Posted On April 24, 2018
Infertility is defined as a state in which a couple, desirous of a child cannot conceive after 12 months of unprotected intercourse. But, if a couple approaches a doctor for infertility, they should be evaluated to see that they do not have any major problems.
Initial evaluation of the female:
Infertility, the inability to conceive after 1 year of unprotected intercourse, is estimated to affect one in six couples at some point in their life. Investigations should be normally be instigated as soon as the couple seeks help, as gross irregularities that one could come across during history taking or examination can be corrected immediately. There are many situations unique to the Indian set up, like couples staying separately, or working for long hours with no time for intimacies, interference from overbearing family members, being just some of them. Social stigma attached to infertility is also peculiar to the subcontinent.
It is important to try and start counselling in the presence of only the husband and wife, without interference from relatives or friends. . In India, the male partner quite often refuses to be involved in discussions. If the male partner refuses to meet the gynaecologist, it would be better to talk to the female partner alone, confidentially, as this would bring out many points in the history, which may be masked, in the presence of parents or friends. For example, H/O medical termination of pregnancy before marriage, or the presence of children by another marriage, are quite often suppressed unless the woman is interrogated separately.
Investigations include careful history taking, examination, blood investigations and other specialised investigations focused to determine if the woman has any of the eitiological factors responsible for infertility.
Initial evaluation of a patient:
A careful history should include questions to know :
- Whether the couple are staying together, and the frequency of intercourse.
- There is pain during intercourse
- Regularity of menstruation
- H/O abortions/deliveries
- Associated History of any medical disorders
BMI:Determination of body mass index(BMI) is important, as both obesity as well as being too underweight can be causes of disorders of ovulation and pregnancy wastage. Determination of BMI is made from the height and weight (Kg/m2). The normal range is 20-25kg/m2. BMI of >30 falls in the obesity range.
A cursory examination can reveal stigmata of hyperandrogenism, like acne, hirsuitism, and male pattern of balding , which are suggestive of Poycystic ovarian syndrome(PCOS). Hirsuitism can be graded and given a “Ferriman Gallway” score.
Virilisation is a higher grade of androgenism with very high circulating androgen levels and causes deepening of the voice, increase in muscle bulk,cliteromegaly and breast atrophy beside the other signs of hyperandrogenism. Other than severe PCOS,it could also be seen in congenital adrenal hyperplasia(CAH) , androgen secreting tumors and Cushing’s syndrome.
Acanthosis nigricans is a sign of profound insuin resistance and is usually visible as hyperpigmented thickening of the skin folds of the axilla and neck, associated with PCOS and obesity.
Any thyroid swelling should be noted.
Breasts should be examined to look for galactorrhoea. It is important to know that examination of breasts, vagina, or even stress can elevate prolactin levels and therefore, blood tests should never immediately follow examination of the patient.
Local examination: It is mandatory to do a per vaginal (PV) and per speculum examination as it can give a lot of valuable information. The advent of Utrasonography has led to a reluctance to do vaginal examination. However, a PV has, quite often led to the discovery that the couple are not even aware of the need for proper penile insertion into the vagina for completion of intercourse. Some such couple who have not even consummated their marriage have been known to undergo expensive investigations for infertility. Acute retroversion and retroflexion of the uterus with the cervix lying almost close to the urethra will need proper counselling. The average gynaecologist asks the patient to lie for half an hour in the supine position with a pillow under her buttocks so that the cervix dips into the pool of semen in the vagina. However, in the retroflexed uterus, the supine position may not serve that purpose. Irregularities in the fornices , specially the posterior fornix is suggestive of either endometriosis or post infective adhesions, and such findings on initial evaluation should prompt the clinician to start evaluating and treating the patient straight away. Acute pelvic infection is another finding which can be missed if one solely relies on ultrasound reports. These “misses” are more likely in the patient who comes with reports from many doctors and more so when some investigative reports show gross abnormalities like resistant PCOD or Azoospermia in the male, just to name a few. The doctor who sees the patient with many reports, may just omit Per vaginal examination, thus missing out a recent infection or polyp or endometriosis.
A per speculum examination can sometimes reveal cervicitis or endometrial polyps, or even simple trichomonal infection and if they are detected and treated after proper examination it can improve results in a fertility clinic.
Endocervical swabs and tests for Chlamydia detection:
Chlamydia trachomatis can cause cervicitis , salpingitis and endometritis in women, although symptoms can be mild and non-specific1. Antibodies can be tested in serum and antigens in endocervical swabs. Some clinics routinely test serum for anti chlamydial antibodies. The presence of chlamydial antibodies predicts tubal damage in 90% of cases. Chlamydial antigen can be detected by enzyme linked immunosorbent assy in (ELISA) of endocervical swabs. A sensitive urinary assay also has been developed for the screening of past chlamydial infection. However, Chlamydia detection tests may be negative in the presence of upper genital infection.
