Ovulation Induction Method of IVF

For IVF (in vitro fertilization) we want to retrieve many good quality oocytes, but for success we need to choose suitable protocols. Ovulation induction is when we allow the follicles to develop and control their maturation until retrieval. Therefore, choosing an adequate ovulation induction method is a very important step. There are many ovulation induction methods below, we will discuss the many factors involved in selecting the method that matches the patients needs.

Ovulation Induction Method

Considerations in Selecting an Ovulation Induction Method

  • Pituitary Hormone (FSH LH)
  • Ovarian Hormone (E2 P4)
  • AMH
  • Age
  • Male factor (semen observation, age)
  • Previous Oocyte Pick-up Cycles
  • Possible number of visits
  • Whether or not there is a limit on the oocyte pick-up day
  • Either one or both members of the couple live far away or overseas

Features of Each Method

Continue reading to see advantages, considerations, purposes, and costs.

Stimulation Method

FSH/HMG injection is administered from the third day of the menstrual cycle. The type and dose vary.

Usually, the dose is 150 IU a day for people in their 20s, 150-300 IU for people in their 30s, 300 IU for people in their late 30s to 40s, and 450 IU for cases with poor response. (Recombinant products such as Gonal F® are used in a slightly smaller amount.) The follicle size can be measured appropriately and the number of oocytes collected can be adjusted.

Agonists (mainly nasal drops, rarely subcutaneous injections) and antagonists (abdominal subcutaneous injections) are used as methods to suppress ovulation before oocyte pick-up. Recently, a new method using MPA (internal use) has been adopted.

There is a short method, a long method, and an ultra-long method depending on the time when the agonist is started.
The short method starts from the first day of menstruation, the long method starts from the high temperature metaphase of the previous cycle, and the ultra-long method starts from several months prior.

The antagonist is usually given as 3mg on the 6th day of the menstrual cycle, and then added every 4 days until the oocyte pick-up schedule is prepared.

The HMG-MPA method is used in combination with 10 mg daily when ovulation is induced.

Advantage ・ The number of oocytes collected is large, and good oocytes can be selected.
・ Easy to secure frozen oocytes.
・ The endometrium does not become thin.
・ The number of developing follicles can be controlled.
・ There are few post-ovulation troubles and fewer vacuoles (especially when an agonist is used).
Points to Consider ・ It is necessary to go to the hospital for injections every day (however, self-injection and injection at a nearby doctor are also possible)
・ May develop ovarian hyperstimulation syndrome (OHSS)
・ If the number of developing follicles is large (10 in our hospital), all embryos will be frozen to avoid ovarian stimulation syndrome, so embryo transfer may not be possible in the same cycle.
Good Candidates ・ Those who have a large number of desired oocytes
・ Those who want to freeze many embryos.
Cost Notes Since the amount of injections increases and the number of frozen oocytes increases, the cost for collecting oocytes at one time is high, but if multiple frozen oocytes can be secured, the number of oocyte pick-ups will decrease accordingly, so on the contrary, in total It can be kept low.

The advantages and disadvantages of each stimulation method are described below.

Agonist Method

Short Method

Advantages ・For 2-3 days immediately after the start of the agonist, flare-up of pituitary hormone (rebounding after suppression) can be used for follicle development.
Points to Consider ・ Agonists cannot be used for oocyte maturation, and HCG is used, which may lead to ovarian hyperstimulation syndrome.
・ If the ovarian reserve is low, the suppression may be too effective and follicle development deteriorates.
Good Candidate The majority of people who have good ovarian reserve.
Remarks There is also an ultra-short method in which the agonist is used for only 2 to 3 days and only flare-up is used, but in that case, it is necessary to use an antagonist to suppress ovulation.
Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発ショート法スケジュール

