Female infertility

Infertility is defined as one year of unprotected coitus without conception. It affects approximately 10-15% of couples in the reproductive age group.

Fecundability is the probability of achieving a pregnancy within one menstrual cycle (about 25% in normal couples)Fecundity is the ability to achieve a live birth within one menstrual cycle.

Aging and fertilityIncreasing age impact negatively on reproductive capacity – women more affected than men. The aging of the reproductive system plays a role, as well as increase in the incidence of spontaneous abortion (majority of early spontaneous abortions after age 35 are due to autosomal trisomies, the incidence of which increases with maternal age).The risk of clinically recognised spontaneous abortion increases from about 10% under age 30, to 18% in the late 30s, and 34% in the early 40s. The frequency of both euploid (normal) and aneuploid (abnormal) abortuses increases with maternal age.Older women have oocytes with impaired meiotic spindle formation or function that could cause the failure of proper chromosome migration.Other factors include the increase incidence of endometriosis, uterine fibroid, cumulative exposures to occupational or environmental hazards also could lessen fertility, complications of STI.

Endocrine changes with agingGerm cell mitotic multiplication reaches its peak of 6-7 million oogonia by 16-20 weeks of pregnancy during fetal life and from this point in time, the germ cell content will irretrievably decrease. At the onset of puberty, the germ cell mass is approximately 300,000 units. Over the next 35-40yrs of reproductive life, during which time only 400-500 oocytes will ovulate, these units will be depleted by atresia to a point at menopause when only a few hundred remain.

In the last 10-15yrs before menopause, there is acceleration of follicular loss. This accelerated loss begins when the total number of follicles reaches approximately 25,000, a number reached in normal women at age 37-38. This loss correlates with a subtle but real increase in FSH and decrease in inhibin.

Alterations in the menstrual cycle characteristic:Prior to the menopause, there is a period with shorter follicular phases, with increased FSH levels, but normal LH levels and luteal phases.The menstrual periods for 10-15yrs before the menopause are regular, but there is a steady decrease in cycle length due to the shortened follicular phase. Cycle lengths are the shortest and with the least variability in the late 30s, a time when subtle but real increases in FSH and decreases in inhibin are occurring.

Women who present with “incipient” ovarian failure have elevated FSH levels and decreased levels of inhibin, but normal levels of oestradiol. The rise in FSH during the later years of reproductive life is in response to declining inhibin production. The specific inhibin involved in this feedback effect on FSH during the follicular phase is inhibin B.The rise in FSH is very apparent after age 40, but there is no change in LH levels until menopause.

These endocrine changes and the decline in ovarian follicles are correlated with a decrease in ovarian volume. A measurement of volume by USS that is equal to or less than 3cm3 predicts a poor response to ovulation induction.

Testing the ovarian reserve:1. The measurement of baseline hormonal levels provides important and prognostic

information. Elevated FSH levels on menstrual cycle day 3 (greater than 12iu/L, but especially if greater than 20iu/L) are associated with poor performance with IVF.

Note: a cycle day 3 FSH level that is > 25iu/L or a maternal age of > 44yrs are both independently associated with a chance of pregnancy close to zero during ovulation induction or with assisted reproduction technologies.

Values can vary between laboratories, significantly due to differences in antibodies and standards used to measure gonadotropin levels. With the most recent assays, day 3 values above 10iu/L are abnormal and are comparable with values greater than 20iu/L with older assays.

Women with one ovary have higher day 3 FSH levels that correlate with reduced outcomes in IVFThe age of change is determined by the rate of oocyte loss, a rate that is genetically programmed in most women.

An elevated oestradiol level on day 3 (greater than 80pg/mL) is also predictive of difficulty in achieving pregnancy. Premature oestradiol elevations are associated with a hurried recruitment of follicles in response to increased FSH secretion, changes characteristic of the years preceding menopause. When both FSH and oestradiol are elevated on day 3, ovarian response to stimulation is very poor.

