Management of Infertility in Females

More than two decades have passed since the birth of Louise Joe Brown in the United Kingdom as a result of the first successful In-Vitro-Fertilization (IVF). Intensive research and innovations in culture techniques, medical and surgical management of infertility have revolutionized the outlook for the infertile couples. Now it is possible to offer treatment to 90% – 95% of couples with success rates varying between 20% – 80% for various modalities of treatment.

Infertility affects men and women of reproductive age worldwide causing considerable personal suffering and disruption of family life. Although estimates of prevalence are not very accurate and also vary from region to region, almost 8% – 10% of couples experience some form of infertility problem during their reproductive lives.

Definition

Infertility is defined as the inability to conceive for at least one year of unprotected intercourse. Treatment may be started early in case of an obvious cause or advanced age of couple. Primary infertility refers to no conception ever in the past while secondary infertility is labeled if there has been a conception irrespective of the outcome of that pregnancy.

Etiology and Diagnosis

Accurate diagnosis is the key to successful treatment. The dictum holds true for infertility as for any other problem in medicine but is often overlooked. At the level of an individual couple, assessment of the cause is often difficult and time consuming. Various factors, which contribute to infertility, can be generally identified following a full and comprehensive investigation of both partners; it is often difficult to attribute infertility to a single factor.

Infection related problems in both males and females are more common in developing countries with poor socio-economic strata. In developed countries and in higher socio-economic groups, major chunk is constituted by ovulatory dysfunction, advanced maternal age, endometriosis and no demonstrable cause.

Distribution of causes between male and female is generally equally divided. The oft quoted rough estimate of causes between partners i.e. 30% female, 30% male, 30% both and the rest idiopathic has generally been vindicated in most of the studies.

There is a well-defined set of investigations to be followed to assess various factors contributing to a couple’s infertility. Detection of one cause does not rule out the presence of other causes since multifactorial infertility is very common. Both partners must be investigated simultaneously and completely, as problem in one partner does not rule out another problem in the other partner. The plan of action must be individualized for every couple after a thorough discussion with the couple. Various factors which influence decision making such as age, duration and type of infertility, likely cause, cost and time involved, social and psychological pressure etc. should be considered.

History and Physical Examination

Complete history taking should includes detailed menstrual and obstetric history, past or present medical problems, surgeries, allergies etc. Duration of cohabitation, sexual problems, sexually transmitted diseases (STD) and any pregnancies from previous cohabitation may not be reported unless specifically asked for. Male partner should be asked for any history of testicular trauma, mumps, operations for mal-descent of testes, sexual problems. Complete general physical examination (GPE) to detect associated diseases such as anemia, hypertension (etc.) should be done. Pelvic examination, quite often is absolutely normal except when some gross pathology such as fibroids, tubo-ovarian masses, active infection etc. may be detected. In males local examination may reveal evidence of local infection or varicocele. Markedly small testes have a clear association with germ cell hypoplasia.

General Investigations

General investigations are done to assess general health status of couples. An infection screen for sexually transmitted diseases (STD) e.g. syphilis, gonorrhoea, chlamydia, Human Immuno deficiency Virus infection (HIV) etc. should be done. Chest X-ray is an integral part of female work up in areas where tuberculosis (TB) is endemic. However in a high percentage of cases of pelvic TB there is no evidence of primary focus on Chest X-ray examination.

Work up of the Male Partner

A detail discussion is not within the scope of this article. Briefly, a routine semen examination after 48 hours of abstinence suffices to screen male partner. In case of abnormal semen parameters, further tests are done to arrive at an etiological diagnosis which include hormone estimation, semen and urine culture, transrectal and scrotal ultrasound and doppler study, aspiration cytology and testicular biopsy.

