When the first IVF baby, Louise Brown, was born in 1978, in- vitro Fertilization (IVF) was still an experimental technique. She was born in a natural cycle IVF of a woman who had bilateral tubal block making IVF the only option for having a child. Prior to this, there was no hope for patients with tubal factor infertility of ever achieving their own child. The results with tubal reconstructive surgery were unsatisfactory and had a high incidence of ectopic pregnancies. The last 3 decades has seen astounding progress in the field of ART. Today, thanks to advances in modern medicine, infertility treatment has become almost a routine procedure. With the advent of better quality ovulation induction drugs and increasing availability and accessibility of Assisted Reproductive Technologies (ART), there have been more than one and a half million babies born with the help of ART. The happiness this has brought to families all over the world is incalculable. Today thanks to ART, tubal disease and tubal factor infertility is easily overcome. The aim of this review is to highlight the importance of identifying hydrosalpinges and its association with reduced fertility outcome using assisted reproductive technologies. The ultimate aim in ART is to improve the take home baby rate and dealing with hydrosalpinx prior to ART is important. The literature review is by the MEDLINE (1966 to November 2008), the Cochrane Library databases, and journal search, for the different options available for the same, and highlights the current modes of treatment.
Hydrosalpinx and ART Outcome
The accepted theory today is that the hydrosalpinx fluid plays a causative role in the reduced pregnancy rate with ART. It is well known that the success of ART for patients with tubal disease with hydrosalpinx is reduced by half compared with patients without hydrosalpinx. During the past decade, the influence of the presence of hydrosalpinx on IVF success rates has been an issue of debate and research. Many retrospective studies have shown an impaired outcome of IVF in the presence of hydrosalpinx and the meta-analyses has demonstrated that the probability of achieving a pregnancy in the presence of hydrosalpinx is reduced by half and even if pregnancy is achieved the incidence of spontaneous abortion is doubled. 1, 2, 3 Hence any surgical intervention blocking the communication between the tube and the uterus would remove the leakage of the hydrosalpinx fluid and restore pregnancy rates. Ideal would be removal of a hydrosalpinx by laparoscopic salpingectomy to improve pregnancy rates. 4, 5, 6 However in some cases this is not feasible due to dense pelvic adhesions making access difficult. In such cases it is recommended that even de-linking the tube from the uterus would help in improving the ART outcome.7
The results of prospective randomized studies on salpingectomy in patients with hydrosalpinges are now forthcoming and greatly assist the debate on whether or not IVF will benefit from salpingectomy. In the study by Strandell et al 5 the diagnosis of hydrosalpinx was made by a previous hysterosalpingography (HSG) or diagnostic laparoscopy, at which time reconstructive surgery had been rejected. The patients were divided into groups, IVF after Salpingectomy and IVF cycle without removing the hydrosalpinges. The authors reported on the outcome of the first IVF cycle and concluded that salpingectomy can be recommended for patients with hydrosalpinges, especially those enlarged enough to be visible on ultrasound and in particular for those affected bilaterally.5 These studies have resulted in the Cochrane library recommendation of Salpingectomy for hydrosalpinges.8.9 While there is clinical evidence supporting the causative role of the fluid itself, there is a lack of knowledge as to how the fluid exerts its negative effects. It is generally believed that the fluid holds a key position in impairing implantation potential.
Sonographically visible Hydrosalpinx - is it a new clinical entity?
The hydrosalpinx that is visible on transvaginal sonography is proposed as a new clinical entity by de Wit et al in 1998 10, although the diagnostic and pathophysiological features of this subgroup are poorly defined. However, transvaginal ultrasound prior to HSG /laparoscopy identifies 34% of the patients with a hydrosalpinx. This means that many of hydrosalpinges present may be missed if one relies on ultrasound alone. 11 It also said, those patients with ultrasonographically visible hydrosalpinx had a poorer outcome if not removed. These also tended to enlarge more during ovarian stimulation. The mechanism of enlargement of hydrosalpinges during ovarian stimulation is unknown.12 In experimental conditions, distal occlusion results in a very slow distension of the mechanically induced hydrosalpinx, taking >12 weeks, while the combination of a distal and proximal block results in a significant distension within 2 weeks. It can be speculated that uterine junctional zone contractions play a fundamental role in the movements of both uterine and tubal fluids. 13,14 The altered fluid movements caused by junctional zone contractions during ovarian stimulation in the presence of a thin-walled hydrosalpinx could be responsible for an adverse effect, e.g. by acting as a mechanical barrier to embryo implantation 12,14,15,16
Is there a role of salpingoscopy in selecting cases for tubal surgery?
