INTRODUCTION
Ovulatory dysfunction is one of the common reasons for infertility and accounts for about 40% of female infertility.1 According to World Health Organization (WHO) classification ovulatory dysfunctions are mainly categorized into: (1) Class I—consisting of hypothalamic pituitary failure,(2) Class II—being hypothalamic pituitary dysfunction, and (3) Class III—representing ovarian failure. The hypothalamic pituitary failure (5 – 10%) and ovarian failure (5%) are less common groups with majority of the ovulatory dysfunction belonging to the Class II category. Polycystic ovarian syndrome (PCOS), which belongs to WHO Class II, is the most common cause of ovulatory dysfunction.1 Diagnosis of PCOS can be made using Rotterdam criteria or National Institute of Health (NIH) criteria. Out of the three criteria (oligo- and/or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound), presence of two are considered essential for diagnosis of PCOS under the Rotterdam criteria.2 Additionally, other endocrine disorders such as congenital adrenal hyperplasia and androgen secreting tumors should be excluded.
Oral ovulogens are drugs, which are mainly used for inducing ovulation in women with anovulatory dysfunction. They are usually the first line of treatment for patients belonging to WHO Class II. They are also used to achieve super ovulation during intrauterine insemination (IUI) in couples with unexplained infertility.3 During in vitro fertilization (IVF) treatment, they may also be combined with gonadotropins for controlled ovarian hyperstimulation (COH), commonly known as mild stimulation protocols.4
Most common oral ovulogens used in contemporary practice are clomiphene citrate (CC), aromatase inhibitors (e.g. anastrozole), and insulin sensitizers such as metformin.1,5,6 Less commonly used drugs are tamoxifen, dexamethasone, and thiazolidinediones (e.g. rosiglitazone).7,82
ORAL DRUGS FOR OVULATION INDUCTION
Clomiphene Citrate
Clinical Case # 1
“A 23-year-old Mrs X and her husband Mr Y, aged 26 years, presented with complaints of inability to conceive from last 1 year. They have been married for 2 years. Menstrual cycles are irregular (40–45 days). No dysmenorrhea. No obvious clinical signs of excess androgen observed during examination. Body mass index 24 kg/m2. On ultrasound, polycystic ovaries were seen. Thyroid-stimulating hormone (TSH) and serum prolactin levels were normal. Husband semen analysis reported as normozoospermia. Wife diagnosed as a case of PCOS. No previous treatment for infertility. The first pharmacological line of treatment for treatment naive PCOS woman is…”
Clomiphene citrate is the first-line drug used to induce ovulation in women with PCOS. It consists of two isomeric components: zu-clomiphene and en-clomiphene. Among the two, zu-clomiphene is considered more potent for ovulation induction.1 The estrogen receptors in hypothalamus are blocked by clomiphene citrate, which prevents a negative feedback of estrogen, causing a release of gonadotropin releasing hormone (GnRH). The release of GnRH results in increase in endogenous gonadotropins—follicle stimulating hormone (FSH) and luteinizing hormone (LH)—from the anterior pituitary, which promotes follicular development in the ovary. The negative impact of estrogen receptor blockade by CC at the endometrial and cervical level is considered to be the reason for lower pregnancy rates (30– 40%) even though ovulation is achieved in almost 80% of the PCOS women.1
Though the starting dose is 50 mg daily for 5 days and can be initiated from anytime between day 2 to day 5 of menstrual cycle, many clinicians prefer 100 mg daily as the starting dose. The reason for this is higher ovulation rate (67%) with 100 mg compared to 46% following 50 mg dosage, without any apparent increase in multiple pregnancy rate.9 The follicular development can be documented by an ultrasound by day 12–14 at least in the index cycle. Those with follicular development can be advised timed intercourse for at least 1 week after ultrasound. The routine administration of human chorionic gonadotropin (hCG) as a trigger for follicular rupture during ovulation induction with CC has not been found to be beneficial.10
Ultrasound monitoring helps in identifying those women who have responded to a particular dose of CC and the same dose can be adhered to for subsequent treatment cycles. In few cases, hyper-response can be noted and when more than three dominant follicles are noted, it is advisable to cancel the cycle and advise sexual abstinence for next 2 weeks.
