoital test may show only a few motile sperm; or an endometrial biopsy may show endometrium consistent with ovulation but lagging behind chronological menstrual dates. It is often difficult to weigh or prioritize these findings when counseling infertile couples or planning treatment programs. Adding to the complexity of the situation, there are few data regarding the predictive validity of these tests despite their widespread use. Thus, short of the absolute infertility factors mentioned (eg, azoospermia or bilateral tubal obstruction), an abnormal test result cannot be said to be the cause of infertility in a particular couple. As an example, we performed a study that used standard infertility tests plus two others (sperm antibodies and cervical culture for Mycoplasma hominis and Ureaplasma urealyticum) on 32 fertile and 32 age- and race-matched infertile couples in an effort to find factors that discriminated between these two groups [9]. At least one abnormal infertility test was found in 69 percent of fertile and 84 percent of infertile couples. Tubal damage and endometriosis were more common in infertile couples (22 versus 3 percent, and 16 versus 0 percent, respectively); there were no other significant differences between the two groups. The uncertain causal relationship between an abnormality on infertility testing and the actual cause of infertility make it difficult to estimate the relative frequency of the causes of infertility. Nevertheless, it is instructive to estimate the frequency with which various factors are found in association with infertility as a rough proxy for their relative importance. One population-based study found the following results [10]: Male factor 23 percent Ovulatory dysfunction 18 percent Tubal damage 14 percent Endometriosis 9 percent Coital problems 5 percent Cervical factor 3 percent Unexplained 28 percent The following discussion will attempt to guide the interpretation of standard diagnostic infertility tests by reviewing the available data on their predictive validity. Semen analysis As previously mentioned, azoospermia represents an absolute barrier to pregnancy. At the other end of the spectrum, men with large numbers of motile sperm with normal morphology will probably be fertile. Although widely used thresholds for normal semen measurements have been published by the World Health Organization (WHO) [11], these norms for sperm concentration, motility and morphology fail to meet rigorous clinical, technical, and statistical standards. The WHO cutoff for sperm concentration (20 million sperm/mL) is based on a 1951 comparison of semen from fertile and infertile men [12]; the cutoff for motility (50 percent) has no statistical basis in a comparison of fertile and infertile men; and no specific cutoff for morphology is provided because of a paucity of data. Semen specimens from a large sample of fertile and infertile men, using contemporary methods of semen analysis, were used to estimate threshold values for sperm concentration, motility and morphology [13]. Recognizing that there is broad overlap in the values of these semen measurements in fertile and infertile samples, two cutoff values were determined so as to define a "gray zone" or indeterminate range between fertile and subfertile cutoffs . It should be emphasized that the "strict" method of morphology assessment was used [13]. These thresholds can be used in clinical practice as a screen for further evaluation of male infertility, or for counseling as to the likelihood that the male partner is contributing significantly to the infertility. Postcoital test The postcoital test provides information on the interaction between sperm and cervical mucus [14]. It is performed one to three days before ovulation, and involves taking a sample of cervical mucus two to twelve hours after coitus. According to standard definitions, the cervical mucus should show ferning and >5 cm spinnbarkeit (defined as the distance a mucus thread can be pulled before breaking) At least five motile sperm per high power field should be seen. The validity of this test has been questioned, despite its widespread use as part of infertility evaluations [15]. Similar to the results of semen analysis, the test has not been carefully evaluated. Many studies included infertile couples with a variety of infertility diagnoses, but an attempt was made to correlate the results of the postcoital test with subsequent pregnancy. There has been no large study comparing postcoital test results between fertile and infertile couples. The best studies are those that follow infertile couples with no other known cause of infertility, and compare pregnancy rates according to the results of the test. In the three studies of this design, there were significant differences in pregnancy rates between couples with normal and abnormal postcoital tests: ���¢�¢â�š�¬���¢ In one series, 14 percent of cycles with a normal postcoital test (>5 forwardly moving sperm/high power field) resulted in pregnancy, as compared with 3 percent with an abnormal test [16]. ���¢�¢â�š�¬���¢ In a second study, 35 percent of cycles with a normal postcoital test (>5 sperm/high power field with >50 percent forward motility) resulted in pregnancy, as compared with 12 percent with an abnormal test [17]. A third report found that pregnancy occurred in 60 percent of couples with a normal postcoital test (>5 motile sperm/high power field), as compared with 8 percent of those with an abnormal test [18]. Nevertheless, a study of 444 infertile couples found that routine use of the postcoital test in the infertility investigation lead to more tests and treatment compared to couples who did not receive the postcoital test [19]. However, the pregnancy rate at 24 months was no higher in couples who had the postcoital test versus those who did not. Assessment of ovulation A clinical assessment of ovulation can be made from the menstrual history: Amenorrhea signifies the absence of ovulation and certainly represents a cause of infertility. At the other extreme, predictable cyclic menses almost always reflect regular ovulation, and probably also assure normal serum concentrations of the hormones commonly ordered in infertility evaluations, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and androgens. Oligomenorrhea implies irregular menses and erratic ovulation. Oligoovulation does not represent an absolute barrier to pregnancy; however, the likelihood is reduced. A basal-body-temperature chart may be used to confirm the clinical impression of ovulation. There will be a biphasic curve during an ovulatory cycle, with temperatures in the luteal phase higher by 0.5 to 1.0 due to progesterone production by the corpus luteum . However, these charts can be difficult to interpret. The onset of the LH surge precedes ovulation by approximately 38 hours. Detection of the LH surge can be accomplished by the patient using an over-the-counter urinary test kit. These kits provide colorimetic assays in which a blue or pink color appears when the urinary LH concentration exceeds a certain threshold, usually 40 IU/L. It is helpful to begin testing several days before anticipated ovulation to establish a few negative tests. Ovulation can be presumed to occur on the day after evidence of a urinary LH surge. Menses would then be expected 14±2 days after the presumed date of ovulation. Although the urinary assays are positive approximately 95 percent of the time when the serum LH exceeds 40 IU/L, the clinical utility of the test, as measured by the proportion of LH surges detected using the at-home once-a-day method, is only about 85 percent. This is because once-a-day testing may miss an LH surge due to variations in the renal clearance of LH and the skill with which