The question to address is how the patients that are most suitable for functional surgery can be selected?
The studies of Dechaud et al, 17, Strandell et al18 indicated that the removal of thick-walled hydrosalpinges as well as the ones which are sonographically visible. Also, always remember that the sonographically visible hydrosalpinx is likely to be a thin-walled hydrosalpinx. Thick-walled hydrosalpinges with a mean diameter of 1–2 cm, a wall thickness of 2–10 mm and a frequently obliterated lumen are not likely to distend during ovarian stimulation and are, or become, visible at ultrasound. 19, 20
Vasquez et al, 21. 22 in a prospective study concluded that the mucosal adhesions are the most important factor in determining fertility outcome. Their study with thin-walled hydrosalpinges showed that in the presence of normal or flattened mucosa but no mucosal adhesions there was a 58% pregnancy rate and a low risk of tubal pregnancy. However, thin-walled hydrosalpinges with mucosal adhesions had a high rate of tubal pregnancy, and thick-walled hydrosalpinges with fibrosis of the wall are incompatible with a normal pregnancy. 20,21,22
However, tubal endoscopy has not yet gained widespread clinical acceptance23. Several studies on hydrosalpinges have shown that when salpingoscopy can exclude the presence of mucosal adhesions it thereby identifies the subgroup with a >50% intra-uterine and a <5% tubal pregnancy rate following reconstructive surgery 24,25,26,27,28,29. Functional surgery is, therefore, indicated in patients with thin-walled hydrosalpinges with minimal or no mucosal adhesions. It is, however, unclear whether these patients represent the same subgroup as the patients with sonographically visible hydrosalpinx.
Many retrospective studies have shown that hydrosalpinx is associated with poor IVF outcome. 3,4,15,30,31,32 Recent data suggest that patients with hydrosalpinx constitute a heterogeneous population with potentially different outcomes. 20,32,33 It would be valuable to identify a subset of patients who would benefit most from elective salpingectomy. The area of major concern is whether or not there is an impact on ovarian function. Many studies have reported that there is no effect on ovarian repsonse3,4,20,34, some mention equivocal response 32,33,35,36 and some show that there is definite decrease in ovarian response due to affection of the blood supply during salpingectomy37 The role of hydrosalpinx aspiration at oocyte retrieval still awaits evaluation in a well designed prospective trial. 38,39,40
Constituents of Hydrosalpinx fluid15
Epidermal growth factor (EGF)
Tumor necrosis factor- (TNF-)
Why is there reduced fertility with hydrosalpinx?
The answer to this will be evident only when we understand the possible mechanisms causing embryo-toxicity. As yet there are no clearly defined reasons. However there have been a variety of cause-effect postulations by different authors. The hydrosalpinx fluid is suggested to act on two different target systems: directly on the transferred embryos or on the endometrium and its receptivity for implantation, or both. There are many theories postulated but none actually proven. We mention them all in brief here as it is not possible to discuss them all at length. 3,4,6,7,9,13,14,15,31,32,33
In spite of so much research and so many theories, there is no single explanation over period of decades. The evidence clearly points to an adverse effect in the presence of hydrosalpinx and these are due to:
Questions regarding the mechanism of toxicity of hydrosalpinx fluid that are still unanswered
Hydrosalpinx is a common cause of female infertility. Lower implantation and pregnancy rates have been reported in women with hydrosalpinges. How hydrosalpinx exerts its negative effect on the implantation process is not clearly understood. It is intriguing that there is an effective treatment (salpingectomy) for its management but we don't know how and why it works. It is not only of academic interest to know, it is also of clinical value. In women who are identified to have hydrosalpinges during controlled ovarian stimulation during IVF, aspiration of hydrosalpinges during oocyte collection may be effective in improving pregnancy rates. Laparoscopic surgery has a place in the diagnosis and management of hydrosalpinx. Further randomized trials are required to assess other surgical treatment options for hydrosalpinx, such as laparoscopic salpingostomy, laparoscopic or hysteroscopic tubal occlusion, and drainage of hydrosalpinx before or during oocyte retrieval.49,50
Mifepristone and Antiprogesterone - Its usefulness in Obstetric & Gynaecology
