Principles and Practice of Controlled Ovarian Stimulation in ART 1st ed.

5. Oral Ovulogens in IUI and IVF

Sankalp Singh Swati Singh1 and C. Mohamed Ashraf1

(1)

Department of Reproductive Medicine, Craft Hospital and Research Center, Chandapura, Kodungallur, Thrissur, Kerala, 680664, India

Sankalp Singh

Email: sankalp489@gmail.com

Abstract

Oral ovulogens constitute the most commonly used intervention in a subfertile couple. They have the advantage over the gonadotropins of being of lower cost, safer and easy to administer. The main ovulogens utilized are clomiphene, letrozole and metformin. Trials have failed to show any conclusive advantage of clomiphene and letrozole over one another in women with anovulatory PCOS. Ovulation rates with both are in range of 70–80 % and pregnancy rate per cycle around 20–25 %. Clomiphene also constitutes an important place in mild stimulation for IVF since it possesses properties to prevent premature LH surge. Major problems with clomiphene are the negative effects on endometrium and cervical mucus which can be resistant and repetitive necessitating alternative therapies. Letrozole also has been used sparingly in IVF with reasonable success. Its further usage is marred by unfounded fears about foetal anomalies based on a flawed study leading to the drug getting prohibited in many countries. Metformin constituted the standard of care for PCOS not too long ago. Now, enough evidence exists to render it useful only in very small subsets of women, including mainly the ones with glucose intolerance and sometimes in obese and clomiphene-resistant cases. Also, the adverse effect profile of metformin does not augur well for it. Further research might open more gates in this important aspect of care with advent of safer and more efficacious alternatives including orally active gonadotropins.

Keywords

OvulogensAnovulationClomipheneLetrozoleMetformin

5.1 Introduction

The number of couples with subfertility is on a steep rise even with the most conservative estimates. Be it male factor, tubal factor, endometriosis or PCOS, the rise is pretty much eminent with few expected geographic variations in the aetiology. This has brought ovulation-inducing medicines, especially oral ovulogens, into the forefront as a first-line therapy in many of these cases.

The main group catered with oral ovulogens is undoubtedly of that with anovulation. It affects approximately 21 % of the subfertile population.

There are three classes of anovulatory subfertility as per WHO [1]:

·               WHO 1: hypogonadotropic hypoestrogenic (10 %)

·               WHO 2: normogonadotropic normoestrogenic (80 %, majority being PCOS)

·               WHO 3: hypergonadotropic hypoestrogenic (10 %)

The oral ovulogens have a role primarily in WHO 2 anovulation, while the WHO 1 and 3 have to be targeted with injectables as discussed elsewhere.

5.2 Definition of Ovulation Induction (OI) and Controlled Ovarian Stimulation (COS)

In the strict sense of the term, OI refers to the triggering of ovulation.

In the clinical context, it refers to the type of ovarian stimulation for anovulatory women aimed at restoring normal fertility by generating normo-ovulatory (mono-ovulatory) cycles.

COS for IUI aims to induce development of two to three follicles in order to improve chances for conception.

OI is primarily aimed at women where the cause of subfertility is anovulation or male factor, while COS is for those with unexplained subfertility where the aim is to increase the number of gametes available for fertilization.

5.3 Physiology of COS

5.3.1 FSH Threshold

FSH level starts rising during the luteo-follicular transition in a woman with regular menstrual cycles. This kick-starts growth of the antral follicles once the FSH level rises above the threshold level. The threshold level differs for different follicles as it is dependent on the sensitivity of the follicles to FSH which in turn is dependent upon the number of FSH receptors in a given follicle. This is termed as FSH threshold concept.

5.3.2 FSH Window

The duration of the time for which FSH remains above this critical threshold determines the number of dominant follicles selected from the recruited cohort for preferential growth. This is known as FSH window, during which the follicles whose threshold is crossed keep on getting recruited for growth. Longer the window remains open, greater the number of follicles recruited for growth.

All the ovulogens, whether oral or injectable, work on this principle. They push the FSH above the threshold and keep the window open for a longer amount of time allowing the follicles to get recruited. In a normal cycle, as the follicle grows, the increase in oestradiol and inhibin from the growing follicle reduces the FSH level through the negative feedback on hypothalamus and pituitary leading to a fall in FSH secretion. The fall of FSH below the threshold then closes the FSH window and causes the atresia of the follicles other than the dominant follicle.

