DIAGNOSIS AND TREATMENT OF UNEXPLAINED INFERTILITY.
Friday, 04 February 2011

 

Infertility is generally defined as the inability to conceive after 1 year of regular unprotected intercourse.

The infertility evaluation is usually initiated after 1 year of trying to conceive, but in couples with advanced female age (> 35 years), most practitioners initiate diagnostic evaluation after an inability to conceive for 6 months.

 

Unexplained infertility is diagnosed when all the standard elements of infertility evaluation yield normal results.

 

Thus, at a minimum the diagnosis of unexplained infertility implies-

A normal semen analysis.

An objective evidence of ovulation.

·          A normal uterine cavity.

·         Bilateral tubal patency.

The incidence of unexplained infertility ranges from 15 % to 30 % of the infertile couples.

Basic infertility evaluation for diagnosis of unexplained infertility:-

Evaluation should be offered to all couples who have failed to conceive after a year or more of unprotected intercourse. But sometimes, regardless of duration of infertility, immediate evaluation should be offered as in following cases-

 - Woman older than 35 years of age.

 - Woman with irregular or infrequent menses.

- Woman with a history of pelvic infection or endometriosis.

- Men with known or suspected poor semen quality.

The evaluation of infertility focuses on the couple and not on one or the other partner, regardless of past reproductive performance.

The reproductive process is obviously complex. However for purpose of evaluation it can be effectively broken down into its most important & basic component parts as follows –

(1) Male factor - Sperms must be deposited at or near the cervix, at or near the time of ovulation, ascend into the fallopian tubes & have the capacity to fertilize the oocyte.

(2)Ovarian factor - Ovulation of a mature oocyte must occur , ideally on a regular , predictable cyclic basis.

(3) Cervical factor - Cervix must capture, filter, nurture & release sperms into the uterus & fallopian tubes.

(4)Tubal factor - Fallopian tubes must capture ovulated ova & effectively transport sperms & the embryo.

(5) Uterine factor - the uterus must be receptive to embryo implantation & capable of supporting subsequent normal growth & development of foetus.

(1)     

The Male Infertility evaluation:-     

Male factor infertility is the only cause of infertility in approximately 30 % of couples & a contributory factor in another 20% to 30%. Evaluation of the male partner should include history, physical examination & semen analysis.

History should include important elements like, prior paternity, history of cryptorchidism, medical & surgical history, sexual dysfunction, history of consumption of any medication, tobacco, alcohol or illicit drugs and history of exposure of environmental toxins & heat.

 Local physical examination should be done so as to diagnose any penile or testicular abnormalities, varicocele & absence of vas deferens.

If semen analysis is abnormal, it should be repeated after at least 1 month. The laboratory should follow the WHO guidelines regarding the reference ranges for the sperm concentration, morphology & motility in a semen sample.

 

The WHO criteria for a normal semen analysis are as given below.

Criteria

Parameters

Volume

2.0 – 5.0 ml

pH

> 7.2

Liquefaction time

Within 60 minutes

Sperm concentration

> 20 million/ml

Total Sperm Count

>40 million/ejaculate

Motility

>50% or

>25% progressive forward motility

Morphology

>50% with normal morphology

(Kruger “strict” criteria)

Viability

>75% live

White Blood cells ( Round Cells)

<1 million/ml

 

The probability of male infertility increases with the number of major semen parameters (The sperm concentration , motility & morphology ) in the sub fertile range.

The probability is 2-3 times higher when any one is abnormal & 16 times higher when all three are abnormal. 

If any abnormality is repeatedly detected on a semen analysis then the patient should be referred to an andrologist or an urologist. 

 

The Female Infertility evaluation:-  

 

Any evaluation of infertility begins with a careful history & physical examination. This will help us to identify any symptom or signs that suggest a specific cause & help to focus  evaluation on a particular factor that would be most likely responsible for infertility.

History should include a detailed menstrual history regarding cycle length & characteristics & severity of dysmenorrhoea & previous pregnancy outcomes. Sexual dysfunction & coital frequency should be enquired about. Past medical or surgical history, any episodes of PID or STDs should be asked. Symptoms of thyroid disease, galactorrhoea or hirsuitism suggest endocrinal abnormalities. 

It is very important to examine the weight & calculate the BMI for the female partner.

Any signs of thyroid enlargement, breast secretions or androgen excess should be looked for.

A through abdomino-pelvic examination should be done for evidence of pelvic or abdominal tenderness, organ enlargement, mass, vaginal or cervical abnormalities & any mass or tenderness or nodularity in the adnexa .

Irregular menses indicate ovulatory dysfunction. Previous history of treatment for CIN with evidence of cervicitis & cervical stenosis suggests cervical factor.