Antiprogesterone compounds can antagonize the biological action of the progesterone or inhibit its synthesis as it has high affinity to progesterone receptors. It sensitises the uterus to prostaglandins and therefore most useful as safe and effective method of medical termination of early pregnancy. Besides, it is used for ripening the cervix prior to first trimester as well as second trimester termination and even prior to induction of labour. It is now shown to be useful and effective postcoital agent for contraception and also as a contraceptive by preventing implantation or by inhibiting ovulation. The drug has high affinity to progesterone receptors and also binds to glucocorticoid receptors and to a lesser extent to androgen receptors. Besides, its action on myometrial and endometrial decidual cells promises its usefulness in management of endometriosis and fibromyoma. The success rate of oral Mifepristone and Misoprostol for first trimester termination is about 95%. Pre treatment by Mifepristone prior to second trimester abortion with prostaglandins reduces the induction abortion interval to about 6 hours. It increases the myometrial responsiveness to prostaglandins and oxytocin and also induces cervical ripening when induction of labour is indicated. Cabrol et al (1985) have used Mifepristone for induction of labour successfully. 54.5% of patients in Frydman's series had onset of labour compared to 18.2% who received placebo. The author has used this drug since about 2 decades for first and second trimester termination as well as induction of labour with great satisfaction. It is most important to use the proper dose and timely use of Misoprostol or appropriate prostaglandins in correct dose and route. In author's experience, the success rate in first trimester has been 95.6% (780 cases) and in second trimester 97%. Pre treatment with Mifepristone reduced the induction abortion interval from 17 hours to 6.4 hours. Home use of Misoprostol has been tried at FPA centres and Larsen & Toubro Health Centre with success rate of 89% and 94% respectively. Sublingual vaginal and oral routes were compared at Larsen &Toubro Health Centre with equal success.
Mifepristone in Leiolyoma: Mifepristone is observed to decrease fibroid size by 49% after 12 weeks of treatment. The decrease in fibroid volume is similar to that achieved with GnRH agonist therapy and Mifepristone did not reduce the bone density or caused hot flushes etc. Mifepristone administered in a daily dose of 25 or 50 mg, is effective in arresting growth and reducing the volume of uterine leiomyomas with marked alleviation of pain. Randomised study was carried out with either 5 or 10 mg of Mifepristone daily for 6 months in an open label study. 19 of 20 subjects taking 5 mg and all 20 subjects taking 10 mg completed all 6 months of the study. Mean uterine volume shrank by 48% (P<001) in the 5 mg group and 49% (P<001) in the 10 mg group – a non significant difference.
Mifepristone in endometriosis: As endometriosis is a common condition with a high prevalence in cases of infertility, its treatment with Mifepristone can be very useful in management of dysmenorrhea , chronic pelvic pain dysparenunia etc. This medical therapy has been shown to be very efficient in reducing pelvic pain as soon as amenorrhea is created and maintained. Regression but not elimination of the endometriotic implants is obtained by medical therapy. Clinical data support the hypothesis that efficacy of medical therapy is largely achieved by preventing cyclic bleeding in the implants. In general, lesions of endometriosis regress by 55% following Mifepristone treatment.
Both these indications need further studies and establishment of proper dosage. Mifepristone against metastatic breast cancer is not satisfactorily effective.
Reports describing Mifepristone treatment for Cushing's syndrome shows amelioration of the undesirable effects of excessive cortisol.
Some studies show objective improvements in 25% of subjects in cases of unrespectable meningiomas.
Although this drug is yet under trial, for some of the above indications, its usefulness in gynecology and obstetrics is well establised.
What is Newborn Screening (NBS) Test?
Newborn Screening (NBS) Test is done on Newborn babies to detect certain Treatable Metabolic disorders. These disorders are caused by the accumulation of chemicals produced naturally in the body to abnormally high levels.
These Disorders are present in the baby since birth and are hence termed as Inborn Errors of Metabolism.
This test is usually performed when your baby is 24-72 hrs old. The aim of this test is to detect the metabolic disorder as soon as possible after birth (NOT POSSIBLE TO DETECT IT BEFORE BIRTH) so as to make available maximum treatment options and thus achieve a healthy future for the child.
Why should a baby do Newborn screening?
