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:

Female infertility could be due to ovulatory dysfunction, tubal blocks, cervical hostility, immunological factors or tuboperitoneal causes. Each one of these aetiolgies should be investigated one after another, with the least invasive tests being done initially. After preliminary evaluation, ovulation should be assessed by various methods.   Next the tubal factor should be evaluated. If a pelvic examination shows any abnormalities, a laparoscopy should be done to evaluate the pelvis and the peritoneal cavity simultaneously.  If pelvic examination is normal, a hysterosalpingogram could be done.

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.

Medical therapy:

 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. 

1. 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. 

6.  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. 

Intrauterine insemination:

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:

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.

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