Fertility Blaze
Fertility Blaze 2017 › Fertility Blaze Vol-4, No-2, 2017

Evaluating the Landscape of Clomiphene Citrate (CC) Protocols

INTRODUCTION AND PREVALENCE

According to the World Health Organization – the International Committee for Monitoring Assisted Reproductive Technology (WHO-ICMART) glossary infertility is defined as a failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.1Sexual and reproductive health. Available from: http://www.who.int reproductivehealth/topics/infertility/definitions/en/ [Accessed on 24th May 2017]   Infertility varies across regions of the world and is estimated to affect 8 to 12% of couples worldwide. The WHO estimates of primary infertility in India are 3.9% (age-standardised to 25-49 years) and 16.8% (age-standardised to 15-49 years), using the “age but no birth” definition. Estimates of infertility vary widely among Indian states from 3.7% in Uttar Pradesh, Himachal Pradesh and Maharashtra, 5% in Andhra Pradesh and 15% in Kashmir.2Adamson PC, Krupp K, Freeman AH, et al. Prevalence and correlates of primary infertility among young women in Mysore, India. Indian J Med Res. 2011;134(4): 440–446   The fertility of a couple depends upon several factors in both the male and female partner. The male and female partners are evaluated to determine the cause of infertility.3Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]

Causes of female factor infertility:4Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician. 2007; 75:849-56, 857-8

  • Ovulation disorders (e.g., polycystic ovary syndrome, premature ovarian failure)
  • Tubal factors (e.g., pelvic inflammatory disease )
  • Endometriosis
  • Uterine/cervical factors (e.g., Fibroids, polyps, poor cervical mucus)

Causes of male factor infertility:4Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician. 2007; 75:849-56, 857-8

  • Unknown
  • Primary hypogonadism (e.g., Klinefelter syndrome, orchitis, varicocele, Y chromosome defect)
  • Secondary hypogonadism (e.g., Pituitary adenoma, sarcoidosis, tuberculosis, trauma)
  • Altered sperm transport

Factors that affect the fertility of both sexes include the following:5About infertility. Available from: http://www.hfea.gov.uk/infertility.html [Accessed on 24th May 2017]  6Puscheck EE. Infertility. Available from: http://emedicine.medscape.com/article/274143-overview#showall [Accessed on 24th May 2017]

  • Environmental/occupational factors
  • Toxic effects related to tobacco, marijuana, or other drugs
  • Excessive exercise
  • Inadequate diet associated with extreme weight loss or gain
  • Advanced age
  • Medical conditions such as diabetes, epilepsy and thyroid and bowel diseases
  • Lifestyle factors such as stress, being overweight or underweight and smoking

ANOVULATION

Ovulation is the result of a maturation process that occurs in the hypothalamic-pituitary-ovarian (HPO) axis and is orchestrated by a neuroendocrine cascade terminating in the ovaries.7Hernandez-Rey AE. Anovulation. Available from: http://emedicine.med scape.com/article/253190-overview#showall [Accessed on 24th May 2017]   Ovulation usually occurs about 12 to 14 days before the next menstrual period3Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]   (Figure 1).8Lu Kong L, Tang M, Zhang T, et al. Nickel Nanoparticles Exposure and Reproductive Toxicity in Healthy Adult Rats. International Journal of Molecular Sciences. 2014;15(11):21253-69. DOI: 10.3390/ijms151121253

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Ovulatory disorders occur if there is any alteration which results in a failure to release a mature ovum. Anovulation may manifest in a variety of clinical presentations, from luteal insufficiency to oligomenorrhoea.7Hernandez-Rey AE. Anovulation. Available from: http://emedicine.med scape.com/article/253190-overview#showall [Accessed on 24th May 2017]   Anovulation is a major cause of infertility. Based on the circulating concentrations of gonadotropin and oestrogen, WHO has classified infertility into three categories:9Palshetkar N, Roongta N. Protocols for Ovulation Induction. Available from: http://www.fogsi.org/wp-content/uploads/2015/05/pdf/editor/ dr_reshma_pai/5.pdf [Accessed on 24th May 2017]