5.4 Couple Evaluation Before Administering Ovulation-Inducing Medicines

It is mandatory to do a complete evaluation of the couple before OI/COS to increase its effectiveness and to reduce the risks. This should include a semen analysis along with physical examination for the male and an ultrasound to check the ovarian reserve apart from physical examination for the female. Underlying pathologies like thyroid and prolactin disorders, diabetes, hyperandrogenism, overweight and obesity should be screened and corrected before embarking for OI/COS.

5.5 Monotoring of an OI/COS and IUI Cycle

A baseline ultrasound should be done to rule out any ovarian or uterine pathology (Fig. 5.1). The first cycle should be monitored with ultrasound to note the number of growing follicles more than 12 mm in size, endometrial thickness, cervical mucous thickness and confirmation of ovulation (see Fig. 5.1). Patients with more than two growing follicles should be counselled for risk of multiple pregnancy and mild hyperstimulation. These patients should be given lower dose of medicine in the next cycle. Patients with less than 7 mm endometrium and thin layer of cervical mucous need oestrogen supplementation and, if possible, dose reduction in next cycle. Although majority of patients with CC (47.2 %) have endometrium of more than 9 mm but approximately 10 % patients have ET less than 6 mm2 [2].

A319836_1_En_5_Fig1_HTML.gif

Fig. 5.1

Standard plan of OI and follicular monitoring in first cycle

5.6 Classes of Oral Ovulogens (Table 5.1)

Table 5.1

Oral ovulogens: mechanism, dosage, success, and adverse effects

Ovulogen

MOA

Dosage

Ovulation rate

Pregnancy rate per cycle

Adverse effects

Clomiphene

Antiestrogen

50–100 mg/day

70–80 %

22 %

Hot flushes

Antiestrogenic effects on endometrium and cervical mucus

Tamoxiphene

Antiestrogen

10–40 mg/day

Nearly same as CC

Nearly same as CC

Hot flushes

Letrozole

Aromatase inhibitor

2.5–5 mg/day

70–80 %

20–27 %

Hot flushes, leg cramps and gastrointestinal disturbances

Metformin

Insulin sensitizer

1.5–2 g/day

   

G.I upset

Lactic acidosis

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3.

5.6.1 Clomiphene

Clomiphene is the oldest and most commonly used oral ovulogen. It still has a place in ovulation induction and is now also being used in minimal stimulation protocols in IVF. These are nonsteroidal triphenylethylene derivative which acts as selective estrogen receptor modulators(SERM), thus having both estrogen agonist and antagonistic actions [3].

5.6.1.1 Relevant Pharmacology and Mechanism of Action (MOA)

Oral dose is absorbed fast. Serum levels of zuclomiphene peak 6 h after oral intake. It is metabolized in liver and excreted in intestine. Final serum levels of zu- and enclomiphene are determined by its metabolism and weight of the women. It is generally agreed that enclomiphene is the more potent is omer and it is rapidly cleared from serum, making it theoreticlly more appealing as an ovulogen [4]. Females with higher BMI have larger plasma volume and thus have lower serum levels of clomiphene. Both isomers have long half-life. Serum half-life of zuclomiphene is 14.2–33.4 days and enclomiphene about 2.5–11.8 days [5].

Even after discontinuation of the drug, 50 % of dose can be detected in serum after 5 days, and its metabolites can be found up to 6 weeks. Zuclomiphene tends to accumulate over consecutive cycles with 50 % rise in serum level in next cycle [6].

Clomiphene acts as a competitive antagonist to 17 ß oestradiol at the level of nuclear receptor complex as the binding of clomiphene to the oestrogen receptor is more prolonged than oestrogen [7], which results in a pseudo-hypo-oestrogenic state. However, in hypo-oestrogenic condition clomiphene may show oestrogen agonistic action. Its primary site of action is hypothalamus as an oestrogen antagonist and secondarily at pituitary as a weak agonist, increasing the sensitivity of pituitary to GnRH. Serum LH levels start rising 2–3 days after admnistration by its direct action on pituitary [8].

Anovulatory PCOS patients have high GnRH pulse frequency. In these patients CC increases gonadotropin secretion by increasing GnRH pulse amplitude [9], while in ovulatory patients with normal GnRH pulse it acts by increasing pulse frequency [10]. It causes moderate rise in gonadotropin levels. In anovulatory patients gonadotropins rise by 50 % [7]. LH surge usually occurs 5–12 days after last clomiphene tablet.

5.6.1.2 Dosage and Effectiveness

CC can be started any day from cycle day 2 to 5 [11]. One study has reported lower ovulation rates when CC was started immediately after spontaneous or induced bleed [12].

