Induction of Ovulation in Practice
Anovulatory Disorders:
– Most experts have moved away from this terminology (WHO class 1, 2, 3) & assign women to 1 of the 4 most common ovulatory disorders:
1. Hypogonadotropic hypogonadism (hypothalamic amenorrhea).
2. PCOS.
3. POI (primary ovarian insufficiency; premature ovarian failure).
4. Hyperprolactinemia.
1. Hypogonadotropic hypogonadism:
– Include functional hypothalamic amenorrhea (such as anorexia nervosa, exercise & stress) & isolated GnRH deficiency.
– Hormonal abnormalities include low serum estradiol & low or low-normal FSH dt.presumed decreased hypothalamic secretion of GnRH.
– AMH levels are low to normal as no follicular development.
– Reversing the lifestyle factors that contribute to the anovulation (low weight, excessive exercise or any condition that leads to energy deficiency) should be attempted before considering ovulation induction with medications.
– They are unlikely to respond to clomiphene citrate, but you can give one course of clomiphene prior to initiating pulsatile GnRH or Gn therapy.
– For those who ovulate, clomiphene citrate can then be continued.
– For those who do not ovulate, we suggest pulsatile GnRH as first-line therapy. If pulsatile GnRH is unavailable in your place, Gn therapy should be initiated, with both LH & FSH (these women do not respond to FSH alone).
2. Polycystic ovary syndrome (PCO):
– Represent the largest group of anovulatory women encountered in clinical practice (70-85 % of cases).
– Serum estradiol & FSH levels are normal, whereas LH may either be normal orelevated.
– The criteria for diagnosis have been referred to as the “Rotterdam criteria”
…. 2 of the following 3 are required to make the diagnosis of PCO:
1. Oligo- &/or anovulation.
2. Clinical $/or biochemical signs of hyperandrogenism.
3. Polycystic ovaries (by U/S).
– In obese women with PCO, weight loss should be attempted before starting treatment with ovulation induction agents as it restores spontaneous ovulation in many women.
– Women with PCO should be screened for impaired glucose tolerance before starting ovulation induction because of the associated risk of pregnancy complications.
3. Primary ovarian insufficiency:
– Defined as menopause before age 40 years.
– In most cases, the follicle pool is exhausted dt.accelerated follicle loss of unknown origin.
– The only effective option is IVF with donor oocytes.
– Only we have to replace the estrogen deficiency dt the increased risk of osteoporosis &cardiovascular disease.
4.Hyperprolactinemia:
– These women are anovulatory because hyperprolactinemia inhibits Gn secretion dt.inhibition of GnRH.
– So, if you measured FSH & LH, you will find them low normal or decreased.
– The measurement can be performed at any time.
– The usual normal range for serum prolactin is approximately 5-20 ng/mL.
– If an initial prolactin level is slightly elevated (21-40 ng/mL) or only borderline high, the test should be repeated before the patient is considered to have hyperprolactinemia as the hormone increase during sleep, strenuous exercise & with emotional or physical stress.
– MRI of the head should be performed in a patient with any degree of hyperprolactinemia to look for a mass lesion in the hypothalamic-pituitary region, unless the patient is taking a medication known to cause hyperprolactinemia.
– If the MRI shows a normal hypothalamic-pituitary region & there are no obvious causes of hyperprolactinemia, the diagnosis of idiopathic hyperprolactinemia is made.
– The treatment of choice for anovulatory women with hyperprolactinemia is dopamine agonists.
Goals of Induction of Ovulation :
– Induce monofollicular rather than multifollicular development & subsequent ovulation with a singleton pregnancy
– Take care, PCOS represents a risk factor for developing OHSS following ovarian stimulation with Gn.
– Start with the least invasive & simplest treatment option; subsequent options should depend upon ovarian response .
……First line>>>Weight loss for high BMI
……First line>>>Clomiphene or Letrozole with or without metformin
……Second line>>>FSH injections
……Second line>>>Ovarian drilling
……Third line>>>IVF
Induction of Ovulation Patient Selection :
– Women with hypothalamic amenorrhea (↓ GnRH) are hypoestrogenemic& are therefore unlikely to respond to Clomid. Instead, pulsatile GnRH is the first-line therapy & if pulsatile GnRH is unavailable, Gn therapy should be initiated, with both LH & FSH (these women do not respond to FSH alone).
– For women with PCOS, starts with exercise & weight loss, if high BMI, followed by ovulation induction with either Clomid or Letrozole.
– For women with primary ovarian insufficiency (POI), all ovulation induction strategies are unsuccessful.
– The treatment of choice for anovulatory women with hyperprolactinemia is dopamine agonists (will be discussed later).
CLOMIPHENE CITRATE
– Clomid has been the most widely used agent for ovulation induction for over 50 years.
– It was used as an experimental treatment option for amenorrhea caused by endometrial cancer.
– It is used most effectively in women with PCOS.
– Predictors of ovulation: younger age, lower BMI & presence of oligomenorrhea (rathe than amenorrhea )
– Weight loss should always be attempted before initiating ovulation induction in overweight or obese women with PCOS.
– Of those who ovulate, 30-40% conceive.
– Take care, fertility potential declines rapidly after 40 years of age.
– Clomid is considered as a first-line therapy for ovulation induction in non-obese women with PCOS (BMI <30).
– For obese women with PCOS (BMI ≥30), Letrozole rather than Clomid is cosidered as the first-line drug for ovulation induction because it appears to result in higher cumulative live birth rates.