Bacterial vaginosis causes up to 50% of vaginal infections. It is associated with infective complications following gynaecological surgery, first and second trimester miscarriage and premature labor/delivery. There is also an increased risk of miscarriage after IVF in women found to have bacterial vaginosis. Screening for bacterial vaginosis can be useful in the investigation of infertility.
Investigating the female further, should be target oriented, to determine if the woman has ovulatory disorder, tubal factor, cervical factor or immulogical cause for infertility. As against semen analysis for the male, which is a simple test, most of the investigations for dertermining female factor of infertility are cumbersome and some invasive, so one has to be careful in deciding which patient should undergo the investigation, and the frequency with which she has to undergo the tests.
Oligo ovulation or anovulation is the commonest female factor of infertility. Empirical treatment for infertility is most often targeted at correcting ovulatory disorders. Documenting ovulation before starting therapy for oligo/Anovulation would be ideal instead of empirical treatment, which can have draw backs, like reduced cervical mucus with the use of prolonged clomiphene therapy. The following investigations can help ascertain if a woman is ovulating.
History: Irregular periods are suggestive of anovulation. Women who are having regular menstrual cycles (frequency of 23-35days, with no more than 2-3 days variation each month) have a greater than 95% chance that they are ovulating.
Basal body temperature chart: The temperature of the woman is taken every day before rising from bed and noted. Just after ovulation the temperature rises by 0.2-0.50 C due to a rise in progesterone levels and remains higher than the preovulatory phase. It is a retrospective diagnosis and can strain the patient, though it is a fairly good method of documenting ovulation. However, a flat BBT chart does not necessarily mean anovulation, as 10-75% of ovulatory cycles fail to show a rise in BBT.
Serum progesterone measurements:A serum progesterone value greater than 30nmol/L in the luteal phase suggests ovulation. However, in a woman with an erratic cycle, it is difficult to know when to do a progesterone measurement. In such patients, if the progesterone level is 15-30, it need not mean anovulation as it may be in the proliferative phase of menstruation. Thus the progesterone value has to be co-related with the onset of menstruation. Progesterone levels combined with USG is more useful.
Endometrial biopsy: A secretory endometrium in the second half of the cycle suggests ovulation. It is an invasive method and is not resorted to in current day practice.
Urinary LH kits: Urinary LH is measured using reagent strips by the patient herself . In response to a preovulatory surge in estradiol, LH levels surge in the bloodstream and spill into the urine. The kit measures the LH as it accumulates in the urine and a midcycle surge predicts ovulation.
Ovulation induction kits can help couples to time intercourse. The testing should be carried out at the same time every day starting two to three days before expected ovulation. 3 drops of urine is put on the kit. A colour change predicts ovulation in 12-24 hours. The true window of fertilization is actually short (usually <24 hours), but the sperm can remain in the cervical mucus for 72 hours. Thus even if the monitor predicts several days of LH surge, the sperm in the mucus can still reach the ovum in case of ovulation, on any one of these days.
However, this is a prospective test and ovulation cannot be confirmed , as increase in LH levels may not always end in ovulation. In patients with elevated LH levels, like in PCOD, the LH levels may remain high, the kits showing positive surge every day of the month.
Ultrasound: Ultrasonography as an investigative tool is basically used for detecting ovulation and timing ovulation. By and large, transvaginal sonography is preferred over the older method of transabdominal sonography. Rarely, wives with vaginismus, or whose husbands have erectile dysfunction or premature ejaculation may find transvaginal sonography painful. In such patients, abdominal sonography may be needed to monitor ovulation.
Abdominal vs Vaginal sonography: Transabdominal ultrasound does not allow adequate visualization in patients with obesity, scars of abdominal surgery, or patients with ovaries fixed in the deep pelvis. Follicle structures are better seen on Trans-vaginal ultrasonography. Follicle diameter measured by transabdominal ultrasound are greater by an average 3.2mm .
Assessment of follicles: A baseline scan should be done on day 3-5 of the cycle, to rule out ovarian cysts or persisting corpus luteal cysts from the previous cycle. If a cyst is detected, it would be apt to commence ovarian stimulation only after the patient has had another spontaneous menstrual bleed, which indicates that the endogenous secretion of ovarian hormones has returned to baseline levels. This can be corroborated by the finding of a thin endometrial lining (<5mm). A baseline scan also can rule out the presence of hydrosalpinges,or submucous fibroids.
In the diagnosis of PCOD, calculating the ovarian volume is important. It is calculated by the formula, for a prolate ellipsoid,(0.5 ×length×breadth×thickness).