Only if we detect the presence of an IEM then can we initiate treatment. And the only way presently to detect the presence of an IEM before the onset of symptoms is by NBS.
If we wait for the symptoms to appear then it may become too late and the child could face its consequences which could be Life threatening in some while others may slow down physical development or cause mental retardation or other problems.
When we do detect the problem what can be done?
Logically there are just two options:-
INCIDENCE OF IEM's (GOA SCREENING PROGRAM)
Over 400,000 babies (or about 1.5%) born in India each year are affected by a metabolic disorder (Inborn Errors of Metabolism (IEM) – An Indian Perspective by Dr. N. B. Kumta) and many of these babies could have lead a normal healthy life if these disorders were detected and treated early. The primary benefit of the screening program is that by identifying and treating disorders before symptoms appear, many affected babies can lead normal healthy lives into adulthood and be productive citizens of the state. NBS is the norm in most Western countries with the United States making it mandatory in all 50 states.
The incidence rate of these disorders in India is virtually unknown but the incidence is believed to be much higher than the world incidence, due to the high levels of consanguinity. In the 'Heal to Heal' Newborn Screening program in Goa under the auspices of the State Government, approximately 1 in every 200 babies is diagnosed with a metabolic disorder. While high, this statistic may well be representative of the true incidence rate for these disorders across India. Since June 2008, Goa state Government has been screening all newborns born in Goa government healthcare facilities for 50+ disorders. In the first 12 months of Goa's 'Heel to Heal' Newborn Screening program we have gained astonishing insight into the incidence of these disorders in India.
1st & 2nd Year Goa Data (103 Cases)
How is the Test Performed?
The only internationally accepted method of NBS is by Dried Blood Spot (DBS). The first step is to make a small prick on your baby's heel (commonly known as a "heelstick"). A few drops of blood from the baby's heel are then placed on a special type of filter paper.
The paper is allowed to dry and is then sent to a newborn screening laboratory where several different tests are performed.
Which Tests are performed?
The list of test that should be performed is based on American College of Medical Genetics (ACMG) criteria:
a. Core Panel or High scoring: Those Disorders that can be well detected and Effective Treatment is available.
b. Secondary Panel or Moderately scoring: Those Disorders that part of the differential diagnosis Core Panel.
c. Not Appropriate or Low scoring: These are those Disorders that require further scientific evidence to be included into the first 2 categories and hence are not intended to be included for newborn screening at this time.
How to get the test done and costs involved.
A Parent/Doctor needs to get in touch with the laboratory that specializes in performing these tests. The laboratory will provide the filter paper on which the blood needs to be collected and sent to the Newborn Screening Laboratory. The approximate cost for screening 51 Disorders is between Rs4500-Rs5,000 in India.
"Real knowledge is to know the extent of one's ignorance." - Confucius
One of the most important causes of female factor infertility is anovulation. Management of ovulatory dysfunction and the ability to induce ovulation with the resultant pregnancy was a big milestone in infertility treatments. The commonest cause of anovulation is polycycstic ovarian disease (PCOS). Polycystic Ovarian Syndrome (PCOS) is a common and heterogeneous disorder of women of reproductive age, characterized by chronic anovulation and hyperandrogenism. Clomiphene Citrate (CC) is the first drug of choice used in management of anovulatory infertility. Unfortunately, despite the high rates of ovulation, pregnancy rates per cycle remain relatively low with the use of CC. An antiestrogenic effect of Clomiphene on the endometrium has been postulated. When CC fails, the only recourse available till now was the use of gonadotropins for the treatment of anovulation.
Mitwally and Casper (2001)1 have shown that the use of CC may be complicated owing to the anti-estrogenic effects on endometrial development. To deal with this, patients are increasingly offered `controlled' ovarian stimulation combined with intrauterine insemination or IVF as 1st line treatment, regardless of the type of infertility (Fauser) 2. This alteration in treatment strategy is not based on sound scientific evidence and is likely to result in substantially higher multiple pregnancy rates and a major increase in overall treatment costs.2 ESHRE Rotterdam Workshop Group, 2003 concluded in their report “ Gonadotropin injections in patients with normogonadotrophic anovulation can be seen as a time-consuming and ineffective treatment modality with high complication rates.”