  • Hypothalamic-pituitary failure/hypogonadotropic hypogo nadism (WHO-I)
  • Hypothalamic-pituitary-ovarian axis dysfunction/normogo nadotropic (WHO-II)
  • Premature ovarian failure/Hypergonadotropic hypo gonadism (WHO-III)

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder which accounts for approximately 80% of women with anovulatory infertility.10Balen AH, Morley LC, Misso M, et al. Polycystic The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human Reproduction Update. 2016;1–22,. doi:10.1093/humu pd/dmw025   Based of symptomatology incidence varies between 4-5% to 21% (menstrual abnormalities) and 3.5-9% (hyperandrogenism). It is important that, 40% of women with oligomenorrhoea, 84% of women with hirsuitism and 100% of women presenting with severe acne, have PCOS as their aetiology.11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]   The management of anovulation is complex. It includes lifestyle modification (diet and exercise), medical care and surgical care. The goal of pharmacotherapy is to relieve symptoms and minimise complications.7Hernandez-Rey AE. Anovulation. Available from: http://emedicine.med scape.com/article/253190-overview#showall [Accessed on 24th May 2017]   Medications to treat anovulation include clomiphene citrate (CC), tamoxifen citrate, aromatase inhibitors, insulin sensitizers, metformin, rosiglitazone, pioglitazone, gonadotropins, GnRH analogues, bromocriptine and cabergoline.11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]

USE OF CLOMIPHENE CITRATE (CC) FOR OVULATION INDUCTION

Introduction

The introduction of CC into clinical medicine in 1967 revol- utionised the treatment of infertility in general and of PCOS in particular. It is available as a racemic mixture of trans (62%) and cis (38%) isomers.10 CC is a weak oestrogen-like hormone that acts on the hypothalamus, pituitary gland, and ovary to increase levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).3Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]

Mechanism of action

CC is an anti-estrogenic and exerts this effect by competitive binding with oestrogen 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 oestrogen, CC induces FSH stimulation of LH receptors in granulosa cells. This results in growth of the dominant follicle and its subsequent maturation.11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]   Although CC is known to have a relatively long half life, approximately 85% of the drug is excreted from the body after seven days11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]   12Antal I The importance of micronization in the design of dosage forms I. Theoretical and biopharmaceutical aspects. Acta Pharm Hung.2006;76(2): 95-103.   (Figure 2)13Thomas S, Sudharshini S. Polycystic ovarian syndrome: Treatment options for infertility. Curr Med Issues. 2016; 14(4): 87-93. DOI: 10.4103/0973-4651.194459

Indications

Despite the use of CC in controlled ovarian stimulation, its original indication of ovulation induction for WHO group II classification of oligo- or anovulation, particularly when associated with PCOS, remains its most frequent and most successfully treated indication.14Homburg R. Clomiphene citrate—end of an era? A mini-review Human Reproduction. Advance Access publication. 2005; 20(8):2043–2051 doi:10.1093/humrep/dei042

Pre-requisites before treatment

Before any infertility treatment begins, a woman and her partner should undergo an infertility evaluation to be sure that CC is the best treatment. This evaluation includes:3Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]  11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]

  • Evaluation of male partner
  • Complete history and physical examination
  • Age and duration of infertility
  • Cause of infertility
  • Galactorrhoea and prolactin levels
  • Thyroid function
  • Pituitary function by baseline hormonal evaluation

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Recommended Dose of CC

Recently The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines along with The American College of Obstetricians and Gynecologists (ACOG) recommendations state that CC should be used for a maximum of 12 months in patient’s lifetime and for a maximum of six months continuously. According to ACOG Practice Bulletin 2002, the maximum dose of CC is 250 mg/day, but a dose above 150 mg/day is avoided as there are adverse effects of the cumulative doses in the same cycle on the endometrium and has systemic side effects.11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]