The preovulatory follicle grows at a rate of 2-3 mm per day and is 17-25mm at the time of ovulation. Inner diameter of the follicle is measured, in 2 dimensions,Anteroposterior and longitudinal, and the mean taken.
Pregnancy is associated with follicles of larger size at the time of ovulation are usually those greater than 20mm. Largest diameter of the preovulatory follicle is 16-18mm in normal or clomiphene stimulated cycles.
Ultrasound features of ovulation are:
- Reduction in size of the follicle
- Loss of definition of the folllicular wall,
- Presence of fluid in the pouch of Douglas
- Multiple echoes in the follicle.
- Change in texture of endometrium.
Timing of ultrasound: Beside the base line scan, for monitoring follicular growth, Ultrasound assessment is usually carried out one or two days before expected ovulation and repeated every one or two days till after ovulation. In stimulated cycle, where HCG or GnRh analogues are given to stimulate ovulation, the trigger injection is given when the dominant follicle is 18mm, and insemination timed 36 hours later.
Evaluation of endometrium: The sonographic appearance of the endometrium may reflect an adequately receptive tissue and may be related to the success or failure to achieve pregnancy. Endometrial thickness, measured in the plane through the central longitudinal axis of the uterus between the interfaces of the endometrium and myometrium represents the estrogenic activity of the uterus. In the normal cycle, the endometrial thickness ranges from 6-12mm in the late follicular phase and is usually 10-12mm at around the time of ovulation. Periovulatory endometrium has a characteristically three line pattern. The middle layer represents the lumen of the endometrial cavity. The mucus in the lumen makes the cavity echogenic, represented as the middle line. A thin or homogenous endometrium in the pre-ovulatory phase may be associated with poor fertility outcome. Endometrium becomes hyperechoic in the luteal phase.
Colour Doppler sonography in infertility: Poor uterine flow is a cause for infertility7. Measuring uterine bloodflow using resistance index and pulsatility index
In the uterine artery has been useful in predicting success in IVF cycles. Sustained diastolic flow in the uterine artery during early and midsecretory phase is associated with a high chance of success in IVF cycles8. Women with poor uterine perfusion could have their embryos preserved for transfer at a later date, when their endometrial receptivity is better.
Endocrine profile: A baseline endocrine profile quite often is helpful in evaluating and monitoring treatment of anovulation.
Endocrine profile is optimally performed during the first 3 days of the cycle. The initial workup should include measurement of thyroid stimulating hormone, prolactin, and cycle day 3 FSH and estradiol levels.
Thyroid disease is found very commonly in reproductive age women and should be assessed by doing a Thyroid Stimulation test,(TSH) which is the most sensitive test of thyroid function- an elevation suggesting hypothyroidism. Hypothyroidism can also elevate prolactin levels.
Prolactin levels fluctuate throughout the day, reaching a nadir in the morning, and therefore, testing should be done in the morning6.
Women with hyperandrogenism should in addition undergo determination of testosterone, dehydroepiandrosterone sulphate (DHEAS), and 17- hydroxyprogesterone (17OHP) levels. Women with PCOS should have a fasting glucose or 2-hour glucose tolerance test. Some workers use glucose to insulin ratio or simply insulin level to gauge the degree of insulin resistance.
Luteal phase deficiency used to be assessed by measuring progesterone levels, but progesterone is secreted in pulses every 2-3 hours, and therefore may not indicate actual levels.
Tests for Ovarian reserve: In every woman, there is a resting follicle pool, which represents the ovarian reserve, from which follicles will be recruit ed for maturation. The term “ovarian reserve” refers to a woman’s current supply of oocytes and is associated with reproductive potential. A diminished ovarian reserve greatly decreases a patient’s chances for conception. Abnormal results may predict a lower pregnancy rate, but the possibility of pregnancy cannot be totally ruled out. Ovarian reserve can be assessed by Biochemical tests, Dynamic tests, Sonography and Ovarian biopsy4.
FSH: Basal (Day 3) FSH levels indicate ovarian responsiveness. An FSH level>15IU/ml indicates that ovarian activity is minimal.
Estradiol: In older women, a more advanced follicular recruitment by cycle day 3 results in high serum estradiol concentrations in the early follicular phase. Basal levels of Estradiol >80pg/ml is associated with higher cancellation rates in IVF.
Inhibin: Inhibin is a polypeptide produced by granulose cells of the ovary. Inhibin levels below 45pg/ml demonstrated a poorer response to ovulation induction in ART cycles.
Serum Mullerian hormone (AMH): AMH is produced by granulosa cells and it regulates the transition from resting primordial follicles into growing follicles. Levels decline with advancing female age. The advantage is that levels do not fluctuate with menstrual cycle.