patients can use the test. Definitive confirmation of ovulation can be obtained by measurement of serum progesterone in the mid-luteal phase, 18 to 24 days after the onset of menses. Normal mid-luteal phase serum progesterone concentrations usually vary from 6 to 25 ng/mL (19 to 80 nmol/L), but the value may be lower if the blood sample is collected in the interval between a pulse of LH secretion [20]. Thus, a single low value cannot reliably detect an abnormal luteal phase, since it may be obtained between LH pulses. Luteal phase defect Even if the history and temperature chart are consistent with ovulation, there may be a luteal phase defect that can cause impairment of normal implantation and therefore infertility. This defect was initially described as a defect in the corpus luteum production of progesterone, but it can also be caused by a poor endometrial response to progesterone stimulation [21]. In addition to measurement of serum progesterone, an endometrial biopsy is useful to assess the adequacy of luteal phase hormone effects on the endometrium. The development of normal endometrial tissue in the luteal phase is well standardized, allowing an experienced pathologist to date the endometrium accurately . An endometrial biopsy is considered to be normal if the assigned date from the histologic examination is within two days of the actual date calculated from the previous LH surge as day 14. The results of the endometrial biopsy should be interpreted with reference to ovulation rather than to onset of the next menstrual period, but the date of the next menses should be recorded to assess the length of the luteal phase. An important problem is that luteal phase defect is often present in fertile women. In one study, for example, endometrial biopsies were performed in repeated (5 to 10) menstrual cycles in the same five fertile women . Using a criterion of more than two days lag in a single cycle, 18 of 35 biopsies (51 percent) were out of phase; 11 (31 percent) were out of phase using a criterion of more than three days lag. Defining luteal phase defect as out-of-phase biopsies in two consecutive cycles (30 pairs of cycles); the incidence was 27 percent for two days lag and 7 percent for three days lag. Nevertheless, there does appear to be a correlation between luteal phase defects and infertility. In one report, a defect (defined as delayed histological endometrial maturation of more than two days in two different menstrual cycles) was found in 46 of 355 infertile women (13 percent) versus only 1 of 25 fertile women (4 percent) [23]. Similar results were obtained in another study which evaluated the prevalence of luteal phase defect in 68 fertile women and four groups of infertile women: 21 women with endometriosis; 48 with unexplained infertility; 34 with tubal factor; and 39 with male factor [24]. Daily salivary progesterone concentrations were similar in all the groups. However, if a luteal phase defect was defined as an endometrial lag of more than two days, the overall prevalence in the infertile women was significantly higher than in the fertile women (14 versus 4 percent). The rate was particularly high in the women with unexplained infertility (21 percent) and endometriosis (29 percent), as compared with those with tubal (3 percent) or male factor infertility (8 percent). The last report provides solid support for a link between luteal phase defect and infertility. Further evidence comes from studies showing the abrupt appearance of an integrin adhesion molecule in normal day 20 endometrium (eg, at the time of implantation) and its absence in some women with luteal phase defect [25]. Thus, although fertile women may have a luteal phase defect [26], it is more common in infertile women, particularly those without defined nonovulatory factors such as tubal obstruction or partners with poor quality semen [24]. It is reasonable to investigate the possibility of luteal phase defect in infertile women, preferably with a timed endometrial biopsy. Uterine factor A wide variety of uterine abnormalities have been linked to infertility and/or spontaneous abortion, including congenital uterine anomalies (particularly uterine septum), abnormalities associated with in utero exposure to diethylstilbestrol (eg, a T-shaped uterus), fibroids (especially if submucous or cornual), polyps, and synechia from prior intrauterine manipulation. However, each of these anomalies can also occur in fertile women. Like other possible infertility factors, the absence of data on the frequency of these uterine abnormalities in matched fertile and infertile women has not allowed a true causal link to be established. Uterine fibroids can be identified by physical examination and ultrasonography, while submucous fibroids can be identified by hysterosalpingography or hysteroscopy. It makes sense to perform hysterosalpingography to evaluate both uterine and tubal factors (see below) for most infertility evaluations. Hysteroscopy can be used to evaluate further abnormalities diagnosed by hysterosalpingography, and to surgically treat synechia, submucous fibroids, polyps, or a septum. However, in the absence of symptoms, caution must be exercised in recommending hysteroscopic surgery for infertility (particularly primary infertility or secondary infertility with no history of spontaneous abortion), because its efficacy in comparison with expectant management has not been demonstrated. Tubal and peritoneal factors The major cause of tubal infertility is pelvic inflammatory disease. Other conditions, such as severe endometriosis or pelvic adhesions from a nontubal intraabdominal infection or previous surgery, may also interfere with egg pick-up by the fallopian tube. Tubal abnormalities can be diagnosed by hysterosalpingography and laparoscopy. The former usually documents the presence and location of tubal obstruction, but it is less effective than laparoscopy for the diagnosis of damaged tubal epithelia, partial tubal obstruction, or peritubal adhesions. Estimation of the sensitivity and specificity of hysterosalpingography in detecting tubal abnormalities typically uses laparoscopy as the gold standard; the latter occasionally demonstrates proximally obstructed tubes that are patent on hysterosalpingography. In one series of 200 women, for example, hysterosalpingography revealed obstruction in 95 of 102 fallopian tubes that were found to be obstructed at laparoscopy, yielding a sensitivity of 93 percent [27]. Only one of the fallopian tubes found to be obstructed at laparoscopy appeared completely normal radiographically, while the other six showed dilatation or other abnormalities. The specificity of correctly identifying normal tubes was 90 percent. However, the sensitivity and specificity of hysterosalpingography with respect to tubal abnormalities other than obstruction was lower in this report. If the criterion is "all tubal abnormalities," hysterosalpingography can miss 20 to 30 percent of abnormal findings detected at laparoscopy. Endometriosis occurs with a higher frequency among infertile than fertile women, often without symptoms. In one study, for example, 143 women undergoing diagnostic laparoscopy for infertility and 257 fertile women undergoing laparoscopic tubal ligation were evaluated for the presence or absence of endometriosis [28]. Endometriosis was found in a significantly higher proportion of infertile than fertile women (38 versus 5 percent). Approximately one-third of the women found to have endometriosis had no symptoms or signs of the disease. In addition, 85 percent of the cases were American Fertility Society stage I or II, and would probably not have abnormalities detected by hysterosalpingography. The substantial difference in rates of endometriosis