Work up of the female partner

Endometrial Biopsy (EB): A timed EB in mid or late luteal phase, assessed according to standard criteria has been a gold standard for luteal preparation of endometrium. Proliferative or out of phase endometrium suggests ovulatory dysfunction. TB endometritis can be picked up by histology, acid fast bacilli (AFB) smear and culture for AFB, or polymerase chain reaction (PCR) done on endometrial tissues. In long standing anovulation EB is important to rule out endometrial hyperplasia or carcinoma.

Hormone assay: A routine Thyroid Stimulating Hormone (TSH) and prolactin assay quite frequently pick up sub-clinical hypothyroidism and hyperprolactinaemia respectively. Basal FSH (follicle stimulating hormone) done on day 2 or 3 of the menstrual cycle is an accepted predictor of ovarian sensitivity. Detailed hormonal assessment of LH, FSH, Testosterone, DHEA-S etc. are not usually required for routine infertility patients. Even in cases of oligomenorrhoea/amenorrhoea, who get spontaneous or progesterone induced withdrawal do not need detailed hormonal studies.

Hysterosalpingography (HSG): HSG has stood the test of time as the simple, relatively cost-effective and reliable method of tubal evaluation. Although both positive and negative predictive values are near 70% – 80%, still it is very good screening method.

Ultrasonography (USG): USG has revolutionized and become an indispensable tool in the management of infertility. The advent of high resolution transvaginal scans (TVS) and ease of examination due to close proximity of uterus and ovaries to vagina have made it possible to almost see through these structures. Tumours , inflammatory masses, malformations, endometrial lesions can be diagnosed with much greater accuracy. The convenience, safety and reliability of USG has made it possible to do repeated examinations for a serial study to follow the evolution of developing follicle.

Endoscopic Studies: Without a diagnostic hysteroscopy and laparoscopy, infertility work up remains incomplete especially in long standing cases. A direct visualization of endometrial problem such as polyps, fibroids, septae and adhesions, which otherwise would be missed, is of utmost importance. Similarly, laparoscopy is the only reliable method to diagnose endometriosis, pelvic adhesions, TB and fimbrial phimosis. Advances in endoscopic techniques such as salpingoscopy and mini-laparoscopy will allow us to see ‘more’ with greater safety and reliability.

Treatment Modalities

Infertility treatment in females can be described under three main categories: (a) Medical; (b) Surgical; © Assisted Reproduction techniques (ART).

A. Medical Management

Ovulation induction – The successful therapy of ovulatory disorders is the most dramatic advancement in gynaecological endocrinology. Today if lack of ovulation is the only cause operating in a particular couple, the chances of conception with treatment equals that of normal fertile population. Super-ovulation strategies and ART have improved the rates of success in every normo-ovulatory women.

Clomiphene Citrate (CC) – Clomiphene is an orally active nonsteroidal agent distantly related to diethylstilbestrol. CC is a week estrogen and modifies hypothalamic activity by affecting concentration of intracellular estrogen receptors. CC therapy does not directly stimulate the ovaries but supports a sequence of events that form the physiological features of a natural cycle. In other words, it resets the disturbed hypothalamo-pituitary-ovarian axis in cases of polycystic ovarian disease (PCOD). In contrast, CC acts as an antagonist in uterus, cervix and vagina which may be responsible for many CC failures. Absent or infrequent ovulation is the chief indication for CC therapy. Cases of ovarian failure are unresponsive to any form of ovulation induction. Patients who are more likely to respond to clomiphene are anovulatory women who have normal gonadotrophin and estrogen production but do not cycle and women with inadequate luteal phase. Women who are deficient in gonadotroph ins and are hypoestrogenic can not be expected to respond to CC. In normally cycling women a few cycles of CC treatment may be justified and do improve results in cases of infertility of no demonstrable cause by correcting certain minor ovulatory dysfunctions.

