Fertility Blaze
Fertility Blaze 2017 › Fertility Blaze Vol-4, No-1, 2017

Ovulation Induction Protocols in IUI: Role of Clomifene Citrate

Ovulation Disorders: An Introduction

Ovulation disorders account for about one-third (30%) of infertility cases, and often present with amenorrhoea (an absence of periods) or oligomenorrhoea (irregular periods).1Hamilton-Fairley D, Taylor A. Anovulation. BMJ 2003;327(7414):546-549.  2Katsikis I, Kita M, Karkanaki A, et al. Anovulation and ovulation induction. Hippokratia. 2006;10(3):120-127. As follows, induction of ovulation using medical or surgical methods appears an enticing option in infertility attributable to ovulation disorders; though it is also prudent to consider the fact that not all causes of anovulation might be amenable to treatment by ovulation induction. It is in fact the underlying cause of anovulation that will determine whether ovulation induction is possible in any particular case of subfertility; making patient selection an important deciding factor for optimal and desired outcomes through subsequent clinical approach to ovulation induction.1Hamilton-Fairley D, Taylor A. Anovulation. BMJ 2003;327(7414):546-549.  2Katsikis I, Kita M, Karkanaki A, et al. Anovulation and ovulation induction. Hippokratia. 2006;10(3):120-127.  3Fauser BCJM, Barbieri RL, Crowley WF Jr, et al. Overview of ovulation induction. Available at: http://www.uptodate.com/contents/overview-of-ovulation-induction [Accessed on 21/9/2016]. Table 1 depicts causes that may be suitable or unsuitable for ovulation induction. The World Health Organization (WHO) has classified ovulation disorders into three broad groups: Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism) – 10%; Group II: hypothalamic pituitary dysfunction (predominately polycystic ovary syndrome; PCOS) – 85%; and Group III: ovarian failure – 5% (Table 2).4WHO classification of ovulatory disorders. Available at: http://www.tealefenning.org.uk/phpBB2/who-classification-of-ovulatorydisorders- t425.html [Accessed on 21/9/2016].  5Loret de Mola JR. Amenorrhea. Available at: http://clinicalgate.com/amenorrhea-2/#bib3 [Accessed on 21/9/2016]. The categorization thus shows that PCOS is the predominant cause of subfertility due to anovluation, and consequently has been a study model in several studies in the past.

Management of Anovulation

Pre-treatment Evaluation of Ovulatory/Anovulatory Function

Before initiating any therapy for subfertilty suspected due to anovulation, it is important to establish the presence of ovulatory dysfunction. As objective evidence of ovulation is the key to successful treatment in such cases, it remains an important monitoring strategy as well. In most cases, a menstrual history may be all that is required since presence of regular and predictable menstrual cycles itself indicates that the woman is ovulating. Generally, many patients with abnormal uterine bleeding, oligomenorrhea,or amenorrhea might therefore not require more intensive investigations to establish anovulation. Yet, additional testing may be necessary given the need to seek an underlying cause because specific treatment may be indicated and some causes may also have associated health implications and consequences.6Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham,Alabama. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2015;103:e44-50. Table 3 depicts several tests that are available and when done at appropriate time might help to delineate the anovulation and its category.1Hamilton-Fairley D, Taylor A. Anovulation. BMJ 2003;327(7414):546-549. Serial measurements of basal body temperature (BBT) is a simple method for evaluating ovulatory function; however,it is no longer considered the preferred method for most infertile women since it cannot reliably define the time of ovulation. Serum progesterone provides a reliable and objective measure of ovulatory function if obtained at the appropriate time. In this context, it has been proposed that considering the range of normal variation in ovulatory cycles, measurement of serum progesterone should generally be obtained about 1 week before the expected onset of the next menses, rather than on any one specific cycle day (e.g., cycle-day 21). A progesterone concentration > 3 ng/mL provides presumptive but reliable evidence of recent ovulation. Urinary luteinizing hormone (LH) determinations using commercial ‘ovulation predictor kits’ can identify mid-cycle LH surge, which precedes ovulation by 1 to 2 days. The test provides an indirect evidence of ovulation and can correlate well with the peak in serum LH. Transvaginal ultrasonography can reveal the size and number of developing follicles, and also provides presumptive evidence of ovulation and luteinization.Endometrial biopsy can demonstrate secretory endometrial development, but is no longer recommended for evaluation of ovulatory or luteal function in infertile women because it lacks both accuracy and precision. Biopsy should therefore be limited to those in whom specific endometrial pathology is strongly suspected. Furthermore, other evaluations aimed at identifying the underlying cause and defining the best choice of treatment for anovulatory infertile women may also be indicated; for instance, serum thyroidstimulating hormone (TSH) and prolactin determinations to identify thyroid disorders and/or hyperprolactinemia.In women with amenorrhea, measurements of serum follicle-stimulating hormone (FSH) and estradiol can help to distinguish women with ovarian failure (high FSH, low estradiol) from those with hypothalamic amenorrhea (low or normal FSH, low estradiol). This could be important for subsequent management because those with ovarian failure may be candidates for oocyte donation, while those with hypothalamic amenorrhea (low or normal FSH,low estradiol) would require exogenous gonadotropin stimulation for ovulation induction.6Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham, Alabama. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2015;103:e44-50.