Dynamic tests for ovarian reserve:
Clomiphene challenge test: Clomiphene is administered at the oral dose of 100mg between days 5 and 9 and FSH levels measured twice, once on the 2ND and 3rd day and again on the 9-11th day. A total FSH level >26IU indicates poor ovarian reserve. However, basal FSH levels have been found to correlate better than clomiphene challenge test to know ovarian reserve.
Gonadotropin Analogue Stimulation Test (GAST): GAST evaluates the estradiol serum concentration change from cycle day 2 to day 3 after the administration of a supraphysiological dose of a GnRH agonist. The prompt response of E2 levels, reflect the ovarian reserve.
Exogenous FSH Ovarian Reserve test (EFORT): In this test, following the measurement of basal FSH and estradiol levels, estradiol respose 24 hours following a 300IU FSH injection on day 3 is determined. However, it is a costly test and therefore, not routinely used.
Antral follicle count (AFC): AFC is the number of follicles smaller than 10mm in diameter, detected by TVS, in early follicular phase. A count of 8-12 indicates good ovarian reserve and a normal response to IVF. A count of 6 or less suggests the need for higher stimulation protocols. In one study, AFC< 3 had 68.8% cancellation rates in IVF.
Ovarian volume: In women with small ovaries(<3cm3) the cancellation rate of IVF is higher.
Colour Doppler sonography in ART: Ovarian blood flow, Endometrial blood flow, etc can be assessed with colour Doppler. Good flow indicates good endometrial receptivity. If endometrium is non receptive as per Doppler studies, in ART cycles, precious embryos can be stored till another cycle, where the endometrium has been made receptive.
Tests to assess tubal patency:
All patients who seek evaluation of fertility need to have their tubes evaluated at some point of time. Even patients with obvious anovulation or azoospermia, will need tubal evaluation, if pregnancy is not achieved after treatment for a few cycles. Patients with prior pelvic inflammatory disease, sexually transmitted diseases such as gonorrhoea or Chlamydia trachomatis, or a history of septic abortions are most likely to have tubal disease. Patients with positive antichlamydial antibodies are likely candidates for tubal infertility.
Tubal patency can be evaluated through hysterosalpingography, sonosalpingogram,ultrasound contrast hysterosalpingography and laparoscopy.
Hysterosalpingography:Hysterosalpingography involves the X-ray imaging of the pelvis while a contrast medium is injected into the uterus through a cannula positioned in the cervical canal. The uterine cavity and tubes can be imaged in real time and the spill of the radioactive medium into the pelvis noted. X-rays are taken while the dye passes through the uterus and after it spills into the pelvis .
Cannulas used: In India, either metal cannulae that can be screwed into the cervical canal, or balloon catheters that are passed into the uterine cavity itself are used.
Contrast medium:A water soluble medium is usually used and will be absorbed after an hour. Sometimes the cause of an apparent blockage is a mucus plug, which might be flushed through the tube by the contrast medium. Thus there are reports of an increased chance of pregnancy in the 2 or 3 months that follow either an HSG.
Timing: An HSG should be performed optimally within 10 days of a menstrual period when there should be no risk of a pregnancy. The HSG can be uncomfortable, especially if there is either tubal spasm or a tubal obstruction. Tubal spasm can occur and antispasmodics have been employed. A slow injection of dye can prevent tubal spasm.
Antibiotic prophylaxis: Routine antibiotic prophylaxis is recommended with a 3-5 day course of doxycyclin to treat silent pelvic infection, particularly, chlamydia.
Characteristic findings: The cavity of the body of the uterus is usually triangular, sometimes with a concave or convex fundus.
- Filling defects that are in the uterine cavity can sometimes be due to air bubbles. These defects have to be distinguished from endometrial polyps.
- Irregular filling defects could be caused by intrauterine adhesions, which could be a cause of recurrent abortions.
- Submucous fibroids can show as filling defects.
- Partial or complete septum can be diagnosed on HSG by seeing the contrast free longitudinal filling defect in the centre.
- Unicornuate uterus will show the dye filling only one side of the uterus with the tube.
- Tubal blocks and the site of block can be diagnosed on HSG. A free spill of dye into the peritoneal cavity indicates patent tubes.
- Hydrosalpinx can , often with multiple strictures and a beaded appearance; occasionally the tube is rigid, with a “pipe stem” appearance.
- Pelvic tuberculous may lead to calcification, which can be seen on an X-ray.
Sonosalpingography2: An 8f foley’s urinary catheter is inserted into the uterine cavity and 2.5-3.0ml saline is injected into the bulb to stabilise it. While concentrating on scanning the space between the cornu and the ovary on either side, 20ml saline along with air is pushed through the Foleys catheter . Patent tubes distend with the mixture of agitated saline and air-bubbles gush past the ovary. As an extension,in a procedure called hydrogynecography, after giving Atropine and antispasmodics orally half an hour before, 300 ml of normal saline is injected to flood the pelvis, delineating all sorts of adhesions, flimsy and dense. However, one has to be sure there is no active pelvic infection before doing the procedure.
