Disorders of ovulation account for approximately 30–40% of the problems identified in infertile women. They may present with oligomenorrhea or amenorrhea. Classification of ovulatory problems was done by WHO into 3 groups:
• Group I | Hypothalamic pituitary failure (Hypogonadotropic hypogonadism). |
• Group II | Hypothalamic pituitary dysfunction (Normogonadotropic, e.g. PCOD). |
• Group III | Ovarian failure (Hypergonadotropic hypogonadism). |
Usually treatment is simple and effective. However, not all cases of anovulation are amenable to treatment by ovulation induction.1 It is the cause of anovulation that will determine whether ovulation induction is possible (Tables 1.1 and 1.2).
Before taking up a patient for ovulation induction a complete investigation for confirmation and cause of 2anovulation should be carried out (Table 1.3).
|
|
This is necessary to determine which ovulation inducing drugs are to be used, in how much dose and whether any adjuvants are needed.
|
Tests for Ovulation
Clinically ovulation is indicated by regular menstrual cycles, midcycle pain and changes in cervical mucus. There are many methods of confirming ovulation. They are all based on the effects of hormonal events taking place in the body during ovulation. These tests are also used to assess the effectiveness of any ovulation induction treatment.
Basal Body Temperature (BBT)
It is body temperature under basal conditions at rest. For practical purposes BBT is measured each morning before arising from bed with an oral glass thermometer, having an expanded scale, typically ranging from 96°F to 100°F and marked in tenths of a degree. Irregular sleep patterns and smoking can interfere with tests results.5
BBT recordings are based on the thermogenic properties of progesterone. As levels rise after ovulation, BBT also increases. BBT varies between 97°F and 98°F during the follicular phase of the cycle. The thermogenic shift in BBT occurs when progesterone concentrations rise above approximately 5 ng/mL, 1 to 5 days after LH surge and up to 4 days after ovulation.2 The temperature rise is usually abrupt but may be gradual and difficult to define. BBT generally falls to its lowest level on the day before ovulation, but the nadir in BBT cannot be reliably identified until after the temperature rises and remains elevated.3 It then increases by 0.4 – 0.8° over the average preovulatory temperature during the luteal phase and falls again to baseline levels just before or after the onset of menses. A biphasic pattern usually is readily evident. A normal luteal phase documents temperature elevation for 11 days at least. Menses begin 12 days or more after the rise in temperature. In pregnancy BBT remains elevated because of the sustained production of progesterone by the corpus luteum stimulated by human chorionic gonadotropin.
Advantages
- Relatively low cost.
- BBT recordings can also reveal an abnormally long follicular phase or short luteal phase.
Disadvantages
- Increases stress.
- Women may menstruate regularly and predictably but do not exhibit a clearly biphasic BBT pattern.
- The most fertile period passes once the rise in temperature is seen. BBT tracings are useful when recordings are viewed in retrospect to show ovulatory pathology.
Luteal Serum Progesterone Levels
Progesterone levels generally remain below 1 ng/mL during the follicular phase, rise slightly on the day of the LH surge (1–2 ng/mL) and steadily thereafter, peak 7 to 8 days after ovulation, and then decline over the days preceding menses. Any level greater than 3 ng/mL provides reliable objective evidence that ovulation has occurred.4 It is usually performed in the midluteal phase around day 21 of menstrual cycle.
Serum progesterone levels have also been used to measure the adequacy of luteal function. Accurate judgment requires daily serum progesterone determination because the corpus luteum progesterone secretion is pulsatile in nature, closely correlating with distinct pulses in pituitary LH release. Levels ranging from as low as 2 ng/mL to as high as 40 ng/mL can be observed, within brief intervals of time.5 However, daily estimations are both costly and impractical. Sampling during the morning hours when progesterone concentrations are generally high and less erratic may be helpful.6 A sum of 3 measurements obtained between the 5th and 9th day after ovulation totaling 30 ng/mL or more have also been recommended.7 A single measurement greater than 10 ng/mL at day 21 of menstrual cycle is often used. However, random serum progesterone concentrations defy confident interpretation of adequacy of luteal phase and have little value beyond documenting ovulation.
Advantages
Disadvantages
- False-negative or-positive due to fluctuating levels.
- Multiple samples required for accuracy.
Midcycle LH Surge
It is a relatively brief event, typically lasting for 48 and 50 hours. LH has a short half-life and is rapidly cleared via the urine. Ovulation predictor kits turn positive when the urinary LH concentration exceeds a threshold level normally seen only during the LH surge. The threshold level for the ELISA kit is 40 mIU/mL.