In case no follicular development is noted, the daily dose of CC can be increased by 50 mg and a maximum of 150–200 mg per day is advised. 3Women who do not respond to the maximum dose of CC are categorized under CC resistance, and those who respond but do not conceive after three to six treatment cycles are known as CC failure. It is advisable to restrict the number of CC cycles to a maximum of 12, due to potential threefold increase in risk of ovarian malignancy in future.11
For women with CC resistance which signifies a severe form of PCOS, next treatment options include aromatase inhibitors, gonadotropins, insulin sensitizers and in some cases, laparoscopic ovarian drilling.1,12 In cases of CC failure, tubal evaluation is warranted to rule out tubal pathologies before moving to alternative options.
Clomiphene citrate may cause side effects such as nausea, hot flushes, and rarely visual disturbances.1 In case of any visual disturbance following CC is noted, it should be promptly discontinued and alternative ovulation induction agents should be offered.
Some of the less common CC regimens include stair step protocol and using CC for longer duration.
In stair step protocol, starting dose of CC (50 mg) is given for 5 days from day 2 of the menstrual cycle and ultrasound is done on day 11–14.13 In case no follicle develops, the dose is increased by 50 mg (100 mg for 5 days) and started immediately while the ultrasound is planned 1 week after the first follicular ultrasound. If no response is noted again, then the daily dose is increased to 150 mg for 5 days and repeat ultrasound done 1 week later. In clinical practice, this protocol reduces time to ovulation (23–35 days) compared to standard cyclical protocol (55–88 days). PCOS women with anovulation are more suited for this protocol than oligo-ovulation.
Clomiphene citrate is sometimes used in couples with unexplained infertility. In the Cochrane review, no significant increase in clinical pregnancy rates following CC compared to expectant management after pooling results from two trials (OR 1.03, 95% CI 0.64–1.66).11 In unexplained infertility, use of CC should be avoided since it has no proven benefit, though it increases risk of multiple pregnancies.
Aromatase Inhibitors
Clinical Case #2
“A 27-year-old Mrs X and her husband Mr Y, age 36 years, presented with complaints of inability to conceive from last 6 years. They have been married for 7 years. Menstrual cycles are irregular (40–45 days). No dysmenorrhea. No obvious clinical signs of excess androgen observed during examination. Body mass index 26 kg/m2. On ultrasound, polycystic ovaries were seen. TSH, serum prolactin, and testosterone levels were normal. Husband semen analysis reported as normozoospermia. Wife diagnosed as a case of PCOS. She gives history of ovulation induction with CC with no response at 200 mg daily dose (CC resistance). 4Hysterosalpingography demonstrated patent tubes. Sugar levels are normal. The next possible medical option for such women with CC resistance is…”
Aromatase inhibitors act at the ovarian level and prevent the conversion of androgen to estrogen. The reduced systemic levels of estrogen release the hypothalamo-pituitary axis from the negative feedback exerted by estrogen, thus resulting in increase in FSH levels. The higher androgen levels in the ovary also increases follicular sensitivity to FSH.14 Unlike CC, aromatase inhibitors do not exert peripheral antiestrogenic action and are cleared from systemic circulation more rapidly due to shorter half-life (48 hours) compared to CC which has a prolonged half-life (2 weeks). Another advantage of aromatase inhibitor is reduced chances of multifollicular development due to intact estrogen negative feedback mechanism, which reduces FSH levels with rising estrogen.14 With CC, this negative feedback mechanism is interrupted due to blockade of estrogen receptors by CC.
