Clomiphene Citrate – Ovulation Induction / IUI

Clomiphene Citrate

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)

 

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.