Lifestyle Modifications

Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first option for these women.7Vause TDR, Cheung AP. Ovulation induction in polycystic ovary syndrome. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can 2010;32(5):495-502. However, if patients remain unresponsive to these lifestyle interventions, and if have documented anovulation, they may be suitable for ovulation induction with or without intrauterine insemination (IUI).

Ovulation Induction Protocols and IUI

Ovulation induction and IUI are appropriate approaches for use in infertile women having normal fallopian tubes and where more complex treatments might not be appropriate.The method in IUI involves placing of specially prepared,concentrated “washed” sperm into the uterine cavity,bypassing the cervix (Figure 1). Therefore, ovulation induction will be typically useful in women having an abnormality of ovulation.8Ovulation Induction/Intrauterine Insemination. Available at: https://www.ivf.com.au/sites/ivf.com.au/files/leaflets/patient-dl-ovulationinduction-iui-8may2015.pdf [Accessed on 22/9/2016].  In general, there are three main protocols for IUI: natural, clomifene, and gonadotrophin stimulated.9Bhaskar J. Ovarian stimulation in IUI-Overview. Available at: http://www.slideshare.net/LifecareCentre/ovarian-stimulation-in-iuioverview-sr-jyoti-bhaskar [Accessed on 22/9/2016]. The commonly prescribed ovulation induction drugs thus include clomifene citrate and gonadotropins [FSH, LH, human menopausal gonadotropin (hMG), chorionic gonadotropin (hCG)].10American Society for Reproductive Medicine. Medications for inducing ovulation. Patient information series. Available at: http://www.socrei.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ovulation_drugs.pdf [Accessed on 22/9/2016]. Nonetheless, the most common protocol involves use of the clomifene citrate.11ESHRE Capri Workshop Group. Intrauterine insemination. Hum Reprod Update. 2009;15(3):265-77.  These drugs are used in much lower doses than in in-vitro fertilization (IVF), and enhance the chances of successful treatment by stimulating production of 2 or 3 follicles,and preferably one follicle to avoid multiple pregnancies.12Intrauterine insemination patient information. Available at: http://www.embryoland.gr/images/datafiles/29.pdf [Accessed on 22/9/2016].   FSH ovarian stimulation treatment is only modestly better but multiple birth rates are a concern. Therefore, if more than 3 follicles develop, it is advisable to cancel the cycle and restart on a lower drug dose. Usually, the prevention of premature LH surges and luteal phase support do not appear to be major necessities in IUI cycles,11ESHRE Capri Workshop Group. Intrauterine insemination. Hum Reprod Update. 2009;15(3):265-77.   but might be required in individual cases.

Antiestrogen Treatment: Clomifene Citrate

It has been approximately five decades since the first evidence demonstrated that administration of clomifene citrate could induce ovulation in >75% of women with amenorrhea. This was a major advance in reproductive medicine, and clomifene quickly became popular for ovulation induction because of its ease of administration and minimal side effects.13Moy I, Ekpo G. Clomifene citrate use for ovulation induction:When, why, and how? Available at: http://contemporaryobgyn.modernmedicine.com/contemporary-obgyn/news/clinical/clinicalpharmacology/Clomifene-citrate-use-ovulation-inductionwh?page=full [Accessed on 22/9/2016].  14Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].  The drug, though ironically initially synthesized as a synthetic estrogen for possible use as a contraceptive, has been the most widely used treatment for fertility enhancement for more than 40 years,and thousands of anovulatory women have been able to enjoy maternity thanks to this simple, cheap and relatively safe treatment.2Katsikis I, Kita M, Karkanaki A, et al. Anovulation and ovulation induction. Hippokratia. 2006;10(3):120-127.  14Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].   Accordingly, clomifene citrate still holds its place as a first-line therapy for ovulation induction in WHO type II anovulatory infertility (normogonadotrophic normoestrogenic anovulation; subfertile anovulatory patients with PCOS), with gonadotrophins and laparoscopic ovarian surgery as second-line options.15Hashim HA. Management of women with clomifene citrate resistant polycystic ovary syndrome – an evidence based approach. Available at: http://cdn.intechopen.com/pdfs-wm/29510.pdf [Accessed on:22/9/2016].   16ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Hum Reprod Update.2012;18(5):586-99.   WHO group II ovulatory disorders, including PCOS, is thus the primary indication for the use of clomifene citrate. Luteal phase deficiency is another clear indication for its use, while it has also been used in women with unexplained infertility often in combination with IUI.13Moy I, Ekpo G. Clomifene citrate use for ovulation induction:When, why, and how? Available at: http://contemporaryobgyn. modernmedicine.com/contemporary-obgyn/news/clinical/clinicalpharmacology/Clomifene-citrate-use-ovulation-inductionwh?page=full [Accessed on 22/9/2016]. Certainly, the fact that clomifene citrate is an orally administered, relatively cheap preparation, has proved a huge advantage over its ompetitors.17Homburg R. Clomifene citrate-end of an era? a mini-review. Human Reproduction 2005;20(8):2043-2051.