CC is given in 50-100 mg dose starting on 3rd day of a spontaneous or induced withdrawal bleed. The administration of CC early in the cycle favors multiple follicular recruitment and reduces the antiestrogenic effects on uterus. Dose can be increased up to 200-250 mg per day. However, maximum pregnancies are achieved at 50-100 mg dose. Monitoring of cycle with basal body temperature chart, LH kits or USG is highly desirable to evaluate the efficacy of cycles. In properly selected cases, 80% women can be expected to ovulate and approximately 40% become pregnant. Of these, 5% pregnancies may be multiple almost entirely twins. There have been some reports of high order multiple pregnancies and hyper-stimulation. Minor side effects include vasomotor flushes (10%), abdominal distension, bloating, pain, soreness, breast discomfort, nausea, vomiting, visual symptoms, headache, dryness and loss of hair.

CC and dexamethasone (DEX) – Patients with hirsutism and high circulating androgen concentrations are more resistant to CC. DEX 0.5 mg to blunt the night-time peak of ACTH is added to decrease the adrenal and intra-ovarian androgens. Sometimes, dramatic response can be obtained. However, indiscriminate and long term use of this potentially harmful drug should be avoided.

CC and Bromocriptine (BRC) – Elevated prolactin levels interfere with the normal function of the menstrual cycle by suppressing the pulsatile secretion of GnRH. This is manifested clinically by ovulatory dysfunction ranging from subtle ovulatory dysfunction to total suppression of ovarian activity with hypoestrogenic amenorrhoea. Bromocriptine (BRC) is a dopamine antagonist which directly inhibits pituitary secretion of prolactin. It is a highly successful treatment of hyperprolactinaemic anovulation and may be combined with CC or gonadotrophin’s for more resistant cases. Normoprolactinaemic galactorrhoea also responds well to BRC. Normoprolactinaemic anovulatory cycles sometimes respond to addition of BRC. However, results are controversial and extended empirical therapy should be avoided.

Eltroxin (Elt) – Hypothyroidism, even if subclinical, should be treated and monitored to achieve euthyroid state. Empiric use of thyroid extract or eltroxin is of no use.

Metformin – Orally active anti-diabetic agent is the latest addition to adjuvent drugs. It acts by lowering insulin resistance and improved peripheral utilization of glucose. In obese, hirsute women, metformin with diet control may significantly reduce weight and improve results of ovulation induction.

Gonadotrophins – Pituitary gonadotrophins are available as purified preparations extracted from urine of post-menopausal women. Some commercial preparations are listed below:

Recently more pure recombinant preparations prepared through genetic engineering have come in the market. Field trials have confirmed their efficacy.

The main indications of gonadotrophin therapy include CC failures, hypogonadotrophic-hypogonadism and controlled ovarian hyperstimulation (COH) for ART. Treatment with Gonadotrophins is very costly, time consuming and have potential serious side effects. Thus, the case must of selected very carefully after proper evaluation, counseling and complete infertility work up. Treatment should be monitored with serial USG and E2 (estradiol) measurements. Dose and duration of therapy depend on the indication, ovarian sensitivity, and target number of follicles to be recruited. In a patient with anovulation unifollicular ovulation is the aim, but 3-4 follicles are desirable in COH combined with IUI. For IVF, GIFT (gamete intrafallopian transfer) and ICSI (intra cytoplasmic sperm injection) 8-10 follicles give most satisfactory results.

Multiple gestation and hyperstimulation syndrome are the two major complications. These can be reduced to minimum with their judicious use. The most significant aspect of gonadotrophin therapy is that it achieves pregnancy in an otherwise untreatable situation. A 90% anovulation and 50 – 70% pregnancy rate can be expected.

Human Chorionic Gonadotrophin – Human Chorionic Gonadotrophin (hCG) a peptide hormone is naturally secreted exclusively by trophoblast since very early pregnancy. It has a structural and functional similarity with LH. Thus it makes an excellent surrogate for LH to trigger ovulation in CC or HMG induced cycles. When the follicle size is greater than 18 mm along with simultaneous thickening of endometrium to more than 8 mm, hCG 5000-10,000 IU I/M can be given. Ovulation occurs to 36-48 hours after the hCG. Intercourse or IUI or ovum-pick up can be timed accordingly. HCG also supports the corpus luteum when given in doses 1500-2000 IU I/M on day 3, 6, 9 post ovulation.