Usual starting dose is 50 mg/day for 5 days in women less than 50 kg, while in women with weight more than 75 kg,100 mg/day can be started. Approximately 46–52 % patients ovulate with 50 mg/day, 21–22 % ovulate with 100 mg/day and 8–12 % will need 150 mg/day [13]. Dose higher than 100 mg/day is not approved by US FDA. Patients hypersensitive to CC can be started with 25 mg/day. Doses higher than 150 mg/day are not used due to high LH level and anti-oestrogenic action. Approximately 15–20 % anovulatory patients do not ovulate with these doses [14].

Lower ovulation rates are seen in women with higher BMI, higher free androgen index, insulin resistance and large ovarian volume [15]. There is no reliable predictor of ovarian response to CC [1617]. Failure to ovulate with CC for 6 months is termed as clomiphene resistance. An overall cumulative pregnancy rate of 55–73 % is seen in patients treated with CC [18]. Despite high ovulation rates, PR is low, and this is due to anti-oestrogenic action of CC on endometrium causing several dysfunctions and making cervical mucus thick and hostile for sperm penetration [1921].

Lower pregnancy rates are seen in older women, hyperandrogenic PCOS with severe cycle disorder [22] and obese women. The landmark study by Legro et al. reported 28 % LBR in women with less than 30 kg/m2 BMI vs. 16 % LBR in women with more than 35 kg/m [23].

Up to 71–87.5 % of pregnancies occur in first three cycles. The cumulative PR among anovulatory patients who ovulate with CC 50 mg/day, 100 mg/day and 150 mg/day for 3 months are 50 %, 45 % and 33 %, respectively, and further at 6 months are 62 %, 66 % and 38 %, respectively [18]. Since most of the pregnancies occur in first three to six cycles, treatment beyond six cycles is not recommended. Failure to conceive despite ovulation with clomiphene citrate is termed as CC failure.

Miscarriage Rate

There is 23 % miscarriage rate in CC conceptions probably due to hypersecretion of LH causing early resumption of meiosis. In an analysis of CC conceived patients,75 % patients who aborted had LH more than 10 IU/L as compared to 37 % in ongoing pregnancy group [24].

Multiple Pregnancy

As CC can result in multifollicular growth, the rate of multiple pregnancy is 6–8 % in anovulatory patients and 2.6–7.4 % in unexplained infertility patients [25], with majority being twins. Rarely it results in triplet (1 %), quadruplet (0.3 %) or quintuplet pregnancy (0.1 %) in all CC-induced pregnancies.

In a meta-analysis of 11,599 IUI cycles, during monofollicular growth the absolute pregnancy rate was 8.4 with 0.3 % multiple pregnancy, while after multifollicular growth the absolute pregnancy rate was 15 % with 2.8 % multiple PR. The pooled OR for multiple pregnancies after two follicles was 1.7 (99 % CI 0.8–3.6) and increased significantly for three and four follicles (2.8 and 2.3, respectively) [26].

5.6.1.3 Clomiphene and IUI

CC is the most common protocol for IUI and results in 5–7 % pregnancy rate per cycle even after seven cycles [27]. Prior to using IVF, IUI with clomiphene ovarian stimulation is relatively cheap, and many couples will conceive and not require IVF [28].

Anovulatory patients do not need IUI [29], unless cervical or male factor is abnormal. However, for patients with unexplained infertility, CC with IUI is superior to expectant management. But CC without IUI is not superior to expectant management. A recent Cochrane review found that CC was not superior to expectant management or placebo for live birth (odds ratio [OR] 0.79, 95 % CI 0.45–1.38; p = 0.41) or for clinical pregnancy per woman randomized both with intrauterine insemination (IUI) (OR 2.40, 95 % CI 0.70–8.19; p = 0.16), without IUI (OR 1.03, 95 % CI 0.64–1.66; p = 0.91) and without IUI but using human chorionic gonadotropin (hCG) (OR 1.66, 95 % CI 0.56–4.80; p = 0.35) [30].

LH surge monitoring or ovulation trigger is needed to time IUI. Traditionally, ovulation trigger is usually given with urinary hCG 5,000 IU s/c once the follicle reaches 18 mm and IUI performed 36 h post trigger or after ovulation is detected on ultrasound. A recent study challenged this practice and showed that ovulation trigger at follicular diameter of 24 mm was associated with thicker endometrial thickness (9 mm) and higher probability of pregnancy [31].

