Ovulation induction

Ovulation induction is the stimulation of

Scope

The term ovulation induction can potentially also be used for:

• Final maturation induction, in the sense of triggering oocyte release from relatively mature ovarian follicles during late follicular phase. In any case, ovarian stimulation (in the sense of stimulating the development of oocytes) is often used in conjunction with triggering oocyte release, such as for proper timing of artificial insemination.^[4]
• in vitro fertilization, and the aim is generally to develop multiple follicles (optimally between 11 and 14 antral follicles measuring 2–8 mm in diameter),^[5] followed by transvaginal oocyte retrieval, co-incubation, followed by embryo transfer of a maximum of two embryos at a time.^[6]
• The treatment for an underlying disease in cases where anovulation or oligovulation is secondary that disease (such as endocrine disease). For example, weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women.^[7]

However, this article focuses on medical ovarian stimulation, during early to mid-

Ovulation induction helps reversing anovulation or oligoovulation, that is, helping women who do not ovulate on their own regularly,^[2] such as those with polycystic ovary syndrome (PCOS).^[1]

Regimen alternatives

The main alternatives for ovulation induction medications are:

• selective estrogen-receptor modulators), as well as letrozole (an aromatase inhibitor).^{[citation needed}
  ]
• Follicle-stimulating hormone, directly stimulating the ovaries. In women with anovulation, it may be an alternative after 7 to 12 attempted cycles of antiestrogens (as evidenced by clomifene citrate), since the latter ones are less expensive and more easy to control.^[9]

Antiestrogens

Clomifene citrate

Dosage is generally 2.5 to 7.5 mg daily over 5 days. A higher dose of up to 12.5 mg per day results in increased follicular growth and a higher number of predicted ovulations, without a detrimental effect on endometrial thickness, and is considered in those who do not respond adequately to a lower dose.[15]

Tamoxifen

Tamoxifen affects estrogen receptors in a similar fashion as clomifene citrate. It is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate.^[16]

Follicle-stimulating hormone

Preparations of follicle-stimulating hormone mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive. The urinary preparations are equally effective and less expensive, but are not as convenient to administer as they are available in vials versus injection pens.

Gonadotropin-releasing hormone pump

The

In the Nordic countries, letrozole is practically the standard initial regimen used for ovulation induction, since no formulation of clomifene is registered for use there.^[19][20]

India banned the usage of letrozole in 2011, citing potential risks to infants.^[21] In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India.^[22]

Technique

Although there are many possible additional diagnostic and interventional techniques, protocols for ovulation induction generally consist of:

• Determining the first day of the
  progestin
  for 10 days.
• Daily administration of the ovulation induction regimen, starting on day 3, 4, or 5,^[23] and it is usually taken for 5 days.^[9][24]
• Sexual intercourse or artificial insemination by the time of ovulation.

Ultrasonography

• Aspiration of supernumerary follicles until one or two remain.[26]^[27]
• Converting the protocol to IVF treatment with embryo transfer of up to two embryos only.^[26]
• Selective fetal reduction. This alternative confers a high risk of complications.^[26]
• Proceeding with any multiple pregnancy without fetal reduction, with the ensuing risk of complications. This alternative is not recommended.[26]

Lab tests

The following laboratory tests may be used to monitor induced cycles:^[28]

• Serum estradiol levels, starting 4–6 days after last pill
• Adequacy of luteinizing hormone surge
  LH surge
  by urine tests 3 to 4 days after last clomifene pill
• Post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per
  HPF
• Mid-luteal progesterone, with at least 10 ng/ml 7–9 days after ovulation being regarded as adequate.

Final maturation induction

As evidenced by clomifene-induced cycles, however, triggering oocyte release has been shown to decrease pregnancy chances compared to frequent monitoring with LH surge tests.[28] Therefore, in such cases, triggering oocyte release is best reserved for women who require intrauterine insemination and in whom luteinizing hormone monitoring proves difficult or unreliable.^[28] It may also be used when luteinizing hormone monitoring has no shown an luteinizing hormone surge by cycle day 18 (where cycle day 1 is the first day of the preceding menstruation) and there is an ovarian follicle of over 20 mm in size.^[29]

Repeat cycles

Ovulation induction can be repeated every menstrual cycle. For clomifene, the dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved.^[28][30] However, at a dosage of 200 mg, further increments are unlikely to increase pregnancy chances.^[28]

It is not recommended by the manufacturer of clomifene to use it for more than 6 consecutive cycles.^[31][32] In women with anovulation, 7–12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate) are recommended before switching to gonadotrophins, since the latter ones are more expensive and less easy to control.^[9]

It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.^[28]

Risks and side effects

Ultrasound and regular hormone checks mitigate risks throughout the process. However, there are still some risks with the procedure.

Ovarian hyperstimulation syndrome occurs in 5–10% of cases.^[33] Symptoms depend on whether the case is mild, moderate, or severe, and can range from bloating and nausea, through to shortness of breathe, pleural effusion, and excessive weight gain (more than 2 pounds per day).

Multiple pregnancy

There is also the risk that more than one egg is produced, leading to twins or triplets. Women with

Other treatments for anovulation are mainly:

• Weight loss: Obese women are less fertile in both natural and ovulation induction cycles and have higher rates of miscarriage than their counterparts of normal weight; they also require higher doses of ovulation-inducing agents. Weight loss results in significant improvement in pregnancy and ovulation rates in such patients.^[7]
• In vitro fertilization, including controlled ovarian hyperstimulation
  .
• In vitro maturation is letting ovarian follicles mature in vitro, and this technique can potentially be an alternative both to anovulation reversal and oocyte release triggering. Rather, oocytes can mature outside the body, such as prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body.^[37] However, there still isn't enough evidence to prove the effectiveness and security of the technique.^[37]
• Laparoscopic ovarian drilling: This 'update' of ovarian wedge resection employs a unipolar coagulating current or puncture of the ovarian surface with a laser in four to ten places to a depth of 4±10 mm on each ovary. An analysis was conducted of the first 35 reports, mostly uncontrolled series, in which 82% of 947 patients ovulated following the operation and 63% conceived either spontaneously or after treatment with medications to which they had previously been resistant.^[38]

References