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Mechanism of Action of Clomifene Citrate

Clomifene citrate can exert its effects on the hypothalamus,pituitary, ovary, and uterus. However, the majority of the evidence suggests that the primary site of action is the hypothalamus, where it appears to bind to hypothalamic estrogen receptors, thereby blocking negative feedback effect of circulating endogenous estrogen. This consequently results in elevated plasma concentrations of FSH and LH.14Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/ mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].   When clomifene is administered to normally cycling ovulatory women, there is an increase in LH pulse frequency, but not amplitude, thereby suggesting an increase in hypothalamic gonadotropinreleasing hormone (GnRH) pulse frequency. In contrast,when the drug is administered in women with PCOS,who already have a high frequency pattern of GnRH at baseline, it produces an increase in GnRH amplitude,plus an increase in the daily plasma concentrations of LH and FSH.14Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].   Consequently improved GnRH secretion stimulates pituitary production of FSH, which in turn drives follicular growth and maturation with emergence of one or more dominant follicles. The levels of LH and FSH fall again after the typical 5-day course of therapy is completed. In successful treatment cycles, one or more dominant follicles emerge and mature. This generates a rising tide of estradiol that ultimately triggers the midcycle LH surge and ovulation.18Rao K. (2014). Principles & Practice of Assisted Reproductive Technology. 1st ed. New Delhi: Jaypee Brothers Medical Publishers.   Furthermore, evidence derived from in-vitro studies also suggest that clomifene citrate has a pituitary site of action as well, where it causes an increase in gonadotropin response to GnRH.14Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].

Earlier considered an antiestrogen, clomifene citrate was recently reclassified as a selective estrogen receptor modulator, having both an estrogen agonist and antagonist effect. However, it has been that the agonist properties of clomifene manifest only when endogenous estrogen levels are extremely low, and thus it is the antagonistic effects that prevail.13Moy I, Ekpo G. Clomifene citrate use for ovulation induction:When, why, and how? Available at: http://contemporaryobgyn.modernmedicine.com/contemporary-obgyn/news/clinical/clinicalpharmacology/Clomifene-citrate-use-ovulation-inductionwh?page=full [Accessed on 22/9/2016].   The peripheral ovarian actions of clomifene are for the most part secondary to the effects of elevated FSH and LH on ovarian follicular development, In the uterus,cervix, and vagina, it acts primarily as an antiestrogen; this may partly explain the ‘discrepancy’ between the ovulation and conception rates seen with clomifene. Clomifene citrate has no apparent progestational, corticotropic, androgenic, or antiandrogenic effects, nor does it interfere with the thyroid or adrenal function.1414Seli E, Arici A, Barbieri RL, et al. Ovulation induction with Clomifene citrate. Available at: http://cursoenarm.net/UPTODATE/contents/ mobipreview.htm?22/32/23041?source=HISTORY [Accessed on 22/9/2016].

Overall data thus suggest that both the estrogenic and antiestrogenic properties of clomifene may participate in the initiation of ovulation.19Clomifene Citrate. Available at: http://www.rxresource.org/prescription-information/Clomifene-Citrate-Rebel-Distributors- Corp.html [Accessed on: 22/9/2016].   There are two clomifene isomers – zuclomifene and enclomifene – and they have been found to have mixed estrogenic and antiestrogenic effects. Nevertheless, available evidence indicates that enclomifene is the more potent antiestrogenic isomer and the one primarily responsible for the ovulation-inducing actions of clomifene citrate.20Mitwally MF, Casper RF. Induction of ovulation. Available at: http://clinicalgate.com/induction-of-ovulation/ [Accessed on 22/9/2016]   Enclomifene may affect the hypothalamus as an estrogen antagonist, and thus blocks both negative and positive feedback of estrogen,consequently causing alterations in GnRH pulsatility.Zucolmiphene may weakly affect the pituitary as an estrogen agonist, and can slightly increase the sensitivity of the pituitary gland to GnRH.21Zhang XJ, Liu SY, Fu W, Sun XX. The association of serum estradiol level with outcomes of Clomifene citrate/human menopausal gonadotropin ovarian stimulation for in vitro fertilization and embryo transfer. Reprod Biol Endocrinol. 2015;13:114.   The overall effect of Clomifene compounds thus triggers the release of both FSH and LH from the anterior pituitary. FSH stimulates the development of follicles, which then release estradiol.Once serum estradiol reaches a critical level, it triggers the release of LH and ovulation. In the past, GnRH agonists and antagonists have been used to prevent this, but in recent years it has been noted that the administration of clomifene citrate until the day before hCG prevents the premature LH surge. This is because enclomifene acts as an estrogen antagonist at the hypothalamus, and not only blocks the negative feedback of estradiol, but also its positive feedback resulting in blockage of the LH surge.However, despite the blockade of premature LH surge, the level of LH is adequate for development of follicles to the late phase.21Zhang XJ, Liu SY, Fu W, Sun XX. The association of serum estradiol level with outcomes of Clomifene citrate/human menopausal gonadotropin ovarian stimulation for in vitro fertilization and embryo transfer. Reprod Biol Endocrinol. 2015;13:114.   This method could therefore provide better results compared to an agonist and antagonist protocol of assisted reproduction.