5.6.1.4 Clomiphene in IVF

The recent interest in mild/minimal stimulation and low-cost IVF has made CC an important weapon in the arsenal of a reproductive medicine practioner. It is started from day 2–3 of periods and can be either given for 5 days as in OI with addition of antagonist taking care of premature LH surge or till a day prior to trigger injection. The latter, apart from follicular growth, helps prevent premature LH surge due to its antagonistic action on the oestrogen receptor in the hypothalamus strongly inhibiting the positive feedback of the rising oestradiol level [32].

The largest study done till date has been of 43,433 cycles from Japan. CC was started from day 3 at 50 mg/day and was continued until the day before maturation trigger. If the ultrasound on day 8 suggested good number of follicles growing, 150 units of HMG or FSH were added. Emergency oocyte retrieval due to the premature LH surge was required in 3.5 % of cases. The ovulation rate was between 2 and 3 % confirming the efficacy of CC in preventing premature LH surge. The oocyte retrieval rate and embryo cleavage rate were 83 and 64 % respectively. The live birth rate in the study was 11.1 % [33].

A recent meta-analysis exploring the efficacy of CC-antagonist protocol vs. the conventional non-CC protocol evaluated seven trials with total of 702 women. There was no significant difference in the parameters of live birth (p = 0.26), clinical pregnancy (p = 0.12) and number of oocytes retrieved. Importantly, significant reduction in OHSS (1/216 = 0.5 % vs. 9/217 = 4.1 %, p = 0.01), consumption of gonadotropins and duration of COH were seen [34].

In our centre, we have been using the continuous CC protocol by starting CC on day 2 till the day prior to trigger. We add FSH 75–150 IU from day 4 of CC to recruit more follicles. Of 440 cycles with this protocol, the clinical pregnancy rate per started cycle is 29.8 % (unpublished data).

5.6.1.5 Unconventional Regimens for CC Resistance (Fig. 5.2)

A319836_1_En_5_Fig2_HTML.gif

Fig. 5.2

Action plan of OI with clomiphene resistance in PCOS. OCP Oral contraceptive pill, LOD Laparoscopic ovarian drilling

In case there is clomiphene resistance, the woman can be put on extended regimes with clomiphene. However, adverse effects of clomiphene on the endometrium must be kept in mind.

Extended Clomiphene

CC given for more than 5 days can achieve acceptable ovulation rate. In an RCT of women with CC resistance, hMG 75 IU from day 3–7 was compared with extended CC group, which was given 100 mg CC from day 2 to 9. The gonadotropin group had significantly higher ovulation rates (57.6 versus 28.1 %; p < 0.001) and pregnancy rates (20.2 % vs. 11.4; p = 0.03) when compared to extended CC [35].

Stair Step Protocol

In this protocol CC 50 mg for 5 days is given. If there is no dominant follicle (DF) on cycle day 14 (i.e. DF more than 11 mm), patients are given CC 100 mg for 5 days followed by repeat scan starting on day 19. If still there is no DF on day 23, then cycle was cancelled. This regimen acheives ovulation faster without the need to induce withdrawal bleed between treatment cycles, while the control group underwent stimulation with 100 mg in the next cycle after withdrawal bleed. When comparing the outcome, the ovulation rates/cycle were 43.3 % vs. 33.3 %, cycle cancellation rates were 50 % vs. 56.6, clinical pregnancy rates/cycle were 16.7 % vs. 10 % and endometrial thicknesses on hCG day (mm) were 8.3 ± 2.1 mm vs. 9.3 ± 2.4 mm in stair step vs. control group [36].

5.6.1.6 Side Effects

Side effects are mostly caused due to pesudo-hypo-oestrogenic environment. About 64–78 % women complained of mood swings, while 10 % women complained of hot flushes during the course of medication. Breast tenderness, nausea and pelvic discomfort are noted in 2–5 % women. Visual disturbances in the form of blurring of vision, scotoma, diplopia and light sensitivity are rare (<2 %). Visual symptoms are usually reversible but warrant discontinuation of further treatment with CC. Some clinicians suggest lower dose in next cycle. Optic neuropathy is very rare. Mild OHSS is found in 13 % patients, but severe OHSS is rare [37].

5.6.1.7 Contraindication

As clomiphene is metabolized in liver, it is contraindicated in patients with chronic liver disease. Functional ovarian cysts may become larger with clomiphene. History of blurring of vision or scotoma with use of clomiphene contradicts its use. Although it does not increase the risk of congenital anomalies [38], still it should be avoided during pregnancy. There is no cause/effect relationship between any OI agent and invasive ovarian neoplasia even when used for more than 12 months [39].