Menorrhagia with uterine enlargement suggests uterine factors.

Worsening dysmenorrohea with findings of nodularity in cul de sac suggest endometriosis , whereas a history of pelvic infection , septic abortion , ruptured appendix , ectopic pregnancy, myomectomy or adnexal surgery , raises suspicion of  tubal disease.

 

Screening tests:-

 

Some investigations that should be performed as screening test before starting any treatment of infertility are as follows: Blood group Rh factor, Complete haemogram, Screening for sexually transmitted infection like HIV syphilis & hepatitis B, Plasma glucose level, & Pap smear screening.   

Major cause of female infertility is ovulatory dysfunction ( 40% )  & tubal &  

Pelvic pathology ( 40% ) , uterine & cervical pathology is generally uncommon ( 10%)

The standard infertility evaluation includes the following investigations –

·         A follicular phase transvaginal ultrasound.

·         Assessment of ovulation.

·         Hysterosalpingogram  
    & sometimes –

·         Tests for ovarian reserve

·         Laparoscopy    

 

Transvaginal Sonography:-  

 

Trans vaginal ultrasound evaluation in the follicular phase is used to identify uterine fibroid , polyp & congenital cavitary anomalies such as septate uterus. At the same time ovarian volume & antral follicle counts can be obtained as a test for assessment of ovarian reserve 

Sonohysterography , an office procedure which involves assessment of uterine cavity with concurrent instillation of sterile water for diagnosis  of condition like uterine polyp, submucous fibroid, Ashermans syndrome ( intrauterine synechiae ).  

 

Assessment of ovulation:-

 

Ovulatory dysfunction is present in 40% of infertile woman & 15% of infertile couples. Ovulatory dysfunction usually manifests itself in menstrual disturbances. Hence a patient with menstrual abnormality should be investigated for underlying cause such as polycystic ovaries, thyroid disease, hyperprolactinemia & hypothalamic causes secondary to weight changes. Other methods used to evaluate ovulation include Basal Body Temperature (BBT) recording, urinary Luteinizing Hormone (LH) by ovulation predictor kits, mid luteal serum progesterone testing  & Transvaginal ultrasound.

           BBT recordings  are based on the thermogenic properties of progesterone. The body temperature rises by about 0.5 degree centigrade after ovulation. The day before temperature rise is the day of ovulation.

          Ovulation predictor kits  measure  the urinary LH levels. It has to be done on a daily basis & is useful to women who do not have long menstrual cycles. They can be used by couples to appropriately time intercourse as the LH surge is followed by ovulation within 14 -26 hrs.

           Mid luteal progesterone levels are measured around day-21 in women with 28 day cycles or 7 days before the expected date of menstruation. Serum progesterone more than 3mg/ml suggest that ovulation has occurred.

            A Transvaginal ultrasound examination before & after ovulation can record a large developing dominant follicle  which disappears following ovulation. Small amount of fluid in Pouch of Douglas & identification  of corpus luteum is also considered as an evidence of ovulation. 

 

Assessment of Ovarian Reserve:-

 

Ovarian Reserve” describes the size & quality of the remaining ovarian follicular pool.

Ovarian reserve testing is strongly justified for the women with any of the following characteristics:

- Age older than 35.

- Unexplained infertility (regardless of age)

- Family history of early menopause.

- Previous ovarian surgery (Cystectomy, drilling, Chemotherapy, Radiation).

- Smoking.

- Demonstrated poor response to exogenous gonadotropin stimulation.

Ovarian reserve can be tested by following methods:

1) Serum FSH levels on cycle day 3 of above 10-15-IU/ml are considered as abnormal. But it should be repeated in 2-3cycles if results are normal especially in older women.

2 ) A higher cycle day 3 oestradiol concentration ( greater than 80 pg/ml ) also predicts low fecundability.

3 ) Clomiphene citrate challenge test. This is a more sensitive test.Serum FSH levels on cycle day 3 & cycle day 10 after treatment with clomiphene citrate100mg/day on cycle days 5-9.In women with a normal day 3 FSH level, a high day 10 value has a poor prognosis.

4 ) Antimullerian Hormone (AMH) levels.

5 ) Antral follicle count – Ovarian volume & early follicular phase  (cycle day 3) antral follicle count reflects the size of resting follicular pool.

Unexplained infertility may be because of premature decline of ovarian reserve.

 

Hysterosalpingography(HSG):- (for Assessment of intrauterine contour & tubal patency)

 

An HSG consists of radiographic evaluation of uterine cavity & fallopian tubes after injection  of  a radio opaque medium trough the cervical canal. HSG accurately defines the size & shape of uterine cavity & yields clear images of uterine malformations like unicornuate uterus, septate or bicornuate uterus. However, regarding tubal patency, false negative results are common & patent fallopian tubes on  HSG do not confirm that ovum pick up will occur,eg.women with severe endometriosis may have adherent ovaries in the cul de sac with normal fallopian  tubes.