between fertile and infertile women suggests an association that might seem sufficient to prompt laparoscopy in asymptomatic infertile women with normal fallopian tubes. However, laparoscopy is an expensive procedure, and this approach would only be reasonable if treatment of endometriosis favorably affects fertility. Surgical treatment enhances fertility for women with advanced endometriosis. Its value in early-stage disease has been more controversial, but a recent trial suggested benefit in infertile women. In this study, 341 infertile women with minimal or mild endometriosis were randomly assigned during diagnostic laparoscopy to undergo resection or ablation of visible endometriosis, or diagnostic laparoscopy alone [29]. Pregnancy lasting 20 weeks or longer was more likely in women who had resection or ablation (cumulative probability 31 versus 18 percent with diagnostic laparoscopy alone). A subsequent randomized trial of laparoscopic treatment of endometriosis, however, failed to confirm efficacy [30]. Thus there is still controversy as to whether laparoscopic treatment of endometriosis for infertility in the absence of other symptoms is warranted . Role of hysterosalpingography and laparoscopy In summary, the role of hysterosalpingography and laparoscopy in the evaluation of infertile women is incompletely defined. It can be argued that the former should be included as a standard component of the initial evaluation, because it can often eliminate the need for laparoscopy. A woman in her late 30s who has severe bilateral proximal tubal obstruction, for example, might be counseled to proceed with in vitro fertilization, thereby bypassing the discomfort and risks of laparoscopy. In addition, a woman in whom hysterosalpingography is normal and who is otherwise a candidate for donor insemination because of azoospermia, or for ovulation induction because of chronic anovulation, might reasonably undergo such treatment without first having laparoscopy. If no conception occurs after a specified number of cycles (eg, six), then laparoscopy might be warranted. Laparoscopy may be indicated in the initial evaluation of infertile women who have significant symptoms of endometriosis or who have a history of appendicitis, previous pelvic surgery, pelvic inflammatory disease, or other conditions that suggest pelvic pathology. Diagnostic laparoscopy may also be indicated in unexplained infertility when the standard evaluation fails to identify a cause. SUGGESTED PROTOCOL FOR THE INITIAL EVALUATION OF INFERTILITY As noted above, infertility is defined as the inability to conceive after one year of intercourse without contraception. The physician should counsel couples about the limits of our knowledge of infertility tests before initiating an infertility evaluation. Once this is understood, a standard infertility evaluation can be nearly completed during a single menstrual cycle: Semen analysis can be performed at any time during the menstrual cycle, preferably collected on site after 48 to 72 hours of abstinence. Hysterosalpingography should be performed during the period between the cessation of menses and ovulation. A home urinary ovulation test should be done on days -5 to -1 (day 0 = day of ovulation). The LH surge is taken to occur on the day before ovulation (eg, day -1); it may be useful to measure serum LH to confirm the urinary surge, although there can be considerable variability in this assay. ���¢�¢â�š�¬���¢ A postcoital test, which provides information about the interaction between sperm and cervical mucus, can be performed, if desired, between days -2 to 0, 8 to 12 hours after intercourse. We perform an endometrial biopsy 7 to 10 days after ovulation which approximates the window of implementation. If barrier conception has not been used, there is a danger of performing the biopsy in a pregnant uterus, and informed onset is recommended. Others prefer to obtain the biopsy on luteal day 11 to 12, after a negative serum pregnancy test. Whether laparoscopy should be performed as part of the initial evaluation depends upon the findings of the other tests and the history, as described above. As the infertility evaluation proceeds, each abnormal test must be interpreted with respect to its degree of departure from "normality" (when this is known). In addition, treatments directed at correcting the abnormality should continue for only so long as the likelihood of pregnancy warrants the cost, both financial and emotional. References 1 Gray, RH. Epidemiology of infertility. Curr Opin Obstet Gynecol 1990; 2:154. 2 Templeton, A, Fraser, C, Thompson, B. Infertility--epidemiology and referral practice. Hum Reprod 1991; 6:1391. 3 Aral, SO, Cates, W Jr. The increasing concern with infertility. Why now?. JAMA 1983; 250:2327. 4 Guttmacher, AF. Factors affecting normal expectancy of conception. JAMA 1956; 161:855. 5 Dunson, DB, Baird, DD, Wilcox, AJ, Weinberg, CR. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod 1999; 14:1835. 6 Dunson, DB, Colombo, B, Baird, DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002; 17:1399. 7 Trussell, J, Wilson, C. Sterility in a population with natural fertility. Popul Stud 1985; 29:269. 8 Mosher, WD, Pratt, WF. Fecundity and infertility in the United States 1965-88, National Center for Health Statistics, Hyattsville, MD, 1990. 9 Guzick, DS, Grefenstette, I, Baffone, K, et al. Infertility evaluation in fertile women: A model for assessing the efficacy of infertility testing. Hum Reprod 1994; 9:2306. 10 Hull, MG, Glazner, CM, Kelly, NJ, et al. Population study of causes, treatment and outcome of infertility. Br Med J 1985; 91:1693. 11 World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction, 4th ed, Cambridge, England, Cambridge University Press, 1999. 12 MacLeod, J, Gold, RZ. The male factor in fertility and infertility. II. Spermatozooan counts in 1000 men of known fertility and in 1000 cases of infertile marriage. J Urol 1951; 66:436. 13 Guzick, DS, Overstreet, JW, Factor-Litvak, P, et al. Sperm morphology, motility and concentration in fertile and infertile men. N Engl J Med 2001; 345:1388. 14 Overstreet, JW. Evaluation of sperm-cervical mucus interaction. Fertil Steril 1986; 45:324. 15 Griffith, CS, Grimes, DA. The validity of the postcoital test. Am J Obstet Gynecol 1990; 162:615. 16 Hull, MG, Savage, PE, Bromham, DR. Prognostic value of the postcoital test: Prospective study based on time-specific conception rates. Br J Obstet Gynaecol 1982; 89:299. 17 Portuondo, JA, Echanojauregui, AD, Herran, C, Agustin, A. Prognostic value of postcoital test in unexplained infertility. Int J Fertil 1982; 27:184. 18 Skaf, RA, Kemmann, E. Postcoital testing in women during menotropin therapy. Fertil Steril 1982; 37:514. 19 Oei, SG, Helmerhorst, FM, Bloemenkamp, KW, et al. Effectiveness of the postcoital test: Randomised controlled trial. BMJ 1998; 317:502. 20 Filicori, M, Butler, JP, Crowley, WF Jr. Neuroendocrine regulation of the corpus luteum in the human: Evidence for pulsatile progesterone secretion. J Clin Invest 1984; 73:1638. 21 Jones, GS. Some newer aspects of the management of infertility. JAMA 1949; 141:1123. 22 Davis, OK, Berkely, AS, Naus, GJ, et al. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil Steril 1989; 51:582. 23 Balasch, J, Creus, M, Marquez, M, et al. The significance of luteal phase deficiency in infertility: A diagnostic and therapeutic approach. Hum Reprod 1986; 1:145. 24 Li, TC, Dockery, P, Cooke, ID. Endometrial development in the luteal phase of women with various types of infertility: Comparison with women of normal fertility. Hum Reprod 1991; 6:325. 25 Lessey, BA, Damjanovich, L, Contifaris, C, et al. Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest 1992; 90:188. 