Dr Mandakini Parihar
Past Chairperson, Family Welfare Committee, FOGSI
Past President, NMOGS
Vice President Elect, FOGSI (2012)
Email : email@example.com
Ovulation Induction – Back to Basics
“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.
Table 4: monitoring on CC cycles
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.
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