Oral Medication

Clomiphene Citrate

Clomid, or clomiphene citrate, or Serophene is a medication that is commonly used for the treatment of infertility. Clomid was originally developed for treatment of anovulation. The medication will often induce ovulation in women that do not develop and release an egg (ovulate) on their own, such as in women with polycyctic ovaries.

Clomid is also frequently used to stimulate extra follicles develop in the ovaries of women that already ovulate without medications. In these cases the hope is that there will be an improvement in the chance for getting pregnant by increasing the number of follicles developing in the ovaries - and therefore the number of eggs releasing. This is referred to as controlled ovarian hyperstimulation or sometimes called superovulation.

Clomid is generally started early in the menstrual cycle and is usually taken for five days either from day 3 through 7 or from day 5 through day 9

Clomid is usually started at a dose of one tablet, or 50mg daily.

Infertility specialist clinics will often add intrauterine insemination to clomiphene cycles in order to increase the chance for pregnancy. Insemination is particularly beneficial for women that already ovulate on their own and are using the Clomid to get extra egg production.

Clomid Side Effects

Clomid treatment has some potential for adverse effects. Side effects are definite "cons" of clomiphene use. Adverse effects are seen in some, but not all women using the drug.

• Mood swings, psychological / emotional side effects
• Hot flashes
• Abdominal discomfort
• Visual disturbances
• Ovarian cyst formation
• Nausea
• Thinning of the uterine endometrial lining
• Reduced production of cervical mucous - this can lower fertility (bypassed by insemination)
• Increased risks for twins and multiple pregnancy (this is sometimes a desired outcome)
• 92% singletons and around 7% twins
• Abdominal discomfort, ovarian cyst formation and nausea are also sometimes seen as side effects of clomiphene use.

Action of Letrozole

• Reduces estrogen level by 97-99%
• Releases the hypothalamo pituitary ovarian axis from negative effect of estrogen,
• More GnRh and FSH & LH Stimulates folliculogenesis in ovary.
• Acts locally in ovary to increase sensitivity to FSH.
• Rise in estrogen – physiological.

Letrozole Advantages

• No depletion of estrogen receptors in endometrium, allows proper development of endometrium.
• No effect on endometrial thickness (Fisher et al.,2002).
• Better quality of cervical mucus.
• Short half life ( 2 Days).
• Lower abortion rate, esp. in PCO pt.
• Better endometrial morphology and cervical score than CC.
• Does not adversely affect the final stage of maturation, fertilization or early cleavage of human oocytes.
• Incidence of ovarian carcinoma lower than CC.
• Increased uterine blood flow – better implantation rate.
• High pregnancy rate (16.7 Vs. 5.6 % per pt) – more physiological level of estrogen.
• Decreased chances of miscarriage, OHSS and multiple pregnancy rate.
• Dose of FSH when used in conjunction, reduced to half.

Dose Schedule

• 2.5 – 5 mg once daily from D3 – D7 for 5 days
• 20 mg as single dose on D3.
• Note : 2.5 mg daily adopted from daily dose of Letrozole for breast cancer treatment.
• Five days duration taken from 5 days cc regime.

D 3 – D 7 allows sufficient time for Letrozole to clear from the body at the time of ovulation & implantation

Side effects:

• Nausea
• Vomiting
• Constipation
• Diarrhoea
• Abdominal pain
• Dyspepsia
• Anorexia

• Musculoskeletal pain
• Arthralgia
• Headache
• Fatigue
• Dizziness
• Pruritus

Complications with CC and Letrozole

• OHSS.
• Multiple pregnancy - 10% twins.
• Ovarian enlargement or cyst formation.
• Increase abortion rate.
• Congenital anomaly
  • 2.4 % in Letrozole group
  • 4.8 % in CC group – Togas Tulandi

Clomid and Letrozole with injectable gonadotropins

Sometimes clomiphene is used in conjunction with injectable gonadotropins, particularly when the female is not responding and ovulating well with Clomid alone. Injectable gonadotropins contain FSH hormone. Therefore we can boost the FSH level in the blood by adding the injectable FSH product. There are several protocols for adding the injectables in a Clomid cycle. It is important to monitor follicle development with ultrasound scans and blood hormone levels when injectable FSH products are used. This is because using Follistim, Gonal-F, Menopur, or (injectable FSH brand names) with Clomid can greatly increase the follicle number. One example of a monitored Clomid + injectable protocol is shown here:

• Clomiphene pills taken days 3 to 7
• Start injectable FSH product (Follistim, Gonal-F, Bravelle, Menopur) on day 10 at a dose of 75 units per day
• Monitor response with estradiol and LH blood levels and ultrasound follicle scans starting on day 13
• Repeat monitoring visits as indicated by the egg production response in the ovaries
• Trigger ovulation with 10,000 units of HCG when one or two follicles are measuring about 17 to 19mm in diameter

It is very important to avoid stimulation of too many mature (or close to mature) follicles because of the risks of multiple pregnancies – including twins, triplets and higher.

Injectable Gonadotropins

Injectable fertility medications, called gonadotropins, contain follicle stimulating hormone (FSH) which causes development of one or multiple follicles when injected into women that do not ovulate.

These medications are given by intramuscular injections or subcutaneous injections on a daily basis. The injections are started early in the menstrual cycle and are continued for approximately 8-14 days until one or more mature follicles are seen with ultrasound examination of the ovaries. At that point an injection of HCG is given which induces ovulation to occur approximately 36 hours later.

Over 90% of anovulatory women can have ovulation induced with this type of therapy. Pregnancy rates per month are better than those with use of Clomid and for relatively young women with no other contributing causes to the infertility pregnancy rates per month of approximately 15% can be expected when this form of treatment is combined with intrauterine insemination. Pregnancy rates with injectable gonadotropins combined with intercourse are somewhat lower.

This type of therapy is usually tried for 3-6 months and if it does not result in a pregnancy in vitro fertilization should be considered.

Ultrasound and blood monitoring of the stimulation cycle is essential when using injectable gonadotropins as there are substantial risks associated with overstimulation if the ovaries should over respond to the medication.

This monitoring is usually done 3 times a week during the time the woman is taking the injectable medications. This adds substantially to the cost of the cycle. Some health insurance plans will pay for the entire cost of ovulation induction including insemination if that is desired. Other health insurance plans will pay for some (or none) of the costs associated with this treatment.

Complications associated with use of these medications include the possibility of overstimulation, called ovarian hyperstimulation syndrome, or OHSS. OHSS is reported to occur in approximately 1% of cycles. Hyperstimulation involves enlarged ovaries, abdominal pain, and fluid build-up within the abdomen. It may require hospitalization in extreme cases to control pain or manage the syndrome. Carefully monitored use of injectable gonadotropins can almost always avoid severe overstimulation.

Multiple pregnancy is also a possibility when these medications are used. In general approximately 75% are single, 20% are twins, 5% are triplets and 1% are quadruplets or higher.

The risk of multiple pregnancy increases with the number of mature follicles that are seen on ultrasound examination of the ovaries. However, it is often not possible to stimulate the patient so that only one mature follicle develops and multiple follicle development is usually the rule.

When many mature follicles develop the couple and the physician can have a discussion about the risks of multiple pregnancy and there is always the option of canceling the cycle by not giving the injection that causes ovulation. This essentially eliminates the risk of any pregnancy (single or multiple) occurring in that cycle.