Clomifene Treatment Regimens

The standard treatment regimen of clomifene citrate involves giving it orally starting from the 2nd to 5th day after the onset of menses for 5 days;22Deshpande H. (2016). Practical management of ovulation induction.1st ed. New Delhi: Jaypee Brothers Medical publishers.   if a woman does not have spontaneous periods, a period can be induced by taking an oral progestin for 5-12 days.23Dong X, Zheng Y, Liao X, et al. Does progesterone-induced endometrial withdrawal bleed before ovulation induction have negative effects on IUI outcomes in patients with polycystic ovary syndrome? Int J Clin Exp Pathol. 2013;6(6):1157-1163.   Although,ovulation rates, conception rates, and pregnancy outcome appear similar regardless of whether treatment begins on cycle day 2 to 5,24Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA.Is Clomifene citrate stair-step protocol a good alternative to gonadotrophins in Clomifene-resistant PCO patients? Prospective study. J Obstet Gynaecol Res. 2016;42(5):547-53..   there is some evidence which suggests that early administration of clomifene (starting on the day after the last dose of the oral progestin without waiting for the withdrawal bleeding) might be associated with slightly higher ovulation and pregnancy rates, when compared to the conventional clomifene administration (starting on day 2 of the withdrawal bleeding).25Elguindy A, Hussein M, El-Shamy R. Early Clomifene citrate for induction of ovulation in women with polycystic ovary syndrome: a randomized controlled trial. Journal of American Science 2013;9(12):418-422.  

The standard dosage of clomifene citrate is 50-100 mg of clomifene per day for 5 consecutive days.10American Society for Reproductive Medicine. Medications for inducing ovulation. Patient information series. Available at: http:// www.socrei.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ovulation_drugs.pdf [Accessed on 22/9/2016].   Clomifene would be more effective if taken in a bolus daily rather than in divided doses because it would more readily pass the blood-brain barrier.26Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update.1996;2(6):483-506.   However, lowest effective dose has to be established for each individual. Furthermore,it is important to monitor a patient’s response and determine whether the dose given results in ovulation.Same dose may be given in subsequent cycles if ovulation is documented but no conception occurs. In general,ovulation can be seen in about 50% women with the 50 mg dose. However, if ovulation does not occur at this dose, clomifene citrate is increased by 50 mg increments in subsequent cycles until ovulation happens. It has been observed that some women who do not ovulate with 50 mg of clomifene citrate may respond and ovulate at higher doses using a step-up regimen with doses increasing by 50 mg with each anovulatory cycle (22% with 100 mg, 12% with 150 mg, 7% with 200 mg, and 5% with 250 mg).24Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA.Is Clomifene citrate stair-step protocol a good alternative to gonadotrophins in Clomifene-resistant PCO patients? Prospective study. J Obstet Gynaecol Res. 2016;42(5):547-53..   27Gysler M, March CM, Mishell DR Jr, et al. A decade’s experience with an individualized Clomifene treatment regime including its effect on the postcoital test. Fertil Steril 1982;37:161-167.   Among anovulatory women who ovulate with clomifene citrate, the cumulative conception rates at 3 months are 50%, 45% and 33% for 50 mg/day, 100 mg/day or 150 mg/day, respectively, whereas conception rates at 6 months are 62%, 66% and 38% respectively.24Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA.Is Clomifene citrate stair-step protocol a good alternative to gonadotrophins in Clomifene-resistant PCO patients? Prospective study. J Obstet Gynaecol Res. 2016;42(5):547-53..  28Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89(3):505-22.   The data thus suggests that treatment with doses up to 150 mg is reasonable before considering alternatives. However, doses in excess of 100 mg/day are not approved by the United States Food and Drug Administration (FDA).22Deshpande H. (2016). Practical management of ovulation induction.1st ed. New Delhi: Jaypee Brothers Medical publishers.   29Scalia A. Fertility clinical and managed care considerations for the specialty healthcare pharmacist. Available at: http://media.specialtycme.org/PDF/20140401_Infertility.pdf [Accessed on 22/9/2016].  