Protocol for Starting CC

The first day of bleeding is called cycle day 1. CC is usually started on day 2, 3, 4, or 5 of the menstrual cycle at a dose of 50 mg once-daily for five days. If ovulation does not occur during the first month, the CC dose is increased by 50 mg each month until ovulation occurs11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]  (Figure 3).13Thomas S, Sudharshini S. Polycystic ovarian syndrome: Treatment options for infertility. Curr Med Issues. 2016; 14(4): 87-93. DOI: 10.4103/0973-4651.194459

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Monitoring of CC Induced Cycles

Results of CC Therapy

CC is the first drug of choice used in management of anovulatory infertility. Ovulation is seen in 70-80% of patients–however only 40% of these will conceive. There is a 5% multiple pregnancy and development of ovarian hyperstimulation syndrome (OHSS) though rare can be life threatening condition.11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]

Benefits of Micronisation

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.15,16 Accordingly, several pharma-ceutical processing techniques are used for enhancement of solubility of poorly soluble drugs. The importance of micronisation is based on Noyes-Whitney equation, where the particle characteristics influence the active surface contacting with the dissolution medium, theoretically the solubility, and the boundary layer around the particle under certain hidrodynamic conditions (Figure 4).11Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]

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It is a simple technique that refers to transfer of coarse drug powder to an ultrafine powder with the mean particle size in the range of 2–5 μm and only a very little fraction of the particles lie below 1 μm size range. 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.17Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol. 1998;20(3):211-5   18Krishnaiah YSR. Pharmaceutical Technologies for Enhancing Oral Bioavailability of Poorly Soluble Drugs. J Bioequiv Availab. 2010;2:28- 36. doi:10.4172/jbb.1000027

Adverse Effects

Risks of CC therapy include a slightly increased rate of multiple pregnancies. Common side effects of CC include hot flashes, headaches, abdominal bloating and pain, nausea and vomiting, mood changes, and breast tenderness. Visual symptoms such as blurring, double vision, or seeing spots occur in 1 to 2% of women, and usually resolve when treatment stops.3Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]

NOVEL CC ‘STAIR-STEP’ PROTOCOL VS. TRADITIONAL PROTOCOL

Traditional used CC protocol for ovulation induction involves a starting dose of 50 mg per day for 5 days during the follicular phase. If ovulation does not occur, the dose is often increased by 50 mg in the next cycle after a progesterone-induced withdrawal period. A new protocol is the stair-step protocol in which the increasing daily CC dose is administered without intervening menses between the dosages.19Abd Elsalam WY, Mohammed EM, Safwat HI. Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome:a randomized controlled trial. NY Sci J. 2017;10(1):113-119. doi:10.7537/marsnys100117.19.   In this protocol, once failure to ovulate to a given dose is recognized by day 14–21, the higher dose of CC is started immediately without first inducing a withdrawal bleed with progestin. The advantage of this protocol is a shorter time to achieve ovulation when increasing doses of CC are required. In addition, inducing a menstrual bleed with progestins before clomiphene therapy in anovulatory women has been associated with a lower conception and live birth rate compared with women in whom CC was started in the follicular phase remote from spontaneous or induced menses20The Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertility and Sterility. 2013;100(2):341–8. http://dx.doi.org/10.1016/j.fertnstert.2013.05.033   (Figure 5).21Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA. Is clomiphene citrate stair-step protocol a good alternative to gonadotrophins in clomiphene-resistant PCO patients? Prospective study. J. Obstet. Gynaecol.Res. 2016. doi:10.1111/jog.12940

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LUTEAL PHASE CC FOR OVULATION INDUCTION