Methods
LH surge can be detected by the following methods:
- ELISA: It is the commonly used method.
- RIA: It is very accurate.
- Slide test.
Principle of ELISA Test
It contains 2 antibodies one directed against α subunit which is attached to enzyme alkaline phosphates and the other against the β subunit which is attached to test pad. When LH is present in urine, a sandwich is formed and the enzyme is available to convert a noncolored substance to chromogen (blue). The color intensity produced is proportional to the concentration of LH in the urine sample.
Time of test: The first morning void would be an ideal specimen to test because it is typically the most concentrated. However, results correlate best with the serum LH peak when testing is performed in the late afternoon or early evening hours (4.00 to 10.00 PM), probably because LH surges often 8begin in the early morning hours and are not detected in urine until several hours later.2 Twice daily testing decreases the frequency of false-negative results.
Precautions:
- Testing must be done on a daily basis as test is positive on only a single day, occasionally on two consecutive days.
- Patients should be advised to avoid drinking large volumes of fluids a short time before they plan to test as results are sensitive to the volume of fluid intake.
Interpretation: Ovulation generally follows within 14 to 26 hours after detection of the urine LH surge and almost always within 48 hours.8 The period of greatest fertility includes the day of LH surge detection and the following 2 days. The day after the first positive test generally is the one best for timed intercourse and artificial insemination.8,9
Accuracy of test: The accuracy of many ovulation predictor kits available varies. The kits predict ovulation with greater than 90% probability.9,10 The positive and negative predictive values of these tests are 90% and 96%, respectively. If the urine is checked twice a day sensitivity increases to 97–99%. About 5–10% of women do not produce positive results either because of failed recognition by the antibody used or because their peak urinary LH concentration does not rise above the threshold set by the kit manufacturers. True false-positive tests are rare but equivocal results are not and can be both confusing and frustrating. About 28.7% of patients undergoing ultrasound-monitored IUI (intrauterine insemination) cycle had a spontaneous LH surge before ovulation triggering was scheduled. This could affect pregnancy rates following IUI. Hence, LH surge may have a more important role than ultrasound monitoring in timing IUI or coitus.119
False-positive: False-positive results may occur with intake of these drugs.
- Oral contraceptive pill
- Danazol
- Exogenous hCG
- hMG
- Clomiphene citrate.
Advantages
- Noninvasive
- Widely available
- Not time consuming
- Predict when ovulation will occur unlike other methods which are analyzed in retrospect
- Helps to define the length of the follicular and luteal phase and to identify other cycle abnormalities.
Disadvantages
- Tedious
- False-negative results because of short duration of LH surge.
- Accuracy is affected by fluid intake.
Endometrial Biopsy
Endometrial biopsy is a test of ovulation based on the characteristic histological changes in the endometrium resulting from the action of progesterone. During the follicular phase of the menstrual cycle, the endometrium exhibits a proliferative pattern, reflecting the growth stimulated by rising levels of estrogen derived from the dominant ovarian follicle. During the luteal phase, progesterone secreted by the corpus luteum causes the secretory transformation of the endometrium. 10Anovulatory women are always in the follicular phase and have a proliferative endometrium which can become hyperplastic with extended exposure to a constant estrogen growth stimulus. The histologic features of the secretory endometrium change, with the duration of progesterone exposure. The experienced pathologists can “date” the endometrium, providing a retrospective estimate of how many days have passed since ovulation occurred. The observed date can then be compared to the actual date of sampling. In recent years it has been more accurately defined prospectively, by the number of days elapsed since the detection of the LH surge or ultrasound observation of follicular collapse. Histologic and sampling dates that agree, within a 2-day interval, have generally been considered normal. Dates more than 2 days “out of phase” in two consecutive cycles is the standard criterion for the diagnosis of luteal phase deficiency.12 The best time for the biopsy is controversial. Some advocate the premenstrual phase, when the endometrium might best reflect the cumulative effects of corpus luteum function, while others have argued that the midsecretory phase, coinciding with the putative implantation window, is more relevant being able to identify abnormalities of endometrial maturation which may go undetected.13 A careful and systematic study has revealed that normal variations in histologic characteristics among individuals, between cycles in individuals and among different observers are simply too great to reliably define a specific luteal day or even a narrow interval of days.
To conclude the body of the available evidence supports the conclusion that the traditional endometrial histologic dating is not a valid diagnostic tool. Consequently, endometrial dating cannot be used to guide the clinical management of women with reproductive failure and should no longer be regarded as an important element of their evaluation.11
Advantages
- Simple office procedure.
- Few complications.