5.7 Alternatives/Adjuncts to Clomiphene in Case of Resistance or Failure

In case of clomiphene resistance or failure, there are other oral alternatives and adjuncts to clomiphene like tamoxifen, aromatase inhibitors, insulin sensitizers and dexamethasone. Before going on to other alternatives if the woman is overweight she must be asked to lose weight as her response to ovulation improves with weight loss. Besides oral alternatives gonadotropins can be tried. Gonadotropins are either overlapped with clomiphene or given as a sequential regime. In case of a PCOS woman laparoscopic ovarian drilling may be performed to improve response to clomiphene.

5.7.1 Clomiphene vs. Tamoxiphen

Tamoxiphen is also a SERM with anti-oestrogenic action at hypothalamus but oestrogenic action at endometrium and vagina, while its action on cervical mucosa is controversial. It is given 20–60 mg/day for 5 days. A meta-analysis comparing CC and tamoxiphen found similar results [odds ratio (OR) 0.755, 95 % confidence interval (CI) 0.513–1.111]. Despite theoretical superiority of tamoxiphen pregnancy rates per cycle (OR 1.056, 95 % CI 0.583–1.912) or per ovulatory cycle (OR 1.162, 95 % CI 0.632–2.134) were not significantly different although there was a trend towards higher PR per ovulatory cycle with tamoxiphen [40].

5.7.2 Clomiphene with Dexamethasone

Dexamethasone reduces circulating DHEAS, testosterone and LH levels. Additionally, it may act directly on pituitary to suppress the action of oestradiol [41] (Table 5.2). It may also act directly on follicles or indirectly through GH or IGF −1. In a prospective, double-blind, placebo-controlled, randomized study of 230 CC-resistant PCOS women with normal DHEAS level, addition of 2 mg dexametasone from day 5 to 14 of period increased both the ovulation rate from 20 to 88 % and pregnancy rate from 4.2 to 40.5 % [42].

Table 5.2

Putative actions of dexamethasone

Increases endometrial thickness

Increasing serum GH

Increasing serum IGF-1

Affecting LH activity and ovarian steroidogenesis

Elevation in serum FSH levels by direct action on pituitary

Inhibiting adrenal androgens secretion

5.7.3 Aromatase Inhibitors (AIs)

AIs are highly potent and highly selective inhibitors of aromatase enzyme. It has been more than half a century since AIs entered the market. However, the first two generations were associated with significant adverse effects. Things have improved immensely since the introduction of third generation of AIs including letrozole and anastrozole. Though these medicines were primarily introduced for women with oestrogen-dependent malignancies, especially breast cancer [43], their usage for ovulation induction have opened a new avenue of research. The two molecules widely researched include letrozole and anastrozole with more focus on the former.

The first reported use for infertility treatment in anovulatory women was in 2001 in women who failed to ovulate with clomiphene citrate. They were given 2.5 mg of letrozole on days 3–7 of the menstrual cycle. With letrozole use, 9 out of 12 women ovulated and 25 % became pregnant [44].

5.7.3.1 Relevant Pharmacolgy and Mechanism of Action (MOA)

Letrozole is discussed in detail as it is the most researched of the aromatase group. Letrozole is 100 % bioavailable following oral administration and has a terminal half-life of around 45 h.

The rate-limiting step in oestrogen synthesis is the conversion of androgens (androstenedione and testosterone) into oestrogens (oestrone and oestradiol, respectively) and is catalyzed by aromatase or oestrogen synthetase enzyme.

Aromatase is a microsomal cytochrome P450 hemoprotein-containing enzyme (a product of the CYP19 gene). This enzyme is expressed in various tissues in the human body including ovaries, uterus, brain, breast and adipose tissues. Aromatase inhibitors selectively target the aromatase enzyme, which is the last in the cascade of steroidogenesis, thus depleting the oestrogen levels in target tissues.

Due to the presence of the aromatase enzyme in brain as well as ovaries, it is likely that the fertility effects of AIs are the result of dual actions at central and peripheral levels.

At the central level, lowered circulating oestrogens as a result of blocked oestrogen synthesis in brain and other tissues would release the hypothalamus and/or pituitary from the oestrogen-negative feedback on the production and release of gonadotropins. This action differs immensely from that of clomiphene, as there is no depletion of oestrogen receptors. This leads to an increase in gonadotropin secretion, which stimulates the growth of the ovarian follicles. It also increases the level of activins, which further stimulates synthesis of FSH by a direct action on the gonadotropes [45].