26 MacLeod, J, Gold, RZ. The male factor in fertility and infertility. II. Spermatozoon counts in 1000 men of known fertility and in 1000 cases of infertile marriage. J Urol 1951; 66:436. 27 Chen, YM, Ott, DJ, Pittaway, DE. Efficacy of hysterosalpingography in evaluating tubal and peritubal disease in 200 patients with infertility. Rays 1988; 13:27. 28 Verkauf, BS. Incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla Med Assoc 1987; 74:671. 29 Marcoux, S, Maheux, R, Berube, S, et al. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997; 337:217. 30 Parazzini, F, et al. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Hum Reprod 1999; 14:1332. SECTION 3 - DEFINING INFERTILITY . RESOLVE Inc. is a support group with information about infertility. INFERTILITY AND RELATED NEWSGROUPS This newsgroup relates to all issues related to infertility. Some discussions might include: - Impact infertility has on self-image and self-esteem. - Impact infertility has on a couple's relationship. - Impact infertility has on relationship with family and friends. - Impact of infertility on jobs and dealing with co-workers. - Dealing with the fertile world (pregnant women everywhere). - Doctor-patient relationship issues. - Advice on finding and personal recommendations of doctors and clinics. - Discussion on low-tech methods of improving the odds of pregnancy. - Medical diagnosis and treatments (personal stories and advice). - Medical discussions range from the setting up of the first doctor consultation to doing high-tech treatments like in-vitro and new areas such as immunological infertility. - Emotional and medical issues related to pregnancy loss after infertility treatment, as well as infertility resulting from inability to carry a pregnancy to live birth. - Alternative medical methods (acupuncture, herbs, visualization . . .) - Coping methods of dealing with stress and treatments. - How personal beliefs (religion) overlaps with infertility. - Money and insurance issues related to paying for treatments. - Humor by those who have been there. - Emotional vents about anything related to infertility issues. - Pregnancy announcements, which include brief personal history. - Adoption as a family building choice. - Discussion about life without being a parent (childfree choice). - Discussion about using donor sperm, donor egg, or surrogacy. - Other miscellaneous topics related to life while infertile. . A.1 What is Infertility? Infertility is the inability to conceive after a year of unprotected intercourse in women under 35, or after six months in women over 35, or the inability to carry a pregnancy to term. Couples who have known barriers to fertility, such as endometriosis, polycystic ovarian syndrome, male factor infertility, irregular cycles, etc., do not need to sit out the traditional "waiting period" to seek expert care for infertility. See INCIID's glossary for more terms and definitions. B.1 How long does it take to ovulate after the first positive result on the KIT (Ovulation Predictor Kit)? You will most likely ovulate 8-48 hours after the first positive result on your OPK, and usually within 24-36 hours. Also, you do not need to keep testing for your LH surge once you get the first positive result. It is the first positive result that you are after. B.2 How long after HCG does ovulation occur and how do we know? Ovulation occurs 36-40 hours after the HCG injection.. Eggs will release in this timeframe if they have not been retrieved. B.3 How long do sperm live after timed intercourse or after IUI? Normal, healthy sperm live approximately 48-72 hours. (Abnormal sperm may have a shorter life, which may vary according to sperm health.) We do know that washed sperm can survive in the IVF incubator for up to 72 hours. But it���¢�¢â�š�¬�¢â�ž�¢s reported thatsperms can stay alive for five days in female tubes. B.4 How long are eggs able to be fertilized? Eggs are able to be fertilized for about 12-24 hours after ovulation. The older the woman, the shorter this time becomes. 2.5 How long does it take for fertilization to occur? Fertilization occurs within 24 hours after ovulation. 2.6 How long does it take for implantation to occur? Implantation occurs about 5-10 days after ovulation. 2.7 How soon can I take my Pregnancy Test (Beta HCG or Home Pregnancy Test)? The earliest that a sensitive blood test can pick up any HCG at all is 5-7 days after ovulation. Your quantitative serum beta test can be reliable about 10-12 days after ovulation, if you have not taken a HCG booster. Extremely sensitive home pregnancy tests might in some cases be reliable as soon as 12 dpo. If you have taken a HCG booster, then you may have a reliable test at 14 days past ovulation. The serum beta is the most reliable test. Any level over a 5 is generally considered a positive result, although having a second blood test two days later should show the numbers nearly doubling. The "average" level of hCG is about 25 at 10 dpo, 50 at 12 dpo, and 100 at 14 dpo. Note that there is a difference between a qualitative and a quantitative test. A qualitative test gives a yes or no answer. Your HCG level has to be above 50 units to get a positive result. Quantitative tests give a value to the amount of pregnancy hormone in your blood. It gives a specific number. Anything greater than 5 is considered positive. Considering that it is possible to implant as late as 10 dpo, a qualitative beta might produce a false negative if used for an early pregnancy test. 2.8 How do you determine the first day of your cycle? CD1 is the first day you see a red flow, not just intermittent spotting. There is no universal rule for the cutoff time for that date. Some RE's use midnight, others use 5 p.m., but most often CD1 is considered the first day of full flow that begins before mid-afternoon. Again, spotting does not count unless it is a continuous (not intermittent) spotting. Continuous spotting does count as CD1. The fact that the rules of thumb for calculating CD1 are so arbitrary suggests that you've got a little bit of leeway for variation. 3.1 What should my progesterone level be? Progesterone will be less than 1.5 Ng/ml until the LH surge. It peaks about seven days after ovulation, when it reaches 15 Ng/ml or more. But note, if you are above 10 in the luteal phase, your progesterone level is probably fine. When it drops between 2-4, menstruation begins. (This is why use of progesterone supplements can delay the start of your period). Additionally, you may get very high progesterone levels after IVF because so many follicles were created. (Progesterone is made by the corpus luteum, which is the site on the ovary from which the egg is released. The more eggs are produced, the more progesterone is produced.) Most doctors use a high level of progesterone supplementation in the luteal phase, which can also result in very high progesterone levels. There is no progesterone level that indicates pregnancy, only an hCG level over 5 determines that. It is also worth nothing that progesterone pulses, so the level varies throughout the day. Some doctors suggest testing first thing in the morning after fasting for the most accurate result. A high progesterone level gives more information than a low reading in that a "good" level indicates sufficient progesterone to carry a pregnancy; a lower level (in the 5-15 range) does not spell doom. 3.2 What should E2 numbers ideally be during an injectables cycle? You should see 150-200 per mature follicle. (Note: E2 tends to be somewhat lower on pure FSH cycles. You may use this as a guideline, but your physician will be your best guide in this case.) It ideally should be 100 or over after three days of LH-containing injectables. It ideally should be 100 or over after 4-5 days of injectable recombinant FSH. No chart can show ideal E2 levels since E2 varies per number and size of the follicles. 