Induction of Ovulation Pretreatment Evaluation
– The presence of ovulatory dysfunction (amenorrhea or irregular menses) must be established.
– If the diagnosis of ovulatory dysfunction is uncertain, a low value (<2 ng/mL) of midluteal serum progesterone conc. is more definitive.
– Laboratory testing: pregnancy test, TSH & prolactin to exclude pregnancy, thyroid disease &hyperprolactinemia because these require different treatments.
– Serum FSH should also be measured as women diagnosed with primary ovarian insufficiency are unlikely to respond to Clomid.
– Women with PCOS &hirsutism should have a 17-hydroxyprogesterone measured; if late-onset congenital adrenal hyperplasia is diagnosed, glucocorticoid therapy is a potential alternative for ovulation induction.
– Obese women with PCOS should be screened for diabetes & encouraged to lose weight before considering ovulation induction.
– HSG should be performed if the women have not conceived after 3 ovulatory cycles to exclude another tubal pathology preventing pregnancy.
– For women >35 years, do serum AMH; if <1.0 ng/mL, shift the woman for assisted reproductive interventions instead of Clomid.
Induction of Ovulation Cycle :
– Initial course: 50 mg once daily for 5 days, begin from 5th day of cycle (can start from 2nd, 3rd or 4th day) following either spontaneous or induced bleeding. However, available data suggests that conception rates may be lower in women after a spontaneous period or progestin-induced withdrawal bleed compared to anovulatory cycles without progestin withdrawal.
– Dose adjustment: Subsequent doses may be increased to 100 mg once daily for 5 days only if ovulation does not occur at the initial dose.
– Maximum dose: 100 mg once daily for 5 days for up to 6 cycles. The maximum
recommended dose in women with PCOS is 150 mg daily (ESHRE/ASRM 2008).
– Once ovulation is achieved, the same dose should be continued for 4-6 cycles.
– The couple is advised to have intercourse every other day for ONE week beginning 5 days after the last day of Clomid.
– Discontinue if ovulation does not occur after 3 courses of treatment; or if 3 ovulatory responses occur but pregnancy is not achieved.
Induction of Ovulation Monitoring :
– Determination of the ovulatory LH surge by urinary LH kits is what most clinicians recommend in practice.
– The LH surge typically occurs 5-12 days after Clomid administration is completed.
– Ovulation almost always occur within 48 hours after the detection of the urinary LH surge.
– Therefore, the interval of highest fertility is the day of the LH surge & the following 2 days.
– A mid-luteal (1 week after ovulation) serum progesterone conc. >3 ng/mL (ideally >10 ng/mL) provides reliable evidence that ovulation has occurred.
– Some expert groups, such as RCOG & NICE, suggest serial transvaginal U/S to monitor the number & size of the developing follicles & to time hCG administration if necessary. Serial transvaginal ultrasound may also provide evidence of ovulation (follicle enlargement followed by collapse suggests ovulation). Some advocate U/S monitoring of just the first clomiphene cycle in order to exclude hyperresponse with the dose used.
– The management of ovarian enlargement/theca lutein cysts from ovarian stimulation is controversial. Withholding Clomid in these cases until the cyst(s) disappear either spontaneously or after suppression with COC is recommended.
– Induction of ovulation by Clomid increases the probability of multifetal pregnancy. The risk may be reduced by U/S monitoring & withholding hCG, IUI, or intercourse if >2 follicles >15 mm diameter are seen.
Induction of Ovulation Outcomes :
– 60-85% of anovulatory women dt. PCOS, ovulate in response to Clomid. Of those who ovulate, 50% do so at a dose of 50 mg daily for 5 days.
– After 6 months of treatment, the pregnancy rate per cycle falls substantially despite regular ovulation.
– Failure to conceive despite ovulatory cycles, particularly at higher doses, may be due to Clomidantiestrogenic effects on the cervical mucus & on the endometrium; impairing implantation.
– As noted above, HSG should be performed, if not already done, in any woman who fails to conceive within 3-6 treatment cycles.
– Failure to conceive after a maximum of 6 ovulatory treatment cycles indicates a need to further evaluate for factors potentially causing infertility or to change to another treatment strategy.
Induction of Ovulation Modified Regimens :
– Addition of ovulatory dose HCG: absent or inadequate midcycle LH surge may result in a failure to ovulate or a short luteal phase, despite Clomid-induced follicular development. In this situation, exogenous hCG single dose 10,000 IU intramuscular may be added to the regimen. It is given when transvaginal U/S (TVS) shows that the dominant follicle has reached 18-20 mm in diameter. It should be noted that premature administration of hCG acts like a premature LH surge & may result in follicular atresia. Serial TVS to monitor follicle size is superior & should be used to time HCG administration. Ovulation occurs approximately 36-44 hours after the injection.
– Progesterone supplementation may also be used for luteal phase support in women treated with Clomid dt.theantiestrogenic effects of Clomid on the endometrium & inhibition of steroidogenesis in granulosa & lutein cells, especially with high doses of Clomid.
– Strategies to prevent thin endometrium: giving half-dose Clomid (25 mg/day) or early administration (starting day 1).
– Intrauterine insemination can be added if there is some sort of male factor infertility.
METFORMIN
– A consensus group has recommended against the routine use of metformin (including ovulation induction), except in women with glucose intolerance.
Induction of Ovulation in Practice