For these reasons, a simple, inexpensive and safe alternative to CC for use in anovulatory women was required. Mitwally and Casper proposed that aromatase inhibitors would replace CC in the future as the new primary treatment for ovulation induction in PCO patients. Aromatase inhibitors can be used for ovulation induction or ovarian stimulation with higher pregnancy rates compared with CC.
The aim of this chapter is to address the issue of management of anovulatory infertility with using oral ovulogens, Clomiphene citrate and aromatase inhibitors, and present a review of literature by the Medline and journal search, for the different options available for the same, and highlight the current recommendations for the treatment using these oral fertility inducing agents.
Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility.
As there are no well-accepted criteria for diagnosis, the incidence of PCOS is not really known. However, it is postulated to be about 20-30% in the general population. Based of symptomatology incidence varies between 4-5% to 21% (menstrual abnormalities) and 3.5-9% (hyperandrogenism). It is important to remember that, 40% of women with oligomenorrhoea, 84% of women with hirsuitism and 100% of women presenting with severe acne, have PCOS as their etiology. (1,2,3,4,5)
Management of Anovulation
Table 1: Drugs that can be used for anovulation
Note: This chapter is going to discuss Clomiphene Citrate and Aromatase inhibitor, Leterozole. All other drugs are discussed in other parts of this book.
Clomiphene Citrate (CC) was first synthesized in 1956 and has been available for clinical use since 1967. It is structurally similar to estrogen and hence binds competitively with estrogen receptor resulting in its pharmacologic action. CC is a triphenyl chloroethylene derivate in which four hydrogen atoms are substituted by three phenyl rings and 1 chloride anion. It is available as a racemic mixture of trans (62%) & cis (38%) isomers.
Mechanism of Action
Clomiphene does not directly result in ovulation but it reduces ovulation by amplifying the physiological events of a normal ovarian cycle. It is anti-estrogenic & exerts this effect by competitive binding with estrogen receptors. It can be classifies as first generation of SERM's (Selective Estrogen Receptor Modulator) developed and hence the concentration of these receptors is reduced. As a result, there is elimination of the negative-feedback on the Hypothalamic-Pituitary axis. This results in activation of GnRH secretion and the resultant increase in FSH and LH pulses. CC influences FSH secretion over LH. In the presence of baseline estrogen, CC induces FSH stimulation of LH receptors in granulosa cells. This results in growth of the dominant follicle and its subsequent maturation. Occasionally, its antiestrogenic action does result in poor endometrial growth and change in cervical mucus. However, adding a short term estrogen therapy prior to ovulation does not help in improving pregnancy rates. (10,11,12)
It cannot be used in patients who are in WHO Group I as presence of an intact H-P-O axis is essential for CC action. It is reserved for use only in WHO Group II women with anovulation and the commonest cause is PCOS (12,13,14,15)
Table 2: Indications for CC use
Table 3: Pre-requisites before CC Therapy
Recommendations for CC usage
Till date, CC is the most used drug for ovulation induction and timing of ovualtion. It has also been used indiscriminately for many years. However, concerns about possible linkage with later life ovarian cancer, has led the RCOG to issue guidelines to be adhered to and followed. The recent RCOG guidelines along with ACOG recommendations state that CC should be used for a maximum of 12 months in patients lifetime and for a maximum of 6 months continuously. Hence, it is necessary that all cycles with CC be carefully monitored for evidence of ovulation (15,16,17)
Protocol for Starting CC
Therapy is usually started with 50 mg dose per day for 5 days from cycle D2, D3 or D5. If there is no evidence of ovulation, the dose can be increased in increments of 50 mg every month upto a maximum of 250 mg. However, in clinical practice we, do not use doses higher than 150 mg due to its marked antiestrogenic effect.
Monitoring of CC induced cycles
As there is a probable associated link with use of CC for more than 12 months (6,7,8)
and ovarian malignancy in later life, it is necessary that all cycles with CC be monitored.
Results of CC Therapy
70-80% of patients will show evidence of ovulation using CC and hence it still remains the first drug of choice. However, only 40% of these will conceive. There is a 5% multiple pregnancy and development of OHSS though rare can be life threatening condition. (18,19)
There are rarely reported side-effects with CC, but vasomotor flushes, bloating or distension, visual cysts, headache and loss of hair have been reported. Ovarian Hyperstimulation can also result, though extremely rare. (15,18,19)
CC Resistance: (Ovulation Failure)
It is a very commonly used terminology and is defined as “failure to ovulate with 3 months of use at 150mg/day of 5 days”. The commonest cause for this is PCOS, and is seen in about 20% of patients.