The Clomiphene Challenge test:It is a bioassay of FSH response (which reflects ovarian follicular inhibin capability). Clomiphene is administered in a dose of 100mg/day on days 5-9. The level of FSH on day 10 is compared with the baseline level on day 3. An exaggerated FSH response of 26iu/L or more was 2 standard deviations above the control values in this study, and this increase in FSH was associated with a significant prospect of failure to achieve pregnancy.

Remember that there is a wide variety of FSH assays (the newer assays provide numbers that are approximately 70% of the older results), and clinicians must become familiar with the values provided by their own laboratories.

There is a high incidence of abnormal responses in women over age 35, and 85% of women with increased FSH levels respond poorly to ovarian stimulation. About 10% of women in the general infertility population have an abnormal response to the Clomiphene challenge test. Women with unexplained infertility had a 38% incidence of abnormal tests.This test of ovarian reserve is more sensitive than just measuring basal FSH levels in predicting the potential for pregnancy in both assisted and natural reproduction.

An abnormal response to the clomiphene challenge test indicates a poor prognosis no matter the woman’s age.Older women with normal hormone levels and normal responses to clomiphene still have diminished chances of pregnancy.

Indications for Clomiphene challenge test (as well as a day 3 oestradiol level)1. All infertile women age 30 and above.2. women of any age with unexplained infertility.3. women who respond poorly to ovulation induction.

Note: for practical purposes, equivalent results can be expected on days 2, 3, and 4 of the menstrual cycle.

Although an abnormal clomiphene challenge test at any age indicates a very poor prognosis, it does not indicate an absolute inability to achieve pregnancy.

Far less certain is the need for these tests in the women over 40, because even normal test do not provide reassurance of adequate ovarian reserve. An abnormal test in a woman over 40, however, can be used to bolster advice to consider ovum donation.

The Role of the Physician:1. The first goal is to seek out and to correct the causes of infertility.2. To provide accurate information and to dispel the misinformation commonly gained

from friends and mass media3. To provide emotional support for the couple during a trying period – a valuable adjunct

to the effort of the physician are support groups for infertile couples.4. The counselling of couple concerning the proper time to discontinue investigation and

treatment, to consider adoption, and/or to move on the assisted reproductive technologies. This is especially important in unexplained infertility.

The Female infertility Investigation:Use of questionnaire – mailed to the patient for completion prior to initial clinic visit for infertility investigation – the questionnaire provide information that ranges from previous medical events and sexuality to recreational, social and vocational activities. Patients often write comments regarding their past history and their feelings that are difficult to express during an office interview.At the initial visit both partners are expected to be present – it gives the physician an opportunity to inform both partners of their role in infertility and the need for investigating both of them, starting with the male. Since male factor accounts for approximately 35% of infertility, examination of the semen should be an early diagnostic step in the investigation. If abnormal, further diagnostic procedures in the women should be deferred until decisions are reached regarding the man. If the semen is normal, attention is directed to the woman.

History taking – frequency of coitus, any sexual problems should be ascertained. Fetal wastage is definitely higher in diethylstilbestrol exposed women, while there is still some uncertainty, evidence suggests that primary infertility is also more common. Impact of smoking on pregnancy There is good evidence that fecundity is reduced in men and women who smoke, and the risk is greater with smoking at an early age. There is a dose-response relationship between the number of cigarettes smoked and how long it takes to achieve pregnancy. Marijuana inhibits the secretion of GnRH and can suppress reproductive function in both men and women, and cocaine use is known to reduce spermatogenesis. Studies have failed to confirm an adverse impact of caffeine on fertility, although high levels of intake may be associated with a delay in conception. Failure to ovulate is the major problem in approximately 40% of female infertility; another 40% is due to tubal pathology and pelvic pathology, and less than 10% is due to problems such as anatomic abnormalities or thyroid disease.

Laboratory testing should be directed by clinical judgment.Women with a negative rubella titre should be immunized and attempts for pregnancy delayed for 3 months.