Ding N et al., conducted a systematic review and meta-analysis to assess the efficacy of late luteal phase CC administration relative to early follicular phase CC for ovulation induction for PCOS. Late luteal phase group was associated with a number of higher total follicles (MD 1.82; 95% CI 0.86–2.78, p<0.00001) and significant higher endometrial thickness on the day of HCG (MD 0.88; 95% CI 0.78–0.99, p<0.00001) compared with early follicular group. It appeared that late luteal phase CC for ovulation induction might be an effective method for ovulation induction in women with PCOS compared to conventional CC administration.22Ding N, Chang J, Jian Q, et al. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a systematic review and meta-analysis. Gynecological Endocrinology. 2016. DOI: 10.1080/ 0951 3590.2016.1197196

A prospective, randomised, controlled trial conducted on 252 women (cycles) with PCOS to test a new protocol of luteal phase administration of CC for ovulation induction. Patients in Group 1 (n=126) received 100 mg of CC daily for 5 days starting on day 5 of menses, and patients in Group 2 (n=126) received 100 mg of CC daily for 5 days starting the next day after finishing medroxy progesterone acetate (MPA) (before with drawal bleeding). The total number of follicles and the number of follicles ≥14 mm during stimulation were significantly greater in Group 2. The endometrial thickness at the time of human chorionic gonadotrophin (hCG) administration was significantly greater in Group 2 as compared to Group 1 (7.84 ± 1.22 and 8.81 ± 0.9, respectively). Serum E2 levels were also significantly higher (p < 0.05) in Group 2 as compared to Group 1 (449.61 ± 243.45 vs. 666.09 ± 153.41 pg/mL). Pregnancy occurred in 13 patients (10.3 %) in Group 2 and in 11 patients (8.7 %) in Group 1. Thus, luteal phase administration of CC in patients with PCOS leads to increased folliculargrowth and endometrial thickness, which might result in a higher pregnancy rate.23Kosar O, Ozaksit G, TaskinMI. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome. Archives of Gynecology and Obstetrics. 2014;290(4): 771–775. DOI: 10.1007/s004040143280y

A prospective, randomised, controlled trial was conducted to evaluate a novel protocol of luteal phase administration of CC for ovulation induction in women with PCOS. A total of 212 women with PCOS were divided into early CC group (n= 110, 100 mg daily starting the next day after finishing MPA for 5 days) and late CC group (n=102, 100 mg of CC daily for 5 days starting on day 3 of the menses). There were more ovulating patients in the early CC group (59.1% vs. 51.9%), without significant differences. The total number of follicles and the number of follicles > or=14 mm and > or = 18 mm during stimulation were significantly greater in the early CC group. The endometrial thickness at the time of hCG administration was significantly greater in the early CC group (9.1 +/0.23vs. 8.2 +/0.60 mm). Pregnancy occurred in 23/110 cycles in the early CC group (20.9%) and 16/102 cycles(15.7%) in the late CC group. Thus, early administration of CC in patients with PCOS leads to more follicular growth and endometrial thickness, which might result in a higher pregnancy rate.24Badawy A, Inany H, Mosbah A, et al. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a novel protocol. Fertil Steril. 2009;91(3):83841. doi:10.1016/j.fertnstert.2008.01.016. Epub 2008 Mar 7.

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ADVANTAGES OF CC OVER LETROZOLE

Letrozole is aromatase inhibitors which is a non-steroidal compound that suppresses oestrogen biosynthesis by blocking the action of the enzyme aromatase which converts andro-stenedione and testosterone to oestrogens. They are widely used for the treatment of post-menopausal women with advanced breast cancer. It is given orally in a dose of 2.5–5 mg/day and is almost free of side effects. Fatemi et al., conducted a small pilot study comparing CC (100 mg/day) with letrozole in intrauterine insemination (IUI) cycles demonstrated significantly less estradiol and fewer follicles developing in the letrozole cycles.14Homburg R. Clomiphene citrate—end of an era? A mini-review Human Reproduction. Advance Access publication. 2005; 20(8):2043–2051 doi:10.1093/humrep/dei042