記号説明

Long method

Advantages ・ Since the pituitary hormone is completely suppressed before the fertility drug is started, follicle development becomes uniform.
・ There is almost no possibility of ovulation. Therefore, it is easy to control oocyte pick-up date.
Points to Consider ・Since the pituitary hormone is completely suppressed, the injection amount is increased.
・ If the ovarian reserve is low, follicles will not grow.
・Contraception in the previous cycle is required.
・ Agonists cannot be used for oocyte maturation, and HCG is used, which may lead to ovarian hyperstimulation syndrome.
Good Candidate ・Polycystic ovary (PCO)
・ Younger people
・Those who need to control the oocyte pick-up date

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発ロング法スケジュール

記号説明

Ultra-Long Method

ウルトラロング法薬剤

Ovulation induction begins after pituitary hormone is completely suppressed for several months. At the time of beginning injections, there is no menstruation. Subcutaneous injections such as Leuprorelin®, nasal drops Buserelin®, and Sprecure® are used to suppress the pituitary gland. The rest is the same as the long method. For people with endometriosis, especially adenomyosis, it is often done to improve the implantation environment.

Advantages ・Implantation environment for people with endometriosis improves
Points to Consider ・Follicles do not grow when ovarian reserve is low
・Pituitary suppression continues for a while 
・The amount of injection increases because the pituitary hormone is completely suppressed
Good Candidate ・Those with endometriosis
・Those with uterine fibroids

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発ウルトラロング法スケジュール

記号説明

Antagonist Method

HMG Cetro Method

HMGセトロ法薬剤

HMG injections begin on the 3rd day of the menstrual cycle. From the 6th day of the menstrual cycle, Cetrotide® 3 mg is subcutaneously injected into the abdomen. Medication is aded every 4 days until the follicle is fully developed and oocyte pick-up is decided.

Advantages ・Since the pituitary hormone is not suppressed from the initial stage, follicles are more likely to grow than the agonist method.
・Unlike agonists, pituitary suppression does not take a long time and is temporary.
・The risks related to OHSS are reduced because oocyte maturation can be performed with agonist nasal drops without using HCG.
Points to Consider ・Due to the high cost of antagonist medication, the cost is high if follicle development is slow.
・Compared to agonists, there is a slight possibility of premature ovulation.
Good Candidate ・Those who have 3 or less developing follicles when using the short method.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発HMGセトロ法スケジュール

記号説明

HMG-MPA Method

HMG injection and oral medication are used, starting from the 3rd day of the menstrual cycle.

Advantages

・Since the internal medicine is very cheap, the cost can be reduced.
・If self-injection is used, there are few restrictions on the dates of visit.
・Since the pituitary hormone is not suppressed from the initial stage, follicles are more likely to grow than the agonist method.
・Unlike agonists, pituitary suppression does not take a long time and is temporary.
・The risks related to OHSS are reduced because oocyte maturation can be performed with agonist nasal drops without using HCG.
・ A "random start method" can be used to induce ovulation regardless of the menstrual cycle is possible.

Points to Consider

・ Fresh embryo transfer is not possible.
・Compared to agonists, there is a slight possibility of premature ovulation.

Good Candidate

・Those who want to reduce the number of visits.
・ In the case of the random start method, those who are far away, those who need urgent ovulation induction such as before breast cancer treatment.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発HMG-MPA法スケジュール

記号説明

Medium Stimulation Method

Medium Stimulation Method

From the 3rd day of the menstrual cycle, oral medication and HMG injection proceeds every other day.

Advantages

・ If self-injection is used, there are few restrictions on the date of visit.
・If there is a risk of OHSS, it is safe because oocyte maturation can be performed with agonist nasal drops without using HCG.
・A "random start method" can be used regardless of the menstrual cycle.

Points to Consider

・Fresh embryo transfer is not possible.

Good Candidate

・Those who want to reduce the number of visits.
・ In the case of the random start method, those who are far away.
・ Those who do not mind that letrozole is not applicable and its use as an ovulation inducer has not yet been generally approved.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発中刺激スケジュール

記号説明

Low/Medium Stimulation Method

Natural Method

As a general rule, medicine is not used, whether oral or injection. However, antagonists and HMGs may be used once or twice to prevent ovulation before oocyte pick-up.