Postcoital test (Sims-Huhner test):

It provides information about the receptivity of cervical mucus, and the ability of sperm to reach and survive in the mucus.Oestrogen levels peak just prior to ovulation, and this provides maximal stimulation of the cervical glands. This results in outpouring of clear, watery mucus. The cervical mucus earlier in the menstrual cycle, when oestrogen level is lower or 2 to 3 days after ovulation, when progesterone level increases (progesterone counteract the oestrogen effect on cervical mucus) is thick, viscid, and opaque.Postcoital test should be performed around the time of the expected LH surge as determined by a previous basal body temperature chart (the best time for the PC test is the day prior to the first temperature elevation) or by the length of prior menstrual cycles. Timing of PC test can also be determined using ultrasonography or LH monitoring.PC test is usually performed between 2 and 8 hours after coitus, cervical mucus is removed with a nasal polyp forceps or tuberculin syringe and examined for macroscopic and microscopic characteristics. The couples should also abstain from intercourse for 48 hours prior to the post coital test.The stretchability (spinnbarkeit) of the mucus at midcycle should be 8-10cm or more. At midcycle the mucus contains 95-98% water and should be watery, thin, clear, acellular, and abundant. When dried on a slide, it should form a distinct fern pattern.

Poor mucus at midcycle can be a physical barrier that decreases sperm penetration and is associated with decreased chance for fertility.Attempted treatment for poor cervical mucus at midcycle:Administering 0.625mg of conjugated oestrogens daily for the 8 or 9 days preceding the expected time of ovulation. In a 28-day cycle that would be between days 5 and 13.If initial treatment of the poor mucus, fails to yield desired result, the dose is increased to 1.25mg/day.Oestrogen therapy has no demonstrable benefit for the poor mucus which is, on occasion, associated with the use of clomiphene citrate.

The most logical approach to overcome the barrier of thick cervical mucus is the use of intrauterine insemination (IUI) of washed sperm. If poor cervical mucus is the sole problem, IUI for 3-4 cycles is associated with a cumulative pregnancy rate of 40-50%.

Other uses of the PC test:1. Information concerning the male partner – absence of sperm in mucus, could a pointer

to presence of sexual problems, and the need for a detailed review of the semen specimen.

2. 21 or more sperm/high power field (HPF) is almost always associated with a sperm count above 20 million/ml – PC test can never be a substitute for semen analysis: it gives very little information about morphology (there are considerably fewer abnormal forms in the cervical mucus compared to the ejaculate).

If PC test repeatedly shows no sperm or only dead sperm despite good mucus – caution patient against the use of lubricants such as K-Y jelly or surgilube, which have been shown to have spermicidal effect in vitro. If lubrication is necessary use vegetable oil which does not interfere with sperm motility. If after re-checking the semen, it was found to be normal, the pH of the cervical mucus at midcycle should be determined. Good results have been reported using a precoital douche of 1 tablespoon of sodium bicarbonate in 1 quart of water when a poor PC test was associated with a pH below 7.Sperm antibody testing should be performed in cases where there are no sperm or mostly nonmotile sperm or in situations where good mucus contains sperm that are shaking and not moving progressively.

Hysterosalpingography:Indications – history of PID, septic abortion, ruptured appendix, tubal surgery or ectopic pregnancy

HSG is performed 2-5 days after cessation of a menstrual flow. If there is a prior history suggestive of PID, an erythrocyte sedimentation rate is obtained prior to the HSG and, if elevated, antibiotic therapy is given. The procedure is then postponed for a month when a repeat ESR is obtained. Only if the ESR is normal is the HSG scheduled. If masses or tenderness are revealed by the pelvic examination at any time, the HSG should be bypassed and the pelvis evaluated by laparoscopy. If there is a documented history of PID, the risk of a serious reinfection following HSG is too high, and it should be replaced by laparoscopy.If an HSG is performed in a patient who is at questionable risk for infection, a water-soluble rather than an oil dye should be used because of the faster absorption. The overall risk of infection with HSG is probably less than 1%, although in a high-risk population serious infection can occur in approximately 3% of cases.