GnRH analogues – GnRH is an ultra short acting decapeptide secreted by hypothalamus. Long acting analogues have been synthesized. When given for short duration (1-2 days) these have a flare effect on secretion of gonadotrophins from anterior pituitary. If the administration is continuous, complete down regulation of gonadotrophin receptors of anterior pituitary occurs followed by complete suppression of FSH and LH secretion. Addition of these analogues to stimulation protocols in ART cycles have resulted in convenient schedules, low cancellation rates, better quality of oocytes and higher success rates.

Medical Management of Endometriosis – Endometriosis is an enigmatic disease characterized by ectopic endometrial glands and stroma. While infertility is easily understood in moderate and severe endometriosis which may cause structural distortion of tubes, ovaries and pelvic peritoneum. Minimal and mild disease is more frequently detected in infertile females than fertile counterparts, the mechanism of infertility remains elusive. There is no role of medical therapy alone in stage III and IV disease when fertility is the concern. In early disease, a 6 month trial of therapy may be given in young women with short duration of infertility. Success rates in general remain low. All medical methods rely on medical induction of temporary pseudo menopause and hypoestrogenic state. Continuous high dose gestogens, danazole – a testosterone derivative and GnRH-a are the three main options available. All these are costly, poorly tolerated and most importantly, add approximately a year of iatrogenic infertility to the duration of infertility. However, fairly satisfactory palliation of symptoms can be achieved when fertility is not desired.

Medical Management: Treatment of Infections – Pelvic infections, such as chlamydia, gonorrhoea, post-abortal and postpartum infections, pelvic inflammatory disease associated with intrauterine contraceptive devices, lead to permanent structural and functional damage to the fallopian tubes. Resurgence and alarmingly high incidence of TB make it an important cause of intractable infertility. The extent of damage depends on the severity and chronicity. Thus all pelvic infections must be prevented and treated early wherever possible. Medical treatment can only do the microbial clearance. Any structural or functional damage is more likely to be permanent.

B. Surgical Treatment

Dilatation and Curettage (D and C) – D and C may be done for gynaecological indications and primarily have a diagnostic role. Empirical dilatation and curettage, still widely prevalent, does not enhance fertility and should be condemned. Cervical stenosis acquired after previous curettage for abortion sometimes responds dramatically to cervical dilatation.

Cervical cauterization – The role of cervical erosion and chronic cervicitis is ill understood in infertility. However, any infection should be treated. Cryocauterization of cervix is safe and simple and have a minimal risk of cervical stenosis as compared to conization and thermal cautry.

Tuboplasty – Microsurgical tubal recanalization after sterilization operation has success rates of 60% – 70% in experienced hands. For tubal damage due to other causes, tubal reconstructive surgery can be done in selected cases but with a guarded prognosis. Success rates vary between 10% – 30% and there is a high incidence of ectopic pregnancy. Long standing tubal infertility, bipolar disease, tubercular etiology, badly damaged tubes, previous failed tuboplasty and previous laparotomies have very low success rate; IVF is the preferred method in these cases.

Myomectomy – Relationship of myoma to infertility appears coincidental. However when myomas are big, multiple or positioned submucosally, they do cause infertility and/or abortions and need removal. Post myomectomy pregnancy rates are generally low and other causes of infertility must be looked into.

Hysteroscopic Surgery – With advances in instrumentation, techniques and growing experience, hysteroscopic surgery has become an important tool for an infertility specialist. Sub-mucous myomas, intrauterine synachiae, septae and foreign bodies can be successfully removed transcervically without scarring the uterus. It is safe, can be done as a day care procedure and gives very satisfactory results in experienced hands.