CC Failures: (Conception Failure)
There are patients who ovulate but fail to conceive on CC therapy. If a patient has 3 ovulatory cycles with CC and does not conceive then she is labeled as CC failure and should be started on alternative therapy. It needs to rule out CC associated reproductive dysfunction and evaluation of other causes of infertility. This may also due to antiestrogenic effect of CC on cervical mucous and endometrium, but remains to be proven
Role of Adjuvants
There is no evidence today that addition of estrogens, corticosteroids or bromocriptice has any improvement in pregnancy rates and hence empirical use of these agents has now been abandoned.
However, Corticosteroids can be added only in cases where there is an increased DHEAS levels, as this will suggest an increase in the adrenal androgens which is sometimes seen in patients of PCOS. ( 20,21).
In patients with normoprolactinemic anovualtion, but with presence of galactorrhoea can be given Bromocriptine if therapy with CC alone fails. Use of bromocriptine is reserved for hyperprolactinemic anovulation. (22).
Addition of estrogen may help in improving the anti-estrogenic actions of CC but do not improve the pregnancy rates and hence their use is not recommended. ( 23).
The detail discussion of each alternative is outside the purview of this chapter.
The gold standard for improving insulin sensitivity is obese PCOS should be weight loss, by diet and exercise. Weight loss (of as little as 5%of the body weight) alone can improve the fundamental aspects of the endocrine system of PCOS and result in low circulating androgen levels and spontaneous resumption of menses.
Women with PCOS are like desert survivors, who fare better with less than their optimum weight. At least 50% of PCOS are obese. This is characterized by increased opoid activity and beta-endorphin release to stimulate insulin resistance. Leptin (Ob-protein) is secreted in adipose tissues and is protein bound in blood. An increasing BMI co-related with increase incidence of hirsuitism, cycle disturbances and infertility . Obese women (BMI >30kg/m2) should be encouraged to loose weight, as ovulation induction treatments are less effective when BMI is > 28-30kg/ m2. (24,25,26)
Letrozole – An Aromatase Inhibitor in Anovulation
From the studies by Mitwally and Casper(77), it seems to suggest that an effective alternative to CC in the management of PCOS has been found. The use of aromatase inhibitor is based on the same principal of anti-estrogenic environment and hence seems effective. Letrozole is given in the dose of 2.5 –5 mg/day from day 2 or 3 of the cycle for 5 days. It acts by increasing the pituitary secretion of FSH and hence results in the growth of the follicle. There is no blocking of the estrogen receptors and hence there is no adverse action on the cervical mucus and endometrial lining as seen with CC. Hence, it may explain the increased responsiveness to the drug and its effectiveness in CC resistant patients.
Larger double blind studies are required before it will replace CC, but the early results are very encouraging. It has also shown some benefit in poor responders. The advantage is also its shorter half life and hence it does not persist in the circulation in the peri-ovulaotry period unlike CC. The detrimental effects of CC are also see on the endometrium and cervical mucus as it competitively blocks the estrogen receptors. Letrozole on the other hand, is an enzyme modulator and does not block the estrogen receptor and hence a better cervical mucus and endometrial lining.
Rationale for the use of Aromatase Inhibitors in anovulatory women
Pharmacological agents used for ovulation induction, either block estrogen receptors or block estrogen synthesis and hence, release the hypothalamo-pituitary-ovarian (HPO) axis from the negative feedback effect of plasma estrogen, thereby facilitating follicular growth and ovulation. Aromatase is the enzyme responsible for the conversion of androgens to estrogens. Aromatase inhibitors blocks this conversion of androgens to estrogen and results in a relative deficiency of estrogen. This results in increased FSH secretion from the pituitary in the presence of an intact HPO axis.