There were initial concerns about teratogenic effect of letrozole, an aromatase inhibitor. Subsequent studies have not shown increased congenital anomaly rate following the drug.15
Anastrozole, another aromatase inhibitor, is being used in clinical practice as an alternative oral ovulogen to CC. The recommended dose of anastrozole is 1 mg daily for 5 days from day 2 of menstrual cycle.16 The ovulation rates following anastrozole are comparable to CC (67% vs. 68%).5 It may have role in treating CC resistant PCOS women who constitute about 20–25%.17,18
Tamoxifen
Tamoxifen, a triphenyl ethylene derivative, is less commonly used drug for ovulation induction purpose. It is sometimes used in women who experience side effects following CC and rarely in CC resistant PCOS cases.8,19 The dosage is between 20 mg and 40 mg daily from day 2 or day 3 of menstrual cycle for 5 days. Live birth rates following tamoxifen were not significantly different compared to CC.8
Dexamethasone
Clinical Case #3
“A 27-year-old Mrs X and her husband Mr Y, aged 36 years, presented with complaints of inability to conceive from last 6 years. They have been married for 7 years. Menstrual cycles are irregular (40–45 days). No dysmenorrhea. No obvious clinical signs of excess androgen observed during examination. Body mass index 26 kg/m2. On ultrasound, polycystic ovaries were seen. TSH, serum prolactin, and testosterone levels were normal. Her dehydroepiandrosterone (DHEA) level is elevated. Husband semen analysis reported as normozoospermia. Wife diagnosed as a case of late onset congenital adrenal hyperplasia. 5She wants regularization of cycles and wishes to conceive. The recommended medical option for such women with late onset congenital adrenal hyperplasia (CAH) is…”
The role of dexamethasone as an ovulation induction agent is mainly confined to treating endocrinological conditions such as late onset congenital adrenal hyperplasia. However, it has been also offered in CC resistant PCOS case with normal levels of dehydroepiandrosterone sulfate (DHEAS). A randomized trial found significantly higher ovulation rates (75% vs. 15%; p < 0.01) with CC and dexamethasone compared to CC with placebo in women with CC resistance.20 The low dosage of 0.5 mg per day from day 1 to day 14 of menstrual cycles is generally recommended. Earlier study has found better pregnancy rates with higher dose of 2 mg per day instead of low dose.20
Insulin Sensitizers
Clinical Case # 4
“A 28-year-old Mrs X and her husband Mr Y, aged 36 years, presented with complaints of inability to conceive from last 4 years. They have been married for 7 years. Menstrual cycles are irregular (40–45 days). No dysmenorrhea. No obvious clinical signs of excess androgen observed during examination. Body mass index 30 kg/m2. On ultrasound, polycystic ovaries were seen. TSH, serum prolactin, and testosterone levels were normal. Husband semen analysis reported as normozoospermia. Wife diagnosed as a case of PCOS. She gives history of ovulation induction with CC with no response at 200 mg daily dose (CC resistance). Hysterosalpingography demonstrated patent tubes. She is diagnosed with impaired glucose tests. She has been advised weight reduction and given dietary advice. The next possible medical option for such women with CC resistance is‥”
Most common insulin sensitizer used in PCOS women is metformin. Though its influence on weight reduction is not clearly established, it is commonly advised in PCOS women with impaired glucose.2 It is also an option in women with CC resistant PCOS. In a randomized controlled trial (RCT) which included women with CC resistance, intervention arm consisted of metformin for 6 months followed by CC again. In the control arm, ovulation induction with gonadotropin was planned. No significant difference in clinical pregnancy rates was observed in the two groups and lower cost of metformin was an added advantage.21 Recent update has reported improvement in menstrual cycle regularity and ovulation rate following metformin compared to placebo.22 Metformin is associated with severe gastrointestinal side effects, which can lead to patient compliance issues. Usual recommended dose is 500–1,500 mg daily though it should be initiated with low dose and gradually titrated after assessing the tolerance.226
Since metformin is considered safe in pregnancy, clinicians continue its use during pregnancy once the woman conceives. This is done to help in improving metabolic profile and reduce the risk of gestational diabetes in PCOS women. A recent large trial however did not show any improvement in complication rate during pregnancy by continuing metformin throughout the gestation.23
There is paucity of trials evaluating other newer insulin sensitizers such as thiazolidionedines and d-chiro-inositol. Thiazolidionedines are mainly used for treating type 2 diabetes mellitus. Due to their beneficial action in improving insulin resistance, many clinicians have advocated its use in women with PCOS. A study found young PCOS women with pioglitazone had improvement in menstrual symptoms.24
However, there are ongoing concerns regarding side effects, weight gain, and safety during pregnancy with these drugs. Though many of these drugs showed initial promise, currently the evidence is insufficient to recommend their use for ovulation induction purpose.22,25
Oral Ovulogens for Ovarian Stimulation during Intrauterine Insemination
Commonly, ovarian stimulation is combined with intrauterine insemination (IUI) to achieve super ovulation (more than one follicle) in couples with unexplained infertility, mild male factor, or minimal endometriosis. Various agents are used for ovarian stimulation such as CC, aromatase inhibitors, gonadotropin or combination of oral ovulogens with gonadotropins.