Seyedoshohadaei F et al ., conducted a randomised single-blinded prospective controlled clinical trial to compare the effectiveness of clomiphene, tamoxifen and letrozole in ovulation induction outcomes in isolated non-PCOS anovulatory patients. A total of 150 anovulatory infertile women, who had isolated non-PCOS were divided into three groups. Group A received CC 50 mg to maximum 150 mg for 5 days; Group B received tamoxifen 10 mg to maximum 30 mg for 5 days and Group C received letrozole 2.5 mg for 5 days, to maximum 7.5 mg until ovulation was induced. The main outcome measures were: number of mature follicles, endometrial thickness, pregnancy rate, multiple pregnancy rate, live birth and miscarriage. Overall ovulation rate was 60 (73.4%), in group A was 39 (78%), in group B was 24 (68%) and in group C was 37 (74%). Pregnancy rate in groups A was 32 (64%), in group B was 20 (40%), and in group C was 25 (50%). Live birth rate was 22 (44%) in A, 17 (34%) in B and 21 (42%) in C. Miscarriage rate with CC was 10 (20%) while this was 3 (6%) in tamoxifen and 4 (8%) in letrozole group (p=0.05) (Table 1). CC showed higher pregnancy rate. Thus it was considered as the first-line therapy for ovulation induction.25Seyedoshohadaei F, Zandvakily F, Shahgeibi S. Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation. Iran J Reprod Med. 2012 Nov; 10(6): 531–536

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Liu C et al., conducted a prospective randomised controlled trial to compare the therapeutic efficacy of CC and letrozole (LE) on ovulation, pregnancy, and live birth in women with PCOS; and to ensure if LE can replace CC as the first-line therapy for ovulation induction in these women. A total of 268 anovulatory PCOS patients were treated by CC or CC plus metformin and LE or LE plus metformin for three continuous cycles or conception.

The primary measures like ovulation rates, pregnancy rates, and live birth rates were calculated and compared. The ovulation rate was significantly higher in the group LE than the group CC; however, no significant difference was noted between the groups LE and CC, CC, and CC+MET, or LE and LE+MET in the pregnancy rate, abortion rate, and live birth rate. No birth defect was found in the total of 63 newborns. Thus, CC regimen was still recommended to be the first-line therapy of ovulation induction for PCOS.26Liu C, Feng G, Huang W, et al. Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial. Gynecol Endocrinol. 2017:1-5. doi: 10.1080/ 09513590.2017.1332174. [Epub ahead of print]

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CONCLUSION

The most common cause of infertility in women is anovulation. The WHO classification offers a useful frame for diagnosis and treatment. PCOS is the most common cause of oligoovulation and anovulation. The most popular drug used in ovulation induction is CC.For the optimisation of the physicochemical characteristics of drug, dissolution enhancement and appropriate bioavailability, there is need of micronisation. A novel “stairstep” CC protocol in women who is PCOS CC-resistant proves to be efficacy and safe. Luteal phase administration of CC in patients with PCOS leads to increased follicular growth and endometrial thickness, which results in a higher pregnancy rate. Thus, the present data shows that new protocol of CC treatment leads to more follicular growth and endometrial thickness, resulting in the ovulation induction and higher pregnancy rate.