3.3 What should my uterine lining be at ovulation and at implantation? As you approach your LH surge, it should be above 6 mm, ideally between 8 and 12 mm. (If it is much more than that, it may be advisable to ask about a hysteroscopy or sonohysterogram to see if perhaps there is a polyp inside the uterus). You want to have a triple stripe pattern around the time of the LH surge and ovulation. Towards the time of implantation, you want to have a more integrated HH or IE pattern. The triple stripe occurs in response to estradiol; the HH/IE conversion is in response to progesterone. It should also be noted that, although most doctors prefer the above pattern of linings, there is no conclusive research on whether a better pattern actually results in higher pregnancy rates. 3.4 I have just had a 3-day FSH test taken, and I am concerned about the results. One of the best starting points is the Dr. Sable's article on FSH: Good Eggs, FSH Levels and Ovarian Reserve. In addition, here's what Carolyn Coulam, M.D. has to say about follow up to FSH: If these bloods were drawn on day three of a cycle, the results would imply decreased ovarian reserve or eggs available. To confirm this we would draw blood for inhibin B. If the inhibin B is low consideration should be given to donor eggs. Inhibin B is a protein made by the granulosa cells that surround the eggs. FSH is more of an indirect measurement of ovarian reserve. 3.5 How do we know if the sperm count is adequate for IUI? Besides the number of sperm, the percentage with rapid forward-progressive motility and with normal morphology at the time of insemination are important to know. If the functional sperm count (number with normal morphology and rapid forward-progressive motility) exceeds 1 million; chances for pregnancy with well-timed IUI are excellent. See Semen Analysis fact sheet for more information. 4.1.1 How big should my lead follicle be before I take my HCG shot? A lead follicle should be at least 16 mm on an hMG like Pergonal, it should be at least 18 mm on a recombinant FSH like Gonal-F, and should be about 22 mm on Clomid. Occasionally Gonal-F can produce mature eggs in smaller follicles, in which case other measurements such as E2 and progesterone should be used to indicate maturity. (The difference in ideal size is due to the difference in mechanisms by which the medications work. For example, the mechanism by which Clomid works often takes a bit longer because it is indirect. Therefore, the follicle has more time to grow before the egg is actually mature). 4.1.2 How much do follicles grow each day? Follicles grow 1 to 2 mm a day both while taking ovulatory stimulants and after the HCG shot. 4.1.3 Will smaller follicles "catch up" in time to release eggs? Follicles generally need to be at least 15-16 mm to contain fertilizable eggs (although it is possible in rare cases for follicles to be as small as 14 mm and still contain fertilizable eggs). If the smaller follicles are close in size to the lead, they may "catch up" and release. HCG will usually result in most mature follicles releasing eggs. Otherwise, most likely only the lead follicle will ovulate. 4.1.4 Do I usually have more than one follicle on an unstimulated cycle? Yes, it is normal to have numerous small follicles develop, but usually only one will continue to maturity without stimulation. 4.2 I have leftover cysts on my ovaries. My doctor wants me to sit out this cycle. 4.2.1 What causes these cysts? A corpus luteum, or functional cyst, is simply a leftover follicle that has outstayed its welcome. Some continue to produce progesterone and estrogen, which may delay the arrival of the next period. 4.2.2 Will they go away? Functional cysts almost always go away with time. Birth Control Pills are sometimes prescribed to hasten their resolution. 4.2.3 How big do they need to be to reduce chances of pregnancy? Research has shown that any cyst 10 mm or larger is associated with a lower chance of getting pregnant. In a study on women doing IVF, those that had a 10 mm cyst at the beginning of a cycle had half the pregnancy rate of those who had no cysts (and the groups were equal on all other relevant characteristics). So it does not eliminate your chances of pregnancy, but it does sharply decrease them. 4.2.4 Why do they reduce my chances of pregnancy? Cysts do not eliminate the possibility of pregnancy in a cycle, but they do reduce it. They do this through two mechanisms. First, physically, they can crowd out the development of new follicles. Also, if the cyst is secreting hormones at the wrong time of the cycle, (for example, progesterone during the follicular phase), it interferes with the chemical balance required for good quality ovulation and drastically reduces the chances of pregnancy. 4.2.5 If I have cysts of any size, should I be concerned? It is normal to have small cysts, which may be very small leftover follicles or follicles that are preparing for the next cycle. Anything under 10 mm shouldn't be cause for concern as long as your baseline hormone levels are in range. 4.3 What exactly is an endometrial biopsy? In an endometrial biopsy (EMB), a small catheter is threaded into the uterus and a sample is taken of the lining, or endometrium, during the last week of your cycle. (It causes brief cramping for which Ibuprofen, taken ahead of the procedure, is helpful). Once the sample is obtained, it is rated according to the day of a 28-day cycle for which it would be typical. For example, a lining at the beginning of the luteal phase is different from a lining at mid luteal phase or during the follicular phase. An out-of-phase endometrium means that the endometrial appearance is typical of a time in the cycle other than the time it was taken. This biopsy does have the potential to disrupt a pregnancy in progress. Many doctors will test for pregnancy before doing the biopsy, to be on the safe side. An EMB may also be done to check for abnormal cells in the endometrium (hyperplasia). This is a concern when a woman has very infrequent periods (bleeding less than once per three months) or when ultrasound reveals a thick lining. For this purpose, the EMB can be done on any cycle day. 4.4 How long should I use Clomid before I move to Injectables/IUI? The vast majority of Clomid pregnancies occur during the first 4-5 ovulatory cycles. Some physicians also indicate that of those pregnancies, the majority occur during the first 3 attempts. (Also, if you do not stimulate well on Clomid at a reasonably high dosage, you might consider moving on to Injectables earlier. The maximum dosage is 150 mg., according to the manufacturer, and it may be wise to move on if unsuccessful after two cycles at that dosage). The average number of cycles on Clomid before moving on is three to six. 4.5 How many times should I try IUI before moving on to IVF? Once a patient has had 3-6 IUI cycles with injectables, they might consider moving to IVF as the chance of a successful IUI cycle is reduced. 4.6 What is the maximum recommended dosage for Clomid? As mentioned about, the maximum dosage is 150 according to manufactures. It may be wise to move on if there is no response to 150 mg, as the risk of antiestrogenic side effects of Clomid increase sharply as the dosage goes up. 4.7 Should I be taking Clomid on days 3-7 or on days 5-9? In theory, days 3-7 of Clomid lead to more follicles and fewer side effects on the lining and the mucus. Days 5-9 lead to better development of just a few follicles. It seems to make a difference for some women and does not make any difference in others. Little conclusive research on the issue exists. 