At the peripheral level, aromatase inhibition leads to temporary accumulation of intraovarian androgens since the conversion of the androgen to oestrogens is blocked by inhibition of the aromatase enzyme. This can lead to an increase in responsiveness of the ovarian follicle to FSH as a result of either a direct action of testosterone on the augmentation of FSH receptor expression [46] or indirectly by increasing the IGF-1 levels [47].

The chances of having a monofollicular growth is higher with AIs compared to clomiphene as the increasing oestradiol level towards mid and late follicular phase reduces the FSH levels, thus allowing only the follicles with highest number of FSH receptors to sustain growth while the others undergo atresia. In case of clomiphene, the longer half-life of clomiphene allows the oestrogen receptors in the hypothalamus and pituitary to be blocked for longer duration leading to growth of more than one follicles in many women.

The oestradiol level per growing follicle is 40–60 % lesser in cycles where AIs are utilized for ovulation induction or COS. This is in line with the reduced functioning of the intraovarian machinery responsible for converting androgens to oestrogens. Theoretically, these reduced levels can be of help during IVF cycles as supraphysiological steroid levels are the major factors leading to advancement of the endometrial maturity. Though appealing, it has not been proven yet.

5.7.3.2 Dosage and Effectiveness in Ovulation Induction

Ovulation induction with letrozole is shown to have an ovulation rate of 70–84 % and a pregnancy rate of 20–27 % per cycle [48].

The indication most widely studied for letrozole usage has been that of PCOS, including ones with clomiphene resistance. There has been no formal dose-finding study for OI or COS. In fact, the doses used have been directly extrapolated from that used for breast cancer. The commonest dose of letrozole used is 2.5 mg for 5 days from day 2 to 3 of spontaneous or withdrawal bleed. Though dosage schedules of 5 and 7.5 mg have also been used, they did not incur any significant advantage in terms of pregnancy rates, though the total number of follicles growing were higher with higher dosage [49].

As for the dosage, different length of letrozole supplementation has been studied as well. Extended letrozole therapy for 10 days was tried in 218 patients who had previously failed clomiphene citrate at 100 mg for 5 days. They were randomized to receive either 5 mg of letrozole for 5 days or 2.5 mg for 10 days, both starting on day 1 of the menstrual cycle. Ovulation rates were similar at 65.7 % for the extended versus 61.8 % for the short course while a mean of three follicles more than18 mm were seen in the extended regimen compared to 1.8 in the short regimen. Pregnancy rates with the short and extended regimens were 12.4 % and 17.4 % respectively [50].

AIs with added gonadotropins can be used if more than one follicle are required to be grown as in case of unexplained infertility. This obviously will have attendant risk of OHSS and multifoetal gestation, so it should be used cautiously. Letrozole and clomiphene have been tried in unexplained infertility in many studies, the former at dosage between 2.5 and 7.5 mg/day and the latter at 100-mg/day dosage. A recent meta-analysis showed equivalence in terms of pregnancy rate in between both ovulogens, though the numbers of growing follicles were lesser with letrozole [51].

There have been many studies done in PCOS comparing clomiphene with letrozole, and the results have been mixed. But in the recent Cochrane review on the role of aromatase inhibitors in anovulatory PCOS comprising of 26 RCTs (5,560 women), it was shown that letrozole when compared to clomiphene had significantly better live birth rate (OR 1.63, 95 % CI 1.31–2.03, n = 1,783) and clinical pregnancy rate (OR 1.32, 95 % CI 1.09–1.60, n = 2,066) [52]. The reviewers advised caution in interpreting the results, as the quality of evidence was low. Nevertheless, it means that letrozole is at least as effective, if not better than clomiphene in this group of women. In clomiphene-resistant PCOS, when compared with placebo, letrozole was shown to have 33.3 % ovulation rate compared with nil in the placebo group [53].

5.7.3.3 Aromatase Inhibitors and IVF

It has been nearly a decade since AIs have been used in IVF, and they are yet to find a defined place. A significant number of trials are conducted studying their role in IVF. The only randomized trial conducted in normo-responders evaluating the addition of letrozole in patients with normal ovarian response undergoing IVF or ICSI with antagonist protocol showed a higher trend for both implantation and ongoing pregnancy rates in the letrozole group, though it did not reach statistical significance. Most of the trials done for use of letrozole in IVF have been for poor responders. Since the earlier trials were done before Bologna criteria came up, they have varying inclusion criteria. One recent RCT done on 55 women with poor response as per Bologna criteria comparing microdose flare protocol with GnRH antagonist/letrozole protocol showed no statistically significant difference in total number of oocytes retrieved and pregnancy rate but showed a higher cycle cancellation in letrozole group (p < 0.001) [54].

