First line of drug used for ovulation induction and ovarian stimulation in most anovulatory or oligo-ovulatory infertile women with adequate estrogen (PCOS – WHO type II)
Brands available in India:
Siphene, Clome, Clofert, Clome, Fertomid, Fertotab, Oviphene, Cerofene, Folistim, Ovoar, Rejun, Ubiphene.
- Most commonly used drug for ovarian stimulation
- Used since 1960s
- No change in success (ovulation and pregnancy rates) since introduction
- Pregnancy category X drug
- long half life of 5-21 days
- can be stored in body fat.
- (accumulation around the crucial times of implantation, organogenesis and embryogenesis)
Chemical structure & pharmacokinetics
- Non steroidal triphenylethylene derivative
- Exhibits estrogen agonist and antagonist action
- Acts mainly as an anti-estrogen
- Agonist action – when endogenous estrogen levels are extremely low
- Mixture of two stereoisomers (Enclomiphene, Zuclomiphene)
|more potent||less potent|
|half life- few days||weeks – 1 month|
|ovulation induction – stimulation||peripheral action|
- Cleared through liver and excreted in stool
- 85% clearance in 6 days
Mechanism of action:
- structurally similar to estrogen
- binds to estrogen receptors throughout the body
- binding may last upto weeks
- such extended binding depletes estrogen receptor (ER) concentrations by interfering with normal process of estrogen receptor (ER) replenishment.
- Hypothalamus is the main site of action.
- Clomiphene increases GNRH pulse frequency.
- increases pulse amplitude in pituitary.
Mechanism of action:
- ER depleted in hypothalamus
- due to negative feedback
- GnRH release from hypothalamus
- FSH,LH from pituitary
- FSH, LH levels rise for 5 days and fall later
- one or more dominant follicles emerge and mature
- rising estrogen and ovulation
Prerequisite for success with clomiphene:
- Presence of adequate estrogen levels in the body
- intact Hypothalamic-pituitary axis (to produce endogenous production)
Clomiphene ovarian stimulation protocol:
- started from 2nd – 5th days of menses (spontaneous / progestin induced).
- Dose: (12.5mg – 250mg / day)
- starting dose: 50 mg per day x 5 days.
- dose increased by 50 mg every cycle till ovulation occurs.
- once ovulation occurs, the same dose can be used for subsequent cycles.
- higher doses / day of starting does not increase success.
- dose needed for ovulation correlated with body weight.
- 50% of women respond to 50 mg / day
- success low with doses more than 150 mg / day
- failure to repond to 150 mg / day – require alternate / combined regimens
Pregnancy rate with Clomiphene citrate
- Anovulatory women
- highest in the first 3 cycles of use.
- reduced after 3 cycles and lowest after 6 cycles.
- not advisable to continue Clomiphene after 6 cycles of use.
- Ovulatory women
- not efficacious in terms of increasing the pregnancy rate.(Fujii et al, The effects of clomiphene citrate on normally ovulatory women.Fertil Steril.dec,1997)
Results of clomiphene use:
- in WHO type II anovulation – 60-80% ovulate. (2/3rd with cc 50/100 mg/day)
- upto 60% cumulative pregnancy rate after upto 3 ovulatory cycles.
- upto 85% cumulative pregnancy rate after 5 ovulatory cycles.
- in anovulatory young women with anovulation as the only cause of infertility.
- in ovulatory infertile women – lesser pregnancy rate as they have other coexisting infertility factors.
Adverse effects of clomiphene citrate
- safe and well tolerated with mild side effects.
- side effects
- due to medicine (breast tenderness,pelvic discomfort, nausea, hot flashes, visual disturbances, pre menstrual symptoms)
- due to ovulation ( Multiple pregnancy – 8%, OHSS – rare)
- severe side effects are rare (blurred vision, double vision, scotomata, optic neuropathy)
- visual side effects are contraindications to continue treatment.
- ovarian cancer – no clear association.
- congenital anomalies – slight increase in cardiac defects.
- pregnancy loss – slightly higher.
Failure of clomiphene citrate
- Ovulation failure / clomiphene resistance – failure to ovulate with clomiphene stimulation.
- due to Insulin resistance ( in PCOS)
- inappropriate indication (WHO type 1 and 3 (thyroid disorders,congenital adrenal hyperplasia,hyperprolactinemia)
- Clomiphene pregnancy failure – failure to achieve pregnancy after ovulation with clomiphene.
- anti-estrogenic effects of clomiphene.
- due to other factors (male,endometriosis,tubal,endometrial receptivity)
Anti-estrogenic effects of clomiphene citrate:
- endocervix – cervical mucus
- endometrium – endometrial growth ( endometrial thickness reduced – 30%, reduction in glandular density, number of vacuolated cells, decreased blood flow in peri-implantation stage and early luteal phase )
- ovary – corpus luteum function
- ovum – maturation, fertilization
- embryo – development
Measures to reduce anti-estrogenic effects ?
1.Estradiol administration during clomiphene treatment.
- few studies showed improved pregnancy rates with few reported (shimoya et al, 1999), (gerli et al, fert ster, 2000)
- few studies showed no improvement in outcome (ben-ami et al, gyn-ob 1994)
- few studies showed deleterious effect (bateman et al, fert ster 1996)
2.Starting clomiphene early in menstrual cycle.
3.combine with Tamoxifen / use tamoxifen as an alternative to clomiphene. (not successful)
Phytoestrogens in clomiphene cycles.
- High dose phytoestrogens (soy iso-flavones) have been tried in clomiphene iui cycles to overcome to anti-estrogenic effects on the endometrium. (Unfer et al, j soc gyn, 2004)
- needs more studies to confirm the effects.