REFERENCES

  1. Sexual and reproductive health. Available from: http://www.who.int reproductivehealth/topics/infertility/definitions/en/ [Accessed on 24th May 2017]
  2. Adamson PC, Krupp K, Freeman AH, et al. Prevalence and correlates of primary infertility among young women in Mysore, India. Indian J Med Res. 2011;134(4): 440–446
  3. Hornstein MD, Gibbons WE. Patient education: Ovulation induction with clomiphene (Beyond the Basics). Available from: https://www. uptodate. com/contents/ovulation-induction-with-clomiphene-beyond-the-basics [Accessed on 24th May 2017]
  4. Jose-Miller AB, Boyden JW, Frey KA. Infertility. Am Fam Physician. 2007; 75:849-56, 857-8
  5. About infertility. Available from: http://www.hfea.gov.uk/infertility.html [Accessed on 24th May 2017]
  6. Puscheck EE. Infertility. Available from: http://emedicine.medscape.com/article/274143-overview#showall [Accessed on 24th May 2017]
  7. Hernandez-Rey AE. Anovulation. Available from: http://emedicine.med scape.com/article/253190-overview#showall [Accessed on 24th May 2017]
  8. Lu Kong L, Tang M, Zhang T, et al. Nickel Nanoparticles Exposure and Reproductive Toxicity in Healthy Adult Rats. International Journal of Molecular Sciences. 2014;15(11):21253-69. DOI: 10.3390/ijms151121253
  9. Palshetkar N, Roongta N. Protocols for Ovulation Induction. Available from: http://www.fogsi.org/wp-content/uploads/2015/05/pdf/editor/ dr_reshma_pai/5.pdf [Accessed on 24th May 2017]
  10. Balen AH, Morley LC, Misso M, et al. Polycystic The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human Reproduction Update. 2016;1–22,. doi:10.1093/humu pd/dmw025
  11. Parihar M. Optimizing Ovulation Induction. Available from: http:// www. fogsi. org/optimizing-ovulation-induction/ [Accessed on 24th May 2017]
  12. Antal I The importance of micronization in the design of dosage forms I. Theoretical and biopharmaceutical aspects. Acta Pharm Hung.2006;76(2): 95-103.
  13. Thomas S, Sudharshini S. Polycystic ovarian syndrome: Treatment options for infertility. Curr Med Issues. 2016; 14(4): 87-93. DOI: 10.4103/0973-4651.194459
  14. Homburg R. Clomiphene citrate—end of an era? A mini-review Human Reproduction. Advance Access publication. 2005; 20(8):2043–2051 doi:10.1093/humrep/dei042
  15. Dhingra D, Bhandari A, Sharma RB, et al. Enhancement of dissolution rate of slightly soluble drug Clomiphene Citrate by Solid Dispersion. Int. J Chem Tech Res.2010;2(3):1691-1697.
  16. Kalepua S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B. 2015;5(5):442–453
  17. Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol. 1998;20(3):211-5
  18. Krishnaiah YSR. Pharmaceutical Technologies for Enhancing Oral Bioavailability of Poorly Soluble Drugs. J Bioequiv Availab. 2010;2:28- 36. doi:10.4172/jbb.1000027
  19. Abd Elsalam WY, Mohammed EM, Safwat HI. Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome:a randomized controlled trial. NY Sci J. 2017;10(1):113-119. doi:10.7537/marsnys100117.19.
  20. The Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertility and Sterility. 2013;100(2):341–8. http://dx.doi.org/10.1016/j.fertnstert.2013.05.033
  21. Salaheldin AbdelHamid AM, Rateb AM, Ismail Madkour WA. Is clomiphene citrate stair-step protocol a good alternative to gonadotrophins in clomiphene-resistant PCO patients? Prospective study. J. Obstet. Gynaecol.Res. 2016. doi:10.1111/jog.12940
  22. Ding N, Chang J, Jian Q, et al. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a systematic review and meta-analysis. Gynecological Endocrinology. 2016. DOI: 10.1080/ 0951 3590.2016.1197196
  23. Kosar O, Ozaksit G, TaskinMI. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome. Archives of Gynecology and Obstetrics. 2014;290(4): 771–775. DOI: 10.1007/s004040143280y
  24. Badawy A, Inany H, Mosbah A, et al. Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a novel protocol. Fertil Steril. 2009;91(3):83841. doi:10.1016/j.fertnstert.2008.01.016. Epub 2008 Mar 7.
  25. Seyedoshohadaei F, Zandvakily F, Shahgeibi S. Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation. Iran J Reprod Med. 2012 Nov; 10(6): 531–536
  26. Liu C, Feng G, Huang W, et al. Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial. Gynecol Endocrinol. 2017:1-5. doi: 10.1080/ 09513590.2017.1332174. [Epub ahead of print]
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