Patient with HSG showing dilated fallopian tubes risk developing PID – they should be given Doxycycline, 200mg after the procedure, followed by 100mg bid for 5 days. Many physicians routinely administer prophylactic antibiotics (doxycycline, 100mg bid for 5 days, beginning 2 days before the procedure).

Only 3 films are usually required following HSG – a preliminary before dye is injected, a film showing spill of dye from one or both tubes, and a delayed film to show spread of dye through the peritoneal cavity.

Use of prostaglandin synthesis inhibitor 30 minutes prior to the procedure can decrease the pain many women experience with HSG.

The dye should be injected slowly to reveal abnormalities of the uterine cavity – especially in women with intrauterine diethylstilbestrol exposure (uterine contour abnormalities). Usually 3 to 6 ml of dye is required to fill the uterus and tubes.

If dye goes through one tube rapidly and fails to enter the other tube, it usually means that the dye-containing tube presents the path of least resistance. In this situation the nonfilling tube is usually normal.Evidence of distal tubal disease on HSG is usually confirmed when laparoscopy is performed.Note: a normal HSG study does not rule out pelvic pathology, especially adhesions or endometriosis.

While the diagnostic usefulness of the HSG is established, its value as a therapeutic procedure in infertility is a subject of some controversy. Does an HSG enhance fertility, and, if so, is the effect seen with both oil and water-soluble dyes? A conception rate of 41.3% within 1 year of an HSG with oil media has been reported, whereas the rate was only 27.3% when water-solube agents were employed.Evidence indicates the HSG with Ethiodol (oil media) is a very useful therapeutic as well as diagnostic tool in women with infertility.

The effect of the oil dye on fertility could involve any of a number of mechanisms:1. It may produce a mechanical lavage of the tubes, dislodging mucus plugs.2. it may straighten the tubes and thus breakdown peritoneal adhesions.3. it may provide a stimulatory effect for the cilia of the tubes.4. it may improve the cervical mucus.5. the iodine may exert a bacteriostatic effect on the mucous membranes.

6. Ethiodol decreases in vitro phagocytosis by peritoneal macrophages. If the same effect occurs in vivo it could decrease macrophage activity and thus aid fertility by inhibiting the release of cytokines and decreasing phagocytosis of sperm.

Another notable reason for criticizing the oil medium is that it slowly absorb and may cause granuloma formation. Granulomas are found very infrequently, and they can also follow the use of water dyes. An additional fear with oil dye is embolization.

HSG is less sensitive than sonohysterography in the identification of uterine polyps or myomas. Sonohysterography involves the injection of saline into the uterine cavity by means of a size 8 paediatric Foley catheter with the balloon inflated within the cervix, followed by ultrasonography of the uterus. Similarly, saline or albumin-based fluids can be tracked by USS as they course through the fallopian tubes into the peritoneal cavity, providing evidence of tubal patency without use of x-ray.

Hysteroscopy:Hysteroscopy is an endoscopic procedure which ensures direct visualization of the uterine cavity using an hysteroscope. It is good for differentiating between endometrial polyps and submucous leiomyomas, establishing the definitive diagnosis and treatment of intrauterine adhesions, and for the diagnosis and treatment of intrauterine congenital anomalies (uterine septal defects).Hysteroscopy is complimentary to HSG, however, due to cost – it should be reserved to pursue abnormalities identified by other techniques, especially when operative intervention is planned.

Falloposcopy:Hysteroscopic directed falloposcopy can be utilized to transvaginally examine the entire length of the tubal lumen. This technique confirmed that the tubal ostium can undergo spasm, and intraluminal debris if present, can be a cause of tubal obstruction. The obstruction can be cleared by cannulation or balloon tuboplasty, or even by HSG. Visualization of the tubal lumen can also be achieved through the distal end at the time of laparoscopy.