Advantages ・ Hospital visits are few.
・Because no ovulation inducer is used, the burden on the body is little.
・Continuous cycle oocyte pick-up is possible.
Points to Consider ・ Impossible if the menstrual cycle is irregular.
・Since oocytes are collected each time, the number of oocyte pick-ups increases.
・Sometimes it is an empty follicle.
・If ovulation occurs prematurely, it may not be possible to collect oocytes.
・Since only one oocyte can be collected, there are cases where embryo transfer or freezing is not possible due to poor fertilization or division.
Good Candidate ・Those who are 44 years old or older, have low ovarian reserve such as low AMH, or who request this.
・When FSH is high.
Cost The cost for each cycle of oocyte pick-up is the lowest because the number of oocytes collected is one and freezing costs are often unnecessary.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発完自然周期スケジュール

記号説明

Clomiphene (Clomid® or Cellophene®) method

クロミフェン法薬剤

Start taking medicine from the 3rd day of the menstrual cycle. The number of developing follicles may be adjusted in combination with HMG injection and Cetrotide.

Advantages ・Since it is an oral drug, the number of hospital visits is small.
・Continuous oocyte pick-up is possible.
・ First choice of PCO patients.
・The cost per cycle is low because the number of oocytes collected is small and the number of frozen oocytes is small. (However, if it is unsuccessful, it will be carried out from oocyte pick-up, so the cost per 2 to 3 cycles will be slightly higher.)
Points to Consider Since the endometrium becomes thin, fresh embryo transfer may be impossible.
Good Candidate ・ Those who want a natural method as much as possible but don’t mind a few medicines/precautions.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発クロミフェンスケジュール

記号説明

Sexovid® Method

セキソビット法薬剤

This uses a medication called Cyclophenyl. It is a non-steroidal fertility drug with a weak estrogenic effect. It is said to act on the pituitary gland and promote gonadotropin secretion, but there are still many unclear points. It has a weaker ovulation-inducing effect than clomiphene. Injections may be used as well during the cycle. Medication is taken for 5 days, starting from the 3rd day of the menstrual cycle.

Advantages ・ Since it is an oral drug, the number of hospital visits is small.
・ Continuous oocyte pick-up is possible
・Compared to clomiphene, the endometrium does not become thinner, so embryo transfer in the same cycle is often possible.
Points to Consider ・Ovulation induction is weak, and the number of developing follicles is 1 in most cases. Oocytes cannot be frozen this way.
・Compared to clomiphene, LH surge is more likely to occur when the follicle is small, and the risk of ovulation before oocyte pick-up is high.
Cost Similar to natural cycle.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発セキソビットスケジュール

記号説明

Letrozole (or anastrozole®) method

レトロゾール法薬剤

Originally used as a treatment for postmenopausal breast cancer. It is said that it inhibits aromatase, which is an enzyme required to convert male hormones to estradiol in the ovary, so it suppresses estradiol generation and increases FSH secretion with negative feedback to induce ovulation, but there are still unclear points. Used in the same way as clomiphene from the 3rd day of the menstrual cycle.

Advantages ・It has little anti-estrogen effect and the endometrium does not become thin.
・Follicles may develop even in cases of decreased ovarian reserve where clomiphene does not work.
Points to Consider ・Its use as an ovulation inducer has not yet been generally approved.
Good Candidate ・Examples of stunted follicle growth with clomiphene.
・History of breast cancer.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発レトロゾールスケジュール

記号説明

HRT-OPU Method

Uses estrogen to cause follicle development by the rebound effect.

Good Candidate ・ Those who have difficulty in developing follicles.

Schedule example (Average schedule. The actual schedule is decided on an individual basis.)

排卵誘発エストロゲンリバウンドスケジュール

記号説明

Cost Simulation