Ultrasound contrast hysterosalpingography : It is now possible to perform an HSG using ultrasonography and an ultrasound contrast medium which contains galactose microparicles(“Echovist”) and is therefore free of the possible risks of radiation.
Caution: Both Sonosalpingogram and hysterosalpingography should not be performed in the presence of active pelvic infection. These investigations are contraindicated in the presence of adnexal masses.
Advanntages of hysterosalpingography:
It gives a permanent pictorial record of the findings.
Tubal pathologies like hydrosalpinx and beaded tubes can be seen more specifically
Uterine pathologies like unicornuate uterus, septate uterus/bicornuate uterus,T-shaped uterus, etc, are better delineated on hysterosalpingogram.
In the presence of air bubbles, intrauterine adhesions cannot be diagnosed conclusively.
Advantages of Sonosalpingogram: Since most infertility clinics have an ultrasound machine in their clinic, with just an addition of facilities to detect tubal patency, tubal patency test can be done immediately with the evaluation of infertility.
Additional findings like fibroids, uterine polyps,etc can be diagnosed more accurately on sonosalpingogram.
1.. In hydrosalpinx, tubal flow may give a false impression of tubal patency.
2..Expertise in ultrasonography has a higher learning curve compared to HSG
- Spill of fluid has to be detected immediately, while the liquid flows out. However, the site of the block cannot be pinpointed, as cornual, fimbrial, etc. This can affect planning of management. Cornual blocks are better managed hysteroscopically, while fimbrial blocks or midtubal blocks due to external adhesions need laparoscopic management.
4.. Findings of the fluid coming out of the tube may be subjective and objective reports cannot be given.
Laparoscopy and hysteroscopy: Laparoscopy is not done as an initial investigative tool, unless there are obvious stigmata of endometriosis clinically. Hysteroscopy should always accompany laparoscopy for infertility, as many findings like incidental polyps can be detected on hysteroscopy. Laparoscopy can ascertain tubal patency, presence of adhesions or endometriosis which can alter the tubo-ovarian anatomy. Peri-hepatic adhesions, pathognomonic of chlamydial infection, should be looked for in all laparoscopies for infertility. Laparoscopy is usually resorted to after many failed cycles of treatment of infertility. Laparoscopy should always be done in centres where operative corrections are possible in cases where there are detrimental anatomical factors for infertility.
Cervical factor of infertility and Immune factor of infertility
Cervical receptivity was tested by doing the post coital test, where live sperms were quantified in the cervical mucus after intercourse. However, this test is no longer performed.
Presence of antisperm antibodies in the serum of the infertile couple and in the cervical mucus also used to be looked for, but the utility of this test is currently being questioned.
Initial evaluation of the male:
The simplest evaluation in male infertility is the semen evaluation. Semen should be collected after two days abstinence into a wide bore container and preferably examined within half an hour of collection. If the semen parameters are abnormal, the male should be examined to see if the testes are of normal size and for the presence of varicocoele. Grossly big varicocoeles should undergo surgical correction. If the count is very low and if the hair growth on the face is low there could be Klinefelter-s syndrome. Estimation of serum FSH and Testosterone could be helpful in planning treatment in patients with very low counts.
A semen analysis report contains macroscopic and microscopic evaluation. Macroscopic evaluation includes an assessment of semen color, volume, and viscosity.
Colour-Normal semen has a pearly, opalescent colour. Blood tinged or purulent semen is abnormal.
Volume: The mean normal volume suggests incomplete sample collection. But if repeated semen analyses shows low volume, it is abnormal. If it is less than 0.5ml,and there are no sperms in the ejaculate, one must think in terms of retrograde ejaculation and examine the urine for sperms immediately after ejaculation. If the volume is low and the ejaculate contains sperms, a post coital test should be done to see if adequate sperms reach the cervical mucus. If not, the couple may benefit from intrauterine insemination with husband-s sperms.
Viscosity and liquefaction: Many laboratories in rural areas do not evaluate this parameter at all. If the woman does not liquefy within half an hour on standing, even with a good count, the couple may not achieve conception.
Sperm density: Sperm density should be 20 million or more sperm per milliliter. Normally 40% or more sperms are motile. Azoospermia is defined as absence of spermatozoa in the ejaculate. The ananlysis should be repeated twice to confirm the diagnosis. Motility is a more important parameter of sperm function compared to count.
Abnormal forms should be less than 40% .
Presence of pus-cells could be indicative of prostatitis and may need prolonged antibiotic therapy.