Disorders of Ovulation:This accounts for approximately 20% of the causes of infertility in couples. There can be anovulation or severe oligoovulation.Anovulatory or oligoovulatory women should be promptly treated with clomiphene citrate to increase the frequency of , or to initiate, ovulation and the drug can be started immediately, even before other areas have been investigated. If anovulation is the only infertility factor, most couples will become pregnant within 3 months of ovulation induction. Women with amenorrhoea or hyperandrogenic anovulation should be evaluated and managed according to the clinical management.

Methods for determining ovulation: 1. Basal body temperature chart:Menstrual periods that occur at monthly intervals marked by premenstrual symptoms and dysmenorrhea are almost always ovulatory. BBT chart is an indirect confirmatory method of determining when a patient has ovulated during her cycle. The temperature can be taken orally with a thermometer immediately upon awakening and before any activity and recorded on a chart. A nadir in the chart, just before elevation of the body temperature is thought to represent the beginning of the LH surge (the occurrence of a nadir is variable and often is not detected). The BBT chart is only able to predict the LH surge only within 2-3 days. A significant rise in temperature is not noted until 2 days after the LH peak, coinciding with a rise in peripheral levels of progesterone to greater than 4ng/ml. the temperature rise should be sustained for 11 to 16 days, falling at the time of the subsequent menstrual period. Physical release of the ovum

probably occurs on the day prior to the first temperature elevation. If an appropriate time of ovulation can be determined by BBT chart, a sensible schedule for coitus is every 36 to 48 hours in a period encompassed by 3 to 4 days prior to ovulation and 2 days after expected ovulation.

The fertilizable life of the human oocyte is estimated to be between 12 and 24 hours, while that of the human sperm is 48-72 hours. The extreme intervals that have achieved pregnancy documented after a single act of coitus are 6 days prior to and 3 days after ovulation.

Usefulness of BBT chart includes serving as a preliminary indicator of ovulation and a tool for advising patients about the timing of intercourse. Several months of charting body temperature is enough to perform this function.

Home urinary LH testing is used to assist with therapeutic and diagnostic timing, for BBT chart. The postcoital test should be performed within 12 hours of a positive urinary LH test.

2. Endometrial biopsy:This can be used for determining, if a cycle was ovulatory. The endometrial biopsy is performed 2 to 3 days prior to the expected period. Although endometrial biopsy, done at the mid-luteal phase is better for diagnosing luteal phase defect, a premenstrual biopsy has the disadvantage of being able to interrupt a pregnancy in a conception cycle.3. Progesterone measurements:A serum progesterone level of less than 3 ng/ml is consistent with follicular phase levels. To confirm ovulation, values at the midluteal phase (midpoint between ovulation and the onset of the subsequent menstrual period) should be at least 6.5 ng/ml and preferably 10 ng/ml or more.

Luteal phase defect – is diagnosed when there is a lag of more than 2 days in the histologic development of the endometrium compared to day of the cycle.Luteal phase defect is a direct consequence of decreased hormone production by the corpus luteum. The underlying cause can be multiple such as decreased levels of FSH in the follicular phase of the cycle, abnormal patterns of LH secretion, decreased levels of LH and FSH at the time of the ovulatory surge, or decreased response of the endometrium to progesterone. Elevated prolactin levels and hypothyroidism can be associated with luteal phase defect, hence the need to assess prolactin and TSH levels in infertile women with less than normal ovulatory cycles.

Treatment of luteal phase defect:Clomiphene citrate remains first choice for the Rx of luteal phase defect – dose is 50mg a day for 5 days, starting on day 3, 4, or 5 of the cycle.Other form of treatment includes the use of exogenous progesterone, 25mg as a vaginal suppository bid starting 2-3 days after ovulation and continuing until menstruation occurs or through the 10th week of a pregnancy. Once a pregnancy is diagnosed, a switch can be made to weekly injections of 17-hydroxyprogesterone caproate (250mg) through the 10th week of pregnancy. A known side effect of exogenous progesterone is prolonged luteal phase and can delay the onset of menses.

Laparoscopy – if considered as an investigative option in infertility after a normal HSG, should be performed after an interval of 6 months from the HSG. This allows time for the fertility enhancing effect of the HSG.