Laparoscopic Surgery – Laparoscopic surgery has now become the primary method of surgical treatment in infertility. Treatment at time of diagnostic laparoscopy is the standard. Adhesiolysis, myomectomy, fulgration of endometriotic implants, removal of cysts and tuboplasties can be done very successfully with good results. In endometriosis, surgery remains the primary mode of treatment. Ovarian drilling and cauterization in cases of PCOD cases have also been used. It has reasonable success rate in inducing spontaneous menstruation and pregnancy rate. Besides being a temporary method, it is fraught with dangers of pelvic adhesions and premature ovarian failure.

Reconstructive surgery for uterine malformation – There is no evidence that major uterine malformations cause infertility. These are more likely to cause abortions and preterm labour. Corrective surgery may be undertaken in selected cases of septate and bicornuate uterii. Certain malformations like transverse vaginal septum or unilateral obstructive lesions may interfere with proper coitus, hamper menstrual outflow and thus need correction.

C. Assisted Reproductive techniques (ART)

ART refers to those procedures where gametes (sperm and oocyte) handling is done in-vitro or outside the body. The simplest of these is insemination and the more advanced techniques include IVF, GIFT and ICSI.

Artificial insemination (AI)

AI is done with husband or donor sperm depending upon the indication. Patency of at least one tube is required for this procedure to be successful. A fraction of motile sperms recovered after various methods e.g. density gradient, swim-up or percoll gradient are injected directly into the uterine cavity under aseptic precautions i.e. intrauterine insemination (IUI). IUI is done as close to ovulation (within 12 hours) as possible, judged by basal body temperature (BBT), home LH kits or most reliably, with ultrasound. Combining IUI with controlled ovarian hyper-stimulation (COH) to produce 2-4 follicles improves the results. Main indications include unexplained infertility, cervical factor, psychosexual problems, moderate oligospermia, early endometriosis, immunological infertility and with ovulation induction. COH with IUI have almost 15 ? 20% pregnancy rate per cycle as compared to IUI or COH alone which have success rate of 7 ? 10%. In severe oligospermia results are not as encouraging and the se cases should be better treated by ICSI. Recovery of active sperms less than 5 million/ml is a poor prognosticator. All sperm recovery techniques recover the motile fraction only. There is no way to improve, concentrate or enhance the fertilizing power of a given sample. Pooling of samples to get higher number of sperms does not improve pregnancy rate. Properly timed IUI is a safe, simple and useful technique when used in selected cases. The main risks are infection and cramps if adequate aseptic techniques are not used. In case sperm separation is not possible, intravaginal or intracervical insemination can be done.

Artificial insemination by donor sperm is generally done when the male partner has a cause of infertility which is not amenable to treatment by ICSI, or ICSI is not feasible or has failed. Donors are carefully selected, screened for sexually transmitted or genetic diseases, matched for blood group and other phenotypic characters of the male partner. Success ra te generally varies between 30 ? 40% per cycle with a cumulative pregnancy rate of 70 ? 80% over 3 cycles. Female partner needs thorough evaluation in case of failure or long standing infertility.

IVF – ET (In-Vitro Fertilization – Embryo Transfer)

In vitro fertilization and embryo transfer involves retrieval of oocytes, fertilization in laboratory and transfer of pre-embryos in the uterus after 2-5 days of culture in laboratory.  This includes following steps: Evaluation and selection of cases, Super-ovulation,Ovum retrieval, Embryo transfer, Pregnancy diagnosis and monitoring, Complications

Primary and absolute indication for IVF is bilateral tubal block. Choice between IVF and microsurgery depends upon the condition of tubes and extent of tubal damage, experience and facilities available. In general the balance has tilted in favor of IVF with gradual improvement in results as compared to those of microsurgery. Other indications include infertility of any etiology of long standing duration such as endometriosis, cervical factor, immunological causes, moderate male infertility, multifactorial and unexplained infertility, anovulatory infertility.