4.8 Why would my physician mix my Clomid treatment with injectables? Mixing injectables and Clomid is an attempt to get some of the stimulant, cervical mucous, and lining benefits of injectables without spending as much money as would be required by doing only injectables. 4.9 I have heard that Clomid is not recommended for women over 40. Why? As women pass 35, many doctors do begin to be more cautious about using it for a couple of reasons. One, women approaching 40 tend to have more lining problems and Clomid can have deleterious effects on the lining. Secondly, if a woman is perimenopausal, the mechanism by which Clomid works is not always effective, because the body is somewhat inured to low Estradiol levels. 4.10 I am on a cycle of injectables or Clomid/injectables. Should I use an Ovulation Predictor Kit? If I don't, how will they time the HCG shot? Some women don't get a positive OPK when they are on injectables or even a mix of Clomid and injectables. You have to base the timing of the HCG shot on the Estradiol levels and follicle sizes. The use of progesterone also helps determine when to give HCG. It is best, for an IUI, to administer HCG when the progesterone level rises over 1.5. 4.11 How long should my partner abstain before the IUI? His semen analysis is normal. For most men, a 2-3 day break is ideal. That gives the "sample" an opportunity to regenerate. Too "old" of a sample raises the risk of poor motility, white cells, and other problems. (An "old" sample would be that which is taken after more than 7 days of abstinence). 4.12 What is a sample protocol for IUI? The simplest protocol is Clomid 50-mg days 3-7 (or 5-9) of the cycle. Use a urine LH or ovulation detector kit daily starting day 11 of the cycle. Perform the IUI the day following the LH surge. With the addition of vaginal ultrasound monitoring on the day of the LH surge or by day 14 if no LH surge, you may be given an HCG injection and IUI performed 36 hours later. Adjustments in the ovulation induction protocol can be made in subsequent cycles depending upon your response (as measured by LH kit and ultrasound). 4.13 What tests should I have after my IUI? You should at least have a 7-dpo-progesterone test. Your RE may also check the pattern and thickness of the uterine lining via ultrasound at the same time. 4.14 Why am I taking Lupron with my cycle? Most commonly, Lupron is given to IUI patients because they have a history of surging prematurely, before it was time to administer the hCG shot. Lupron greatly reduces the chance that this will happen. It is also sometimes used for patients who have a tendency to develop only one dominant follicle, even on ovulatory stimulants. Normally Lupron is only used in conjunction with injectables. 4.15 How should my IUIs be timed? In most cases, doctors who do two IUI's do the first about 24 hours after the HCG shot and the second about 48 hours after the shot. Some studies have shown that doing one IUI about 36 hours after the HCG is equally effective. However, some recent research suggests that higher pregnancy rates may be achieved by doing two IUI's, one at 12 hours past the hCG shot and one at 34 hours. 4.16 What are the logistics of injectables? How many days will I take them? How big are the needles? Who administers the injection? Are they painful? Typically, they are taken daily for 7-12 days (although it is possible to take them as long as 14 days). If you are taking subcutaneous injections, they are administered in the stomach, upper arm or thigh, with a 1/2- or 5/8 inch needle. If they are intramuscular, they are given in the hip/buttocks area using a 1.5-inch needle. The partner usually administers the IM shots. You can also give the IM injection to yourself in the thigh. They feel like a flu shot or vaccine. 4.17 What is the standard IVF protocol? There are several variations on the IVF protocol. Described below is a sample "down regulation" protocol. This is an example of one which doctors commonly start with when the patient is under 35 and has a history of good response to stimulation. In the down regulation protocol, you start the cycle before your stimulation and retrieval cycle. On CD3 of that cycle, your FSH level is measured. On CD21, you do a progesterone test to see if you have ovulated. (If you are annovulatory, they will often put you on a BCP regimen to give you a predictable cycle). If you have ovulated, then you start Lupron shots once a day. The dosage varies from doctor to doctor to some extent. You may start out on 20 units and then drop down to 10 units after five days. Your period should arrive close to its due date. On CD1 or 2, you are tested to ensure that Lupron has shut down your own hormone system, so that they can use drugs for stimulation and have a more predictable cycle. Suppression is determined primarily by your estrogen level, but your doctor may also check progesterone and LH. If you are adequately suppressed and an ovarian scan shows no cysts, you will usually start injectables on CD3 or so. Your Lupron dose may be lowered to 5 units at this time. Your medication dosage depends on your diagnosis, age, and response history if you have taken injectables before. You might take two amps in the morning and two in the evening. After three days of ovulatory stimulants, your follicles and Estradiol levels will be checked. It is good to see the E2 levels above 100 after three days of stimulation. There will not be a great deal of follicle development yet. If needed, your medications will be adjusted. You will go in a few days later for a second round of blood work and a follicle check. After that, you might report to your clinic daily for blood work and ultrasounds. Once your follicles have reached an appropriate size and your E2 levels are good, you stop the stims and Lupron, and are given the hCG shot. This is about 34 hours before the retrieval is scheduled. The cut-off for the hCG shot, again, varies. Some clinics check for good blood flow to the uterus and a triple layer pattern in the uterus before retrieval as well. They might use this as a determining factor on whether to order baby aspirin. Retrieval is generally an out patient procedure. It can be done with a local anesthetic or an IV anesthetic. The IV anesthetic is much like the IV sedation used in dental procedures, and is very comfortable. The eggs are retrieved using an ultrasound probe that has a needle at the end of it. They put the needle through the vaginal wall and aspirate the follicles. You will generally start progesterone immediately following the retrieval. The post-retrieval events vary according to whether you are doing a day 3 or day 5 transfer, but you will generally receive updates about the number of eggs retrieved, the number fertilized, and the progress of the embryos. The transfer itself is much like an IUI, although most doctors use u/s to guide the catheter in, because placement is so critical. Pregnancy tests are generally done somewhere between 12 and 14 days after transfer. Two other variants on the down regulation protocol are used in women over 35 or women with a history of poor response. The "flare" protocol has you start Lupron around the same time you start your stims, rather than during the luteal phase of the previous cycle. A "stop" protocol means that you take Lupron for several days but then stop it at some point while you are still taking your stims. Each protocol has its plusses and minuses. Women on the down regulation protocol require a greater amount of stimulation, often over a longer period of time. However, women on stop and flare protocols are more likely to have a premature LH surge and are more likely to develop a single dominant follicle (not a good thing in IVF). 