It is also reliable for diagnosis of submucous myomas & intrauterine adhesions  

 

Hysteroscopy with laparoscopy:- 

 

Hysteroscopy & laparoscopy are definitive methods for diagnosis & treatment of intrauterine & pelvic pathology Direct visualization of pelvic reproductive anatomy can be done under magnification, so as to identify  otherwise unrecognized  factors that influence  fertility such as septate uterus, small endometrial polyps, intra uterine adhesions, endometriosis, pelvic adhesions & other tubal pathologies. Laparoscopy permits evaluation of tubal patency by chromopertubation. Surgical corrections of the above pathologies can be done simultaneously.

Laparoscopy should be performed in women with unexplained infertility, especially in those with signs & symptoms of endometriosis & in those in whom reversible adhesive tubal disease is suspected.  

 

TREATMENT OF UNEXPLAINED INFERTILITY:-

 

Unexplained infertility represents the lower extreme of the normal distribution of reproductive efficiency of the sperm or oocyte function, fertilization, implantation or pre embryo development that cannot be reliably detected by standard methods of evaluation.

The average cycle fecundity observed in untreated women with unexplained infertility is about 2-4 % as compare to normal fertile couple ( 20-25%). Also the likelihood of treatment independent pregnancy decrease progressively with increasing age of the female partner & increasing duration of infertility. Although many couples with unexplained infertility may conceive without treatment, their low & declining cycle fecundity provides ample justification for offering treatment to those who are concerned to consult the physician. The goal of treatment is to increase the monthly fecundity.

All treatments to unexplained infertility are empirical & designed so as to increase the gametes density, bringing together more than the usual number to eggs & sperms in a timely way.

The basic principles for treatment of unexplained infertility are as follows:-

 (1) Counseling & reassurance  (2) Lifestyle changes (3) Ovarian stimulation & superovulation (4) Intrauterine insemination or In Vitro Fertilization as the last report.

(1)Counseling:-  It is the prime responsibility of the clinicians caring for the fertile couple to provide accurate information & to dispel any misinformation regarding the ongoing process of evaluation & treatment. They should provide emotional support to the couple as severe anxieties can have adverse effects on ovulatory function & coital frequency. The couple’s medical , emotional & financial needs & concerns should be effectively addressed in a timely fashion.

(1)     Lifestyle changes:-  Abnormalities of hypothalamic  GnRH & pituitary gonadotropins secretion are relatively common in overweight (BMI >25), obese ( BMI> 30) & underweight (BMI < 17) women. Therefore the female partner should be counseled to achieve normal BMI.

There is mounting evidence that fertility is lower in both men & women who smoke or consume tobacco ,alcohol or drugs like marijuana & cocaine. Consequently it is prudent to discourage or restrict smoking  & consumption of tobacco , alcohol & drugs. Caffeine intake should also be restricted to no more than 250 mg/day ie. 2 cups of coffee as it delays conception & increases the risk of pregnancy loss.

(2)     Ovarian stimulation & superovulation:- Over the past decade , there has been a marked increase in the use of controlled ovarian hyperstimulation (COH) in unexplained infertility. The rationale for COH  even in women with evidence of normal ovulation is that subtle ovulatory defects missed by standard testing may be overcome & that an increased number of eggs available for fertilization may increase the likelihood of pregnancy.

Ovarian stimulation can be achieved by use of clomiphene citrate, aromatase inhibitors like letrozole & exogenous gonadotrophins. Various treatment protocols have been used with varying results.

(3)     Intrauterine insemination:- Intrauterine insemination involves the placement of washed sperms into the uterine cavity around the time of ovulation. IUI with ovulation induction increase the rate of conception. Gonadotropin therapy is superior to clomiphene citrate especially when combined with IUI.

However there is some evidence that COH+IUI cycles should be restricted to 3-6 cycles prior to the considering the treatment with IVF.

(4)      In Vitro Fertilization(IVF) with or without Intra Cytoplasmic Sperm Injection (ICSI):- It is the most expensive , but also the most successful treatment for unexplained infertility when the less costly treatment modalities have failed. It may be the preferred treatment for some & the treatment of last resort for others.

       Ultimately, the clinicians taking care of the infertile couple should plan an optimal treatment strategy based on individual patient characteristics such as age, efficacy of different treatment modalities, side effect profile such as multiple pregnancy & cost considerations & the couples choice of treatment after they have been gives a thorough information about the different treatment options.