The stair-step protocol of clomifene suggests that it is not necessary to induce menses before increasing clomifene doses in non-responsive PCOS patients. Hurst et al30 made this conclusion while retrospectively determining the efficacy of this novel “stair-step” clomifene protocol in women with PCOS not responding to 50 mg clomifene.The stair-step protocol was performed as follows: 50 mg clomifene for 5 days, ultrasonography on days 11-14. If unresponsive, immediately begin 100 mg clomifene for 5 days and repeat ultrasound in 1 week. If still unresponsive,begin 150 mg clomifene for 5 days and repeat the ultrasound in 1 week. The authors compared the stair-step cycles with published historical clomifene outcomes for women who were nonresponsive. Results of the study showed that the time to ovulation was 32-53 days less with the stair-step protocol compared with a traditional regimen. The dosedependent ovulation rate was 64% at 100 mg with the stair-step protocol compared with 22% with a traditional regimen.30Hurst BS, Hickman JM, Matthews ML, et al. Novel Clomifene “stairstep”protocol reduces time to ovulation in women with polycystic ovarian syndrome. Am J Obstet Gynecol. 2009;200(5):510.e1-4.   Many subsequent studies have also determined this efficiency of the stair-step, and suggested that clomifene stair step protocol decreases the time to ovulation and may improve ovulation rates in women resistant to standard clomifene regimen.31Al Ghazali B. Clomifene stair-step protocol for ovulation induction in women with polycystic ovarian syndrome. American Journal of BioMedicine 2014;2(7):840-854.   32Deveci CD, Demir B, Sengul O, et al. Clomifene citrate ‘stairstep’ protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial. Arch Gynecol Obstet 2015;291:179.  

More than 200 mg each day for 5 days are thus generally not helpful, and if patients do not ovulate on a clomifene dosage of 200 mg, it is rational to consider a different treatment. Recommended second-line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery.33Costello MF, Misso ML, Wong J, et al. The treatment of infertility in polycystic ovary syndrome: a brief update. ANZJOG 2012;52(4):400-403.   The use of exogenous gonadotropins is however associated with increased chances for multiple pregnancy;therefore, intense monitoring of ovarian response is required. In some cases, longer courses of clomifene citrate (7-10 days) can be considered in women resistant to standard treatment if other practical alternative (like exogenous gonadotropin therapy) is unavailable.34Fritz MA, Speroff L. (2012). Clinical gynecologic endocrinology and infertility. 8th ed. USA: Lippincott Williams & Wilkins.   Moreover, a trial of stair-step protocol per se remains a good alternative to gonadotrophins in some clomifene-resistant PCOS patients. Recently, a prospective study compared the efficacy and safety of the clomifene citrate stair-step protocol with standard gonadotrophin (FSH) treatment in clomifene-resistant PCOS patients.24 The study cohort consisted of 100 PCOS clomifene-resistant patients; 50 patients received clomifene again but in accordance with the stair-step protocol (Figure 2), and the other 50 received the standard gonadotrophin treatment (FSH step-down regimen) used in the study center. The results showed that there was no difference between the two treatment modalities concerning the ability to achieve a dominant follicle or the clinical pregnancy rate. However, the time to ovulation was significantly shorter with the clomifene stair-step protocol than with the gonadotrophin treatment.Moreover, ovarian hyperstimulation syndrome (OHSS) and ovarian cyst formation were more likely to occur with the gonadotrophin treatment (Table 4). The authors concluded that clomifene stair-step protocol is a simple and well-tolerated option for the management of PCOS patients who have not responded to traditional clomifene protocols, having an efficacy similar to gonadotrophin stimulation.24Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA.Is Clomifene citrate stair-step protocol a good alternative to gonadotrophins in Clomifene-resistant PCO patients? Prospective study. J Obstet Gynaecol Res. 2016;42(5):547-53..  

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Nevertheless, it is important that clomifene citrate treatment be limited to no more than six ovulatory cycles.13Moy I, Ekpo G. Clomifene citrate use for ovulation induction:When, why, and how? Available at: http://contemporaryobgyn. modernmedicine.com/contemporary-obgyn/news/clinical/clinicalpharmacology/Clomifene-citrate-use-ovulation-inductionwh?page=full [Accessed on 22/9/2016].  

Laparoscopic ovarian surgery alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances.Recommended third-line treatment is IVF.28Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89(3):505-22.   35Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011;3:25-35.  