Clomiphene or aromatase inhibitors are combined with gonadotropin to lower total dosage requirement of gonadotropin, which reduces the cost without compromising on IUI outcomes. Clomiphene citrate (100 mg) is started from day 2 of menstrual cycle and continued for 5 days. The gonadotropin (75 IU) is initiated from day 5 and given on alternate days and follicular monitoring is done from day 10. Satisfactory pregnancy rates are achieved using combination of CC and gonadotropin during IUI.26 Similar combination protocol (CC and gonadotropin) also can be used for achieving ovulation induction instead of gonadotropin alone in CC resistant or CC failure cases as pregnancy rates are comparable.12
Use of Oral Ovulogens in Mild Stimulation Protocols
Clinical Case #5
“A 37-year-old Mrs X and her husband Mr Y, aged 46 years, presented with complaints of inability to conceive from last 6 years. They have been married for 7 years. Menstrual cycles are regular. Body mass index 21 kg/m2. 7On ultrasound, normal ovaries and total antral follicle count of 5 was noted. TSH and serum prolactin levels were normal. Husband semen analysis reported as severe oligoasthenozoospermia. Couple underwent for IVF with conventional stimulation of high gonadotropins. Three oocytes were retrieved and cycle was unsuccessful. The couple wishes to try another autologous IVF. The possible options for controlled ovarian hyperstimulation (COH) include…”
Oral ovulogens such as CC and aromatase inhibitors have been used for mild stimulation protocol during IVF. Use of CC in these protocols is quite common and some of the benefits include lower gonadotropin requirements and less cost during IVF.27,28 They also are patient-friendly protocols and pregnancy rate for certain subset of patients is comparable to conventional IVF. The milder stimulation has added advantage of higher yield of euploid embryos compared to conventional high dose gonadotropins.29
The Cochrane review which included 12 trials and 2,536 participants found comparable live birth rates following CC and gonadotropin compared to gonadotropin alone during IVF (OR 0.93, 95% CI 0.69–1.24). The ovarian hyperstimulation syndrome (OHSS) rates were significantly lower in the CC and gonadotropin group (0.8–1.8%) compared to gonadotropin agonist protocol (3.5%).4 The mild stimulation protocol has been advocated in women who had poor response or unsuccessful outcome in previous conventional IVF with high dose of gonadotropins. A recent systematic review which included four trials, evaluated CC with gonadotropin versus conventional gonadotropin alone in poor responders. They found no significant differences in live birth rates (OR: 0.71, 95% CI 0.22–2.2) and clinical pregnancy rates (OR: 1.11, 95% CI 0.80–1.55) following CC with gonadotropin compared to gonadotropin alone.27
Clomiphene citrate has also been used to prevent premature LH surge during IVF instead of GnRH analogs. In this protocol, CC is initiated from day 2 of the cycle and continued till the day hCG trigger is given. Continuous use of clomiphene citrate blocks estrogen receptors’ sites at the hypothalamus and pituitary. Clomiphene used in this fashion mimics the action of a GnRH analog and prevents an LH surge due to rising estrogen levels, a result of follicular development. Low dose gonadotropins 75–150 IU are also added to enhance the response. Hence, conventional GnRH analogs are not required for prevention of premature LH surge.30 This protocol is quite useful in low cost IVF program since the GnRH analogs are not used, and gonadotropin requirement is less.28
KEY SUMMARY POINTS
- Clomiphene citrate is the first choice for inducing ovulation medically in PCOS.
- For CC failure, alternatives are aromatase inhibitors or gonadotropins alone or in combination with CC or aromatase inhibitors.
- If resistant to CC, the next options are aromatase inhibitors, insulin sensitizers, gonadotropins, or surgical intervention for ovarian drilling.
- Metformin is recommended for women with PCOS who have impaired glucose tolerance and CC resistance. Currently other insulin sensitizers are not recommended for routine ovulation induction due to insufficient evidence.
- Tamoxifen is another alternative antiestrogen which can be advised in CC failure.
- Dexamethasone can be offered as an adjuvant along with CC in women with CC resistance.
- Clomiphene citrate and aromatase inhibitors can be combined with gonadotropins in mild stimulation IVF protocols, especially in poor responders.
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- Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–77.
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- Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1–50.
- Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril. 2004;82:893–902.
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- Hurst BS, Hickman JM, Matthews ML, et al. Novel clomiphene “stair step” protocol reduces time to ovulation in women with polycystic ovarian syndrome. Am J Obstet Gynecol. 2009;200:510.e1–510.e4.
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- Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with Letrozole or Clomiphene citrate. Fertil Steril. 2006;85:1761–5.
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- Elnashar A, Abdelmageed E, Fayed M, Sharaf M. Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study. Hum Reprod. 2006; 21(7):1805–8.
- George SS, George K, Irwin C, et al. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod. 2003;18(2):299–304.
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