4.18 I hear so much about taking baby aspirin. Should I be taking it too? More and more RE's are using this as part of their protocol, especially for patients with histories of miscarriage and lining problems. See the Baby Aspirin fact sheet for the pros and cons of taking baby aspirin. Consult your RE before taking a regular regimen of any over-the-counter-drugs during your fertility treatment. 4.19 Should I take progesterone supplementation during treatment? Some RE's put patients on progesterone during the luteal phase automatically. The underlying concept is that if you wait and find out if the progesterone is low, even at seven days past ovulation (7 dpo), it can be too late because the lining may not be receptive to implantation. Low progesterone can cause implantation failure, because its role is to vascularize and maintain the uterine lining, which is where implantation takes place. Sometimes women require more progesterone support in the luteal phase on injectables, even if they have a good progesterone level. This may have to do with the high levels of estrogen that occur during injectable cycles. There are four different common methods of progesterone supplementation: progesterone in oil shots (PIO), progesterone suppositories or vaginal capsules, Crinone (progesterone) vaginal gel, and oral progesterone. Also, hCG "boosters" given five days or so after the first dose, are commonly used to cause the Corpus Luteum to produce more progesterone. Progesterone, even in the form of over-the-counter creams, should not be taken before ovulation because it can block ovulation and make the cervical mucus hard for the sperm to penetrate. Crinone and suppositories deliver progesterone in a more effective manner than oral supplementation. Oral progesterone is not used by some RE's due to ineffective absorption. Crinone is quite expensive and progesterone suppositories can be messy. Vaginal capsules (identical in appearance to a capsule used for oral medication, but inserted into the vagina) may be a little hard to place, but are quite inexpensive and available in a variety of doses in the same manner as suppositories. PIO shots can be uncomfortable, but they are effective. Discuss the best medication method and dosage with your doctor. 4.20 Should we try a hamster test to determine if we have male factory infertility? Most clinical studies have failed to show a significant correlation between hamster egg penetration and human fertility. A Mannose Receptor Binding Assay of sperm is more useful. 4.21 Should I use a BBT chart? A Basal Body Temperature chart is not a very reliable way to predict ovulation. Although the temperature shift associated with ovulation can be detected on a basal thermometer, it can sometimes take as long as two days before this shift shows up on a BBT. This generally means that by the time a temperature shift is detected, it is too late to time intercourse effectively. Further, there are many things that can negatively affect the reliability of BBT monitoring: A change in sleep patterns, getting up to go to the bathroom in the night, a cold or flu, etc., can all skew the results. Often, couples devote a great deal of unwarranted energy and concern over these tests, which are of very questionable value. The one value in a BBT is to provide a piece of retrospective evidence of ovulation during the past cycle. The presumptive evidence of ovulation is a rise in body temperature for eight days. BBT charts can give your practitioner an idea of your ovulatory history, but remain a dubious tool for timing intercourse. The most reliable method to effectively time intercourse is to test for the LH surge with an ovulation predictor kit. This is a chemical test for the presence of luteinizing hormone (LH), which is released about 24 to 36 hours before ovulation and triggers the final maturation process. Because women generally have the most fertile cervical mucus on or about the day of LH surge, and because sperm can survive for up to 72 hours in the woman's reproductive tract, it is often advised to time intercourse for the day of LH surge. 4.22 My RE wants to me to "coast" for a while on this cycle. Why is he slowing me down? The idea of coasting is either to get a too-high level of Estradiol to drop a bit or to slow down development -- generally eggs are of better quality if the patient has at least 7-8 days of stims. In addition, they may possibly want to slow down some of the lead follicles and get some of the smaller follicles to catch up a little. Several studies have shown that coasting does not reduce success rates for a cycle, and it can also reduce the risk of ovarian hyperstimulation syndrome (OHSS). 4.23 I heard that multiple cycles with fertility drugs increase the chance of getting ovarian cancer. Is this true? No. There is no evidence that shows a statistically significant increase in the ovarian cancer risk. 4.24 My doctor has recommended a hysteroscopy, laparoscopy, or folloposcopy. Where can I get more information? INCIID has an excellent fact sheet on Reproductive Surgeries. 4.25 Do your chances increase with each consecutive cycle? No, each cycle is independent. Your per-cycle chances do not increase. 5.1 I am concerned about the nature of my discharge and/or my cervical mucous during this cycle. You can get many types of discharge when you are on ovulatory stimulants. Usually, cervical mucous will be seen in injectable cycles after the E2 is greater than 200 or so. How much is observed varies very much from patient to patient. Fertile mucous is clear and very stretchy -- similar to egg whites. Often women are not even aware of it, as most of it tends to stay up by the opening of the cervix. You generally cannot predict ovulation, success, or lack of success based on cervical mucous or presence of a discharge when on ovulatory stimulants. Also, vaginal suppositories such as Crinone can create orange or brown discharge in normal situations. Any unusual spotting or discharge needs to be checked by your physician. Note that Clomid often degrades cervical mucous. This needs to be checked by your physician as well. 5.2 I had my egg retrieval. I had more eggs/fewer eggs that I expected. What factors are at work in egg retrieval numbers? The number of eggs retrieved is largely a function of age, responsivity, stimulant/Lupron protocol, good monitoring, and a bit of luck. 5.3 I have a yeast infection! Will this hurt my chances or affect my ovulation predictor kit test results? This will not affect your OPK results or your chances for pregnancy. Check with your doctor on what you use to treat it. 5.4 I am in treatment and I am sick! What should I do? First, you need to consult with your doctor. In the meantime, a simple mild cold should not interfere with pregnancy. If you are running a low-grade fever, chances are it will not interfere with pregnancy. If you have had a fever of 101+ for sustained levels of time, that would be a sign of decreased chances of success. Your doctor may recommend Tylenol. He will also prescribe the best antibiotic for your situation, if you have a bacterial infection. Try to avoid OTC medications until you speak with your doctor, if possible. 5.5 Is it safe to take over the counter (OTC) drugs during treatment? Over the counter drugs can have significant effects on various systems. It is extremely important that you consult your RE before taking an OTC drug during your treatment cycle. This includes herbal remedies and vitamins. 