Treatment of male infertility:
General advice:Men with oligospermia should be advised to abstain from alcohol and smoking as both have deleterious effects on spermatogenesis. Heat can have a detrimental effect and sitting hot baths and wearing tight-fitting underpants and trousers should be avoided. Diabetes, chronic renal failure or thyrotoxicosis should be looked for and treated. As simple an acute illness as a streptococcal sore throat requiring penicillin can result in a temporary azoospermia. It is therefore important to note any such illness in the past 3 months when reviewing the results of semen analyses.
Frequency of intercourse: The concentration of motile sperm in sequential ejaculates decreases in normospermic men. But men with oligozoospermia or asthenozoospermia appear to benefit from sequential ejaculations and they should be advised to have intercourse at least daily, if not twice daily, around the time of ovulation rather than follow the usual advice given to normospermic men of alternate day intercourse.
Pus-cells in the semen should be treated with doxycyclin(100mg/day)_ or ciprofloxacin (500mg/day) for 4-6 weeks. If the condition recurs in 3 months-s time,long-term antibiotic therapy may be tried until a pregnancy has been achieved.
Low motility:Low doses of oral androgens,e.g. fluoxymesterone,10mg twice a week for at least 6 weeks, may be helpful in some cases. The improvement usually last for several months and treatment may be repeated. Injections of hCG(5000IU once or twice a week) have also been used to enhance motility.
Low count: In men with hypogonadotropic hypogonadism as proved by low or low normal range of FSH<LH and Testosterone values will benefit from gonadotropin therapy. Treatment with either hCG alone(In the dose mentioned above) or hMG one amp.IM on alternate days for 45 injections combined with hCG will benefit the patient.
The effect of Clomiphene citrate (in the dose of 25mg/day for 3 months) in idiopathic oligoasthenospermia is controversial. A Cochrane review has mentioned that the endocrine parameters may be improved with Clomiphene,but the reviewers are not convinced about it-s effect in improving pregnancy rates. Other studies have found it to be quite useful. Testosterone administration may be ineffective and may be contraceptive.
Use of anti-oxidants: Reactive oxygen species are highly reactive oxidising agents belonging to the class of free radicals. Excessive production of ROS in semen can overwhelm the antioxidant defense mechanisms of spermatozoa and seminal plasma causing oxidative stress. Antioxidants are a broad group of compounds that destroy free radicals in the body, thereby protecting against oxidative damage to cells.
- Zinc in the dose of 66 mg along with folic acid 5mg per day, was shown to increase sperm count in a randomised controlled study. Biological zinc administratio was shown to improve sperm count in patients with chronic prostatitis in another study.
2.Scott et al concluded in a double blind placebo controlled study that men with placebo controlled study that men with low sperm motility could improve their sperm motility with selenium in the dose of 100umg/day or selenium with vitaminA 1mg, with vitamin C 10mg with vitamin D 15mg for 3 months.
3.Carnitine: :L-Carnitine and acetyl-L carnitine are highly concentrated in the epididymis and play a crucial role in sperm metabolism and maturation. They are related to sperm motility and have antioxidant properties. Carnitine enhances sperm energy production and therefore, motility. In a multicentre study of 100 patients treated with 3 gma carnitine for 4 months significant improvement in sperm motility was reported by Lewin et al, particularly in patients with idiopathic asthenospermis.
4.Con-enzyme Q10: Balercia et al used Co-enzyme Q10 in the dose of 200mg twice daily for 6 months in patients with sperm count >20mill/ml with forward motility <50% with good results. Other than this, there are not many clinical reports on this antioxidant. In India, many pharmaceutical companies market this drug in the dose of 30-50 mg/day for asthenospermia. We still do not know if it is of any use, especially in this dose.
5.Glutathione: Injectable Glutathione 600mg IM on alternate days for a period of 2 months in a study by Lenzi et al resulted in significant improvements in overall motility, progressive motility , velocity, linearity and amplitude of lateral head displacement. Oral Glutathione is of limited value in male infertility.
- Lycopene: Gupta and Kumar treated 30 infertile men with 4 mg lycopene for 3 months and found a significant improvement in sperm counts and motility with no significant changes in sperm morphology. A 20% pregnancy rate was seen during the course of the study.
Surgical treatment:If a varicocoele is present, it may be ligated. The effect of varicocoel ligation on fertility has been controversial. But if the semen parametres are abnormal and the female factors are either not there or corrected, it is reasonable to get this abnormality corrected, as the presence of varicocele is often associated with a decline in spermatogenesis and testosterone production and elevation in serum FSH concentration.