Aromatase inhibitors like Letrozole have been considered as the next candidate for induction of ovulation. Major clinical studies have reported successful induction of ovulation with Letrozole (1,2,3). The use of Letrozole has been known to induce ovulation in 75-80% women (1,6,7). In addition to this, the use of Letrozole has not been associated with the undesirable effects of Clomiphene citrate. The use of conventional agents like Clomiphene citrate despite a good ovulation induction has been shown to be associated with a low fertility, which is possibly attributed to endometrial thinning. This necessitated a need to look for alternative or better ovulation inducing agents. (6,7)
Mechanism of action
Letrozole is an aromatase inhibitor that acts by blocking the synthesis of estrogen. It releases the HPO axis from estrogenic inhibition, facilitating follicular growth, culminating into ovulation. Aromatase inhibitors like CC increase the endogenous gonadotropin secretion, but unlike clomiphene citrate, they do not result in estrogen receptor depletion. It may also possibly have a local effect by increasing androgen concentration and hence the sensitivity of the ovaries to FSH. It therefore decreases the requirement for gonadotropins without negative effects on peripheral estrogen sensitive tissues.
Though Letrozole is labeled as anticancer drug, its use is not associated with classical adverse effects of an anticancer drug such as bone marrow depression, alopecia, mucosal ulcers and infections. The side effects of Letrozole are generally mild, tolerable and transitory in nature and are explainable on the basis of reduced estrogen levels caused by the drug. Moreover, since this drug is meant to be used for only 5 days in a month for induction of ovulation, the incidence and severity of side effects is anticipated to be much less compared to its use in breast cancer. The other aromatase inhibitor used in clinical practice for anovulatory infertility is Anastrozole.
Comparison of the success rate of Letrozole and Clomiphene citrate
Several authors found combined COH and IUI treatment to be very effective in unexplained and mild male infertility (8,9,10,11). Fischer et al (12) compared the effect of clomiphene citrate and letrozole on normal ovulatory women; profiles of both LH and FSH were similar in natural and medicated cycles with letrozole and CC, but E2 level was more than two times higher in clomiphene-treated cycles. Despite significantly lower E2 levels in letrozole-treated women, endometrial development was unaffected in this study. In a selected population of women with endometrium (mean thickness of 5mm) after clomiphene treatment, letrozole treatment in the early follicular phase resulted in a significant increase in midcycle endometrial thickness (mean of 9 mm) (1, 13).
Al-Fozan et al (14), compared the effect of CC and Letrozole in women undergoing superovulation. There was no difference in pregnancy rates or endometrial thickness between the letrozole and the CC groups in his study. But of interest, is that the miscarriage rate was higher in the CC group. The reason is not clear but is probably due to the different mechanisms of action of Letrozole and CC. Fatemi's (15) research suggests lesser multiple gestation with Letrozole, but more studies on larger numbers of multiple-gestation cases with Letrozole are needed to confirm these findings. Other results showed significantly lower estradiol concentrations in the Letrozole group than in the CC group and more follicles were observed in cycles stimulated with 100 mg CC from day 3 to 7 of the cycle than in the Letrozole group. The estrogen levels in women on aromatase inhibitors were found to be 2-3 times lower than those reported in CC cycles, however, endometrial thickness was greater in the aromatase inhibitor cycles (16,17)
In all studies conducted so far, the aromatase inhibitor Letrozole was administered as a 5-day regimen, usually from day 3 to 7 of the menstrual cycle, at a dose of 2.5- 5 mg/day. Mitwally and Casper proposed that aromatase inhibitors would replace CC in the future as the new primary treatment for ovulation induction in PCO patients (16,17).
Combining Gonadotropins and Aromatase inhibitors
The use of gonadotropins in anovulation has given good results with pregnancy rates varying between 20-60%. A major disadvantage of gonadotropin treatment is the high cost of treatment. In addition, there is a higher risk of multiple pregnancies and OHSS when using gonadotropins. Both of these increase the risk to the patient. To reduce the gonadotropin requirement and risk, combination protocols using CC have been in practice.(18). While these protocols were initially popular (19,20), use of gonadotropins plus Clomiphene citrate has been largely abandoned after reports that Clomiphene citrate negatively affects endometrial thickness , sub-endometrial blood flow , oocyte quality, embryo development , and hence ultimately the pregnancy rates(21,22,23). In the only prospective randomized trial, Ransom et al. (23) showed that the endometrium is significantly thinner in the group where CC was used along with gonadotropins. This was even more marked when the number of preovulatory follicles was similar in the only gonadotropins group and the CC + gonadotropins group. Also noteworthy was the fact that, fewer pregnancies were achieved in patients treated with Clomiphene citrate and gonadotropins. The postulated theory for this negative effect is the estrogen receptor suppression by CC and hence affecting the endometrial maturation as well as cervical mucus.