5.6 I am afraid that I might have ovarian hyperstimulation. What can you tell me about this? First, if you are concerned about the possibility of OHSS you should call your clinic as soon as reasonably possible. OHSS (Ovarian HyperStimulation Syndrome) is when you have an unusually large number of mature follicles that release. When these follicles release, there is an unusually high concentration of estrogen-rich fluid in the peritoneal cavity, and the ovaries are generally enlarged far beyond their usual plum size - in some cases, they can swell to softball size. In milder cases, women experience bloating and some pain from the oversized ovaries. The treatment then is just a matter of rest and staying well hydrated. In more severe cases, the estrogen in the peritoneal cavity causes fluid to leak out of the circulatory system into the peritoneal cavity. This can cause marked discomfort and bloating, and can cause difficulty breathing due to pressure on the diaphragm. In the most severe cases, the leaking of the fluid will lead to hypovolemic shock and organ damage because of a lack of perfusion. Although there are exceptions, generally you do not see severe OHSS until the Estradiol gets into the 5000+ range. Mild hyperstimulation can occur at lower levels. As long as your doc keeps a close eye on your dosage and development, the chances of anything other than mild discomfort (especially on a non-IVF cycle) are minimal. The best pre-ovulation predictor of hyperstimulation is the E2 level, but it is not a perfect predictor. If you experience symptoms of OHSS, you should always play it safe and check with your doctor. 6.1 My progesterone was very high. Does this mean I am pregnant? It does not mean you are pregnant. It doesn't even absolutely guarantee a good lining. Nevertheless, it is a good indicator. If you have good progesterone levels, that means that anything that is trying to implant will have a better chance of finding a hospitable place. 6.2 I have spotted, and it is not time for my period. Was it implantation spotting? Implantation spotting is the exception rather than the rule. Sometimes the procedures themselves can irritate the cervix and cause light brown spotting afterwards. Sometimes when the uterus shifts from being estrogen to progesterone dominant you will get a little bit of spotting. Light spotting can be normal, but contact your physician with any concerns. 6.3 My breasts are tender, or I have cramps, or am irritable, nauseated, or bloated, or, I am gaining a small amount of weight. It is not yet time for my pregnancy test. Could these be signs of pregnancy? You are probably feeling the effects of the hormones you are taking. It's really too early to be feeling anything as a result of a pregnancy. Implantation normally takes place about 5-10 dpo, but even after that it takes a couple of days for the hCG (which is what causes pregnancy symptoms) to build up in the blood stream. The presence of these symptoms does not indicate pregnancy, and the absence of them does not indicate a failed cycle. 6.1 My progesterone was very high. Does this mean I am pregnant? It does not mean you are pregnant. It doesn't even absolutely guarantee a good lining. Nevertheless, it is a good indicator. If you have good progesterone levels, that means that anything that is trying to implant will have a better chance of finding a hospitable place. 6.2 I have spotted, and it is not time for my period. Was it implantation spotting? Implantation spotting is the exception rather than the rule. Sometimes the procedures themselves can irritate the cervix and cause light brown spotting afterwards. Sometimes when the uterus shifts from being estrogen to progesterone dominant you will get a little bit of spotting. Light spotting can be normal, but contact your physician with any concerns. 6.3 My breasts are tender, or I have cramps, or am irritable, nauseated, or bloated, or, I am gaining a small amount of weight. It is not yet time for my pregnancy test. Could these be signs of pregnancy? You are probably feeling the effects of the hormones you are taking. It's really too early to be feeling anything as a result of a pregnancy. Implantation normally takes place about 5-10 dpo, but even after that it takes a couple of days for the hCG (which is what causes pregnancy symptoms) to build up in the blood stream. The presence of these symptoms does not indicate pregnancy, and the absence of them does not indicate a failed cycle. 7.1 My period has been usually light or heavy since my last cycle with Clomid or injectables. Or, I have not even gotten it yet, although my beta was negative. Is this normal? Yes, it is normal for menses to be light, heavy, or simply different, due to the hormone levels being different. Also, progesterone supplements can delay the onset of menses. Most women don't start their periods until the progesterone level drops to somewhere between 2-4, which may take a few extra days. 7.2 What constitutes early or late ovulation? Does late ovulation decrease fertility? There is not complete agreement on this. You might consider "too early" to be cycle day 10 and "too late" to be cycle day 20. There are two problems with late ovulation. The first point is that you obviously you have fewer chances (less ovulation) over a given time period. Second is the fact that with late ovulation you may be releasing eggs that have not been matured properly. It is also possible that the other parts of the reproductive system (hormone levels) are not in sync with the egg. That is not to say you cannot conceive if you ovulate late---it happens all the time. It is just that your chances are somewhat reduced. 7.3 My doctor says I am not ovulating regularly. How could I get my period if I do not ovulate? Menstruation only requires development and shedding of the endometrium in response to alternating levels of estrogen then progesterone in the blood stream. These hormones can be produced by the ovary even when an egg does not mature or release. 7.4 I am concerned that I may have poor egg quality. How can I determine my egg quality? You can get somewhat of an idea from the size of the egg and the estradiol level at midcycle. But other factors arise as you get further into your 30s, such as whether the outside covering is too thick to be penetrated easily by the sperm. You really can't diagnose egg quality until you get the eggs out of the follicles, put them under the microscope, and see how they behave. There are some less invasive screenings for ovarian reserve/egg quality such as the Clomid challenge, FSH, and Inhibin B, but they are also not as accurate as looking at the egg directly. 7.5 What causes chemical pregnancies? Many early pregnancy failures are due to genetic abnormalities, mainly "trisomies" where an extra chromosome is present in what should be a pair. Some pathologists believe that the earlier the failure occurs after implantation, the more likely it is to be genetic. You can also have implantation problems that would cause chemical pregnancies such as hypercoagulation, failure to form the needed blood vessels, or autoimmune issues. (For more information read Immunology May be Key to Pregnancy Loss by Carolyn Coulam, M.D.) Note that chemical pregnancies are early miscarriages, not out of whack hormones as the name may imply. 8.1 Should I avoid exercise after ovulation? Swimming and any other low impact exercise that doesn't overheat you is fine. It's best to avoid things like jogging and high impact aerobics. If you wanted to be on the cautious side, you might also avoid picking up anything too heavy during the waiting period (greater than 15 lbs.). 8.2 What about Hot Tubs? If you are trying to become pregnant or are already pregnant, it is safest to avoid raising your core body temperature and therefore it is advisable to refrain from using the hot tub. 8.3 Should I avoid air travel or ground travel after my transfer? Just don't overdo it. Air travel is fine as long as the pressure is maintained, which it generally is in commercial aircraft. |
|
|
IF YOU WANT TO ASK ANY QUESTION Email US! Links to Other FAQ Sites |
|