Safety Profile of Clomifene Citrate

Clomifene citrate is generally well-tolerated since side effects are usually mild. Some side effects are relatively common, but rarely are persistent or severe enough to intimidate completion of the usual 5-day course or next cycle of treatment.18Rao K. (2014). Principles & Practice of Assisted Reproductive Technology. 1st ed. New Delhi: Jaypee Brothers Medical Publishers.   Hot flashes occur in ~10% of women taking clomifene, and typically disappear soon after the last pill is taken. Likewise, mood swings, breast tenderness, and nausea may also be commonly seen.10 Severe headaches or visual problems are uncommon and virtually always reversible. Women who conceive using clomifene citrate have a 5-8% chance of having twins, whereas triplet and higher-order pregnancies are rare (<1%). Ovarian cysts may form in some patients but typically resolve with time.In general, side effects seem more frequent with the higher doses.10American Society for Reproductive Medicine. Medications for inducing ovulation. Patient information series. Available at: http:// www.socrei.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ovulation_drugs.pdf [Accessed on 22/9/2016].  

Adjunctive Treatment Regimens

Many women who prove resistant or refractory to standard clomifene treatment may ovulate in response to alternative and combined treatment regimens.36The Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham,Alabama. Use of Clomifene citrate in women. Fertility and Sterility 2006;86(4): S187-S193.   These involve the use of “insulin sensitizing” agents (e.g., metformin) or other adjuncts (e.g., glucocorticoids), and combinations (e.g., sequential treatment with clomifene and exogenous gonadotropins). A choice among them is not arbitrary,but should be based on specific elements of the patient’s history, laboratory evaluation, and/or observations in prior unsuccessful clomifene treatment cycles.

Clomifene and Metformin

Metformin combined with clomifene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomifene citrate alone.7Vause TDR, Cheung AP. Ovulation induction in polycystic ovary syndrome. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can 2010;32(5):495-502.   However, especially seeing the association of increased weight and insulin resistance with PCOS, metformin addition to clomifene citrate may be particularly beneficial in women with clomifene resistance who are older and who have visceral obesity as well.

Clomifene and Glucocorticoids

In some clomifene-resistant women with PCOS,adjunctive use of glucocorticoids (e.g., dexamethasone or prednisone) with the clomifene treatment may help in inducing the ovulation.37Vital Reyes VS, Tellez Velasco S, Hinojosa Cruz JC, et al. Clomifene acetate and prednisone: alternative approach for the management of patients with chronic anovulation and Clomifene treatment failure.Ginecol Obstet Mex. 2000;68:266-70.  38Elnashar A, Abdelmageed E, Fayed M, et al. Clomifene citrate and dexamethazone in treatment of Clomifene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study. Hum. Reprod.2006;21(7):1805-1808.   The choice of this adjunctive treatment may either be empiric or based on the serum dehydroepiandrosterone sulphate (DHEAS) concentration (>200 g/dL).36The Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham, Alabama. Use of Clomifene citrate in women. Fertility and Sterility 2006;86(4): S187-S193.   It has been observed that ovulation induction by adding dexamethasone (high dose, short course) to clomifene in clomifene-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates.38Elnashar A, Abdelmageed E, Fayed M, et al. Clomifene citrate and dexamethazone in treatment of Clomifene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study. Hum. Reprod.2006;21(7):1805-1808.  

Clomifene and Gonadotropins

Treatment with exogenous gonadotropins alone is an obvious alternative in clomifene-resistant women.However, such anovulatory women who eventually require exogenous gonadotropins to achieve ovulation,and those with unexplained infertility, might benefit from a trial of sequential clomifene/gonadotropin therapy. The gonadotropin used may be either traditional menotropins (hMG) or purified or recombinant FSH. The typical sequential cycle includes a standard clomifene treatment regimen (50 mg/day to 100 mg/day, cycle days 5–9), followed by low-dose hMG or FSH (75 IU/day, cycle days 9–12).=36The Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham,Alabama. Use of Clomifene citrate in women. Fertility and Sterility 2006;86(4): S187-S193.   Treatment thereafter is individualized, likewise as with traditional gonadotropin therapy, based on transvaginal ultrasound examinations.

Preliminary Suppressive Therapy Before Clomifene Citrate

Since anovulation reflects a dysfunctional hypothalamicpituitary-ovarian axis, it may be reasonable to think that an interval of preliminary suppressive therapy might help to restore harmony and ovulatory function in few cases.In this context, limited data suggest that a two-month interval of continuous estrogen-progestin contraception can effectively suppress serum LH and androgen levels,and that ovulation and pregnancy can be achieved with clomifene treatment immediately thereafter in some women who were previously resistant to clomifene.34Fritz MA, Speroff L. (2012). Clinical gynecologic endocrinology and infertility. 8th ed. USA: Lippincott Williams & Wilkins.  