In contrast, a previously reported prospective non-randomized study of 147 poor responders stimulated with antagonist protocol with or without letrozole 2.5 mg for first 5 days of stimulation showed that the letrozole group had higher number of oocytes retrieved and higher implantation rate compared to the control group [55]. AIs have been shown to reduce the dose of FSH when added, thus reducing the cost of stimulation [56].

Letrozole has emerged as a preferred agent for stimulation in women with breast cancer as it is associated with significantly lesser oestradiol levels while having the similar success [57]. We would require larger RCTs before we can conclude firmly about the role of AIs in controlled ovarian stimulation for IVF.

5.7.3.4 Side Effects

The side effects extrapolated from trials in women with breast cancer include hot flushes, leg cramps and gastrointestinal disturbances [57]. Safety concerns pertaining to pregnancy have come into the forefront in the recent years. The concern mainly stems from an American Society for Reproductive Medicine (ASRM) abstract presented in 2005 comparing the outcome of letrozole conceptions with that of natural conceptions, which concluded that the use of letrozole for infertility treatment might be associated with a higher risk of congenital cardiac and bone malformations in the newborns [58]. This led to a major stir in the world of reproductive medicine and was widely covered in the media as the bad news usually spreads like wildfire. The manufacturer of the letrozole, Novartis Pharmaceutical, following the stir, issued a statement [59], advising that the usage of letrozole in premenopausal women, specifically for ovulation induction, is contraindicated. This was one of the biggest body blows to the field of reproductive medicine.

Subsequently, the Indian government has prohibited letrozole usage as ovulation-inducing agent [60]. If the above-mentioned abstract presentation and other following studies are evaluated in detail, it can be clearly seen that the fears are largely unfounded.

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5.7.4 Insulin Sensitizers

The major insulin sensitizers available include metformin and thiazolidinediones.

Metformin is an oral biguanide drug primarily used for the treatment of type 2 diabetes mellitus and belongs to the Food and Drug Administration (FDA) pregnancy category B classification. It is the most studied of the insulin sensitizers. It reduces the peripheral insulin resistance, serum insulin and blood glucose levels. Thiazolidinedione serves as a selective ligand of the nuclear transcription factor peroxisome proliferator-activated receptor. Troglitazone was withdrawn from the market in the year 2000 due to severe hepatotoxicity. The newer agents rosiglitazone and pioglitazone are safer but still are category C drugs as per FDA due to their potential risk of causing foetal growth restriction in animal experiments [65].

A decade ago, management of PCOS was synonymous with prescribing metformin for the women. This has changed since 2007 due to emergence of some robust trials and evidence coming to the contrary. Insulin resistance (IR) seems to have a role in the pathogenesis of PCOS, but whether it has a central role or is present only as a contributory factor to central dysfunction involving hyperandrogenism is far from clear. Decades have gone elucidating the pathogenesis, but no conclusive evidence has been brought forth.

5.7.4.1 Relevant Pharmacolgy and Mechanism of Action (MOA)

The oral bioavailability of metformin is 50–60 % under fasting conditions and is absorbed slowly [66]. Pertaining to its ovarian action, metformin can have either direct effect on the ovary or indirect effect by improving the insulin sensitivity. By improving insulin sensitivity, metformin reduces CYP17 activity in the ovary. As a part of direct action, metformin suppresses androstenedione production from ovarian theca cells and decreases FSH-stimulated 3β-HSD, StAR, CYP11A1 and aromatase activities in granulosa cells leading to reduced basal and FSH-stimulated progesterone and oestradiol levels [67].

5.7.4.2 Dosage and Effectiveness

The usual dosage of metformin is 1.5–2 g/day in divided doses. The start of metformin usually predates the ovulation induction in order to get the maximum effect of the medicine. Peak plasma concentrations (Cmax) are reached within 1–3 h and 4–8 h after taking immediate-release and extended-release formulations respectively [68]. Metformin is not metabolized in the body and is excreted unchanged in the urine, with a half-life of around 5 h [6970]. It is always better to start with a low dose before escalating to avoid the side effect especially on the G.I. tract. Though it has theoretically appealing effects, these have not transformed proportionately into clinical benefits. There have been umpteen numbers of trials evaluating the role of metformin in subfertility associated with PCOS. We will review the use of metformin in PCOS in varying roles:

·               As a first-line monotherapy compared to a placebo or no treatment