Disadvantages
- Invasive.
- Costly.
- Not very accurate: Numerous studies and analyzes have described significant intraobserver and interobserver variations in histologic interpretation that are great enough to affect diagnosis and management in 20 to 40% of individual women.14
Ultrasonography
Although not providing definite positive proof that ovulation actually occurred, serial transvaginal ultrasound examinations offer details about the size and number of preovulatory follicles and provide the most accurate estimate of when ovulation occurs (See Chapter 14).
In its final stages of development, the preovulatory follicle grows at a predictable pace, approximately 2 mm per day (range of 1–3 mm/day). After ovulation, the follicle abruptly decreases in size, its margins become less distinct, the density of internal echoes increases and fluid in cul-de-sac is seen Table 1.4.15 Abnormal patterns of follicle development can also be observed.
The follicle may grow at an abnormal pace, collapse when still relatively small (atresia), or continue to grow or fail to rupture, persisting as a cyst for days after the LH surge (luteinized unruptured follicle).16 3D ultrasound monitoring is a new introduction and is more closer to physiological monitoring.17
Each of the available tests is useful and no one test is necessarily the best. Some are very simple, noninvasive, and inexpensive, and others are more complicated, invasive and costly. Pregnancy is the only sure positive proof of ovulation.
References
- Fairley DH, Taylor A. Anovulation. Br Med J. 2003;327:546–9.
- Luciano AA, Peluso J, Koch El, Maier D, Kuslis S, Davison E. Temporal relationship reliability of the clinical, hormonal, and ultrasonographic indices of ovulation in infertile women. Obstet Gynecol. 1986;75:412–6.
- Quagliarello J, Arny M. Inaccuracy of basal body temperature charts in predicting urinary luteinizing hormone surges. Fertil Steril. 1990;45:334–7.
- Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: Observations on analysis of the normal range. Br Med J. 1984;288:7–9.
- Fillcori M, Butler JP, Crowley WF. Neuroendocrine regulation of the corpus luteum in the human: Evidence for pulsatile progesterone secretion. J Clin Invest. 1984;73:1638–47.
- Syrop CH, Hammond MG. Diurnal variations in midluteal serum progesterone measurements. Fertil Steril. 1987;47:67–70.
- Jordan J, Craig K, Clifton DK, Soules MR. Luteal phase defect: The sensitivity and specificity of diagnostic methods in common clinical use. Fertile Steril. 1994;62:54–62.
- Miller PB, Soules MR. The usefulness of a urinary LH kit ovulation prediction during menstrual cycles of normal women. Obstet Gynecol. 1996;87:13–7.
- Martinez AR, Bernardus RE, Vermeiden JP, Schoemaker J. Time scheduled of intrauterine insemination after urinary lutenizing hormone surge detection and pregnancy results Gynecol Endocrinol. 1994;8:1–5.
- Nielsen MS, Barton SD, Hatasaka HH, Stanford JB. Comparisons of several one step home urinary luteinizing hormone detection test kits to OvuQuick. Fertil Steril. 1998;76:384–7.
- Antaki R, Dean N L, Lapensée L, Racicot M H, Ménard S, Kadoch I J. An algorithm combining ultrasound monitoring and urinary luteinizing hormone testing: a novel approach for intrauterine insemination timing. J Obstet Gynaecol Can. 2011;33(12):1248–52.
- Duggan MA, Brashert P, Ostor A, Scurry J, Billson V, Kneafsey P, Difrancesco L. The accuracy and interobserver reproducability of endometrial dating. Pathology. 2001;33:292–7.
- Casteibaum AJ, Wheeler J, Coutiferis CB, Mastroianni L, Lessey BA Jr. Timing of the endometrial biopsy may be critical for the accurate diagnosis of luteal phase deficiency. Fertil Steril. 1994;61:443–7.
- Scott RL, Snyder RR, Strickland DM, Tyburski CC, Bagnall JA, Reed KR, et al. The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects. Fertil Steril. 1988;50:888–92.
- de Crespigny LC, O'Herlihy C, Robinson HP. Ultrasonic observation of the mechanism of human ovulation. Am J Obstet Gynecol. 1981;139:636–9.
- Matijevic R, Grigic O. Predictive value of ultrasound monitoring of menstrual cycle. Curr Opin Obstet Gynecol. 2005;17(4):405–10.
- Murtinger M, Aburumieh A, Rubner P, Eichel V, Zech M H, Zech M H. Improved monitoring of ovarian stimulation using 3D transvaginal ultrasound plus automated volume count. Reprod Biomed Online. 2009;19(5):695–9.