With the reports about the use of aromatase inhibitors, it was suggested that a specific reversible, nonsteroidal aromatase inhibitor that suppresses estrogen biosynthesis like letrozole or anastrazole, (24), can successfully replace clomiphene citrate in superovulation (1,25). In the study by Healy, letrozole with gonadotropins and was found to be superior than CC plus gonadotropins combination. (26). Similar results were also reported in the studies by Mitwally and Casper. (25)
In another study by Mitwally and Casper, (27) concomitant treatment with letrozole in 12 poor responders increased the number of preovulatory follicles compared with their previous cycles with gonadotropins alone. Surprising is that inspite of low estrodiol levels, the local affects of the potent anti-aromatase effect of letrozole, there is no negative effect on endometrial thickness. It is postulated that this is due to the relatively short half-life of letrozole, which allowed complete endometrial recovery before implantation. There is a definite decrease of gonadotropin requirements in patients treated with letrozole plus gonadotropins compared to gonadotropins alone. (26) Sammour et al, (28) compared letrozole with clomiphene citrate along with gonadotropins for superovulation before IUI and found that although fewer follicles developed, a superior uterine environment was achieved and this resulted in better pregnancy rates in the letrozole group than the CC group.
Outcome of pregnancies achieved with Aromatase inhibitors
One of the concerns with the use of any new agent for fertility treatment is about the potential effects it could have on the off-spring born. There was a concern raised by an abstract submitted for the ASRM meeting though it was never published. The initial fear about the safety of Letrozole has been set aside by the excellent review by Tulandi et al. (29)
There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments. However, it appears that congenital cardiac anomaly is less frequent in the letrozole group. The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on their data. (29).
A concern about the safety of letrozole to the fetus was recently raised in an abstract presentation at the 2005 ASRM meeting (30). The authors reported the outcome of 170 infants of which 20 were lost to follow-up. As a result, 150 babies from 130 pregnancies were compared to a control group of over 36,000 infants born from low risk spontaneously pregnant women in a community hospital. The control population was younger than the letrozole group. A further concern regarding potential law suits was raised by the notice issued to all practicing infertility specialist by Novartis, the makers of Femara® on their website. (31)
In the multicenter study, Tulandi et al (29) obtained complete data from 514 babies of mothers who conceived with letrozole treatment and 397 babies of women who conceived with CC. In the letrozole group, 252 babies were born following the treatment with letrozole alone and another 262 births followed a combination of letrozole and follicle stimulating hormone (FSH) treatment. In the CC group, 293 were born after CC alone and 104 after CC and FSH treatment.
In their study of 911 babies born after infertility treatment, congenital malformations were encountered in 2.4% of newborns in the letrozole group and 4.8% of newborns in the CC group. Major malformations were detected in 1.2% of the babies in the letrozole group and in 3.0% of the babies in the CC group. These rates of major anomalies were not statistically different between the 2 groups, and were similar to the quoted rates of anomalies found in the general population (2–3%) (32,33).
It is suggested Tulandi (29) and others (34) that as the half life of letrozole is approximately 45 hours (range 30–60 hours) it is cleared from the body completely by the time of embryo implantation, as compared to clomiphene citrate which remains in the system due to its longer half life of 5–7 days(34). Letrozole is eliminated as an inactive carbinol metabolite mainly via the kidneys.
Thus, the exposure to the drug predates the critical fetal development period, casting doubt on the biological plausibility of teratogenicity in the use of the drug for ovulation induction.
The mainstay of management of anovulation is to induce regular unifollicular ovulation whilst minimizing risks of OHSS and multiple pregnancies. The first drug of choice is still CC and alternative methods are used only in patients who are CC resistant. Unifollicular ovulation induction requires a subtle approach and this should be the norm especially in PCOS. Increased sensitivity of PCO ovary to exogenous stimulation, puts it at high risk of OHSS. It is hence necessary to achieve follicular maturation in an environment free from high LH, in order to enhance pregnancy outcomes. These lifestyle modifications are the best initial means of improving insulin resistance. In conclusion, increased sensitivity of PCO ovary to exogenous stimulation, puts it at high risk of OHSS. In summary, the different studies seem to confirm the efficacy of aromatase inhibitors in ovulation induction. The results suggest that the aromatase inhibitor, letrozole, may be used as an alternative new first-line treatment for ovulation induction in anovulatory infertile patients.