·               As a first-line monotherapy compared to clomiphene

·               As an adjunct added to clomiphene compared to clomiphene alone

As a Monotherapy First-Line Therapy Compared to a Placebo or no Treatment

The earlier studies favoured metformin as an effective drug for restoring menstrual cyclicity and for inducing ovulation in anovulatory PCOS women. Meta-analysis by Lord et al. showed ovulatory cycles being doubled with metformin compared to placebo with a number needed to treat (NNT) of 4.4 [71]. The recently updated Cochrane review also suggests that the ovulation rate is significantly higher in metformin group (16 RCTs, 1,208 participants; OR 1.81, 95 % CI 1.13–2.93) though with moderately high heterogeneity. Interestingly, in the subgroup analysis, neither the non-obese group (5 RCTs, 441 participants; OR 2.94, 95 % CI 0.81–10.61) nor the obese group (11 RCTs, 767 participants; OR 1.50, 95 % CI 0.95–2.37) was found to benefit from using metformin. The clinical pregnancy rate was higher in metformin compared with placebo (8 RCTs, 707 participants; OR 2.31, 95 % CI 1.52–3.51). In the subgroup analysis the benefit was found confined to the non-obese group only and that too with significant heterogeneity (I2 = 75 %). Importantly, there was no difference in the live birth rates between the two groups (OR 1.80, 95 %CI 0.52–6.16) [72]. As per available high-quality evidence, metformin as a monotherapy has not been shown to confer any significant benefit in terms of improving reproductive outcome compared to placebo.

As a First-Line Monotherapy Compared to Clomiphene

As per the Cochrane review, in the non-obese group, ovulation rates in both groups were similar (2 RCTs, number of cycles = 497; OR 0.87, 95 % CI0.60–1.26; I2 = 0 %) while in the obese group, clomiphene had a better ovulation rate (2 RCTs, number of cycles = 2,044; OR 0.43, 95 % CI 0.36–0.51; I2 = 0 %). The clinical pregnancy rate had opposite effects in obese vs. non-obese women, so it was non-conclusive. The live birth rate in obese women favoured clomiphene (OR 0.30, 95 % CI 0.17–0.52; I2 = 0 %), while that in the non-obese was neutral [72]. One recent systematic review undertaken to answer the role of metformin as the primary ovulation agent in PCOS studied 14 trials and concluded that compared with CC alone, patients treated only with metformin had a reduction in the live birth rate (OR = 0.48, 95 % CI 0.31–0.73, p = 0.0006) [73].

As an Adjunct Added to Clomiphene Compared to Clomiphene Alone

A higher ovulation rate was seen in the Cochrane review with a moderate degree of heterogeneity (I2 = 62 %) when combined therapy was given compared with clomiphene alone (18 RCTs, OR 1.74, 95 % CI 1.50–2.00). Clinical pregnancy was also higher with combined therapy (11 RCTs, 1,208 participants; OR 1.51, 95 % CI 1.17–1.96), though the benefits appeared confined to the obese group. There was no evidence that combined therapy improved the all-important live births compared with clomiphene alone (7 RCTs, 907 participants; OR 1.16, 95 % CI 0.85–1.56) [72].

Overall, the only universal indication of metformin in PCOS is when there is an impaired glycemic control. Otherwise, the evidence is not yet in favour of metformin. It can be argued that metformin can be used in obese PCOS and women with CC resistance in view of mixed evidence at least on ovulation and clinical pregnancy rates if not on live births. The advantage here of metformin would be low cost and lesser chances of OHSS compared to addition of gonadotropins. This needs to be weighed against the significantly increased gastrointestinal side effects of metformin. A recent RCT on 250 CC-resistant women, randomized to either 2.5 mg of letrozole daily or combined metformin–CC for three treatment cycles, showed no difference in the pregnancy rates between the two groups (14.7 % vs. 14.4 %), though the number of ovulatory follicles was higher in the metformin-CC group [74].

5.7.4.3 Side Effects

The commonest side effects are related to the G.I. tract and include diarrhoea, cramps, nausea and vomiting. The most serious, but rare, side effect is lactic acidosis.

Conclusion

Ovulation induction constitutes the most utilized intervention in the treatment of a subfertile couple. A stepwise approach starting with oral ovulogens, then adjuncts and finally injectables or LOD would be the one to be followed, as it would be safer and more cost effective. Clomiphene is, was and will be, at least in the near future, the drug of choice for OI due to its proven track record and absence of valid drug controller-approved medications. It is of utmost importance to assess a given couple individually and plan for targeted treatment rather that a blanket one.

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