Treatment of female infertility
The five cardinal causes of female infertility, viz: ovulatory dysfunction, tubal blocks, cervical factors , endometriosis and immunological infertility should be evaluated and treated. Usually, a patient comes with multiple causes and each cause should be evaluated and treated. Quite often, the clinician falls into the pitfall of trying to treat one cause of infertility, and forgetting other factors which may be co-existing. For example, if a woman has irregular periods, caused by ovulatory dysfunction, the onus of treatment my be in trying to treat anovulation and co-existing vaginal infections or tubal blocks may get overlooked. Thus, it is necessary to try and look at each factor every time the patient visits the doctor.
The commonest factor for female infertility is irregular ovulation and quite often, empiric treatment to correct ovulatory dysfunction is given by the doctor, without any evidence of impaired ovulation. Management of anovulation is given in the section named anovulation and the readed is directed to read it there
Evaluation and treatment of tubal infertility:
The old method of diagnosing tubal block was to do a tube testing where air is injected into the uterine cavity. Patency is confirmed by hearing a gurgling sound in the lower abdomen as heard through a stethescope.This has been found to be an inaccurate method, but is still practised in many centres in India, where patients cannot afford any costlier methods.
Hysterosalpingogram; A radio opaque dye is injected into the uterus and an X-ray taken.The uterus,tube and spillage of dye into the abdomen can be seen. Anatomical abnormalities of the uterus can be evaluated along with any blocks in the tubes. The procedure can be painful. The author sometimes does it under I-V Ketamine in the operation theatre under C-Arm control, but the films are not as clear as the routine HSG.
Sonosalpingogram: Under sonographic control, saline is forced into the uterus through a foley-s bulb and the spillage of fluid in the pouch of Douglas evaluated. Additional information like fibroid uterus can be picked up, but the tube cannot be delineated properly.
Laparoscopy: Ringer lactate with or without the dye methylene blue is injected into the uterus and the spillage of dye into the abdomen noted. There is the added advantage of the chance for evaluating the entire pelvis and correcting any adhesions or endometriotic patches. The disadvantage is the necessity for anaesthesia and the increased cost in private set up.
Many types of intrauterine catheters have come iin the market for the release of proximal tubal obstruction. Using cannulae and guide wires, proximal tubal block can be negotiated under sonographic control, fluoroscopic control or through the hysteroscope. The patient should be aggressively managed to achieve a pregnancy soon after as many of the blocks removed in this fashion tends to recur after some time.
Fimbrial blocks can usually be removed laparoscopically. For patients with totally blocked tubes, IVF-ET may be the only recourse.
Laparoscopy in infertility: Indications:
In the 1980-s there was a tendency to post all infertile patients for routine laparoscopy. However, considering the low yield of positive findings when such an approach is taken, and the morbidity involved in anesthesia, we do not routinely advocate laparoscopy for all infertile patients. If the patient gives history of congestive dysmenorrhoea and there is nodularity in the pouch of Douglas, she probable is suffering from external endometriosis. In such cases, laparoscopic evaluation should not be delayed and should be done as soon as the patient presents herself to the clinician. For patients in whom uterus appears normal on pelvic examination, laparoscopy could be delayed for a few cycles. For patients with polycystic ovarian disease, where treatment with clomiphene citrate has failed, before going in for treatment with gonadotropins, laparoscopic ovarian drilling would be a better option. It is not only cost effective, but also gives an opportunity to evaluate the rest of the pelvis. If medical treatment of infertility does not yield results after five or six months laparoscopic evaluation should be done as it will detect asymptotic adhesions and endometriotic patches. In patients undergoing artificial insemination with donor-s semen (AID) if there is no pregnancy after 3-4 attempts a laparoscopic assessment should be done before trying further inseminations.
Cervical factor of infertility:
Cervical factors account for about 10% of the cases of female infertility. Cervical factor can be detected by a post-coital test. Postcoital test or PCT should be done in the preovulatory phase of the cycle. The couple should abstain from intercourse for 2 days prior to the test, since it takes 48 hours to replete sperm reserves. It could be done between 1-12 hours after intercourse. A normal PCT is defined as good quality cervical mucus and 10 or more progressively motile sperm per hpf. The mucus component should also be evaluated. Cervical mucus acts like a ladder on which the sperm climbs up to reach the uterus It is usually clear, mucoid and copious in midcycle . Lack of adequate cervical mucus or hostility in the cervical mucus can lead to infertility.
When the quality of mucus is poor, the cause could be infection. Infection with Chlamydia trachomatis can be detected with cervical mucus cultures. In India, where health care is not insured, the usual practice is to give empiric therapy with Doxycyclin 100mg daily for 7 days in suspected cases. Besides chlamydia other agents, which could cause vaginitis and secondary cervicitis, should be sought for and treated. There could be vagainal mycosis, Trichomoniasis, or gardnerella vaginitis.These should be treated apporopriately as mentioned in the chapter on leucorrhoea. If the culture is negative, or if empiric therapy with antibiotics fail, there could be either estrogen deficiency or to failure of endocervical cells to respond to normal levels of estrogen. Empiric therapy with Estrogen (Ethinyl estradiol, 0.01mg per day on days 6 to 9,increased to 0.02mg per day on days 10-13 of a 28 day cycle), gonadotropins or cryosurgery for cervicitis
may help. When the PCT is abnormal inspite of good quality mucus, an immulogic cause should be sought for. When medical therapy fails, intra uterine insemination is the next option.