Clomifene and Estradiol Valerate

It is well-known that in addition to successful ovulation induction action, clomifene citrate also exerts undesirable anti-estrogenic effects in the periphery (endocervix,endometrium, ovary, ovum and embryo), which may explain the discrepancy between the ovulation and conception rates observed in clomifene-treated women.However, there is very little or no compelling evidence to support these notions. Available data suggest that any adverse anti-estrogenic effects of clomifene present no significant obstacle in the majority of treated women.39Siebert TI. A study of different clinical and biochemical parameters in polycystic ovary syndrome affecting ovulation induction outcome and fertility potential. Available at: scholar.sun.ac.za/bitstream/handle/10019.1/4076/Siebert,%20T.pdf?sequence=1 [Accessed on 23/9/2016].   For instance, the quantity and quality of cervical mucus production in clomifene treatment cycles may sometimes be reduced, but rarely to the extent that it may interfere with sperm transport or sperm survival. However, to further alleviate the peripheral anti-estrogenic effects of clomifene on endometrium, several strategies have been tried, such as using the half-dose administration of clomifene, early administration of clomifene from day 1-5,using a 3-day clomifene treatment instead of the standard 5-day treatment, or administering exogenous estrogen to facilitate adequate endometrial growth and improve the endometrial thickness.40Takasaki A, Tamura H, Taketani T, et al. A pilot study to prevent a thin endometrium in patients undergoing Clomifene citrate treatment.J Ovarian Res. 2013;6:94.   41cetinkaya K, Kadanalı S. The effect of administering vaginal estrogen to Clomifene citrate stimulated cycles on endometrial thickness and pregnancy rates in unexplained infertility. J Turk Ger Gynecol Assoc.2012;13(3):157-161.   42Bae S, Joo J, Choi J, et al. Clinical outcomes of three- or five-day treatment with Clomifene citrate combined with gonadotropins and a timed intercourse cycle in polycystic ovary syndrome patients. Clin Exp Reprod Med. 2015;42(3):106-110.   43Gerli S, Gholami H, Manna C, et al. Use of ethinyl estradiol to reverse the antiestrogenic effects of Clomifene citrate in patients undergoing intrauterine insemination: a comparative, randomized study. Fertil Steril. 2000;73(1):85-9.  

It has been observed that early (luteal phase) administration of clomifene citrate in patients with PCOS will lead to more follicular growth and endometrial thickness, which might result in a higher pregnancy rate.44Badawy A, Inany H, Mosbah A, et al. Luteal phase Clomifene citrate for ovulation induction in women with polycystic ovary syndrome: a novel protocol. Fertil Steril. 2009;91(3):838-41.   Likewise, exogenous estrogen administration may also increase the clinical pregnancy rate among women with PCOS undergoing ovulation induction.45Moini A, Ahmadi F, Jahangiri N, et al. A randomized controlled trial evaluating the effect of ethinyl estradiol during Clomifene citrate cycles among women with polycystic ovary syndrome. Int J Gynaecol Obstet. 2015;131(2):129-32.   A clinical study conducted to examine the effects of a timed sequence of hormone supplementation with oral estradiol and vaginal progesterone following clomifene citrate therapy demonstrated a potential supportive effect on pregnancy rates in the clomifene plus oral estradiol and vaginal progesterone gel group compared to clomifene alone.46Elkind-Hirsch KE, Darensbourg C, Creasy G, et al. Conception rates in Clomifene citrate cycles with and without hormone supplementation:a pilot study. Curr Med Res Opin. 2005;21(7):1035-40.   Experimental evidence has also suggested that coadministeration with estradiol might help to protect against clomifene citrate-induced apoptosis in ovarian follicular cells, and thereby possibly alleviate the risk of poor development and maturation of oocytes which leads to reduced ovulation.47Chaube SK, Prasad PV, Thakur SC, et al. Estradiol protects Clomifene citrate-induced apoptosis in ovarian follicular cells and ovulated cumulus-oocyte complexes. Fertil Steril. 2005;84 Suppl 2:1163-72.   Recently, a clinical study conducted in 34 normal ovulatory women also found that an addition of estradiol valerate into the clomifene citrate cycle significantly increased the average endometrial thickness.48Satirapod C, Wingprawat S, Jultanmas R, et al. Effect of estradiol valerate on endometrium thickness during Clomifene citratestimulated ovulation. J Obstet Gynaecol Res. 2014;40(1):96-101.   The investigators concluded that the addition of 6 mg/day estradiol valerate for 5 days following the clomifene citrate treatment can prevent the endometrial thinning without perturbing folliculogenesis and ovulation. Thus,although not every woman would be a candidate for estradiol administration, it could be of particular benefit in those with demonstrated lower endometrial thickness.Luteal phase progesterone supplementation in clomifene citrate-IUI cycles can also help to improve the endometrial receptivity.49Elguero S, Wyman A, Hurd WW, et al. Does progesterone supplementation improve pregnancy rates in Clomifene citrate and intrauterine insemination treatment cycles? Gynecol Endocrinol.2015;31(3):229-32.  