A complete infertility work up to assess all the problems is mandatory. The basic pre-requisite for selecting a case is presence of a normal functioning uterus, ability of ovaries to produce enough oocytes and retrieval of more than two million active motile sperms per ejaculate in the male partner. Next step is superovulation or a deliberate controlled induction of multiple follicles in normo or oligo-ovulatory women to recruit around 8-12 follicles. This is achieved by first down regulating the pituitary with GnRH-a and then stimulating with HMG or pure FSH. After at least 4 follicles of > 18 mm diameter are observed on USG, ovulation trigger with hCG is given. Ovum retrieval (OPU) is done transvaginally under ultrasound guided needle aspiration 34-36 hours after hCG. It is a simple procedure and has 60 – 80% oocyte retrieval rate in experienced hands.

The oocytes are incubated with washed spermatozoa and observed for fertilization after 18 and 48 hours for cleavage.

Up to four pre-embryos are transferred transcervically on day two or three after OPU. Currently, there is a trend towards blastocyst culture i.e. till day 5 post pick up and transfer of blastocysts is done. Culture of blastocysts helps in selecting best quality embryos and higher implantation rate. Success rates from 30 ? 50% are being reported. Main complications include a risk of hyperstimulation syndrome and multiple pregnancy. These can be kept to minimum with careful monitoring and planning. Other problems include high cost, time and inconvenience and psychological problems of undergoing long treatment and failure.

Pregnancy once conceived through IVF is like normal intrauterine pregnancy. It can have all other problems which a normally conceived pregnancy may have. There is no evidence of any increased risk of congenital malformations even in long term follow up of off spring.

GIFT (Gamete Intra-fallopian Transfer) – Gamete intra-fallopian transfer is a technique where oocytes after retrieval from the ovaries, either transvaginally or laparoscopically are transferred to the fallopian tube. A success rate of 25% – 30% has been reported. Normal function of fallopian tubes is an essential pre-requisite. Most centres have abandoned GIFT in favor of IVF because of obvious advantages. GIFT is done primarily because of religious beliefs when in-vitro handling of gametes is prohibited.

ICSI (Intra Cytoplasmic Sperm Injection) – Intracytoplasmic sperm injection is the latest technique in the armamentarium of ART specialists. The main indication is severe male factor infertility which include severe oligo-asthenospermia, obstructive azoospermia, maturation arrest (etc). Other indications include repeated IVF failures, idiopathic fertilization failure, immunological infertility or advanced age of female partners.

A single sperm is injected in an oocyte with the help of micromanipulator instead of leaving the oocytes and sperms together in a dish for fertilization. Rest of the procedure and problems are same as for IVF. Success rate comparative to IVF have been obtained with ICSI in those intractable conditions which were not amenable to treatment with IVF.

Ovum and Embryo donation – A gonadal, premature ovarian failure or post-menopausal women with intact functioning uterus can also conceive through this technique. A uterus which responds to exogenous hormones can be prepared for implantation. Oocytes donated by known or unknown donors can be fertilized and embryos transferred in prepared uteri. These pregnancies need exogenous hormonal support for first three months till the placenta takes over. Afterwards these pregnancies behave like all other normal pregnancies.

Cryopreservation – It is possible to cryo-preserve supernumerary embryos and transfer these at a later date. Successful cryo-preservation programmes have improved pregnancy rates per retrieval.

Psychosocial Aspects

The discovery of infertility can provoke a complex psychosocial crisis in either or both members of an infertile couple. The crisis involves an interaction between the physical conditions predisposing to infertility, the medical interventions addressing the problems, social assumptions about parenthood, the reaction of others and individual psychological characters. The process of diagnosing and treating infertility has a profound impact on the lives of affected couples. Education, guidance and counseling of couples go a long way in reducing the stress.

Dr. Umesh N. Jindal

Consultant Gynaecologist,
Gynae and Fertility Research Centre and IVF Clinic,
CMC, Sector 17-C, Chandigarh.

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