An abnormal postcoital test with scant cervical mucus, a poor cervical score, cervical stenosis or an endocervix that is friable and bleeds in response to gentle manipulation may indicate cervical factor with an anatomical basis.
When cervical stenosis is suspected, one can try passing a 2-4mm dilator through the cervical os. If it does not pass or passes with difficulty, a true stenosis should be dagnosed. Application of estrogen vaginal cream (Refer to chapter on menopause) twice daily for 3-4 weeks may soften the stenotic cervix and allow the small dilator to pass. Such patients are difficult to treat and may need intrauterine insemination.
When the cervix appears friable and causes bleeding on passing a dilator. Cervical varicosities should be suspected. Cryosurgery of the cervix may help.
Intra Uterine Insemination is one of the simplest procedures among the procedures called the Artificial reproductive technologies or ART. Semen is washed with special media and centrifuged. The motile sperms from the sample is separated and introduced into the uterine cavity along with a little (0.3-0.6ml) media using special intrauterine cannulae. The common indications are cervical factor infertility & male infertility. But it can be performed in any woman with patent tubes, where all other factors of infertility have been treated and she has what can be termed intractable infertility. The ovaries are usually hyperstimulated with clomiphene citrate and gonadotropins to produce a lot of follicles. The ovulation is monitored using ultrasonography on alternate days and insemination is done on the day previous to the day of expected ovulation. Ovulation is timed by giving HCG injections on the day the follicle reaches the size of 18mm on ultrasonography.Ovulation is expected to occur 36 hors later. Pregnancy rates can vary from 16% to 25% and varies from centre to centre. It is high in cervical factor infertility (50%) and low in male factor infertility where husband-s sperms are used for infertility. Patients expect a lot, almost 100% result, when they come for IUI as it is very stressful having to come for serial ultrasonography and to collect semen in an alien atmosphere. Patients should be told that even a newly married couple who are fertile take 3 or 4 months to conceive and even though one makes sure that ovulation, tubal factor, and cervical factor have been taken care of , there still may be failures at the point where the sperm enters the ovum or at implantation.
IVF-ET is In Vitro Fertilisation and Embryo Transfer. The gametes (ovum and sperm) are taken out of the body and fertilisation done outside the body in vitro. The fertilised embryo is transferred into the uterus. The chance of pregnancy is about 30% in larger units. This procedure was started for patients with blocked tubes, but now the indications have widened to almost all cases of infertility where conventional treatments have failed. The cost of therapy is about Rs.50, 000 to Rs.75, 000 per cycle.
The full forms and short details of modern ART procedures are listed below:
ICSI: Intracytoplasmic sperm injection: In IVF-ET the sperms and ova are incubated together in a petridish and the sperms are expected to penetrate the ova by themselves. As against this, in ICSI, a single sperm is taken into a micropipette and injected directly into the ovum. With this procedure fertilisation rates are higher. It has another advantage that not only men with profound oligospermia(low count) or asthenoteratospermia (low motility with increased number of abnormal forms), but also those with obstructive azoospermia, after microsurgical or direct aspiration of sperm from either the epididymis or testis can be benefitted. Sperms need to be alive, but need not be motile for this procedure.
TESA: Testicular Sperm Aspiration:Sperms are directly taken from the seminiferous tubules and ICSI performed.
PESA: Per Epididymal Sperm Aspiration. Sperms are aspirated from the epididymis and ISCI performed.
Ovum donation: Oocyte donation can be used to treat women with premature ovarian failure of whatever cause and those who do not wish to use their oocytes for genetic reasons. The ovum from a donor is inseminated with the sperm of the patient-s husband and the resultant embryo introduced into the uterus of the infertile woman. As the embryo might genetically be the donor mother-s recently another procedure has been developed. Here the ovum of the infertile woman is taken and the cytoplasm replaced with that of the donor ovum.
Blastocyst transfer:It was found that a lot of failures in ART procedures occurred at the implantation stage, because at the time that the embryo was transferred (In the 4 cell stage) the endometrium was not adequately prepared. Hence, the embryo is grown to reach the blastocyst stage before it is transferred into the uterus.
Preimplantation diagnosis: In women with repeated pregnancy losses, the embryo is developed in vitro. One of the cells is aspirated and chromosomal study performed to see if the embryo is genetically normal. Embryo transfer is done only if the embryo is normal.