Some other potential alternatives that may be used in clomifene-resistant women include hCG, tamoxifen,and aromatase inhibitors.50Kaur S, Saha L. Medical management of Clomifene-resistant polycystic ovarian syndrome: an update. Int J Basic Clin Pharmacol. 2014;3(1):1-9.   They can be useful in select patients, but merit consideration depending on the patient’s age, goals, available resources, and the risk tolerance.36The Practice Committee of the American Society for Reproductive Medicine. American Society for Reproductive Medicine, Birmingham,Alabama. Use of Clomifene citrate in women. Fertility and Sterility 2006;86(4): S187-S193.   A discussion about all these options may be beyond the scope of this mini-review.

Monoisomeric products of clomifene citrate (enclomifene) have also been tested for ovulation induction in prospective randomized studies but without major benefits. A double blind study by Gupta and Kriplani,51Gupta P, Kriplani A. Enclomiphene citrate versus clomiphene citrate for ovulation induction in women with unexplained infertility. Fertility & Sterility 2013;100(3 Suppl):S143.   conducted on women with unexplained fertility, at AIIMS,New Delhi, found that although enclomifene citrate lead to multiple follicle recruitment compared to clomiphene citrate, it had no benefit in terms of better endometrial development. There was no significant difference between enclomifene vs. clomifene groups concerning the day of hCG administration, endometrial thickness on the day of hCG, and clinical pregnancy rates. Here, it might be rational to reiterate the suggestion gained from available evidence and accumulated clinical experience, i.e., any adverse antiestrogenic effects that clomifene citrate may have presents no significant obstacle in the large majority of treated women.

Need for Opting for Micronized Formulation of Clomifene

Various drugs, including clomifene citrate, have poor aqueous solubility and may possess dissolution related absorption problems, potentially altering the bioavailability and resulting in suboptimal drug delivery.52Dhingra D, Bhandari A, Sharma RB, et al. Enhancement of dissolution rate of slightly soluble drug Clomifene citrate by solid dispersion. Int.J. ChemTech Res.2010;2(3):1691-1697.  53Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015;5(5):442-453.   Accordingly,several pharmaceutical processing techniques are used for enhancement of solubility of poorly soluble drugs. This include varieties of physical and chemical modifications of drug, and other methods like crystal engineering, salt formation, solid dispersion, use of surfactant, complexation,and so forth.54Savjani KT, Gajjar AK, Savjani JK. Drug solubility: Importance and enhancement techniques. ISRN Pharm. 2012;2012:195727.   Micronization is such a conventional and effective technique for particle size reduction (reducing the size of solid drug particles to 1 to 10 microns) that increases the dissolution rate of drugs through increased surface area, and has been applied to several drugs such as progesterone and norethisterone.54Savjani KT, Gajjar AK, Savjani JK. Drug solubility: Importance and enhancement techniques. ISRN Pharm. 2012;2012:195727.   55Darwish AMM. Enhancing success of assisted reproduction. Available at: http://library.umac.mo/ebooks/b28351654.pdf [Accessed on 23/9/2016].   56Pant P, Bansal K, Rao PRT, et al. Micronization: An efficient tool for dissolution enhancement of Dienogest. Int J. Drug Dev. & Res.2011;3(2):329-333.   57Bansal K, Pant P, Rao PRT, et al. Micronization and dissolution enhancement of norethindrone. IJRPC 2011;1(3):315-319.   This simple pharmaceutical method can help in better dissolution of drugs, thereby enhancing absorption and bioavailability of the drugs, and consequently enhancing their clinical efficacy.58Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol.1998;20(3):211-5.   59Krishnaiah YSR. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. J Bioequiv Availab 2010;2:028-036.  

Conclusion

Ovulation disorders, often presenting with amenorrhoea or oligomenorrhoea, are a common cause of infertility that might be amenable to ovulation induction dependent on the underlying cause of anovulation. IUI often accompanies ovulation induction, and may be suitable for many women with WHO type II ovulation disorders, which includes PCOS, the most common cause of infertility attributable to ovulation disorders. Several ovulation protocols/drugs are available for this need, but the most common protocol is the use of oral clomifene citrate. Clomifene citrate has been the most widely used treatment for fertility enhancement for >40 years, and still holds its place as a first-line therapy for ovulation induction even if several alternative/combination regimens have been proposed.A stair-step protocol of clomifene is a rational choice to decrease the time to ovulation and improve ovulation rates in women resistant to standard clomifene regimen prior to considering any alternative treatment.

Although few small studies suggest that enclomifene alone can induce ovulation, but overall clinical experience until now does not show any superiority of monoisomeric preparations over the racemic mixture of clomifene citrate.Moreover, it is the racemic mixture of clomifene citrate that is approved for use and not the monoisomeric preparation,and superiority of the latter over clomifene citrate is not justified by well-designed randomized controlled studies.

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